ALTERED STATES OF CONSCIOUSNESS (COMA)
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Consciousness encompasses both the patient’s level of wakefulness and the patient’s ability to interact with the environment. The neurologic substrate for consciousness is the ascending reticular activating system (RAS) comprised of the reticular formation in the brainstem, thalamic intralaminar nuclei, and portions of the hypothalamus. Dysfunction of the cerebral cortex, especially bilateral lesions, can also cause coma.
Many terms, including obtundation, lethargy, somnolence, stupor, and coma, are used to describe the continuum from fully alert and aware, to complete unresponsiveness. Physicians can use a scale, such as the commonly used Glasgow Coma Scale summarized in Table 12–4, but they should also provide qualitative descriptions such as, “opens eyes with painful stimulus, but does not respond to voice.” These descriptions help subsequent observers quantify unconsciousness and evaluate changes in the patient’s condition. Coma is defined by the complete absence of wakefulness and interaction with the environment for at least 1 hour. When coma persists, evaluation for the presence of sleep-wake cycles or absence of all brain function can further delineate the severity of the disorder of consciousness (Table 25–3).
Table 25–3.Gradation of coma. ||Download (.pdf) Table 25–3.Gradation of coma.
| ||Conscious ||MCS ||PVS ||Coma ||Brain Death |
|Awake? ||Yes ||Yes ||Yes ||No ||No |
|Aware? ||Yes ||Partially ||No ||No ||No |
|Motor Responses? ||Present ||Present ||Present ||Absent ||Absent |
|Brainstem Reflexes ||Present ||Present ||Present ||Present ||Absent |
Persistent or permanent vegetative state (PVS) denotes a chronic condition (persistent if > 4 weeks; permanent if > 3–12 months, depending on etiology) in which sleep-wake cycles are preserved, but the patient has no awareness of self or the environment. PVS is sometimes referred to as “wakefulness without awareness.”
Minimally conscious state (MCS) denotes patients who demonstrate sleep-wake cycles and some residual degree of interaction with the environment. For instance, these patients occasionally may have purposeful movements. Thus, MCS involves “partial preservation of consciousness.”
Brain death (death by neurologic criteria) refers to patients in coma who have cessation of all brain function, including cortical activity, brainstem reflexes, and spontaneous respirations.
B. Laboratory and Imaging Diagnostics
Medical causes account for 90% of cases of coma in children; structural causes comprise the remaining 10% (Table 25–4). If the cause of the coma is not obvious, emergency laboratory tests must be obtained, such as blood glucose, complete blood count, urine studies (obtained by catheterization if necessary), pH and electrolytes (including bicarbonate), serum urea nitrogen, liver function tests, and ammonia. Urine, blood, and even gastric contents can be sent for toxin screens if the underlying cause is not obvious. Infection is a common cause (30%), and blood cultures and lumbar puncture often are necessary. However, papilledema or focal neurologic deficits are relative contraindications to lumbar puncture prior to imaging. In obscure cases of coma, additional testing might include oxygen and carbon dioxide partial pressures, serum and urine osmolality, porphyrins, lead, amino acids, and urine organic acids.
Table 25–4.Some causes of coma in childhood. ||Download (.pdf) Table 25–4.Some causes of coma in childhood.
|Mechanism of Coma ||Likely Cause |
|Newborn Infant ||Older Child |
Birth asphyxia, HIE Meconium aspiration, infection (especially respiratory syncytial virus)
Carbon monoxide (CO) poisoning
Croup, tracheitis, epiglottitis
Hemolysis, blood loss
Shunting lesions, hypoplastic left heart
Shunting lesions, aortic stenosis, myocarditis, blood loss, infection
|Head trauma (structural cause) ||Birth contusion, hemorrhage, nonaccidental trauma (NAT) ||Falls, auto accidents, athletic injuries |
|Infection (most common cause in childhood) ||Gram-negative meningitis, enterovirus, herpes encephalitis, sepsis ||Bacterial meningitis, viral encephalitis, postinfectious encephalitis, sepsis, typhoid, malaria |
|Vascular (stroke, often of unknown cause) ||Intraventricular hemorrhage, cerebral venous sinus thrombosis, perinatal arterial ischemic stroke ||Vascular occlusion with congenital heart disease, head or neck trauma, childhood arterial ischemic stroke |
|Neoplasm (structural cause) ||Rare this age. Choroid plexus papilloma with severe hydrocephalus ||Brainstem glioma, increased pressure with posterior fossa tumors |
|Drugs (toxidrome) ||Maternal sedatives; injected pudendal and paracervical analgesics ||Overdose, salicylates, lithium, sedatives, psychotropic agents |
|Toxins (toxidrome) ||Maternal sedatives or injections ||Arsenic, CO, pesticides, mushrooms, lead |
|Epilepsy ||Constant focal motor seizures, electrographic seizures without motor manifestations, drugs given to stop ||Nonconvulsive or absence status epilepticus, postictal state, drugs given |
|Hypoglycemia ||Birth injury, diabetic progeny, toxemic progeny ||Diabetes, “prediabetes,” hypoglycemic agents |
|Increased intracranial pressure (metabolic or structural cause) ||Anoxic brain damage, hydrocephalus, metabolic disorders (urea cycle; amino or organic acidurias) ||Toxic encephalopathy, Reye syndrome, head trauma, tumor of posterior fossa |
|Hepatic causes ||Hepatic failure, inborn metabolic errors in bilirubin conjugation ||Hepatic failure, inborn errors of metabolism |
|Renal causes, hypertensive encephalopathy ||Hypoplastic kidneys ||Nephritis, acute (AGN) and chronic; uremia, uremic syndrome |
|Hypothermia, hyperthermia ||Iatrogenic (therapeutic hypothermia) ||Cold weather exposure, drowning; heat stroke |
|Hypercapnia ||Congenital lung anomalies, bronchopulmonary dysplasia ||Cystic fibrosis (hypercapnia, anoxia) |
Hyper- or hyponatremia
Hyper- or hypocalcemia
Severe acidosis, lactic acidosis
Iatrogenic (NaHCO3 use), salt poisoning (formula errors)
SIADH, adrenogenital syndrome, dialysis (iatrogenic)
Septicemia, metabolic errors
Infection, diabetic coma, poisoning (eg, aspirin), hyperglycemic nonketotic coma
If severe head trauma, intracranial hemorrhage, or increased intracranial pressure is suspected, an emergency CT scan or MRI is necessary. CT is typically faster and superior to MRI for detecting small hemorrhages, but MRI is more sensitive in detecting stroke and anoxic brain injury. Abbreviated MRI protocols are also increasingly being used to rule out hemorrhage and hydrocephalus, sparing the patient from unnecessary ionizing radiation exposure from a CT. Bone windows on CT or skull radiographs may demonstrate skull fractures better. The absence of skull fracture does not rule out coma caused by closed head trauma, such as from abusive head trauma. Treatment of head injury associated with coma is discussed in detail in Chapter 12.
EEG can sometimes aid in diagnosing the cause of coma, such as with nonconvulsive status epilepticus, a specific abnormality (such as periodic lateralized epileptiform discharges seen with herpes encephalitis), or focal slowing (such as with stroke or cerebritis). The EEG also may correlate with the stage of coma and add prognostic information.
Conditions mistaken for coma:
Locked-in syndrome describes patients who are conscious (awake and aware) but cannot demonstrate interactiveness with their environment due to a massive loss of motor function, typically due to a lesion in the pons. Vertical eye movements may be preserved.
Akinetic-mutism denotes a patient who is awake and aware, but does not speak, initiate movements, or follow commands, typically due to lesions of the frontal lobes.
Catatonia refers to patients with abnormal alertness and awareness (though typically not completely absent) secondary to psychiatric illness. Patients often retain the ability to maintain trunk and limb postures.
As with any emergency, the clinician must first stabilize the comatose child using the ABCs of resuscitation. Signs of intracranial pressure and impending brain herniation are another priority of the initial assessment. Bradycardia, high blood pressure, and irregular breathing (Cushing’s Triad) or third nerve palsy (with the eye deviated down and out), and a “blown” pupil (unilateral pupillary dilation) indicate prompt neurosurgical consultation and head CT. Initial treatment of impending herniation includes elevating the head of the bed to 15–30 degrees and providing moderate hyperventilation. The use of mannitol, hypertonic saline, pharmacologic coma, hypothermia, and drainage of cerebrospinal fluid (CSF) are more heroic measures covered in detail in Chapter 14.
About 50% of children with nontraumatic causes of coma have a good outcome. Outcome can be successfully predicted at an early stage in approximately two-thirds of patients by assessing coma severity, extraocular movements, pupillary reactions, motor patterns, blood pressure, temperature, and seizure type. In patients with severe head trauma, a Glasgow Coma Scale ≤ 5, hypothermia, hyperglycemia, and coagulation disorders are factors associated with an increased risk of mortality. Other characteristics such as the need for assisted respiration, the presence of increased intracranial pressure, and the duration of coma are not significantly predictive.
JT: The vegetative and minimally conscious states: diagnosis, prognosis and treatment. Neurol Clin 2011 20:773–786
S: Coma and brain death. Handb Clin Neurol 2013;111:43–61
S: Approach to syncope and altered mental status. Pediatr Clin North Am 2013;60(5):1083–1106
et al: Clinical Report-Guidelines for the determination of brain death in infants and children: an update of the 1987 taskforce recommendations. Pediatrics 2011;128(3):e720–e740
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Recurrent unprovoked seizures or a single seizure with an EEG and/or risk factors suggesting high risk for recurrent events.
Often, interictal EEG changes.
A seizure is a sudden, transient disturbance of brain function, manifested by involuntary motor, sensory, autonomic, or psychic phenomena, alone or in any combination, often accompanied by alteration or loss of consciousness. Seizures can be caused by any factor that disturbs brain function. They may occur after a metabolic, traumatic, anoxic, or infectious insult to the brain (classified as symptomatic seizures), or spontaneously without prior known CNS insult. Genetic mutations are increasingly identified in many patients without prior known cause of seizures.
Epilepsy is defined as two seizures that are separated by at least 24 hours, a single seizure associated with a greater than 60% risk of recurrence or the diagnosis of an epilepsy syndrome. During childhood, the incidence is highest in the newborn period. Prevalence flattens out after age 10–15 years. The chance of having a second seizure after an initial unprovoked episode in a child is about 50%. The risk of recurrence after a second unprovoked seizure is 85%. Sixty-five to seventy percent of children with epilepsy will achieve seizure remission with appropriate medication.
The International League Against Epilepsy (ILAE) has established classifications of seizures and epilepsy syndromes. Seizures are classified as either focal, previously called partial (with suspected seizure onset that can be localized to one part of the brain), generalized (likely involving the whole brain or a network of the brain), or “unknown” if it is not clear if they are focal or generalized.
There are several types of generalized seizures that are recognized with the new classification: generalized tonic-clonic, absence (typical, atypical, and with special features), myoclonic, myoclonic atonic, tonic, clonic, and atonic seizures. New nomenclature is suggested for focal seizures that is based on the presentation of the seizure. The description of the seizure is most beneficial with suggested terms such as “without alteration of awareness,” “hyperkinetic,” “emotional,” or “autonomic” seizure. Such descriptions allow better classification of seizures.
Epilepsy syndromes are defined by the nature of the seizures typically present, age of onset, EEG findings, and other clinical factors. New terminology has been developed for epilepsy syndromes to reflect our growing understanding of underlying etiology. The newest classification allows for classification based on the information that is available at the time of the seizure, with a hierarchical approach whereby patients can be classified by types of seizures, epilepsy type (focal, generalized, combined or unknown), or a specific epilepsy syndrome. In parallel, patients may have an etiologic diagnosis (structural, genetic, infectious, etc.) and may have comorbid diagnoses (ADHD, depression, anxiety, etc.). Tools to aid in the classification of seizures and epilepsy syndromes can be found at the International League Against Epilepsy website https://www.ilae.org/education/diagnostic-manual.
1. Seizures & Epilepsy in Childhood
Characterizing the seizure and subsequent epilepsy syndrome is necessary for accurate diagnosis, which will determine the nature of further evaluation and treatment. This also assists with prognostication (Table 25–5) and research of specific syndromes.
Table 25–5.Seizures by age at onset, pattern, and preferred treatment. ||Download (.pdf) Table 25–5.Seizures by age at onset, pattern, and preferred treatment.
|Seizure Type Epilepsy Syndrome ||Age at Onset ||Clinical Manifestations ||Causative Factors ||EEG Pattern ||Other Diagnostic Studies ||Treatment and Comments |
|Neonatal seizures ||Birth–2 wk ||Can be any seizure type, can be very subtle. ||Neurologic insults (hypoxia/ischemia; intracranial hemorrhage) present more in first 3 days or after 8th day; metabolic disturbances alone between 3rd and 8th days; hypoglycemia, hypocalcemia, hyper- and hyponatremia. Drug withdrawal. Pyridoxine dependency. Other metabolic disorders. CNS infections. Structural abnormalities. Genetic causes increasing recognized. ||May correlate poorly with clinical seizures. Focal spikes or slow rhythms; multifocal discharges. Electroclinical dissociation may occur: electrical seizure without clinical manifestations. ||Lumbar puncture; CSF PCR for herpes, enterovirus; serum Ca2+, PO43–, serum and CSF glucose, Mg2+; BUN, amino acid screen, blood ammonia, organic acid screen, TORCHS, other metabolic testing if suspected. Ultrasound or CT/MRI for suspected intracranial hemorrhage and structural abnormalities. ||Benzodiazepines, phenobarbital, IV or IM; if seizures not controlled, add phenytoin IV. Recent experience with levetiracetam and topiramate. Treat underlying disorder. Seizures due to brain damage often resistant to anticonvulsants. When cause in doubt, stop protein feedings until enzyme deficiencies of urea cycle or amino acid metabolism ruled out. |
|Epileptic spasms ||3–18 mo, usually about 6 mo ||Abrupt, usually but not always symmetrical adduction or flexion of limbs with flexion of head and trunk; or abduction and extensor movements (similar to Moro reflex). Occur in clusters typically upon awakening. Associated irritability and regression in development. ||Etiology identified in approximately two-thirds fitting structural/metabolic or genetic. Tuberous sclerosis in 5%–10%. TORCHS, homeobox gene mutations, ARX, and other genetic mutations. ||Hypsarrhythmia (chaotic high-voltage slow waves or random spikes [90%]); other abnormalities in 10%. Rarely normal at onset. EEG normalization early in course usually correlates with reduction of seizures; not helpful prognostically regarding mental development. ||Funduscopic and skin examination, amino and organic acid screen. Chromosomes TORCHS screen, CT, or MRI scan. Trial of pyridoxine. Consider gene panels. || |
ACTH. Vigabatrin, especially if tuberous sclerosis. B6 (pyridoxine) trial. In resistant cases, topiramate, zonisamide, valproic acid, lamotrigine, ketogenic diet. Early treatment leads to improved outcome.
