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ALTERED STATES OF CONSCIOUSNESS (COMA)
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ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
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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.
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A. Symptoms and Signs
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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).
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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.
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B. Laboratory and Imaging Diagnostics
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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.
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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.
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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.
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Differential Diagnosis
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Conditions mistaken for coma:
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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.
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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.
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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.
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Hirschberg
R, Giacino
JT: The vegetative and minimally conscious states: diagnosis, prognosis and treatment. Neurol Clin 2011 20:773–786
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FJ, Ashwal
S: Coma and brain death. Handb Clin Neurol 2013;111:43–61
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EC, Vashist
S: Approach to syncope and altered mental status. Pediatr Clin North Am 2013;60(5):1083–1106
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Nakagawa
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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
[PubMed: 21873704]
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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.
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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.
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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.
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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.
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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.
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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.
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1. Seizures & Epilepsy in Childhood
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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.
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A. Symptoms and Signs
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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.
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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.”
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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.
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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.
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B. Diagnostic Evaluation
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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.
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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.
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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.
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C. Electroencephalography
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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).
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Differential Diagnosis
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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.
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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.
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Complications & Sequelae
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A. Psychosocial Impact
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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.
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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.
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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.
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“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.
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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.
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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.
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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.
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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.
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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.
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B. Antiepileptic Drug (AED) Therapy
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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.
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2. Treatment strategy
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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.
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3. Long-term management and discontinuation of treatment
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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.
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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.
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C. Alternative Treatments
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1. Adrenocorticotropic hormone (ACTH) and corticosteroids
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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.
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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.
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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.
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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.
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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.
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3. Vagus nerve stimulator (VNS)
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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.
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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.
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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.
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E. General Management of the Child with Epilepsy
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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.
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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.
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2. Privileges and precautions in daily life
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“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.
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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.
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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.
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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.
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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.
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5. School intervention and seizure response plans
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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.
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2. Status Epilepticus
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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.
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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.
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For treatment options, see Table 25–7.
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A. Symptoms and Signs
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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.
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B. Diagnostic Evaluation
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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.
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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.
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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.
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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.
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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.
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Simple febrile seizures do not have any long-term adverse consequences. As noted earlier, there is only a small increase in the risk of developing epilepsy. Cognitive function is not significantly different from that of siblings without febrile seizures.
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Abend
NS, Gutierrez-Colina
AM, Dlugos
DJ: Medical treatment of pediatric status epilepticus. Semin Pediatr Neurol 2010;17:169–175
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Berg
AT, Berkovic
SF, Brodie
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
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Chu-Shore
CJ, Thiele
EA: New drugs for pediatric epilepsy. Semin Pediatr Neurol 2010;17:214–223
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Duffner
P
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
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Fisher
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et al. Instruction manual for the ILAE 2017 operational classification of seizure types. Epilepsia. 2017;58(4):531–542. doi:10.1111/epi.13671.
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Frank
LM
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
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Freeman
JM, Kossoff
EH: Ketosis and the ketogenic diet, 2010: advances in treating epilepsy and other disorders. Adv Pediatr 2010;57:315–329
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Go
CY
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
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Holthausen
H, Pieper
T, Kudernatsch
M: Towards early diagnosis and treatment to save children from catastrophic epilepsy—focus on epilepsy surgery. Brain Dev 2013;35(3)730–741
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Hughes
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
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Ostrowsky
K: Outcome and prognosis of status epilepticus in children. Semin Pediatr Neurol 2010;17:195
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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]
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J, Boylan
G: Treatment of neonatal seizures. Arch Dis Child Fetal Neonatal Ed 2007;92:F148
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Riviello
JJ
et al: Practice parameter: diagnostic assessment of the child with status epilepticus (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2006;67:1542
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IE
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.
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Shany
E, Berger
I: Neonatal electroencephalography: review of a practical approach. J Child Neurol 2011;26:341–355
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S
et al: Phenomenology of prolonged febrile seizures: results of the FEBSTAT study. Neurology 2008;71:170–176
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M, Shinnar
S: SUDEP and other causes of mortality in childhood-onset epilepsy. Epilepsy Behav 2013;28(2):249–255
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RK, Gaillard
WD: Status epilepticus in children. Curr Neurol Neurosci Rep 2009;9:137
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JW: Managing severe epilepsy syndromes of early childhood. J Child Neurol 2009;24:24S
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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.