Occasionally, surgical resection of cortical malformation.
|Febrile convulsions ||3 mo–6 y (maximum 6–18 mo); most common childhood seizure (incidence 2%) ||Usually generalized seizures, < 15 min; rarely focal in onset. May lead to status epilepticus. Recurrence risk of second febrile seizure 30% (50% if younger than 1 y of age); recurrence risk is same after status epilepticus. ||Nonneurologic febrile illness (temperature rises to 39°C or higher). Risk factors: positive family history, day care, slow development, prolonged neonatal hospitalization. ||Normal interictal EEG, especially when obtained 8–10 days after seizure. Therefore, not useful unless complicating features. ||Lumbar puncture in infants or whenever suspicion of meningitis exists. ||Treat underlying illness, fever. Diazepam orally, 0.3–0.5 mg/kg, divided 3 times daily during illness may be considered. Diastat rectally for prolonged (> 5 min) seizure. Prophylaxis with phenobarbital or valproic acid rarely needed. |
|Lennox-Gastaut syndrome) ||Any time in childhood (usually 2–7 y) ||Mixed seizures including tonic, myoclonic (shocklike violent contractions of one or more muscle groups, singly or irregularly repetitive); rare atonic (“drop attacks”) and atypical absence with episodes of absence status epilepticus. ||Multiple causes, usually resulting in diffuse neuronal damage. History of infantile spasms; prenatal or perinatal brain damage; viral meningoencephalitis; CNS degenerative disorders; structural cerebral abnormalities (eg, migrational abnormalities). ||Atypical slow (1–2.5 Hz) spike-wave complexes and bursts of high-voltage generalized spikes, often with diffusely slow background frequencies. Electrodecremental and fast spikes during sleep. ||Dictated by index of suspicion: genetic testing; inherited metabolic disorders, neuronal ceroid lipofuscinosis, others. MRI scan, WBC lysosomal enzymes. Skin or conjunctival biopsy for electron microscopy, nerve conduction studies if degenerative disease suspected. ||Difficult to treat. Topiramate, ethosuximide, felbamate, levetiracetam, zonisamide, valproate, clonazepam, rufinamide, clobazam (approval pending) ketogenic diet, vagus nerve stimulation. Avoid phenytoin, carbamazepine, oxcarbazepine, gabapentin. |
|Doose syndrome ||Any time in childhood (usually 2–7 y) ||Mixed seizures: atonic, myoclonic atonic, atypical absence, tonic seizures and generalized tonic-clonic seizures ||Rarely is etiology found, likely genetic, < 5% with SCN1A, large percentage with family history of febrile seizures ||Generalized spike wave discharges, central theta slowing ||Genetic testing || |
Can be difficult to treat, consider topiramate, felbamate, levetiracetam, zonisamide, valproate, rufinamide, ketogenic diet, VNS.
Avoid phenytoin, carbamazepine, oxcarbazepine, and gabapentin
|Dravet syndrome ||First to second year of life ||Initially prolonged febrile seizure that may be hemiconvulsions, after 1 year of age with multiple seizure types typically sensitive to change in temperature ||85% with SCN1a, others with SCN1B, GABA receptor mutations ||Multifocal epileptiform discharges, generalized epileptiform discharges, mild slowing ||Genetic testing also associated with abnormal gait in adolescent requiring supportive therapy ||Can be difficult to treat, consider topiramate, zonisamide, valproic acid, levetiracetam, ketogenic diet, clobazam, stiripentol. Avoid Na channel blockers such as phenytoin, carbamazepine, oxcarbazepine. |
|Childhood absence epilepsy ||3–12 y ||Lapses of consciousness or vacant stares, lasting 3–10 s, often in clusters. Automatisms of face and hands; clonic activity in 30%–45%. Often confused with complex partial seizures but no aura or postictal confusion. ||Unknown. Genetic component. Abnormal thalamocortical circuitry. ||3/s bilaterally synchronous, symmetrical, high-voltage spikes and waves provoked by hyperventilation. EEG always abnormal. EEG normalization correlates closely with control of seizures. ||Hyperventilation often provokes attacks. Imaging studies rarely of value. || |
Ethosuximide most effective and best tolerated; valproic acid. Lamotrigine, in resistant cases, zonisamide, topiramate, levetiracetam, acetazolamide, ketogenic diet.
Some risk for developing generalized tonic clonic seizures.
|Juvenile absence epilepsy ||10–15 y ||Absence seizures less frequent than in childhood absence epilepsy. May have greater risk of convulsive seizures. ||Unknown (idiopathic), possibly genetic. ||3-Hz spike wave and atypical generalized discharges. ||Not always triggered by hyperventilation. ||Same as childhood absence epilepsy but may be more difficult to treat successfully. |
|Focal seizures ||Any age ||Seizure may involve any part of body; may spread in fixed pattern. ||Often unknown; birth trauma, inflammatory process, vascular accidents, meningoencephalitis, malformations of cortical development (dysplasia), etc. If seizures are coupled with new or progressive neurologic deficits, a structural lesion (eg, brain tumor) is likely. If epilepsia partialis continua (simple partial status epilepticus), Rasmussen syndrome is likely. ||EEG may be normal; focal spikes or slow waves in appropriate cortical region; “rolandic spikes” (centrotemporal spikes) are typical. Possibly genetic. ||MRI, repeat if seizures poorly controlled or progressive. ||Oxcarbazepine, carbamazepine; lamotrigine, gabapentin, topiramate, levetiracetam, zonisamide, lacosamide, and phenytoin. Valproic acid useful adjunct. If medications fail, surgery may be an option. |
|Benign epilepsy of childhood with centrotemporal spikes (BECTS/rolandic epilepsy) ||5–16 y ||Simple partial seizures of face, tongue, hand. With or without secondary generalization. Usually nocturnal. Similar seizure patterns may be observed in patients with focal cortical lesions. Almost always remits by puberty. ||Seizure history or abnormal EEG findings in relatives of 40% of affected probands and 18%–20% of parents and siblings, suggesting transmission by a single autosomal dominant gene, possibly with age-dependent penetrance. ||Centrotemporal spikes or sharp waves (“rolandic discharges”) appearing paroxysmally against a normal EEG background. ||Seldom need CT or MRI scan. ||Often no medication is necessary, especially if seizure is exclusively nocturnal and infrequent. Oxcarbazepine, carbamazepine or others. (See complex partial seizures.) |
|Juvenile myoclonic epilepsy (of Janz) ||Late childhood and adolescence, peaking at 13 y ||Mild myoclonic jerks of neck and shoulder flexor muscles after awakening. Usually generalized tonic-clonic seizures as well. Often absence seizures. Intelligence usually normal. Rarely resolves but usually remits on medications. ||40% of relatives have myoclonias, especially in females; 15% have the abnormal EEG pattern with clinical attacks. ||Interictal EEG shows variety of spike-and-wave sequences or 4–6-Hz multispike-and-wave complexes (“fast spikes”). || |
If course is unfavorable, differentiate from progressive myoclonic syndromes by appropriate studies (eg, biopsies [muscles, liver, etc]).
Imaging may not be necessary.
|Lamotrigine, valproic acid, topiramate, levetiracetam, zonisamide. |
|Generalized tonic-clonic seizures (grand mal) (GTCS) ||Any age ||Loss of consciousness; tonic-clonic movements, often preceded by vague aura or cry. Incontinence in 15%. Postictal confusion and somnolence. Often mixed with or masking other seizure patterns. ||Often unknown. Genetic component. May be seen with metabolic disturbances, trauma, infection, intoxication, degenerative disorders, brain tumors. ||Bilaterally synchronous, symmetrical multiple high-voltage spikes, spikes waves (eg, 3/s). EEG often normal in those younger than age 4 y. Focal spikes may become “secondarily generalized.” ||Imaging; metabolic and infectious evaluation may be appropriate. ||Levitiracetam; topiramate, lamotrigine, zonisamide, valproic acid, felbamate. Combinations may be necessary. Carbamazepine, oxcarbazepine or valproic acid; phenytoin may also be effective. |
Seizures are stereotyped paroxysmal clinical events; the key to diagnosis is usually in the history. Not all paroxysmal events are epileptic. A detailed description of seizure onset is important in determining if an event is a seizure and if there is localized onset (focal seizure). Events prior to, during, and after the seizure need to be ascertained. Although observers often initially recall little except generalized convulsive activity because of its dramatic appearance, careful detailed questions can lead to a better description of the event and situation in which it occurred. An aura may precede the clinically apparent seizure and indicates focal onset. The patient may describe a feeling of fear, numbness or tingling in the fingers, or bright lights in one visual field. The specific symptoms may help define the location of seizure onset (eg, déjà vu suggests temporal lobe onset). Often, the child does not recall or cannot define the aura, though the family may note alterations in behavior at the onset. Videotapes of events have been extremely useful.
Postictal states can be helpful in diagnosis. After many focal seizures and most generalized convulsive seizures, postictal sleep typically occurs. However, postictal changes are not seen after generalized absence seizures. It also helps to determine if there were loss of speech after the seizure (suggesting left hemisphere involvement) or if the patient were able to respond and speak in short order. The parent may report lateralized motor activity (eg, the child’s eyes may deviate to one side or the child may experience dystonic posturing of a limb). Motor activity without impaired awareness supports the diagnosis of focal seizures as do impaired awareness and automatisms previously defined as a “complex partial seizure.”
In contrast, generalized seizures usually manifest with acute loss of consciousness, usually with generalized motor activity. Tonic posturing, tonic-clonic activity, or myoclonus (spasms) may occur. In children with generalized absence seizures, behavioral arrest may be associated with automatisms such as blinking, chewing, or hand movements, making it difficult to differentiate between absence seizures and focal seizures.
Frequently, the child presenting with a presumed first seizure has experienced unrecognized seizures before the event that brings the child to medical attention. Focal, myoclonic, and absence seizures, in particular, may not be recognized except in retrospect. Thus, careful questioning regarding prior events is important in the child being evaluated for new onset of seizures. Events that are perceived as seizures but are not epileptic, such as syncopal events, can also be determined by careful questioning.
Many factors determine the extent and urgency of the diagnostic evaluation, such as the child’s age, the severity and type of seizure, whether the child is ill or injured, and the clinician’s suspicion about the underlying cause. Seizures in early infancy often have an underlying cause that is structural, genetic, or metabolic and will guide prognosis and management. Therefore, the younger the child, the more extensive must be the diagnostic assessment.
It is generally accepted that every child with new onset of unprovoked seizures should be evaluated with an EEG and MRI, although this need not be done emergently. An EEG is very unlikely to yield clinically useful information in the child with a febrile seizure. Other diagnostic studies should be used selectively.
Metabolic abnormalities are seldom found in the well child with seizures. Unless there is a high clinical suspicion of serious medical conditions (eg, uremia, hyponatremia, hypocalcemia, etc), “routine” laboratory tests rarely yield clinically significant information. Special studies may be necessary in circumstances that suggest an acute systemic etiology for a seizure, for example, in the presence of apparent renal failure, sepsis, or substance abuse. Emergent imaging of the brain is usually not necessary in the absence evidence of trauma or of acute abnormalities on examination.
The limitations of EEG even with epilepsy, for which it is most useful, are considerable. A routine EEG captures electrical activity during a very short period, usually 20–30 minutes. Thus, it is useful primarily for defining interictal activity (except for the fortuitous recording of a clinical seizure or in situations when seizures are easily provoked such as childhood absence epilepsy). A seizure is a clinical phenomenon; an EEG showing epileptiform activity may confirm and clarify the clinical diagnosis (for instance, defining an epilepsy syndrome), but it is only occasionally diagnostic (see EEG under diagnostic section earlier in chapter).
It is extremely important to be accurate in the diagnosis of epilepsy and not to make the diagnosis without ample proof. To the layperson, epilepsy often has connotations of brain damage and limitation of activity. A person so diagnosed may be excluded from certain occupations in later life. It is often very difficult to change an inaccurate diagnosis of many years’ standing.
Misinterpretation of behaviors in children is the most common reason for misdiagnosis. Psychogenic nonepileptic events are much less common in children than in adults but must be considered even in the young or cognitively impaired child. The most commonly misinterpreted behaviors are inattention in school-aged children with attention disorders, stereotypies in children with autistic spectrum disorder, sleep-related movements, habit movements such as head-banging and so-called infantile masturbation (sometimes referred to as gratification movements), and gastroesophageal reflux in very young (often impaired) infants. Some of the common nonepileptic events that mimic seizure disorder are listed in Table 25–6.
Table 25–6.Nonepileptic paroxysmal events. ||Download (.pdf) Table 25–6.Nonepileptic paroxysmal events.
Breath-holding attacks (cyanotic and pallid) (see below)
Cyanotic: Age 6 mo–3 y. Always precipitated by trauma and fright. Cyanosis; sometimes stiffening, tonic (or jerking-clonic) convulsion (anoxic seizure). Patient may sleep following attack. Family history positive in 30%. Electroencephalogram (EEG) is not useful. No medication treatment is useful but if the patient is found to be iron-deficient supplementation may reduce events. However, in general reassurance is most important.
Pallid: Usually, there is no apparent precipitant although fright may precipitate. Pallor may be followed by seizure (anoxic-ischemic). Vagally mediated (heart-slowing), like adult syncope. EEG is not useful.
Tics (Tourette syndrome)
Simple or complex stereotyped jerks or movements, coughs, grunts, sniffs. Worse at repose or with stress. May be suppressed during physician visit. Family history often positive for tics or for obsessive compulsive disorder. Diagnosis is clinical. Magnetic resonance imaging (MRI) and EEG are negative. Medications may benefit.
Parasomnias (night terrors, sleep talking, walking, “sit-ups”)
Ages 3–10 y. Usually occur in first sleep cycle (30–90 min after going to sleep), with crying, screaming, and autonomic discharge (pupils dilated, perspiring, etc). May last only a few minutes or be more prolonged. Child goes back to sleep and has no recall of event next day. Sleep studies (polysomnogram and EEG) are normal. Sleep talking and walking and short “sit-ups” in bed are fragmentary arousals. If a spell is recorded, EEG shows arousal from deep sleep, but behavior seems wakeful. Child needs to be protected from injury and gradually settled down and taken back to bed. Medications may be considered in rare instances.
Nightmares or vivid dreams occur in subsequent cycles of sleep, often in early morning hours, and generally are partially recalled the next day. The bizarre and frightening behavior may sometimes be confused with complex partial seizures but occurs during REM (rapid eye movement) sleep, whereas epilepsy usually does not. In extreme or difficult cases, an all-night sleep EEG may help differentiate seizures from nightmares. Frontal lobe epilepsy with sleep related “hypermotor” seizures should be considered.
On occasion, migraine can be associated with an acute confusional state. Usual migraine prodrome of spots before the eyes, dizziness, visual field defects, followed by headache and then agitated confusion is present. History of other, more typical migraine with severe headache and vomiting but without confusion may aid in diagnosis. Severe headache with vomiting as child comes out of spell may aid in distinguishing the attack from epilepsy. However, partial seizures, while brief, may be associated with more prolonged postictal agitation and confusion. Other seizure manifestations are practically never seen (eg, tonic-clonic movements, falling, complete loss of consciousness). EEG in migraine is usually normal and seldom has epileptiform abnormalities often seen in patients with epilepsy. Migraine and epilepsy are sometimes linked: Benign occipital epilepsy may present with migraine-like visual aura and headache. There may be migraine-caused cortical ischemia which leads to later epilepsy. Postictal headache can be confused with migraine.
Benign nocturnal myoclonus
Common in infants and may last even up to school age. Focal or generalized jerks (the latter also called hypnic or sleep jerks) may persist from onset of sleep on and off all night. A video record for physician review can aid in diagnosis. EEG taken during jerks is normal, proving that these jerks are not epilepsy. Treatment is reassurance.
Shuddering or shivering attacks can occur in infancy and may be a forerunner of essential tremor in later life. Often, family history is positive for tremor. Shivering may be very frequent. EEG is normal. There is no clouding or loss of consciousness.
Gastroesophageal reflux (Sandifer syndrome)
Seen more commonly in children with cerebral palsy or brain damage; reflux of acid gastric contents may cause pain that cannot be described by child. Unusual posturing (dystonic or other) of head and neck or trunk may occur, an apparent attempt to stretch the esophagus or close the opening. There is no loss of consciousness, but eye rolling, apnea, and occasional vomiting may simulate a seizure. An upper gastrointestinal series, cine of swallowing, sometimes even an EEG (normal during episode) may be necessary to distinguish from seizures.
Infantile masturbation/gratification movements
Rarely in infants, repetitive rocking or rubbing motions may simulate seizures. Infant may look out of contact, be poorly responsive to environment, and have autonomic expressions (eg, perspiration, dilated pupils) that may be confused with seizures. Observation by a skilled individual, sometimes even in a hospital setting, may be necessary to distinguish from seizures. EEG is normal between and during attacks. Interpretation and reassurance are the only necessary treatment.
Conversion reaction/psychogenic nonepileptic seizures
Up to 50% of patients with nonepileptic seizures also have epilepsy. Episodes may involve writhing, pelvic thrusting, tonic movements, bizarre jerking and thrashing, or even apparently sudden unresponsiveness. Children may be developmentally delayed. Spells must often be seen or recorded with a videorecorder to distinguish from epilepsy but are sometimes so bizarre they are easily differentiated. A normal EEG during a spell is a key diagnostic feature. Combativeness is common; self-injury and incontinence, rare. Within the pediatric population, most patients with psychogenic nonepileptic seizures have a good prognosis without deep seated psychological trauma.
Temper tantrums and rage attacks
Child often reports amnesia for events during spell. Attacks are usually precipitated by frustration or anger, often directed either verbally or physically, and subside with behavior modification and isolation. EEGs are generally normal but seldom obtained during an attack. It should be noted that directed violence is very uncommon following partial seizures but severe agitation can occur.
Teachers often make referral for absence or “petit mal” seizures in children who stare or seem preoccupied at school. Helpful in the history is the lack of these spells at home (eg, before breakfast, a common time for absence seizures). Lack of other epilepsy in child or family history often is helpful. These children often have difficulties with school and cognitive or learning disabilities. Child can generally be brought out of spell by a firm command or touch and if event is interruptible they are unlikely to be seizures. EEG is sometimes necessary to confirm that absence seizures are not occurring.
Emotional disturbances, especially depression but also anxiety, anger, and feelings of guilt and inadequacy, often occur in the patient as well as the parents of a child with epilepsy. Actual or perceived stigmas as well as issues regarding “disclosure” are common. There is an increased risk of suicide in people with epilepsy. Schools often limit activities of children with epilepsy inappropriately and stigmatize children by these limitations.
Epilepsy with onset in childhood has an impact on adult function. Adults with early onset of epilepsy, even when well controlled, are less likely to complete high school, have less adequate employment, and are less likely to marry. Persistent epilepsy results in significant dependence; even when epilepsy is successfully treated, patients with long-standing epilepsy often do not become independent due to driving restrictions and safety concerns.
Children living with epilepsy, particularly with untreated or poorly controlled seizures, can develop reduced cognition and memory. Clearly, epileptic encephalopathy (ie, epileptic activity or frequent seizures are contributing to worse neurocognitive function) does occur, particularly in young children with epilepsies such as infantile spasms (West syndrome), Dravet syndrome, and Lennox-Gastaut syndrome. The impact of persistent partial seizures on development is less clear, although persistent temporal lobe seizures in adults are associated with cognitive dysfunction. It is not likely that interictal epileptiform activity contributes to cognitive impairment in older children, although increased epileptiform burden has been demonstrated to cause mild cognitive problems in some disorders previously thought to be benign, such as benign epilepsy with central temporal spikes (BECTS). Continuous epileptiform activity in sleep is associated with Landau-Kleffner syndrome (acquired epileptic aphasia) and the syndrome of electroencephalographic status epilepticus in sleep (ESES), both of which are associated with cognitive decline.
“Pseudodementia” may occur in children with poorly controlled epilepsy because their seizures interfere with their learning. Depression is a common cause of impaired cognitive function in children with epilepsy. Anticonvulsants are less likely to cause such interference at usual therapeutic doses, although phenobarbital, topiramate, and zonisamide may produce cognitive impairment, which is reversible on discontinuing the medication. Psychosis also can occur after seizures or as a side effect of medications.
Children with epilepsy are at far greater risk of injuries than the general pediatric population. Physical injuries, especially lacerations of the forehead and chin, are frequent in atonic (previously called astatic) seizures (so-called drop attacks), necessitating protective headgear. In all other seizure disorders in childhood, injuries as a direct result of a seizure are not as common, although drowning, injuries related to working in kitchens, and falls from heights remain potential risks for all children with active epilepsy. It is therefore extremely important to stress “seizure precautions,” in particular water safety. Showers are recommended over bathing as they decrease the likelihood of drowning. Ultimately, patients with epilepsy should not participate in activities that could result in serious injury in the case of sudden loss of consciousness, without taking precautions to address that possibility. However, for most activities simple accommodations allow individuals with epilepsy to lead very normal lives.
The greatest fear of a parent of a child with new-onset of epilepsy is the possibility of death or brain injury. There is an increased risk of premature death in children with epilepsy, especially those who have not achieved seizure control. Most of the mortality in children with epilepsy is related to the underlying neurologic disorder, not the seizures. Sudden unexpected death with epilepsy (SUDEP) is a rare event in children. Although children with epilepsy have an increased risk of death, SUDEP occurs in only 1–2:10,000 patient-years. The greatest risk for SUDEP is in children with medically uncontrolled epilepsy. The etiology of SUDEP is not yet known and there is no current proven strategy to prevent SUDEP other than seizure control. Identifying life-threatening disorders (eg, identifying patients with cardiac arrhythmias, especially prolonged QT syndrome) as the cause of misdiagnosed epilepsy is clearly of utmost importance. While SUDEP is rare, increased mortality in children with epilepsy should be mentioned when counseling families.
The ideal treatment of acute seizures is the correction of specific causes. However, even when a biochemical disorder, a tumor, meningitis, or another specific cause is being treated, anti-seizure drugs are often still required.
Caregivers should be instructed to protect the patient against self-injury. Turning the child to the side is useful for preventing aspiration. Placing any objects in the mouth of a convulsing patient or trying to restrain tonic-clonic movements may cause worse injuries than a bitten tongue or bruised limb and could potentially become a choking hazard. Parents are often concerned that cyanosis will occur during generalized convulsive seizures, but it is rare for clinically significant hypoxia to occur. Mouth-to-mouth resuscitation is rarely necessary and is unlikely to be effective.
For prolonged seizures (those lasting over 5 minutes), acute home treatment with benzodiazepines such as rectal diazepam gel (Diastat) or intranasal midazolam may be administered to prevent the development of status epilepticus and has proven to be safe even when administered by nonmedical professionals, including teachers and day care providers, when appropriately instructed.
B. Antiepileptic Drug (AED) Therapy
Several issues should be considered when choosing an anti-seizure medication including effectiveness, side effects (good or bad), risk, and what other medications the patient is already taking. Some medications are good for focal seizures but can make generalized seizures worse (eg, oxcarbazepine and carbamazepine), while other medications are good for most seizure types and are relatively safe (levetiracetam). Many medications may be effective for most seizure types but are thought to be particularly good for certain seizures (clobazam for myoclonic seizures). It is worth noting that most of this “knowledge” is based on experience and expert opinion rather than comparative effectiveness or randomized control trials. In some cases, side effects can help guide treatment; for example, topiramate tends to suppress appetite whereas valproic acid often precipitates weight gain. When weighing risks, side effects, and potential effectiveness, one must consider the impact on the patient and their family’s life.
The goal of anti-seizure treatment is “no seizures and no side effects.” The child with a single seizure has a 50% chance of seizure recurrence. Thus, it is usually not necessary to initiate therapy until the diagnosis of epilepsy is established, that is, there is a second seizure. The seizure type and epilepsy syndrome as well as potential side effects will determine which drug to initiate as discussed earlier. If monotherapy fails, a second, and when necessary a third medication may be required to help reduce seizure frequency. Care must be taken when using multiple anti-seizure medications, as this increases the chance of side effects and often does not substantially improve seizure control. There is some evidence that anti-seizure medications with different mechanisms of action may improve their combined tolerability and effectiveness.
3. Long-term management and discontinuation of treatment
Therapy should be continued until the patient is free of seizures for at least 1–2 years. In about 75% of patients, seizures will not recur following discontinuation of medication after 2 years of remission. Variables such as younger age at onset, normal EEG, undetermined etiology, and ease of controlling seizures carry a favorable prognosis, whereas identified etiology, later onset, continued epileptiform EEG, difficulty in establishing initial control of the seizures, polytherapy, generalized tonic-clonic or myoclonic seizures, as well as an abnormal neurologic examination are associated with a higher risk of recurrence. Most AEDs (with the exception of barbiturates and benzodiazepines) can be withdrawn over 6–8 weeks. There does not appear to be an advantage to slower withdrawal.
Recurrent seizures affect up to 25% of children who attempt withdrawal from medications. Recurrence of seizures is most likely within 6–12 months of discontinuing medications. Therefore, seizure safety precautions will need to be reinstituted, including driving restriction. If seizures recur during or after withdrawal, AED therapy should be reinstituted and maintained for at least another 1–2 years. The majority of children will again achieve remission of their seizures.
C. Alternative Treatments
1. Adrenocorticotropic hormone (ACTH) and corticosteroids
Treatment with ACTH or oral corticosteroids is the standard of care for infantile spasms. Duration of therapy is guided by cessation of clinical seizures and normalization of the EEG. Vigabatrin is an alternative treatment that is also considered standard of care for infantile spasms and has been shown to be superior for infantile spasms resulting from tuberous sclerosis. All other treatments for infantile spasms have a lower likelihood of being effective.
Precautions: It is important to guard against infections, provide GI prophylaxis, and follow for possible hypertension, and discuss the cushingoid appearance and its disappearance. Oral corticosteroids should not be withdrawn suddenly. Side effects in some series occur in up to 40% of patients. In some regions of the country, prophylaxis against Pneumocystis infection may be required. Careful and frequent follow-up is necessary. Visiting nurse services and partnering with a medical home can be very helpful in surveillance such as monitoring blood pressure, weight, and potential adverse effects.
Fasting has been described to stop seizures for centuries and a diet high in fat and low in protein and carbohydrates will result in ketosis and simulate a fasting state. Such a diet has been observed to decrease and even control seizures in some children. This diet should be monitored very carefully (by a clinical team familiar with the ketogenic diet) to ensure sufficient nutrients, including vitamins and minerals, to maintain overall health. Recent reports suggest potential efficacy with a modified Atkins diet or a low-glycemic index diet in older and higher functioning children who will not accept the ketogenic diet.
The mechanism for the anticonvulsant action of the ketogenic diet is not understood. The ketogenic diet requires close adherence and full cooperation of all family members. However, when seizure control is achieved by this method, acceptance of the diet is usually excellent. Families must be cautioned that abrupt withdrawal (accidental or purposeful) of the diet can precipitate seizures and even status epilepticus. Increased use of the ketogenic diet and family support groups have increased the number of palatable recipes for patients and families on the ketogenic diet.
As with all therapies, potential adverse effects can occur with the ketogenic diet. These include acidosis and hypoglycemia, particularly on initiation of the diet. The child should be admitted to a center well versed in managing ketogenic diet to start this treatment. Close follow-up will help prefent risk for renal stones, pancreatitis, and acidosis. In addition, vitamin and minerals need to be followed carefully to avoid deficiencies, especially carnitine, iron, and vitamin D.
3. Vagus nerve stimulator (VNS)
The VNS is a pacemaker-like device that is implanted below the clavicle and attached to the left vagus nerve. A cycle of electrical stimulation of the nerve is established, which has an antiepileptic effect, reducing seizures by at least 50% in over half the children treated. In addition, an emergency mode that is activated by swiping a magnet (of abrupt tachycardia on newer models) may interrupt a seizure. With current technology, the battery in the stimulator may last 7 or more years in many patients.
An evaluation for epilepsy surgery is indicated for all children with medically intractable partial epilepsy (generally defined as failure of two anti-seizure medications at effective doses). The evaluation and surgery should be performed at a center with expertise in epilepsy surgery and which has a dedicated neurosurgeon, epileptologists and neuropsychologists with experience in epilepsy surgery.
The first surgery for treatment of epilepsy took place over 100 years ago, and surgery is now established as an appropriate treatment option for adults and children with epilepsy refractory to medical treatment. Evaluation for possible surgical treatment should begin as soon as it is apparent that a child with focal onset seizures is not responding to standard therapy. Medication resistant (“refractory”) epilepsy is usually defined as failure of two or three anti-epileptic drugs alone or as combination therapy to control seizures. Advances in technology allow for definition and removal of the epileptogenic focus even in young infants. Many centers now have access to variety of resources for identifying the region of seizure onset. Ultimately, the chance of seizure freedom can range from 50% to 95% depending on the clinical circumstance. Some children with more generalized seizures may qualify for other types of surgery, such as corpus callosotomy, that aim to reduce seizure burden.
E. General Management of the Child with Epilepsy
The initial diagnosis of epilepsy is often devastating for families. The patient and parents must be helped to understand the nature of epilepsy and its management, including etiology, prognosis, safety issues, and treatment options.
Excellent educational materials are available for families of a child with epilepsy, both in print and online. An excellent website is http://www.epilepsy.com. Materials on epilepsy—including pamphlets, monographs, films, and videotapes suitable for children and teenagers, parents, teachers, and medical professionals—may be purchased through the Epilepsy Foundation: 8301 Professional Place, Landover, MD 20785; (800) 332–1000. The foundation’s local chapter and other community organizations are able to provide guidance and other services. Support groups exist in many regions for older children and adolescents and for their parents and others concerned.
2. Privileges and precautions in daily life
“No seizures and no side effects” is a motto established by the Epilepsy Foundation. The child should be encouraged to live as normal a life as possible. Children should engage in physical activities appropriate to their age and social group. After seizure control is established, swimming is generally permissible with a buddy system or adequate lifeguard coverage. Scuba diving and high climbing without safety harness is generally not allowed. There are no absolute contraindications to any other sports, although some physicians recommend against contact sports. Physical training and sports are usually to be welcomed rather than restricted. There is some literature that suggests that exercise decreases overall seizure burden and may also be helpful to maintain good bone health.
Depression, anxiety, and attentional difficulties are common comorbidities of epilepsy, particularly in adolescents, and need to be treated as they can be as (or more) debilitating as the seizures. Sleep deprivation and alcohol should be avoided as they can be triggers for seizures for patients with epilepsy. Prompt attention should be given to intercurrent illnesses that can also trigger seizures.
Although every effort should be made to control seizures, treatment must not interfere with a child’s ability to function normally. A child may do better having an occasional mild seizure than being so heavily sedated that function at home, in school, or at play is impaired. Therapy and medication adjustment often require much art and fortitude on the physician’s part.
Driving becomes important to most young people at age 15 or 16 years. Restrictions for persons with epilepsy and other disturbances of consciousness vary from state to state. In most states, a learner’s permit or driver’s license will be issued to an individual with epilepsy if he or she has been under a physician’s care and free of seizures for at least 6–12 months provided that the treatment or basic neurologic problems do not interfere with the ability to drive. A guide to this and other legal matters pertaining to persons with epilepsy is published by the Epilepsy Foundation, and its legal department may be able to provide additional information.
Contraception (especially interaction of oral contraceptive with some AEDs), childbearing, potential teratogenicity of AEDs, and the management of pregnancy should be discussed as soon as appropriate with the adolescent young woman with epilepsy. Daily use of vitamin preparations and high-dose folic acid can be protective against neural tube defects. For the pregnant teenager with epilepsy, management by an obstetrician conversant with the use of AEDs in pregnancy is appropriate. The patient should be cautioned against discontinuing her medications during pregnancy. The possibility of teratogenic effects of AEDs, such as facial clefts (two to three times increased risk), must be weighed against the risks from seizures. All AEDs appear to have some risk for teratogenicity, although valproate carries a particularly high risk for spinal dysraphism as well as being associated with cognitive issues in children exposed to valproate in utero. Dosing may need to be adjusted frequently during pregnancy as blood volume expands. Frequent AED blood levels may be helpful in making these adjustments.