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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.
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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.
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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.
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2. Benign Neonatal Sleep Myoclonus
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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.
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3. Nocturnal Frontal Lobe Epilepsy
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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.
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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.
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5. Restless Legs Syndrome
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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.
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Ahmed
I, Thorpy
M: Clinical features, diagnosis, and treatment of narcolepsy. Clin Chest Med 2010;31:371–381
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Aran
A, Einen
M, Lin
L, Plazzi
G, Nishino
S, Mignot
E: Clinical and therapeutic aspects of childhood narcolepsy-cataplexy: a retrospective study of 51 children. Sleep 2010;33:1457–1464
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Aurora
RN
et al: Practice parameters for the non-respiratory indications for polysomnography and multiple sleep latency testing for children. Sleep 2012;35:1467–1473
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Caraballo
RH
et al: The spectrum of benign myoclonus of early infancy: clinical and neurophysiologic features in 102 patients. Epilepsia 2009;50:1176–1183
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Hoban
T: Sleep Disorders in Children. Ann. N.Y. Acad. Sci 2010;1184(1);1–14
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Kotagal
S
et al: Non-respiratory indications for polysomnography and related procedures in children: an evidence-based review. Sleep 2012;35:1451–1466
[PubMed: 23115394]
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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.
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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.
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A. Symptoms and Signs
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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).
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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.
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B. Laboratory Findings
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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.
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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.
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Differential Diagnosis
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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.
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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.
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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.
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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.
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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.
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A thorough history and physical examination helps diagnose most of these conditions.
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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.
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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.
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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.
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A. Acute/Abortive Treatment
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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.
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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).
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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.
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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.
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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.
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From the few studies regarding long-term prognosis in adolescents presenting with migraines, approximately 25%–40% of adolescents will have remission of migraine symptoms, 40%–50% have persistence, and 20%–25% convert to tension-type headache. Of those with TTH, 20% convert to migraine. Headache severity at diagnosis is thought to be predictive of headache outcome in the long term.
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El-Chammas
K
et al: Pharmacologic treatment of pediatric headaches: a meta-analysis. JAMA Pediatr Mar 1, 2013;167(3):111
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Evers
S: The efficacy of triptans in childhood and adolescence migraine. Cur Pain Headache Rep 2013 Jul;17(7):342
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Gelfand
A: Episodic syndromes that may be associated with migriane: A.K.A. The “Childhood Periodic Syndromes”. Headache 2015:55:1358–1364.
[PubMed: 26234380]
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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
[PubMed: 23771276]
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Hershey
AD: Current approaches to the diagnosis and management of paediatric migraine. Lancet Neurol 2010;9:190
[PubMed: 20129168]
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Lewis
DW
et al: Practice parameter: Evaluation of children and adolescents with recurrent headaches. Neurology 2002;59:490–498.
[PubMed: 12196640]
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Lewis
DW
et al: Headache evaluation in children and adolescents: when to worry? When to scan? Pediatr Ann 2010;39:399
[PubMed: 20666345]
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Orr
SL, Venkateswaren
S: Nutraceuticals in the prophylaxis of pediatric migraine: evidence-based review and recommendations. Cephalalgia 2014;34:568–583
[PubMed: 24443395]
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Richer
L
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.
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PSEUDOTUMOR CEREBRI (IDIOPATHIC INTRACRANIAL HYPERTENSION)
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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.
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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.
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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.
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Differential Diagnosis
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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.
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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.
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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.
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With appropriate workup and treatment, most patients recover from IIH without long-term sequela including visual outcome. Reoccurrence risk is greatest within 18 months.
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Avery
RA
et al: CSF opening pressure in children with optic nerve head edema. Neurology 2011;76(19):1658
[PubMed: 21555733]
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Kosmorsky
GS: Idiopathic intracranial hypertension: pseudotumor cerebri. Headache 2014 Feb;54(2):389–393
[PubMed: 24512582]
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Rogers
DL: A review of pediatric idiopathic intracranial hypertension. Pediatr Clin North Am 2014 Jun;61(3):579–590
[PubMed: 24852154]
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Soiberman
U
et al: IIH in children: visual outcome and risk of recurrence. Childs Nerv Syst 2011 Nov;27(11):1913–1918
[PubMed: 21538129]
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CEREBROVASCULAR DISEASE
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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.