5. School intervention and seizure response plans
Schools are required by federal law to work with parents to establish a seizure action plan for their child with epilepsy. A template for such a plan is available on the Epilepsy Foundation website at https://www.epilepsy.com/sites/core/files/atoms/files/130SRP_MySeizureResponsePlan-fillable.pdf. These plans usually require the approval of the child’s physician. Schools are sometimes hesitant to administer rescue medications. Often, information from the physician, especially that obtained from the Epilepsy Foundation website, will relieve anxieties. School authorities should be encouraged to avoid needless restrictions and to address the emotional and educational needs of all children with disabilities, including epilepsy. The local affiliates of the Epilepsy Foundation can often provide support and education for both families and schools.
Status epilepticus is usually defined as a clinical or electrical seizure lasting at least 15 minutes, or a series of seizures without complete recovery over a 30-minute period. Importantly, this time cut-off keeps getting shorter as more evidence accrues that even relatively short seizures may be harmful to the brain. After 30 minutes of seizure activity, hypoxia and acidosis occur, with depletion of energy stores, cerebral edema, and structural damage. Eventually, high fever, hypotension, respiratory depression, and even death may occur. Status epilepticus is a medical emergency. Aggressive treatment of prolonged seizures may prevent development of status epilepticus. It is generally recommended that treatment with benzodiazepines at home for prolonged seizures be initiated 5 minutes after onset of a seizure. There are currently several forms of benzodiazepines that can be administered safely at home, including rectal valium, intranasal midazolam, sublingual lorazepam, and intramuscular diazepam.
Status epilepticus is classified as (1) convulsive (the common generalized tonic-clonic type) or (2) nonconvulsive (characterized by altered mental status or behavior with subtle or absent motor components). Absence status, or spike-wave stupor, and focal status epilepticus are examples of the nonconvulsive type. An EEG may be necessary to aid in diagnosing nonconvulsive status because patients sometimes appear merely stuporous and lack typical convulsive movements. Status epilepticus that has not responded to two medications is considered refractory status epilepticus and often requires care in an intensive care unit.
For treatment options, see Table 25–7.
Table 25–7.Status epilepticus treatment. ||Download (.pdf) Table 25–7.Status epilepticus treatment.
Airway: maintain oral airway; intubation may be necessary.
Circulation: assess pulse, blood pressure; support with IV fluids, drugs. Monitor vital signs.
Start glucose-containing IV (unless patient is on ketogenic diet); evaluate serum glucose; electrolytes, HCO–3, CBC, BUN, anticonvulsant levels.
Consider arterial blood gases, pH.
Give 50% glucose if serum glucose low (1–2 mL/kg).
Begin IV drug therapy; goal is to control status epilepticus in 20–60 min.
Diazepam, 0.3–0.5 mg/kg over 1–5 min (20 mg max); may repeat in 5–20 min; or lorazepam, 0.05–0.2 mg/kg (less effective with repeated doses, longer-acting than diazepam); or midazolam: IV, 0.1–0.2 mg/kg; intranasally, 0.2 mg/kg.
Phenytoin, 10–20 mg/kg IV (not IM) over 5–20 min; (1000 mg maximum); monitor with blood pressure and ECG. Fosphenytoin may be given more rapidly in the same dosage and can be given IM; order 10–20 mg/kg of “phenytoin equivalent” (PE).
Phenobarbital, 5–20 mg/kg (sometimes higher in newborns or refractory status in intubated patients).
Correct metabolic perturbations (eg, low-sodium, acidosis).
Administer fluids judiciously.
Other drug approaches in refractory status:
Repeat phenytoin, phenobarbital (10 mg/kg). Monitor blood levels. Support respiration, blood pressure as necessary.
Other medications: valproate sodium, available as 100 mg/mL for IV use; give 15–30 mg/kg over 5–20 min.
Levetiracetam may be helpful (20–40 mg/kg/dose IV).
For patients who fail initial intervention consider: midazolam drip: 1–5 mcg/kg/min (even to 20 kg/min); pentobarbital coma; propofol and general anesthetic.
Consider underlying causes:
Structural disorders or trauma: MRI or CT scan.
Infection: lumbar puncture, blood culture, antibiotics.
Metabolic disorders: consider lactic acidosis, toxins, and uremia if child is being treated with chronic AEDs, obtain medication levels. Toxin screen.
Initiate maintenance drug treatment with IV medications: phenytoin (10 mg/kg); phenobarbital (5 mg/kg); valproate IV 30 mg/kg; levetiracetam 20–30 mg/kg. Transition to oral medication when patient can safely take them.
Criteria for febrile seizures are (1) age 3 months to 6 years (most occur between ages 6 and 18 months), (2) fever of greater than 38.8°C, and (3) non-CNS infection. More than 90% of febrile seizures are generalized, last less than 5 minutes, and occur early in the illness causing the fever. Often the fever is not noted until after the seizure occurs. Febrile seizures occur in 2%–3% of children. Acute respiratory illnesses are most commonly associated with febrile seizures. Gastroenteritis, especially when caused by Shigella or Campylobacter, and urinary tract infections are less common causes. Roseola infantum is a rare but classic cause. One study implicated viral causes in 86% of cases. HHV-6 and HHV-7 are common causes for febrile status epilepticus, both accounting for one-third of cases. Febrile seizures rarely (1%–3%) evolve to recurrent unprovoked seizures (epilepsy) in later childhood and adult life (risk is increased two- to fivefold compared with children who do not have febrile seizures). The chance of later epilepsy is higher if the febrile seizures have complex features, such as duration longer than 15 minutes, more than one seizure in the same day, or focal features. Other predictive factors are an abnormal neurologic status preceding the seizures (eg, cerebral palsy or mental retardation), early onset of febrile seizure (before age 1 year), and a family history of epilepsy. Even with adverse factors, the risk of epilepsy after febrile seizures is still only in the range of 15%–20%, although it is increased if more than one risk factor is present. Recurrent febrile seizures occur in 30%–50% of cases. Therefore, families should be prepared to expect more seizures. In general, recurrence of febrile seizures does not worsen the long-term outlook.
The child with a febrile seizure must be evaluated for the source of the fever, in particular to exclude CNS infection. Routine studies such as serum electrolytes, glucose, calcium, skull radiographs, or brain imaging studies are seldom helpful unless warranted based on clinical history or suspicion of abuse. History and the examination should guide the work-up and any treatment amenable underlying infection should be addressed. Meningitis and encephalitis must be considered. Signs of meningitis (eg, bulging fontanelle, stiff neck, stupor, and irritability) may be absent, especially in a child younger than age 18 months.
After controlling the fever and stopping an ongoing seizure, the physician must decide whether to do a lumbar puncture. The fact that the child has had a previous febrile seizure does not rule out meningitis as the cause of the current episode. It is very important, especially in younger children, to exclude CNS infection as a source; these children are not classified as having a febrile seizure. A recent study demonstrated that 96% of children with febrile status epilepticus who received an LP had less than three WBC in the CSF. Therefore, seizure should not be an acceptable explanation for elevated cells in the CSF. Although the yield is low, a lumbar puncture should probably be considered done if the child is younger than age 18 months, and has been pretreated with antibiotics or is under-immunized. Certainly any child with meningeal signs fever and seizure should have an examination of their CSF. Occasionally observation in the emergency department for several hours obviates the need for a lumbar puncture, but in general one should have a low threshold for performing this potentially life-saving test.
EEG is rarely useful. An EEG may be considered if the febrile seizure is complicated, focal, or otherwise unusual, but has little predictive value. In uncomplicated febrile seizures, the EEG is usually normal. If performed, the EEG should be done at least a week after the illness to avoid transient changes due to fever or the seizure itself. In older children, 3-Hz spike-wave discharges, suggestive of a genetic propensity to epilepsy, may occur. In the young infant, EEG findings seldom aid in assessing the chance of recurrence of febrile seizures or in long-term prognosis. Thus, EEG is not recommended for the child with simple febrile seizures.
Prophylactic anticonvulsants are not recommended after a febrile seizure. Only phenobarbital and valproic acid have demonstrated efficacy in preventing febrile seizures; phenytoin and carbamazepine have been shown to be ineffective. Newer antiepileptic drugs have not been studied. Diazepam started at the first onset of fever for the duration of the febrile illness (0.5 mg/kg two or three times per day orally or rectally) may be effective but will sedate a child and possibly complicate the evaluation for a source of the fever. Prophylactic diazepam is also limited by the fact that a seizure is often the first evidence of fever associated with an acute illness. Diastat (rectal diazepam gel) can be used to prevent febrile status epilepticus in the child with a prolonged febrile seizure (one lasting over 5 minutes), often the greatest concern.
Measures to control fever such as sponging or tepid baths, antipyretics, and the administration of antibiotics for proven bacterial illness are reasonable but unproven to prevent recurrent febrile seizures.
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.
DJ: Medical treatment of pediatric status epilepticus. Semin Pediatr Neurol 2010;17:169–175
MT: Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia 2010;51:676–685
EA: New drugs for pediatric epilepsy. Semin Pediatr Neurol 2010;17:214–223
et al: Clinical Practice Guideline—febrile seizures: guideline for the neurodiagnostic evaluation of the child with a simple febrile seizure. Pediatrics 2015;127(2):389–394
et al. Instruction manual for the ILAE 2017 operational classification of seizure types. Epilepsia. 2017;58(4):531–542. doi:10.1111/epi.13671.
et al: Cerebrospinal fluid findings in children with fever-associated status epilepticus: results of the consequences of prolonged febrile seizures (FEBSTAT) study. J Pediatrics 2012;161:1169–1171
EH: Ketosis and the ketogenic diet, 2010: advances in treating epilepsy and other disorders. Adv Pediatr 2010;57:315–329
et al: Evidence based guideline update: medical treatment of infantile spasms. Report of the guideline development subcommittee of the American Academy of Neurology and the practice committee of the Child Neurology Society. Neurology 2012 Jun 12;78(24):1974–1980
M: Towards early diagnosis and treatment to save children from catastrophic epilepsy—focus on epilepsy surgery. Brain Dev 2013;35(3)730–741
JR: Benign epilepsy of childhood with centrotemporal spikes (BECTS): to treat or not to treat, that is the question. Epilepsy Behav 2010;19:197–203
K: Outcome and prognosis of status epilepticus in children. Semin Pediatr Neurol 2010;17:195
et al: Recurrence risk after withdrawal of antiepileptic drugs in children with epilepsy: a prospective study. Eur J Paediatr Neurol 2009 [Epub ahead of print]
G: Treatment of neonatal seizures. Arch Dis Child Fetal Neonatal Ed 2007;92:F148
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
et al: ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia 2017;58(4):512–521. doi:10.1111/epi.13709.
I: Neonatal electroencephalography: review of a practical approach. J Child Neurol 2011;26:341–355
et al: Phenomenology of prolonged febrile seizures: results of the FEBSTAT study. Neurology 2008;71:170–176
S: SUDEP and other causes of mortality in childhood-onset epilepsy. Epilepsy Behav 2013;28(2):249–255
WD: Status epilepticus in children. Curr Neurol Neurosci Rep 2009;9:137
JW: Managing severe epilepsy syndromes of early childhood. J Child Neurol 2009;24:24S
Sleep disorders can originate from abnormalities within the respiratory system, the neurologic system and the coordination (or lack thereof) between these two systems. In order to understand abnormal sleep, one must understand normal sleep, which changes as the child develops. Sleep and its development are reviewed in Chapter 3. Chapter 3 also discusses behavioral considerations in the treatment of sleep disorders. Respiratory abnormalities that are associated with sleep such as obstructive sleep apnea are described in Chapter 19. This discussion focuses on neurologic features of several sleep disorders affecting children.
Narcolepsy, a primary disorder of sleep, is characterized by chronic, inappropriate daytime sleep that occurs regardless of activity or surroundings and is not relieved by increased sleep at night. One half of individuals affected by narcolepsy experience their initial symptoms in childhood. Of children with narcolepsy, 4% are under age 5, 18% are younger than age 10, and 60% are between puberty and their late teens.
Additional symptoms are cataplexy, hypnagogic and/or hypnopompic hallucinations (visual or auditory), and sleep paralysis. Cataplexy is a transient partial or total loss of muscle tone, often triggered by laughter, or other heightened emotional states. Consciousness is preserved during these spells, which can last several minutes in duration. Most patients with narcolepsy will develop cataplexy (60%–90%). Hypnagogic hallucinations are intense visual or auditory hallucinations noted while falling asleep, whereas hypnopompic hallucinations occur while waking from sleep. Sleep paralysis is a brief loss of voluntary muscle control typically occurring at sleep-wake transitions and lasting for minutes.
Abnormally short latency between sleep onset and transition into rapid eye movement (REM) sleep occurs in subjects with narcolepsy. The first cycle of REM sleep usually occurs after 80–100 minutes in normal children. Nocturnal polysomnography and Multiple Sleep Latency Testing (MSLT) can demonstrate abnormal REM latency and are used to diagnose narcolepsy. Human leukocyte antigen (HLA) subtypes DQB1*0602 and DRB1*1501 are associated with narcolepsy, as well as absence of a hypothalamic neuropeptide, hypocretin, which can be measured in CSF. Sleep hygiene and behavior modification are used to treat patients with narcolepsy. In general, medications used for the treatment of narcolepsy in children are off label. CNS stimulants such as amphetamine mixtures are typically used to treat excessive daytime sleepiness. Modafinil and sodium oxybate are an effective treatment in adults; controlled studies in children are lacking. Cataplexy responds to fluoxetine, clomipramine, or sodium oxybate.
2. Benign Neonatal Sleep Myoclonus
Benign neonatal sleep myoclonus is characterized by myoclonic jerks, usually bilateral and synchronous, which occur only during sleep and stop abruptly when the infant is aroused. It is a benign condition that is frequently confused with epileptic seizures. Onset is typically in the first 2 weeks of life and resolves spontaneously in the first months of life, although these may occur as late as 10 months. Clusters of jerks may last from a few seconds up to 20 minutes.
3. Nocturnal Frontal Lobe Epilepsy
Nocturnal frontal lobe epilepsy (NFLE) is characterized by paroxysmal arousals from NREM sleep with hypermotor seizures characterized by bizarre stereotyped hyperkinetic of dystonic motor movements lasting up to 5 minutes. NFLE is a heterogeneous disorder which includes both sporadic and familial forms. Lack of definitive epileptiform abnormalities on EEG recordings may lead to misdiagnoses of a parasomnia, such as night terrors or somnambulism.
Parasomnias are abnormal behavioral or physiologic events that occur in association with various sleep stages or the transition between sleeping and waking. The parasomnias of childhood are divided into those occurring in non-REM sleep (NREM) and REM sleep. The NREM parasomnias consist of partial arousals, disorientation, and motor disturbances and include sleep-walking (somnambulism), sleep talking, confusional arousals, and night terrors, among others. These are discussed in more detail in Chapter 3. The REM sleep parasomnias include nightmares, hypnagogic and hypnopompic hallucinations (as can occur in narcolepsy), and REM sleep behavior disorder, which is characterized by physical and sometimes violent movements during the dream state, and is primarily seen in adulthood. These typically occur during the second half of sleep, when REM comprises a larger part of the sleep cycle.
5. Restless Legs Syndrome
Restless legs syndrome refers to a feeling of needing to move the legs (dysesthesia) that often starts when resting at night. Movement of the legs temporarily relieves the symptoms, though this can interfere with the ability to fall asleep. This disorder can be familial; therefore, a detailed family history may be helpful. Occasionally, anemia (low ferritin) has been noted in adults and children with the disorder; in these cases, improvement has occurred with ferrous sulfate treatment. These are discussed in more detail in Chapter 3.
M: Clinical features, diagnosis, and treatment of narcolepsy. Clin Chest Med 2010;31:371–381
E: Clinical and therapeutic aspects of childhood narcolepsy-cataplexy: a retrospective study of 51 children. Sleep 2010;33:1457–1464
et al: Practice parameters for the non-respiratory indications for polysomnography and multiple sleep latency testing for children. Sleep 2012;35:1467–1473
et al: The spectrum of benign myoclonus of early infancy: clinical and neurophysiologic features in 102 patients. Epilepsia 2009;50:1176–1183
T: Sleep Disorders in Children. Ann. N.Y. Acad. Sci 2010;1184(1);1–14
et al: Non-respiratory indications for polysomnography and related procedures in children: an evidence-based review. Sleep 2012;35:1451–1466
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
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 may 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, neurologic 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 45% of children experience at least one debilitating headache, and up to 28% of adolescents have migraines. First, the clinician must determine if the headache is primary or secondary. Symptoms and signs are the center of evaluation; however, red flags (Table 25–8) may prompt further workup and evaluation. Correct diagnosis of headache disorders will guide treatment and management.
Table 25–8.Red flags for children with headaches. ||Download (.pdf) Table 25–8.Red flags for children with headaches.
Headache in child less than 5 years
Headache occurring in the middle of the night or early morning with or without vomiting
Neurocutaneous stigmata (café au lait spots, hypopigmented macules)
Based on the 2013 International Classification of Headache Disorders, 3rd Edition (beta version) (ICHD-III beta), primary headaches are divided into three major categories: migraine, tension-type, and trigeminal autonomic cephalalgias. Clinical features of migraine without aura and tension-type headache are compared in Table 25–9. Individuals with greater than 15 headaches (migraine or tension-type) per month are considered chronic, and medication overuse must be excluded. Triggers of head pain can include stress, sleep deprivation, dehydration, skipped meals, caffeine, and possibly specific foods (eg, monosodium glutamate or nitrites). Trigeminal autonomic cephalalgias (or sub-category, cluster headache) are rare in children. They present as recurrent, unilateral severe headaches with autonomic dysfunction (watery eye, congestion, facial sweating, miosis, ptosis).
Table 25–9.Classification of TTH and migraine. ||Download (.pdf) Table 25–9.Classification of TTH and migraine.
| ||Migraine Without Aura ||Tension-Type Headache |
|Duration ||2–72 h* ||30 min to 7 days |
|Quality ||Throbbing/pounding ||Pressure tight band |
|Severity ||Moderate to severe ||Mild to moderate |
|Location ||Unilateral/bilateral* ||Bilateral |
|Physical activity ||Worsens headache ||No effect |
|Associated factors |
|a. Nausea +/– vomiting ||a or b ||No change |
|b. Photo and phonophobia || ||Photo or phonophobia but not both |
According to the ICHD-III beta, migraines include childhood periodic syndromes such as cyclic vomiting, abdominal migraine, and benign paroxysmal vertigo of childhood. History of these periodic syndromes may be discovered in children and adolescents with migraines. Infantile colic may also be a precursor or early manifestation of migraine.
Routine laboratory testing has not been found to be helpful, though the evidence is limited. History and examination may prompt screening for general medical conditions as indicated.
Routine neuroimaging is not indicated for children presenting with recurrent headaches and a normal neurologic examination. Red flags as noted in Table 25–8 should at least prompt consideration of imaging. The type of imaging (CT vs MRI) depends on the urgency of evaluation (ie, acute onset severe headache vs worsening headache over 1–2 weeks). See the discussion on pediatric neuroradiologic procedures for discussion on benefits of different imaging modalities.
Secondary causes of headache include broad categories such as head trauma, infection, vascular, intracranial pressure changes, structural, metabolic, toxic, medication, illicit drug related, and hematologic (Table 25–10). Headaches associated with head trauma are those that start within 2 weeks of closed head injury. They can have either features of migraines or tension-type headaches. Neck pain and headache after head trauma warrant evaluation for a dissection, especially if examination is suggestive for a connective tissue disorder such as Marfans. Headaches that worsen with lying down or vomiting without nausea are concerning for increased intracranial hypertension such as IIH, sinus venous clot producing increased CSF pressure, hydrocephalus, or mass. It is worth noting that, in studies evaluating the utility of imaging in pediatric headache, up to 98% of patients with intracranial process requiring surgical intervention had an abnormal neurologic examination. Headaches that worsen with standing and improve with lying down are suggestive of low-pressure headaches caused by a tear in the dura from a preceding LP or spontaneous leak.
Table 25–10.Differential diagnosis of headaches. ||Download (.pdf) Table 25–10.Differential diagnosis of headaches.
|Primary Causes ||Secondary Causes |
| || || |
Medication and illicit drug ingestion and withdrawal are both culprits to secondary headaches. Steroids, vitamin A toxicity, oral contraceptives, and tetracycline are all associated with IIH. Medications that are commonly associated with medication overuse headache include aspirin, acetaminophen, NSAIDs, triptans, and combination analgesics such as acetaminophen, butalbital, and caffeine. Other toxins such as lead, carbon monoxide, or organic solvent poisoning cannot be overlooked.
Infections both of the CNS or systemically are associated with new onset headaches. Additionally, common systemic or other focal infections may cause headaches such as viral upper respiratory infections, strep pharyngitis (especially in younger children), rhinosinusitis (sinus headache), influenza, and Lyme disease. Migraines are frequently misdiagnosed as sinus headaches and physicians should carefully obtain history of pain in the face, ears, or teeth and evaluate for signs of rhinosinusitis on either physical examination or imaging.
Any cause of hypoxia (eg, cardiac, respiratory, altitude, anemia) may cause a bifrontal throbbing headache that may be worsened with exertion, straining, or laying down. Hypercapnia causes a nonspecific headache and may be secondary to sleep apnea or other underlying metabolic or respiratory disorder.
Although eye strain and temporal mandibular joint dysfunction are rare causes of recurrent headaches, they can be simply treated; therefore, when suspected, evaluation by ophthalmology or dentistry, respectively, is indicated. Examination in temporomandibular joint dysfunction can include local pain, deviation of the mandible, jaw clicking, and limitations of chewing motion.
A thorough history and physical examination helps diagnose most of these conditions.
Migraines and tension-type headaches are episodic headache disorders but may transform into chronic headaches when a child has more than 15 headache days per month for three or more months. Risk factors for chronicity include psychological comorbidity, obesity, and excessive medication.
Depression and anxiety are both comorbid with headaches and are associated with increased headache burden and disability, such as school absenteeism and poor school performance. Equally, childhood psychiatric disorders also have increased rates of primary headaches. Maintaining school attendance in children with headaches is a key factor in limiting chronicity and further disability from headaches.
Treatment is divided into two categories: acute/abortive and preventative. Management of headaches should emphasize the necessity for early and adequate treatment during a headache, in addition to self-management skills to reduce frequency and disability such as life-style modification and headache diaries. Pharmacologic preventative treatment can be considered if frequency or disability is significant.
A. Acute/Abortive Treatment
Acute treatment for pediatric migraine includes use of simple analgesics and migraine-specific medications. Any medication used to abort a headache (abortive medication) should be given as early as possible after the onset of headache. Simple analgesics include acetaminophen (15 mg/kg; max dose 650 mg) and ibuprofen (10 mg/kg; max dose 800 mg), often used as first-line therapy. The United States FDA has approved almotriptan (ages 12–17) and rizatriptan (ages 6–17). Studies have shown significant benefit for pediatric migraine using rizatriptan oral (5 mg for 20–39 kg, 10 mg for > 40 kg), almotriptan oral (6.25 or 12.5 mg), zolmitriptan nasal (5 mg > 12 y), and sumatriptan nasal (10 mg for < 40kg, 20 mg for > 40 kg). Occasionally home treatment fails and patients may need IV medications either in an emergency department or infusion center. When a patient fails emergency room treatments, IV dihydroergotamine can be effective with nausea as the most common side effect. All medications used for abortive treatment should be used cautiously to avoid medication overuse headache. Simple analgesics should be limited to 2–3 times per week and migraine-specific medications to less than 1–2 times per week. During a headache biobehavioral techniques include rest, relaxation, and cold/hot packs. Providing the child with a cool dark room in which to rest may provide added benefit.
Any child with headaches should have biobehavioral management as a center point to treatment. This includes sleep hygiene (such as bedtime routine, adequate duration, and good quality of sleep), improved fluid intake, elimination of caffeine, regular nutritional meals, regular exercise and stretching, and stress management. Preventative treatment can be considered in individuals with headache frequency of one or more per week. Treatments should be chosen by optimizing wanted side-effects and minimizing unwanted side effects (eg, using topiramate in an obese child given its side-effect of weight loss).
Treatments are categorized into antiepileptic (eg, topiramate, valproic acid, levetiracetam), antihypertensive (eg, β-blockers, calcium channel blockers), antidepressants (eg, amitriptyline), antihistamine/antiserotonergic (eg, cyproheptadine), and nutraceuticals. Only small randomized double-blinded or open-label studies have tested these agents. The only FDA-approved migraine preventive medication in pediatric populations is topiramate for migraines in adolescents 12–17 years old.
Topiramate, amitriptyline, and cyproheptadine are the most commonly prescribed medications for pediatric headache. If topiramate is started slowly and at low doses, cognitive side effects can be avoided. Peripheral tingling is uncommon and when present usually can be tolerated by most children. Decreased appetite and weight loss should be monitored at routine appointments. Amitriptyline is usually dosed at nighttime given its side effect of sedation, in addition to other common side effects including constipation, dry mouth, and prolonged QT (typically at higher doses). Cyproheptadine is a good medication to use in younger children given its small side-effect profile of primary increased appetite and sedation. Divalproex sodium has not shown efficacy and side effects including weight gain, tremor, hair loss, and teratogenicity warrant caution in adolescent female patients.
Cognitive behavioral therapy is efficacious in significantly decreasing migraine frequency and disability in youth. Coenzyme q10 and magnesium oxide have shown some efficacy in childhood migraine. They may be a useful option for children with low frequency headache, low disability, or individuals who favor nonpharmaceutical options.
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.
et al: Pharmacologic treatment of pediatric headaches: a meta-analysis. JAMA Pediatr Mar 1, 2013;167(3):111
S: The efficacy of triptans in childhood and adolescence migraine. Cur Pain Headache Rep 2013 Jul;17(7):342
A: Episodic syndromes that may be associated with migriane: A.K.A. The “Childhood Periodic Syndromes”. Headache 2015:55:1358–1364.
Headache Classification Committee of the International Headache Society. The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 2013 Jul;33(9):629–808
AD: Current approaches to the diagnosis and management of paediatric migraine. Lancet Neurol 2010;9:190
et al: Practice parameter: Evaluation of children and adolescents with recurrent headaches. Neurology 2002;59:490–498.
et al: Headache evaluation in children and adolescents: when to worry? When to scan? Pediatr Ann 2010;39:399
S: Nutraceuticals in the prophylaxis of pediatric migraine: evidence-based review and recommendations. Cephalalgia 2014;34:568–583
et al: Drugs for the acute treatment of migraine in children and adolescents. Cochrane Database of Systematic Reviews 2016, Issue 4. Art. No.: CD005220. doi: 10.1002/14651858.CD005220.pub2.
PSEUDOTUMOR CEREBRI (IDIOPATHIC INTRACRANIAL HYPERTENSION)
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Signs and symptoms of increased intracranial pressure: chronic or progressive 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.
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.
Presenting features include new or chronic positional headache, vomiting, pulsatile tinnitus, papilledema, and diplopia. Later findings may include visual loss and optic atrophy. Visual symptoms are commonly secondary to transient visual obscurations (TVOs), which are transient (< 1 minute) and reversible alterations of vision in these patients. This must be distinguished from visual field anomalies, which can be permanent. IIH is characterized by increased intracranial pressure as documented by a lumbar puncture performed in the lateral decubitus position in the absence of an identifiable intracranial mass, infection, metabolic derangement, or hydrocephalus.
The cause of IIH is usually unknown, but it has been described in association with a variety of inflammatory, metabolic, toxic, and connective tissue disorders (Table 25–11). Assessing for alternative causes of increased intracranial pressure is essential to the diagnosis. MRI (or urgent CT for critically ill patients) may reveal hydrocephalus, tumor, or abscess. MRV may demonstrate a cerebral sinovenous thrombosis (CSVT), requiring hematological evaluation and consideration of anticoagulation. As noted in Table 25–11, medications, endocrinologic disturbances, and rheumatologic anomalies may all predispose patients to IIH. Lumbar puncture is essential to the diagnosis, as it confirms the presence of increased pressure (above 180–250 mm H2O depending on technique and anesthetic used), but also assesses for white blood cell count, glucose, and protein (looking for an infectious mimicker, such as chronic meningitis). In some inflammatory and connective tissue diseases, the CSF protein concentration may also be increased.
Table 25–11.Conditions associated with idiopathic intracranial hypertension and idiopathic intracranial hypertension mimickers. ||Download (.pdf) Table 25–11.Conditions associated with idiopathic intracranial hypertension and idiopathic intracranial hypertension mimickers.
Medications and metabolic-toxic disorders
Hypervitaminosis A, including use of retinoids
Tetracycline, minocycline toxicity
Nalidixic acid toxicity
Hyperparathyroidism or hyperthyroidism
Systemic lupus erythematosus
Chronic CO2 retention
Infectious and parainfectious disorders
Chronic otitis media (lateral sinus thrombosis)
Dural sinus thrombosis
Minor head injury
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 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.
With appropriate workup and treatment, most patients recover from IIH without long-term sequela including visual outcome. Reoccurrence risk is greatest within 18 months.
et al: CSF opening pressure in children with optic nerve head edema. Neurology 2011;76(19):1658
GS: Idiopathic intracranial hypertension: pseudotumor cerebri. Headache 2014 Feb;54(2):389–393
DL: A review of pediatric idiopathic intracranial hypertension. Pediatr Clin North Am 2014 Jun;61(3):579–590
et al: IIH in children: visual outcome and risk of recurrence. Childs Nerv Syst 2011 Nov;27(11):1913–1918
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Perinatal ischemic stroke is defined as strokes occurring in neonates younger than 28 days old.
Childhood ischemic stroke occurs in children between 28 days and 18 years old.
Neuroimaging is required to make the diagnosis of stroke.
Pediatric arterial ischemic stroke is subdivided into two categories: perinatal arterial ischemic stroke (perinatal AIS) and childhood arterial ischemic stroke (childhood AIS). Generally, perinatal AIS is defined as arterial ischemia occurring in a patient younger than age 28 days and older than 28 weeks gestation. Childhood AIS is any ischemic stroke occurring in a patient between 28 days and 18 years old.
1. Childhood Arterial Ischemic Stroke
Childhood AIS is emerging as a serious and increasingly recognized disorder, affecting 1.6 per 100,000 children per year. There are numerous adverse outcomes, which include death in 10%, neurologic deficits or seizures in 70%–75%, and recurrent ischemic stroke in up to 20%. It is essential to recognize that childhood AIS represents a neurologic emergency, for which prompt diagnosis can affect treatment considerations and outcome. Unfortunately, most pediatric AIS is not recognized until > 24 hours after onset; and treatment considerations matter most in the first few hours after stroke onset. When possible, all children who present with ischemic stroke should be transferred to a tertiary care center that specializes in pediatric stroke management. The evaluation should include a thorough history of prior illnesses, especially those associated with varicella (even in the prior 1–2 years) preceding viral infection, minor head or neck trauma, and familial clotting tendencies. A systematic search for evidence of cardiac, vascular, hematologic, or intracranial disorders should be undertaken (Table 25–12). Although many ischemic strokes are not associated with a single underlying systemic disorder, congenital heart disease is the most common predisposing condition, followed by hematologic and neoplastic disorders. In many instances the origin is multifactorial, necessitating a thorough investigation even when the cause may seem obvious. Arteriopathy is seen in as many as 80% of “idiopathic” patients, and likely confers an increased recurrence risk.