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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.
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1. Childhood Arterial Ischemic Stroke
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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.
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A. Symptoms and Signs
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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.
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B. Laboratory Findings and Ancillary Testing
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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.
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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.
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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.
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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.
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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.
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Differential Diagnosis
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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.
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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.
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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.
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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.
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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.
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2. Perinatal Arterial Ischemic Stroke
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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.”
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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.
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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.
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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.
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CONGENITAL MALFORMATIONS OF THE NERVOUS SYSTEM
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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.
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1. Abnormalities of Neural Tube Closure
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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.
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Diagnosis & Prevention
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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%.
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2. Disorders of Cortical Development
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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.
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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.
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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.
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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.
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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.
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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.
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Differential Diagnosis
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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.
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B. Lissencephaly and Subcortical Band Heterotopia
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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.
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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.
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C. Polymicrogyria with or Without Schizencephaly
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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.
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Treatment of MCD center on early child development intervention and focused symptomatic treatment (eg, attention deficit, hearing impairment, physical therapy for gait abnormalities).
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3. Disorders of Cerebellum Development
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A. Arnold-Chiari Malformations
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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.
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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).
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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.
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B. Dandy-Walker Syndrome
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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.
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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.
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4. Agenesis of the Corpus Callosum
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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.
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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.
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Treatment of hydrocephalus is directed at providing an alternative outlet for CSF from the intracranial compartment. The most common method is ventriculoperitoneal shunting. Other treatment should be directed, if possible, at the underlying cause of the hydrocephalus.
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Doherty
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R, Dobyns
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JS: Molecular genetics of neuronal migration disorders. Curr Neurol Neurosci Rep 2011;11:171
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Bone plates of the skull have almost no intrinsic capacity to enlarge or grow. Unlike long bones, they depend on extrinsic forces to stimulate new bone formation at the suture lines. Although gravity and traction on bone by muscle and scalp probably stimulate some growth, the single most important stimulus for head growth during infancy and childhood is brain growth. Therefore, accurate assessment of head growth is one of the most important aspects of the neurologic examination of young children. A head circumference that is two standard deviations above or below the mean for age requires investigation and explanation.
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ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
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Craniosynostosis, or premature closure of cranial sutures, is usually sporadic and idiopathic occurring in 1 in 2000 live births.
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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.
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Differential Diagnosis
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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.
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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.
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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.
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ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
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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.
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A. Symptoms and Signs
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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.
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B. Laboratory Findings
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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).
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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.
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Differential Diagnosis
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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.
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Treatment & Prognosis
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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.
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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.
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Differential Diagnosis
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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.
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B. Familial Macrocephaly
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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.
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Other causes of macrocephaly are dependent on the etiology such as metabolic or genetic causes.
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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.
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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.
+
Ashwal
S, Michelson
D, Plawner
L, Dobyns
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
[PubMed: 19752457]
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McCarthy
JG
et al: Parameters of care for craniosynostosis. Cleft Palate Craniofac J 2012;49:1S
[PubMed: 21848431]
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+
Olney
AH: Macrocephaly syndromes. Semin Pediatric Neurol 2007;14(3):128–135
[PubMed: 17980309]
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+
Rogers
GF: Deformational plagiocephaly, brachycephaly, and scaphocephaly. Part I: terminology, diagnosis, and etiopathogenesis. J Craniofac Surg 2011;22:9
[PubMed: 21187783]
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Von der
Hagen
et al: Diagnostic approach to microcephaly in childhood: a two-center study and review of the literature. Dev Med Child Neurol 2014;56:732
[PubMed: 24617602]
.
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NEUROCUTANEOUS DYSPLASIAS
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Neurocutaneous dysplasias are diseases of the neuroectoderm and sometimes involve endoderm and mesoderm. Birthmarks and later appearing skin growths suggest a need to look for brain, spinal cord, and eye disease. Hamartomas (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.
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1. Neurofibromatosis Type 1
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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.
Optic glioma.
Two or more Lisch nodules (iris hamartomas).
Distinctive bony lesions, such as sphenoid dysplasia or thinning of long bone with or without pseudarthroses.
First-degree relative (parent, sibling, offspring) with neurofibromatosis type 1 by above criteria.
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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.
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A. Symptoms and Signs
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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.
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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.
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Parents should be examined in detail. Family history is important in identifying dominant gene manifestations.
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B. Laboratory Findings
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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.
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Differential Diagnosis
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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.
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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.
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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.
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The following parameters should be recorded at each annual visit:
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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
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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).
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2. Neurofibromatosis Type 2
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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.
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3. Tuberous Sclerosis
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ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
At least three hypomelanotic macules, each at least 5 mm in diameter.
Angiofibromas, ungual fibromas, intraoral fibromas.
Shagreen patch.
CNS manifestations: subependymal nodules, cortical dysplasias, subependymal giant cell astrocytoma.
Cardiac rhabdomyomas and angiomyolipomas.
Hamartomas.
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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.
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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.
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A. Symptoms and Signs
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1. Dermatologic features
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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.
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++
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2. Neurologic features
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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.
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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.
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4. Cardiopulmonary involvement
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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.
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Retinal hamartomas are often near the disk and usually asymptomatic.
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6. Skeletal involvement
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Cystic rarefactions can be found in the bones of the fingers or toes.
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B. Imaging Studies and Special Tests
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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.
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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.
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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.
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4. Encephalofacial Angiomatosis (Sturge-Weber Disease)
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ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
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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).
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A. Symptoms and Signs
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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.
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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.
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B. Imaging and Special Tests
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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.
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The EEG often shows depression of voltage over the involved area in early stages; later, epileptiform abnormalities may be present focally.
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Differential Diagnosis
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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.
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Management & Treatment
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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.
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5. Von Hippel-Lindau Disease (Retrocerebellar Angiomatosis)
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ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Retinal, central nervous, renal hemangioblastomas.
Visceral cysts.
Less frequently adrenal and extra-adrenal pheochromocytomas, pancreatic endocrine cancers, and endolymphatic sac tumors.
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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.
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The diagnostic criteria for the disease are a retinal or cerebellar hemangioblastoma with or without a positive family history, intra-abdominal cyst, or renal cancer.
+
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AR
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Comi
AM: Presentation, diagnosis, pathophysiology, and treatment of the neurologic features of Sturge-Weber syndrome. Neurologist 2011;17(4):1799
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+
Franz
DN
et al: Tuberous sclerosis complex: neurologic, renal and pulmonary manifestations. Neuropediatrics 2010;41:199
[PubMed: 21210335]
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+
Hirbe
AC, Gutmann
DH: Neurofibromatosis type 1: a multidisciplinary approach to care. Lancet Neural 2014;13(8):1474
[PubMed: 25030515]
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+
Kohrman
MH: Emerging treatments in the management of tuberous sclerosis complex. Pediatr Neurol 2012;46:267
[PubMed: 22520346]
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Krueger
DA, Northrup
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
[PubMed: 24053983]
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Lorenzo
J: Mental, motor, and language development of toddlers with neurofibromatosis type 1. J Pediatr 2011;158:660
[PubMed: 21094952]
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+
Maher
ER, Neumann
HP, Richard
S: von Hippel-Lindau disease: a clinical and scientific review. Eur J Hum Genet 2011;19(6):617
[PubMed: 21386872]
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+
Ruggieri
M
et al: Natural history of neurofibromatosis type 2 with onset before the age of 1 year. Neurogenetics 2013:89–98
[PubMed: 23377185]
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CENTRAL NERVOUS SYSTEM DEGENERATIVE DISORDERS OF INFANCY & CHILDHOOD
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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.
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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.
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Costello
DJ
et al: Leukodystrophies: classification, diagnosis, and treatment. Neurologist 2009;15:319
[PubMed: 19901710]
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Koehler
W: Leukodystrophies with late disease onset: an update. Curr Opin Neurol 2010;23:234
[PubMed: 20216214]
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Kohlschutter
A, Eichler
F: Childhood leukodystrophies: a clinical perspective. Expert Rev Neurother 2011;11(10):1485–1469.
[PubMed: 21955203]