Table 25–12.Etiologic risk factors for ischemic and/or hemorrhagic ischemic stroke. ||Download (.pdf) Table 25–12.Etiologic risk factors for ischemic and/or hemorrhagic ischemic stroke.
Structural heart disease
Vascular occlusive disorders
Cervical/cerebral arterial dissection
Systemic lupus erythematosus
Drug abuse (amphetamines)
Human immunodeficiency virus
Dural sinus and cerebral venous thrombosis
Cortical venous thrombosis
Iron deficiency anemia
Sickle cell disease
Vitamin K deficiency
Prothrombin gene mutation
Methylenetetrahydrofolate reductase mutation
Lipoprotein (a) derangements
Factor V Leiden deficiency
Factor VIII elevation
Systemic lupus erythematosus
Use of oral contraceptives
Antithrombin III deficiency
Protein C and S deficiencies
Intracranial vascular anomalies
Focal cerebral arteriopathy
Connective tissue diseases
Manifestations of arterial ischemic stroke in childhood vary according to the vascular distribution to the brain structure that is involved. Because many conditions leading to childhood ischemic stroke result in emboli, multifocal neurologic involvement is common. Children may present with acute hemiplegia similarly to ischemic stroke in adults. Unilateral weakness, sensory disturbance, dysarthria, and/or dysphagia may develop over a period of minutes, but at times progressive worsening of symptoms may evolve over several hours. Bilateral hemispheric involvement may lead to a depressed level of consciousness. The patient may also demonstrate disturbances of mood and behavior and experience focal or multifocal seizures. Physical examination of the patient is aimed not only at identifying the specific deficits related to impaired cerebral blood flow, but also at seeking evidence for any predisposing disorder. Retinal hemorrhages, splinter hemorrhages in the nail beds, cardiac murmurs, rash, fever, neurocutaneous stigmata, and signs of trauma are especially important findings.
B. Laboratory Findings and Ancillary Testing
In the acute phase, certain investigations should be carried out emergently with consideration of treatment options. This should include complete blood count, complete metabolic panel, serum or urine pregnancy test, disseminated intravascular coagulation (DIC) panel, fibrin split products, erythrocyte sedimentation rate, C-reactive protein, prothrombin time/partial thromboplastin time, anti-factor Xa activity, chest radiography, ECG, urine toxicology, and imaging (see the following section). Subsequent studies can be carried out systemically, with particular attention to disorders involving the heart, blood vessels, platelets, red cells, hemoglobin, and coagulation proteins. Twenty to fifty percent of pediatric ischemic stroke patients will have a prothrombotic state. Additional laboratory tests for systemic disorders such as vasculitis, mitochondrial disorders, and metabolic disorders are sometimes indicated.
Examination of CSF is indicated in patients with fever, nuchal rigidity, or altered mental status when the diagnosis of intracranial infection requires exclusion. Lumbar puncture may be deferred until a neuroimaging scan (excluding brain abscess or a space-occupying lesion that might contraindicate lumbar puncture) has been obtained. In the absence of infection, rheumatologic disease or intracranial subarachnoid hemorrhage, CSF examination is rarely helpful in defining the cause of the cerebrovascular disorder.
EEG may help in patients with severely depressed consciousness. ECG and echocardiography are useful both in the diagnostic approach to the patient and in ongoing monitoring and management, particularly when hypotension or cardiac arrhythmias complicate the clinical course or when the stroke is thought to be embolic in nature.
CT and MRI scans of the brain are helpful in defining the extent of cerebral involvement with ischemia or hemorrhage. CT scans may be normal within the first 12–24 hours of an ischemic stroke and are more useful to exclude intracranial hemorrhage. This information may be helpful in the early stages of management and in the decision to treat with anticoagulants. Given the high incidence of ischemic stroke mimickers in the pediatric population (migraine with aura, Todd’s paralysis, encephalitis, etc.), urgent MRI with diffusion-weighted imaging (DWI) is increasingly used in pediatric stroke centers.
Vascular imaging of the head and neck is an important part of pediatric ischemic stroke management and may include CTA, MRA, or conventional angiography. In studies in which both MRA and cerebral angiography have been used, up to 80% of patients with idiopathic childhood-onset arterial ischemic stroke have demonstrated a vascular abnormality. Vascular imaging is helpful in diagnosing disorders such as transient cerebral arteriopathy, arteriopathy associated with sickle cell disease, moyamoya disease, arterial dissection, aneurysm, fibromuscular dysplasia, and vasculitis. Studies have demonstrated that patients with vascular abnormalities on MRA or conventional angiography have a much greater recurrence risk than patients with normal vessels. When vessel imaging is performed, all major vessels should be studied from the aortic arch. With evidence of fibromuscular dysplasia in the intracranial or extracranial vessels, renal arteriography is indicated.
Patients with an acute onset of neurologic deficits must be evaluated for other disorders that can cause focal neurologic deficits. Hypoglycemia, prolonged focal seizures, a prolonged postictal paresis (Todd’s paralysis), acute disseminated encephalomyelitis (ADEM), meningitis, hemorrhagic stroke, encephalitis, hemiplegic migraine, ingestion, and brain abscess should all be considered. Migraine with focal neurologic deficits may be difficult to differentiate initially from ischemic stroke. Occasionally, the onset of a neurodegenerative disorder (eg, adrenoleukodystrophy or mitochondrial disorder) may begin with the abrupt onset of seizures and focal neurologic deficits. The possibility of drug abuse and other toxic exposures must be investigated diligently in any patient with acute mental status changes.
The initial management of ischemic stroke in a child is aimed at providing support for pulmonary, cardiovascular, and renal function. Patients should be administered oxygen and are usually monitored in an intensive care setting. Typically, maintenance fluids without glucose are indicated to augment vascular volume. Pyrexia should be treated aggressively. Specific treatment of ischemic stroke, including blood pressure management, fluid management, and anticoagulation measures, depends partly on the underlying pathogenesis. Meningitis and other infections should be treated. Sickle cell patients require hematologists to perform urgent exchange transfusion and most patients will require chronic transfusions after hospital discharge. Moyamoya is usually treated with surgical revascularization, while patients with vasculitis are often given anti-inflammatory therapy, such as steroids.
In most idiopathic cases of childhood ischemic stroke, anticoagulation or aspirin therapy is indicated. The Royal College of Physicians Pediatric Ischemic Stroke Working Group recommends aspirin, 5 mg/kg daily, as soon as the diagnosis is made. Aspirin use appears safe but the American Heart Association (AHA) recommends yearly flu-shots and close monitoring for Reye syndrome in pediatric patients. Other groups, such as the American College of Chest Physicians, recommend initial treatment with anticoagulants, such as low-molecular-weight heparin or unfractionated heparin, for 5–7 days (while excluding cardiac sources and dissection) and then switching to aspirin (3–5 mg/days). Recent AHA guidelines support both of these approaches. In some situations, such as arterial dissection or cardioembolic events, heparinization is usually considered. In adults with cerebrovascular thrombosis, thrombolytic agents (tissue plasminogen activator) used systemically or delivered directly to a vascular thrombotic lesion using interventional radiologic techniques has been shown to improve outcome in the appropriate patients. Although case reports exist, studies in children have not been completed. AHA guidelines recommend against the thrombolysis, outside of a clinical trial for children, while equivocating in the case of adolescents. Given the time lag to diagnosis and the lack of evidence in children, tissue plasminogen activator is currently used in less than 2% of US children with ischemic stroke. The use of tissue plasminogen activator (tPA) should be limited to practitioners who are familiar with cerebrovascular disease in children.
Long-term management requires intensive rehabilitation efforts and therapy aimed at improving the child’s language, educational, and psychological performance. Length of treatment with antithrombotic agents, such as low-molecular-weight heparin and aspirin, is still being studied and depends on the etiology. Constraint therapy may be particularly helpful in cases of hemiparesis.
The outcome of ischemic stroke in infants and children is variable. Roughly one-third may have minimal or no deficits, one-third are moderately affected, and one-third are severely affected. Underlying predisposing conditions and the vascular territory involved all play a role in dictating the outcome for an individual patient. When the ischemic stroke involves extremely large portions of one hemisphere or large portions of both hemispheres and cerebral edema develops, the patient’s level of consciousness may deteriorate rapidly, and death may occur within the first few days. In contrast, some patients may achieve almost complete recovery of neurologic function within several days if the cerebral territory is small. Seizures, either focal or generalized, may occur in 30%–50% of patients at some point in the course of their cerebrovascular disorder. Recurrence is up to 14%, and is more prominent in some conditions, such as protein C deficiency, lipoprotein (a) abnormalities, and arteriopathies. Chronic problems with learning, behavior, and activity are common. Long-term follow-up with a pediatric neurologist is indicated and if possible a multidisciplinary ischemic stroke team.
2. Perinatal Arterial Ischemic Stroke
Perinatal arterial ischemic stroke is more common than childhood ischemic stroke, affecting 1:3500 children. Perinatal ischemic stroke has two distinct presentations: acute and delayed. Most patients with an acute presentation develop neonatal seizures during the first week of life, usually in association with a perinatal event. The seizures in acute perinatal ischemic stroke are often focal motor seizures of the contralateral arm and/or leg. The presentation is stereotypical because of the predilection of the ischemic stroke to occur in the middle cerebral artery. The presence of diffusion-weighted abnormalities on an MRI scan confirms an acute perinatal ischemic stroke during the first week of life. Other patients present with delayed symptoms, typically with an evolving hemiparesis at an average of 4–8 months. These patients are termed “presumed perinatal arterial ischemic stroke.”
Acute treatment of a perinatal ischemic stroke is usually limited to neonates with seizures. Unless an embolic source is identified, aspirin and anticoagulation are almost never prescribed. Management is based on supportive care, identification of comorbid conditions, and treatment of seizures. In acute perinatal ischemic stroke, treatable causes such as infection, cardiac embolus, metabolic derangement, and inherited thrombophilia must be ruled out. In appropriate cases, echocardiography, thrombophilia evaluation, and lumbar puncture are indicated. Supportive management focuses on general measures, such as normalizing glucose levels, monitoring blood pressure, and optimizing oxygenation.
Long-term management of perinatal ischemic stroke usually starts with identifying risk factors, which might include coagulation disorders, cardiac disease, drugs, and dehydration. Although prothrombotic abnormalities with the best evidence of association are factor V Leiden, protein C deficiency, and high lipoprotein (a), many practitioners perform an extensive hematologic workup. Maternal risk factors such as infertility, antiphospholipid antibodies, placental infection, premature rupture of membranes, and cocaine exposure are all independently associated with perinatal ischemic stroke.
The prognosis for children who sustain perinatal ischemic strokes has been considered better than for children or adults with ischemic strokes, presumably because of the plasticity of the neonatal brain. The range of cognitive and motor outcomes after perinatal stroke is broad. Twenty to forty percent of patients who experience perinatal ischemic strokes are neurologically normal. Motor impairment affects about 40%–60% of patients and is predominantly hemiplegic cerebral palsy. In acute presentations, MRI can be predictive of motor impairment, as descending corticospinal tract diffusion-weighted MRI signal is associated with a higher incidence of hemiplegia. Language delays, behavioral abnormalities, and cognitive deficits are seen in up to 55% of infants who experience perinatal ischemic strokes. Patients are also at an increased risk for seizures. Ischemic stroke recurs in 3% of neonates and is usually associated with a prothrombotic abnormality or an underlying illness, such as cardiac malformation or infection. Given the low incidence of recurrence, long-term management is largely rehabilitative, including constraint therapies.
et al: Prevention and Treatment of Thrombosis in Pediatric and Congenital Heart Disease: a scientific statement from the American Heart Association. Circulation 2013;128:2622–2703
et al: Symptomatic neonatal arterial ischemic stroke: The international Pediatric Stroke Study. Pediatrics 2011;128:1402–1410
G: Paediatric stroke: pressing issues and promising directions. Lancet 2015 Jan;14(1):92–102
et al: childhood arterial ischaemic stroke incidence, presenting features, and risk factors: a prospective population-based study. Lancet Neurol 2014;13:35–43
et al: Antithrombotic therapy in neonates and children: antithrombotic therapy and prevention of thrombosis 9th ed: American College of Chest Physicians evidence-based clinical guidelines. Chest 2012;141:e737S–801S
et al: Management of ischemic stroke in infants and children: a scientific statement from a Special Writing Group of the American Heart Association Ischemic Stroke Council and the Council on Cardiovascular Disease in the Young. Ischemic Stroke 2008;39:2644–2691
CONGENITAL MALFORMATIONS OF THE NERVOUS SYSTEM
Malformations of the nervous system occur in 3% of living neonates and are present in 40% of infants who die in the first year of life. Structural malformation of the CNS may result from a variety of causes, including infectious, toxic, genetic, metabolic, and vascular insults. The specific type of malformation that results from such insults depends more on the gestational period during which the insult occurs than on the specific cause. The period of induction, days 0–28 of gestation, is the period during which the neural plate appears and the neural tube forms and closes. Insults during this phase can result in a major absence of neural structures, such as anencephaly, or in a defect of neural tube closure, such as spina bifida, meningomyelocele, or encephalocele. Cellular proliferation and migration characterize neural development that occurs from 12–20 weeks gestation. During this period, lissencephaly, pachygyria, agyria, and agenesis of the corpus callosum (ACC) may arise depending on the type of developmental disruption.
1. Abnormalities of Neural Tube Closure
Defects of neural tube closure constitute some of the most common congenital malformations affecting the nervous system, occurring in 1:1000 live births prior to the introduction of folate supplementation (which decreased incidence by 50%–75%). Up to 6% of fetuses with isolated spinal cord defects have an associated chromosomal abnormality (typically Trisomy 13 or 18), which should be screened for upon identification of the defect. Spina bifida with associated myelomeningocele or meningocele is commonly found in the lumbar region. Depending on the extent and severity of the involvement of the spinal cord and peripheral nerves, lower extremity weakness, bowel and bladder dysfunction, and hip dislocation may be present. Delivery via cesarean section followed by early surgical closure of meningoceles and meningomyeloceles is usually indicated. Additional treatment is necessary to manage chronic abnormalities of the urinary tract, orthopedic abnormalities such as kyphosis and scoliosis, and paresis of the lower extremities. Hydrocephalus is very common and usually requires ventriculoperitoneal shunting. For selected patients, pre-natal repair has been shown to reduce the need for VP shunt at one year and result in improved motor function at 30 months of age, though pregnancy and delivery-related complications were higher. This is a promising option for patients who meet the surgical criteria.
In general, the diagnosis of neural tube defects is obvious at the time of birth. The diagnosis may be strongly suspected prenatally on the basis of ultrasonographic findings and the presence of elevated α-fetoprotein and acetylcholinesterase in the amniotic fluid. All women of childbearing age should take prophylactic folate, which can prevent these defects and decrease the risk of recurrence by 70%.
2. Disorders of Cortical Development
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Malformations of cortical development (MCD) can be diffuse, unilateral, or focal, which is dependent on the timing and type of the disruption of brain development.
Clinical presentation is variable and can be divided into two large groups: diffuse MCD with poor neurodevelopmental outcomes and focal or multi-focal MCD with variable, but generally less severe, outcomes.
Malformations of cortical development are known causes of a wide spectrum of developmental and cognitive disabilities as well as epilepsy. They are a diverse group of disorders characterized by disruption of the cortex primarily identified on MRI. Although MCD was historically classified based on stages of brain development disrupted, the field of neurogenetics has revealed over a hundred genetic mutations leading to a wide variety of overlapping structural phenotypes.
MCD can occur when one of the three primary stages of cortical development are disrupted: (1) neuronal proliferation, (2) neuronal migration, or (3) post-migrational development. The genes associated with MCD include cell-cycle regulation, angiogenesis, protein synthesis, apoptosis, cell-fate specification, cytoskeletal structure and function, neuronal migration and basement-membrane function, and inborn errors of metabolism.
Clinical presentation is variable and can be divided into those children who present early with severe neurodevelopmental deficits and diffuse MCD, and those children who present later in childhood with focal seizures or more mild developmental and intellectual disabilities and are found to have focal or multi-focal MCD.
Diffuse MCD is typically associated with a variety of signs including seizures, global developmental delay, feeding, hearing, and vision impairments, poor sleep, abnormal head size, hydrocephalus, behavior problems, autonomic dysregulation, and movement disorders. Typically, there is a higher risk for shortened lifespan in these children.
Focal MCD can be associated with normal development or mild developmental delays. Focal seizures are a common presentation. Neurodevelopmental disabilities may include mild learning disabilities and behavioral concerns (including ADHD). Sometimes, focal MCD is found incidentally when neuroimaging is done for other reasons.
Megalencephaly is an example of neuronal proliferation dysfunction and results in a brain size that is greater than three standard deviations above the mean. On MRI megalencephaly can be associated with normal cortical development, polymicrogyria, and hemimegalencephaly. Associated neurologic outcomes can include normal development, developmental delay, intellectual disability, and seizures. There are several genes and syndromes associated including Neurofibromatosis 1.
B. Lissencephaly and Subcortical Band Heterotopia
Lissencephaly is an example of abnormal migration and increased apoptosis. This severe malformation of the brain is characterized by a smooth cortical surface with minimal sulcal and gyral development. Lissencephalic brains have a primitive cortex with less than the normal six-layered cortical mantle. The pattern of pachygyria (thick gyri) and agyria (absence of gyri) may vary in an anterior to posterior gradient and help guide genetic diagnosis. Patients with lissencephaly usually have severe neurodevelopmental delay, microcephaly, and seizures (including infantile spasms), although there is significant phenotypic heterogeneity. These disorders are autosomal recessive and X-linked. LIS1 mutations on chromosome 17 are sometimes associated with dysmorphic features (Miller-Dieker syndrome). Mutations in the RELN gene, results in a lissencephaly with severe hippocampal and cerebellar hypoplasia. X-linked syndromes involving mutations in DCX and ARX (associated with ambiguous genitalia) affect males with lissencephaly and females with band heterotopias or ACC.
Lissencephaly with hydrocephalus, cerebellar malformations, or muscular dystrophy may occur in Walker-Warburg syndrome (POMT1 mutations and others), Fukuyama muscular dystrophy (FKTN mutation), and muscle-eye-brain disease (POMGnT1 mutation). It is particularly important to identify these syndromes not only because clinical tests are available, but also because of their genetic implications. Lissencephaly may be a component of Zellweger syndrome, a peroxisomal disorder with elevated concentrations of very-long-chain fatty acids in the serum. No specific treatment for lissencephaly is available.
C. Polymicrogyria with or Without Schizencephaly
Polymicrogyria is a post-migrational disorder characterized by an overfolded and malformed cortex that can be associated with schizencephaly, diffuse, or focal, such as bilateral perisylvian polymicrogyria (the classic form). Patients with bilateral perisylvian polymicrogyria may have bulbar dysfunction, variable cognitive deficits, developmental delay, and epilepsy. Etiologies of polymicrogyria vary including genetic mutations, infectious, and vascular causes.
Treatment of MCD center on early child development intervention and focused symptomatic treatment (eg, attention deficit, hearing impairment, physical therapy for gait abnormalities).
3. Disorders of Cerebellum Development
A. Arnold-Chiari Malformations
Arnold-Chiari malformation type I consists of elongation and displacement of the caudal end of the brainstem into the spinal canal with protrusion of the cerebellar tonsils through the foramen magnum. In association with this hindbrain malformation, minor to moderate abnormalities of the base of the skull can occur, including basilar impression (platybasia) and small foramen magnum. Arnold-Chiari malformation type I typically remains asymptomatic for years, but in older children and young adults it may cause progressive cerebellar signs (vertigo, ataxia), paresis of the lower cranial nerves or neck/posterior head pain exacerbated by straining; rarely may it present with apnea or disordered breathing. Posterior cervical laminectomy may be necessary to provide relief from symptoms.
Arnold-Chiari malformation type II consists of the malformations found in Arnold-Chiari type I plus an associated myelomeningocele. Hydrocephalus develops in approximately 90% of children with Arnold-Chiari malformation type II. These patients may also have, hydromyelia, syringomyelia, and cortical dysplasias. The clinical manifestations of Arnold-Chiari malformation type II are most commonly caused by the associated hydrocephalus and meningomyelocele. In addition, dysfunction of the lower cranial nerves may be present. Up to 25% of patients may have epilepsy, likely secondary to the cortical dysplasias. Higher lesions of the thoracic or upper lumbar cord are associated with mild intellectual disability in about half of patients, while over 85% of patients with lower level lesions have normal intelligence quotients (IQs).
Arnold-Chiari malformation type III is characterized by herniation of the cerebellum through the foramen magnum with associated cervical spinal cord defect. Hydrocephalus is extremely common with this malformation.
Despite being described over a century ago, the exact definition of the Dandy-Walker syndrome is still debated. Classically, it is characterized by aplasia of the vermis, cystic enlargement of the fourth ventricle, and rostral displacement of the tentorium. Although hydrocephalus is usually not present congenitally, it develops within the first few months of life. Ninety percent of patients who develop hydrocephalus do so by age 1 year.
On physical examination, a rounded protuberance or exaggeration of the cranial occiput often exists. In the absence of hydrocephalus and increased intracranial pressure, few physical findings may be present to suggest neurologic dysfunction. An ataxic syndrome occurs in fewer than 20% of patients and is usually late in appearing. Many long-term neurologic deficits result directly from hydrocephalus. CT or MRI scanning of the head confirms diagnosis of Dandy-Walker syndrome. Treatment is directed at the management of hydrocephalus.
4. Agenesis of the Corpus Callosum
Agenesis of the corpus callosum (ACC), once thought to be a rare cerebral malformation, is more frequently diagnosed with modern neuroimaging techniques, occurring in 1:4000 births. There does not appear to be a single cause of this malformation. Rather, multiple single and muti-gene mutations have been associated. An underlying genetic cause can be found in up to 45% of cases. It has been found in X-linked conditions, such as ARX mutations (lissencephaly and ambiguous genetalie), recessive conditions such as Andermann syndrome (neuropathy and dementia), and polygenic conditions such as Aicardi syndrome (chorioretinal lacunae, infantile spasms, skeletal abnormalities). No specific clinical pictureis typical of ACC, although many patients have seizures, developmental delay, microcephaly, or eurobehavioral problems (autism, difficulties with social interactions). Interestingly, the malformation may be found coincidentally by neuroimaging studies in otherwise normal patients.
Hydrocephalus is an increased volume of CSF with progressive ventricular dilation. In communicating hydrocephalus, CSF circulates through the ventricular system and into the subarachnoid space without obstruction. In noncommunicating hydrocephalus, an obstruction blocks the flow of CSF within the ventricular system or blocks the egress of CSF from the ventricular system into the subarachnoid space. A wide variety of disorders, such as hemorrhage, infection, tumors, and congenital malformations, may play a causal role in the development of hydrocephalus. Clinical features of hydrocephalus include macrocephaly, an excessive or rapidhead growth, irritability, bulging or full fontanelle, vomiting, loss of appetite, impaired upgaze (known as “sun setting” phenomenon), impaired extraocular movements, hypertonia of the lower extremities, and generalized hyperreflexia. Without treatment, optic atrophy may occur. In infants, papilledema may not be present, whereas older children with closed cranial sutures can eventually develop swelling of the optic disk. Hydrocephalus can be diagnosed on the basis of the clinical course, findings on physical examination, and CT or MRI scan.
Treatment of hydrocephalus is directed at providing an alternative outlet for CSF from the intracranial compartment. The most common method is ventriculoperitoneal shunting. Other treatment should be directed, if possible, at the underlying cause of the hydrocephalus.
WB: A developmental and genetic classification for malformations of cortical development: update 2012. Brain 2012;135(Pt 5):1348–1369
et al: Pediatric perspective on prenatal counseling for myelomeningocele. Birth Defects Res A Clin Mol Teratol 2006;76:645
W: Malformations of cortical development: clinical features and genetic causes. Lancet Neurol 2014;13:710–726
JS: Molecular genetics of neuronal migration disorders. Curr Neurol Neurosci Rep 2011;11:171
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.
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Craniosynostosis, or premature closure of cranial sutures, is usually sporadic and idiopathic occurring in 1 in 2000 live births.
Both idiopathic and genetic etiologies occur in children with craniosynostosis. Syndromic children, that is, those with other physical anomalies, are more likely to have a genetic etiology. For example, Apert syndrome and Crouzon disease are associated with abnormalities of the digits, extremities, and heart, as well as craniosynostosis. An interdisciplinary approach is commonly required given the numerous other systems possibly involved including learning and development, oral health, visual and ocular abnormalities, hearing and middle ear abnormalities, and speech and language development. Craniosynostosis may be associated with an underlying metabolic disturbance such as hyperthyroidism and hypophosphatasia.
The most common form of craniosynostosis involves the sagittal suture and results in scaphocephaly, an elongation of the head in the anterior to posterior direction. Premature closure of the coronal sutures causes brachycephaly, an increase in cranial growth from left to right. Unless many or all cranial sutures close prematurely, intracranial volume will not be compromised, and the brain’s growth will not be impaired. Closure of only one or a few sutures will not cause impaired brain growth or neurologic dysfunction.
A common complaint is abnormal head shape secondary to positional plagiocephaly due to supine sleep position, not from occipital lambdoid suture craniosynostosis. Repositioning the head during naps (eg, with a rolled towel under one shoulder), and “tummy time” when awake are remedies. Rarely is a skull film or consultation necessary to rule out craniosynostosis. Most positional nonsynostotic plagiocephaly resolves by age 2 years.
Management of craniosynostosis is directed at preserving normal skull shape and consists of excising the fused suture and applying material to the edge of the craniectomy to prevent reossification of the bone edges. The best cosmetic effect on the skull is achieved when surgery is performed during the first 6 months of life. Inter-disciplinary team approach to manage all systems affected is essential in providing the best neurologic and psychological outcomes.
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Microcephaly is defined as a head circumference more than two standard deviations below the mean for age and sex. More important than a single head circumference measurement is the rate or pattern of head growth over time. Head circumference measurements that progressively drop to lower percentiles with increasing age are indicative of a process or condition that has impaired the brain’s capacity to grow. Primary microcephaly is present at birth and secondary microcephaly develops postnatally. The causes of microcephaly are numerous. Some examples are listed in Table 25–13.
Table 25–13.Causes of microcephaly. ||Download (.pdf) Table 25–13.Causes of microcephaly.
|Causes ||Examples |
|Chromosomal ||Trisomies 13, 18, 21 |
|Malformation ||Lissencephaly, schizencephaly |
|Syndromes ||Rubenstein-Taybi, Cornelia de Lange, Angelman |
|Toxins ||Alcohol, anticonvulsants (?), maternal phenylketonuria (PKU) |
|Infections (intrauterine) ||TORCHSa |
|Radiation ||Maternal pelvis, first and second trimester |
|Placental insufficiency ||Toxemia, infection, small for gestational age |
|Familial ||Autosomal dominant, autosomal recessive |
|Perinatal hypoxia, trauma ||Birth asphyxia, injury |
|Infections (perinatal) ||Bacterial meningitis (especially group B streptococci), Viral encephalitis (enterovirus, herpes simplex) |
|Metabolic ||Glut-1 deficiency, PKU, maple syrup urine disease |
|Degenerative disease ||Tay-Sachs, Krabbe |
Head circumference should be monitored at every well-child check. However, microcephaly may be discovered when the child is examined because of delayed developmental milestones or neurologic problems, such as seizures or spasticity. There may be a marked backward slope of the forehead (as in familial microcephaly) with narrowing of the bitemporal diameter. The fontanelle may close earlier than expected, and sutures may be prominent. Abnormal dermatoglyphics (neurocutaneous marks) may be present when the injury occurred before 19 weeks’ gestation. Parents’ heads may need measurement to rule out a rare dominantly inherited familial microcephaly. Eye, cardiac, and bone abnormalities may also be clues to congenital infection.
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).
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.
Common forms of craniosynostosis involving sagittal, coronal, and lambdoidal sutures are associated with abnormally shaped heads but do not cause microcephaly. Recognizing treatable causes of undergrowth of the brain such as hypopituitarism or hypothyroidism and severe protein-calorie undernutrition is critical so that therapy can be initiated as early as possible. Refer to Table 25–13 for examples of causes of microcephaly.
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.
A head circumference more than two standard deviations above the mean for age and sex denotes macrocephaly. Rapid head growth rate suggests increased intracranial pressure, most likely caused by hydrocephalus, extra-axial fluid collections, or neoplasms. Macrocephaly with normal head growth rate suggests familial macrocephaly or true megalencephaly, as might occur in neurofibromatosis. Other causes and examples of macrocephaly are listed in Table 25–14.
Table 25–14.Causes of macrocephaly. ||Download (.pdf) Table 25–14.Causes of macrocephaly.
|Causes ||Examples |
|Pseudomacrocephaly, pseudohydrocephalus, catch-up growth crossing percentiles ||Growing premature infant; recovery from malnutrition, congenital heart disease, postsurgical correction |
Increased intracranial pressure
With dilated ventricles
With other mass
Progressive hydrocephalus, subdural effusion
Arachnoid cyst, porencephalic cyst, brain tumor
|Benign familial macrocephaly (idiopathic external hydrocephalus) ||External hydrocephalus, benign enlargement of the subarachnoid spaces (synonyms) |
Megalencephaly (large brain)
With neurocutaneous disorder
Neurofibromatosis, tuberous sclerosis, etc
Metachromatic leukodystrophy (late)
Canavan spongy degeneration
|Thickened skull ||Fibrous dysplasia (bone), hemolytic anemia (marrow), sicklemia, thalassemia |
This can be seen when a neurologically intact preterm infant has rapid head enlargement in the first weeks of life. As the expected normal size is reached, head growth slows and then resumes a normal growth pattern.
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.
Other causes of macrocephaly are dependent on the etiology such as metabolic or genetic causes.
Clinical and laboratory findings vary with the underlying process. In neonates and young infants, ultrasound can be used to evaluate for subdural effusions, hydrocephalus, hydranencephaly, and cystic defects. A surgically or medically treatable condition must be ruled out. Thus, the first decision is whether and when to perform an imaging study.
An imaging study is necessary if signs or symptoms of increased intracranial pressure are present. If the fontanelle is open, cranial ultrasonography can assess ventricular size and diagnose or exclude hydrocephalus. CT or MRI scans are used to define any structural cause of macrocephaly and to identify an operable disorder. Even when the condition is untreatable (or does not require treatment), the information gained may permit more accurate diagnosis and prognosis, guide management and genetic counseling, and serve as a basis for comparison should future abnormal cranial growth or neurologic changes necessitate a repeat study.
W: Practice parameter: evaluation of the child with microcephaly (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 2009;73(11):887–897
et al: Parameters of care for craniosynostosis. Cleft Palate Craniofac J 2012;49:1S
AH: Macrocephaly syndromes. Semin Pediatric Neurol 2007;14(3):128–135
GF: Deformational plagiocephaly, brachycephaly, and scaphocephaly. Part I: terminology, diagnosis, and etiopathogenesis. J Craniofac Surg 2011;22:9
et al: Diagnostic approach to microcephaly in childhood: a two-center study and review of the literature. Dev Med Child Neurol 2014;56:732
Neurocutaneous dysplasias are diseases of the neuroectoderm and sometimes involve endoderm and mesoderm. Birthmarks and later appearing skin growths suggest a need to look for brain, spinal cord, and eye disease. Hamartomas (benign tumors that are histologically normal tissue growing abnormally rapidly or in aberrant sites) are common. The most common dysplasias are inherited autosomal dominantly. Benign and even malignant tumors may develop in these conditions.
1. Neurofibromatosis Type 1
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 plexiform neurofibroma.
Freckling in the axillary or inguinal regions.
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, which is located on chromosome 17q11.2 encoding neurofibromin. Forty percent of patients develop medical complications over their lifetime. Two or more positive criteria are diagnostic; others may appear over time. Children with six or more café au lait spots and no other positive criteria should be followed; 95% develop neurofibromatosis type 1.
The most common presenting symptoms are cognitive or psychomotor problems; 40% have learning disabilities, and 8% have intellectual disability. The history should focus on cutaneous abnormalities causing disfigurement, functional problems, or pain. Café au lait spots are seen in most affected children by age 1 year. The typical skin lesion is 10–30 mm, ovoid, and smooth-bordered. Discrete well-demarcated neurofibromas or lipomas can occur at any age. Plexiform neurofibromas are diffuse and can invade normal tissue. They are congenital and are frequently detected during periods of rapid growth. If the face or a limb is involved, there may be associated hypertrophy or overgrowth.
Clinicians should evaluate head circumference, blood pressure, vision, hearing, spine for scoliosis, and limbs for pseudarthroses. Strabismus or amblyopia dictates a search for optic glioma, a common tumor in neurofibromatosis. The eye examination should include checking for proptosis and iris Lisch nodules. The optic disk should be examined for atrophy or papilledema. Any progressive or new neurologic deficit calls for neuroimaging to rule out tumor of the spinal cord or CNS. Short stature and precocious puberty are occasional findings.
Parents should be examined in detail. Family history is important in identifying dominant gene manifestations.
Laboratory tests are not likely to be of value in asymptomatic patients. Selected patients require brain MRI with special cuts through the optic nerves to rule out optic glioma. A common finding is hyperintense, non-mass lesions seen on T2-weighted MRI images. These “unidentified bright objects” (“UBOs”) often disappear with time. Hypertension necessitates evaluation of renal arteries for dysplasia and stenosis. Cognitive and school achievement testing may be indicated. Scoliosis or limb abnormalities should be studied by appropriate imaging.
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.
Seizures, deafness, short stature, early puberty, and hypertension occur in less than 25% of patients with neurofibromatosis. Optic gliomas occur in about 15%. Although the tumor may be apparent at an early age, it rarely causes functional problems and is usually nonprogressive. Patients have a slightly increased risk (5% life risk) for various malignancies. Other tumors may be benign but may cause significant morbidity and mortality because of their size and location in a vital or enclosed space, for example, plexiform neurofibromas. These “benign” infiltrating tumors can disfigure facially, impair spinal cord, renal, or pelvic-leg function, and are often difficult to treat. PET scans are helpful to detect malignant transformations (most commonly to sarcomas). Experimental trials of interferons and mTOR inhibitors (rapamycin=sirolimus) are ongoing at many centers. Strokes from NF-1 cerebral arteriopathy are rare but needs to be noted; arteriopathy of renal arteries can cause reversible hypertension in childhood.
Genetic counseling and screening is important and the risk to siblings is 50%. The disease may be progressive, but with serious complications only occasionally seen. Patients sometimes worsen during puberty or pregnancy. Annual or semiannual visits are important in the early detection of school problems and bony or neurologic abnormalities.
The following parameters should be recorded at each annual visit:
Child’s development and progress at school
Visual symptoms, visual acuity, and funduscopy until age 7 years (to detect optic pathway glioma, glaucoma)
Head circumference (rapid increase might indicate tumor or hydrocephalus)
Height (to detect abnormal pubertal development)
Weight (to detect abnormal pubertal development)
Pubertal development (to detect delayed or precocious puberty due to pituitary or hypothalamic lesions)
Blood pressure (to detect renal artery stenosis or pheochromocytoma)
Cardiovascular examination (for congenital heart disease, especially pulmonary stenosis)
Evaluation of spine (for scoliosis and underlying plexiform neurofibromas)
Evaluation of the skin (for cutaneous, subcutaneous, and plexiform neurofibromas)
Examination of other systems, depending on specific symptoms
Multidisciplinary clinics at medical centers around the United States can be excellent resources. Prenatal diagnosis is likely on the horizon, but the variability of manifestations (trivial to severe) will make therapeutic abortion an unlikely option. Chromosomal linkage studies are under way (chromosome 17q11.2). Information for lay people and physicians is available from the National Neurofibromatosis Foundation (http://www.nf.org).
2. Neurofibromatosis Type 2
NF-2 is a dominantly inherited neoplasial syndrome manifested as bilateral vestibular schwannomas (VIII nerve tumors), which may appear in childhood (with loss of hearing, etc). Café au lait spots are not part of NF-2. In 50% of the patients, the mutation occurs de novo (neither parent carrying the faulty gene). Tumors of cranial nerve VIII (Schwannomas) virtually never occur in neurofibromatosis type 1 but are pathognomonic in neurofibromatosis type 2, a rare autosomal dominant disease. Café au lait spots are less common in neurofibromatosis type 2. Other tumors of the brain and spinal cord are common: meningiomas, other cranial nerve schwannomas, and ependymomas. Posterior lens cataracts are a third risk.
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
At least three hypomelanotic macules, each at least 5 mm in diameter.
Angiofibromas, ungual fibromas, intraoral fibromas.
CNS manifestations: subependymal nodules, cortical dysplasias, subependymal giant cell astrocytoma.
Cardiac rhabdomyomas and angiomyolipomas.
Tuberous sclerosis (TS) is a dominantly inherited disease. Almost all individuals have deletions on chromosome 9 (TSC1 gene) or 16 (TSC2 gene). The gene products hamartin and tuberin have tumor-suppressing effects, therefore TS patients are more susceptible to hamartomas in many organs and brain tubers and tumors. A triad of seizures, mental retardation, and adenoma sebaceum occurs in only 33% of patients. Parents formerly thought to not harbor the gene are now being diagnosed as asymptomatic carriers.
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.
Skin findings bring most patients to the physician’s attention (Tables 25–15 and 25–16). Ninety-six percent of patients have one or more hypomelanotic macules, facial angiofibromas, ungual fibromas, or shagreen (leathery orange peel) patches. Adenoma sebaceum (facial skin hamartomas) may first appear in early childhood, often on the cheek, chin, and dry sites of the skin where acne is not usually seen. Ash-leaf spots are off-white hypomelanotic macules often oval or “ash leaf” in shape and follow the dermatomes. A Wood lamp (ultraviolet light) shows the macules more clearly. The equivalent to an ash leaf spot in the scalp is poliosis (whitened hair patch). Subungual and periungual fibromas are more common in the toes. Café au lait spots are occasionally seen. Fibrous or raised plaques may resemble coalescent angiofibromas.
Table 25–15.Major and minor criteria for tuberous sclerosis. ||Download (.pdf) Table 25–15.Major and minor criteria for tuberous sclerosis.
|Major Features ||Minor Features |
Facial angiofibromas or forehead plaque
Nontraumatic ungula or periungual fibroma
Hypomelanotic macules (three or more)
Shagreen patch (connective tissue nevus)
Multiple retinal nodular hamartomas
Glioneuronal hamartoma (cortical tuber)
Subependymal giant cell astrocytoma
Cardiac rhabdomyoma, single or multiple
Multiple, randomly distributed pits in dental enamel
Hamartomatous rectal polyps
Cerebral white matter radial migration lines
Retinal achromic patch
“Confetti” skin lesions
Multiple renal cysts
|Definite tuberous sclerosis complex: either two major features or one major feature plus two minor features |
|Probable tuberous sclerosis complex: one major plus one minor feature |
|Possible tuberous sclerosis complex: either one major feature or two or more minor features |
Table 25–16.Common central nervous system degenerative disorders of infancy. ||Download (.pdf) Table 25–16.Common central nervous system degenerative disorders of infancy.
|Disease ||Genetic Defect and Enzyme ||Clinical Presentation ||Laboratory Tests ||Prognosis/Treatment |
|Early Infantile (0–1 year) |
|Globoid cell leukodystrophy (Krabbe) ||Autosomal recessive galactocerebroside β-galactosidase deficiency. Chromosome 14q31 || |
Infantile form first 6 mo
Late-onset form 2–6 y
Irritability with shrill cry
|Elevated CSF protein, prolonged sural nerve conduction, enzyme deficiency in leukocytes, cultured skin fibroblasts. Demyelination and gliosis on MRI || |
Poor. Death usually by 1.5–2 y
Late-onset cases may live 5–10 y
Hematopoietic stem cell transplantation and enzyme replacement therapy are experimental
|Canavan disease/Aspartoacylase deficiency || |
ASPA gene: 17pter-p13
Prevalent in Ashkenazi Jewish
|NAA elevated in blood || |
|Vanishing white matter/Childhood ataxia with CNS hypomyelination || |
Mutation to any of 5 genes encoding eIF2B
Stepwise deterioration with infection or trauma
Genetic testing and characteristic MRI features are diagnostic
Prevention of infection and trauma.
|Megalencephalic leukodystrophy with cysts ||MLC1 and HEPACAM genes || |
Macrocephaly in the first year
|MRI shows fronto-parietal white matter abnormalities with cysts. || |
Antiepileptic drugs to control seizures
|Pelizaeus Merzbacher || |
PLP1 gene mutation
|Nystagmus, poor vision, ataxia, seizures ||MRI with symmetric, confluent white matter signal abnormalities || |
|Aicardi-Goutieres Syndrome || |
Autosomal recessive; one subtype is autosomal dominant;
TREX1 and RNASEH2A-C gene mutations
|Microcephaly, spasticity, developmental delay/regression ||Calcification, MRI with white matter signal abnormalities || |
|Late Infantile (1–5 years) |
|Metachromatic leukodystrophy ||Recessive Arylsulfatase A (ASA) deficiency 22q13 Variant: Saposin B deficiency || |
Infantile form at 18–24 mo; Juvenile and adult forms
Optic nerve atrophy
|CSF protein elevated. Urine sulfatide increased. Enzyme deficiency in leukocytes and fibroblasts. Imaging: diffuse white matter || |
Infantile form death by 3–8 y
Juvenile form death by 10–15 y. Hematopoietic stem cell transplantation is an experimental treatment
|Alexander Disease || |
Autosomal dominant; Often de novo
Mutations in GFAP gene.
Contrast enhancing of gray and white matter
Neonatal form: death by 2 y
Later-onset may have slower course
|Leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate (LBSL) || |
Progressive cerebellar ataxia
Sensory deficits (vibration)
Characteristic MRI findings
Wheelchair dependent in adolescence, early adulthood
|X-linked adrenoleukodystrophy ||X-linked recessive; ABCD1 mutation ||Behavioral changes, chronic progressive spastic paraparesis; hyperpigmentation and adrenocortical insufficiency || |
Very-long-chain fatty acids in plasma
|Variable progression |
|Neuroaxonal leukoencephalopathy with axonal spheriods ||Most cases sporadic. Familial cases reported ||Prominent psychiatric features; seizures, dementia, ataxia. ||Brain biopsy: cerebral white matter degeneration including loss of myelin and axons, gliosis, macrophages and axonal spheroids ||Poor. Supportive treatment |
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.
Renal cysts or angiomyolipomas may be asymptomatic. Hematuria or obstruction of urine flow sometimes occurs; the latter requires operation. Ultrasonography of the kidneys should be done in any patient suspected of tuberous sclerosis, both to aid in diagnosis if lesions are found and to rule out renal obstructive disease.
4. Cardiopulmonary involvement
Rarely cystic lung disease may occur. Rhabdomyomas of the heart may be asymptomatic but can lead to outflow obstruction, conduction difficulties, and death. Chest radiographs and echocardiograms can detect these rare manifestations. Cardiac rhabdomyoma may be detected on prenatal ultrasound examination. Rhabdomyomas typically regress with age; thus, symptomatic presentations are typically in the perinatal period or infancy when rhabdomyomas are largest.
Retinal hamartomas are often near the disk and usually asymptomatic.
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.
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)
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Sturge-Weber disease is a sporadic neurovascular disease, which consists of a facial port wine nevus involving the upper part of the face (in the first division of cranial nerve V), a venous angioma of the meninges in the occipitoparietal regions, and choroidal angioma. The syndrome has been described without the facial nevus (rare, type III, exclusive leptomeningeal angioma).
In infancy, the eye may show congenital glaucoma, or buphthalmos, with a cloudy, enlarged cornea. In early stages, the facial nevus may be the only indication, with no findings in the brain even on radiologic studies. Focal seizures are common in infancy. Cognitive impairment, headache and migraines, and stroke-like signs are other neurologic manifestations. The characteristic cortical atrophy, calcifications of the cortex, and meningeal angiomatosis may appear with time, solidifying the diagnosis.
Physical examination may show hemiparesis on the side contralateral to the cerebral lesion. The facial nevus may be much more extensive than the first division of cranial nerve V; it can involve the lower face, mouth, lip, neck, and even torso. Hemiatrophy of the contralateral limbs may occur. Mental handicap may result from poorly controlled seizures. Late-appearing glaucoma and rarely CNS hemorrhage occur.
B. Imaging and Special Tests
Radiologic studies may show calcification of the cortex; CT scanning may show this much earlier than plain radiographic studies. MRI often shows underlying brain involvement.
The EEG often shows depression of voltage over the involved area in early stages; later, epileptiform abnormalities may be present focally.
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.
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)
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Retinal, central nervous, renal hemangioblastomas.
Less frequently adrenal and extra-adrenal pheochromocytomas, pancreatic endocrine cancers, and endolymphatic sac tumors.
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.
et al: Neurofibromatosis type 2. Lancet 2009;373:1974 [Epub May 22].
AM: Presentation, diagnosis, pathophysiology, and treatment of the neurologic features of Sturge-Weber syndrome. Neurologist 2011;17(4):1799
et al: Tuberous sclerosis complex: neurologic, renal and pulmonary manifestations. Neuropediatrics 2010;41:199
DH: Neurofibromatosis type 1: a multidisciplinary approach to care. Lancet Neural 2014;13(8):1474
MH: Emerging treatments in the management of tuberous sclerosis complex. Pediatr Neurol 2012;46:267
H: International Tuberous Sclerosis Complex Consensus Group: Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuerbous Sclerosis Complex Consensus Conference. Pediatr Neurol 2013;49(4)255–265
J: Mental, motor, and language development of toddlers with neurofibromatosis type 1. J Pediatr 2011;158:660
S: von Hippel-Lindau disease: a clinical and scientific review. Eur J Hum Genet 2011;19(6):617
et al: Natural history of neurofibromatosis type 2 with onset before the age of 1 year. Neurogenetics 2013:89–98
CENTRAL NERVOUS SYSTEM DEGENERATIVE DISORDERS OF INFANCY & CHILDHOOD
The CNS degenerative disorders of infancy and childhood are characterized by developmental arrest and loss, usually progressive but at variable rates, of cognitive, motor, and visual functioning (Tables 25–16). Seizures are common especially in those with gray matter involvement. Symptoms and signs vary with age at onset and primary sites of involvement.
These disorders are fortunately rare. An early clinical pattern of decline often follows normal early development. Referral for sophisticated biochemical testing is usually necessary before a definitive diagnosis can be made. Patients with metachromatic leukodystrophy, Krabbe disease, and adrenoleukodystrophy are candidates for bone marrow transplantation. Treatment of some lysosomal storage diseases, such as Gaucher disease, with enzyme replacement therapy (ERT) has shown promising results.
et al: Leukodystrophies: classification, diagnosis, and treatment. Neurologist 2009;15:319
W: Leukodystrophies with late disease onset: an update. Curr Opin Neurol 2010;23:234
F: Childhood leukodystrophies: a clinical perspective. Expert Rev Neurother 2011;11(10):1485–1469.