Epilepsies in Children
Hema Patel
David W. Dunn
Approximately 3% of the population of the United States is expected to have epilepsy at some time during their lives. Among children, 2% to 5% have a febrile seizure during the first 5 years of life, 2% have a single afebrile seizure, and 0.5% have recurrent afebrile seizures.
Classification
Accurate characterization of epilepsy has practical significance. Differentiation between partial and generalized seizures is important for the appropriate choice of antiepileptic drug (AED) therapy and determination of possible etiology and prognosis. Epileptic syndromes are classified with particular reference to age at onset, etiologic factor, site of seizure onset, and prognosis. Chapter 6 provides clinical descriptions of the different types of seizures.
I. LOCALIZATION-RELATED (FOCAL, LOCAL, AND PARTIAL) EPILEPSIES AND SYNDROMES
Localization-related (focal, local, and partial) epilepsies and syndromes are characterized by partial seizures (simple or complex partial) arising from a focal cortical area with occasional progression to a secondarily generalized tonic-clonic seizure (GTCS). If this progression is rapid, the initial focal nature may be masked. A simple partial seizure is associated with intact consciousness, whereas during a complex partial seizure, consciousness is impaired. EEG shows focal epileptiform discharges overlying the epileptogenic region.
A. Idiopathic localization-related epilepsy with age-related onset
represent a group of epileptic syndromes that constitute approximately one-fifth of all cases of epilepsy with onset before 13 years of age. Idiopathic epilepsy is characterized by genetic predisposition, focal (localization-related) seizures and EEG abnormalities, normal intellect and normal findings at neurologic examination and neuroimaging studies, and an excellent prognosis. Currently, the following syndromes are recognized by the International League Against Epilepsy.
1. Benign childhood epilepsy with centrotemporal spikes (BCECTS).
This disorder was previously known as benign rolandic epilepsy.
BCECTS accounts for 13% to 23% of all childhood epilepsies and 75% of all benign focal childhood epilepsy.
Age at onset is between 3 and 13 years; peak age is 8 to 9 years.
Clinical features include unilateral paresthesias and clonic activity of the tongue, lip and cheek, speech arrest, excess salivation, and occasional progression to a GTCS. Seizures usually are nocturnal, during sleep.
EEG shows frequent, unilateral or bilateral, high-amplitude centrotemporal spikes with a horizontal dipole that are activated by sleep, superimposed on a normal background. Thirty percent have spikes only during sleep. Therefore, a sleepdeprived EEG to include sleep should be obtained if this diagnosis is suspected. Approximately 50% of close relatives may also have EEG abnormalities between ages 5 and 15 years. Only 12% of patients who inherit the EEG abnormality have seizures.
Treatment usually is unnecessary after the first or even the second seizure. AED therapy can be initiated if seizures are frequent or if they are sufficiently disturbing the patient or family. All major AEDs have been reported to be successful even in small doses, such as carbamazepine, oxcarbazepine, valproic acid, gabapentin, phé nobarbital, and phenytoin.
Prognosis is excellent. Approximately 13% to 20% of patients have only a single seizure. Seizures usually resolve within 1 to 3 years of onset and almost always by 14 to 16 years of age. Approximately 1% to 2% persist into adult life.
2. Benign occipital epilepsy (BOE).
Two forms include early onset type (Panayiotopoulos’ type) and late onset type (Gastaut’s type).
BOE occurs less frequently than BCECTS.
Age at onset. Early onset type—4 to 5 years, with female preponderance; late onset type—8 to 9 years, with both sexes equally affected.
Clinical features. Early onset type is characterized by ictal vomiting, eye deviation, often progressing to GTCS seizures, which are usually nocturnal. The late onset type is brief (a few seconds to 2 to 3 minutes) with mainly visual illusions (multicol ored circles or spots) or blindness, followed by hemiclonic convulsions and postictal headaches. Consciousness may be preserved, but it is impaired if the seizure second arily generalizes. BOE is often misinterpreted as basilar (Bickerstaff’s) migraine.
EEG shows occipital paroxysms of high amplitude, often bilateral sharp or spike-slow-wave complexes attenuating with eye opening and activated by sleep. Generalized or centrotemporal spike waves are found in one-third of all cases.
Treatment is similar to that of patients with BCECTS.
Prognosis. BOE carries a good prognosis, although it is not as benign as BCECTS. Clinical remission rates vary from 60% to 90%.
Two syndromes have been recognized among adult patients—autosomal dominant nocturnal frontal lobe epilepsy and benign familial temporal lobe epilepsy.
B. Symptomatic localization-related epilepsy.
Most forms of localization-related epilepsy are symptomatic or acquired. Clinical manifestations depend on the anatomic location of the epileptogenic focus. Temporal lobe seizures (complex partial seizures) are the most common type of symptomatic partial seizures. See Chapter 6.
II. GENERALIZED EPILEPSIES AND SYNDROMES
Generalized epilepsies and syndromes are characterized by seizures that are generalized from onset, usually associated with impairment of consciousness and generalized epileptiform discharges on EEG reflecting involvement of both hemispheres. They include absence seizures, atypical absence seizures, myoclonic seizures, GTCS, atonic seizures, tonic seizures, clonic seizures, and infantile spasms.
A. Idiopathic generalized epilepsy with age-related onset.
In these disorders, which are listed in the order of age of appearance, the seizures and EEG abnormalities are generalized from the onset. Intellect and findings at neurologic examination and neuroimaging are normal (idiopathic). There is a genetic predisposition with no other identifiable etiologic factor.
1. Benign familial neonatal convulsions (BFNC).
This is a rare, autosomal dominant form of epilepsy with a genetic defect localized to chromosome 20q and 8q. The genes encode voltage-gated K+ channels expressed in the brain (KCNQ2 and KCNQ3). Seizures occur during the first week of life, usually the second or third day. Diagnosis requires family history of neonatal seizures and exclusion of other causes such as infection, metabolic, toxic, or structural abnormalities. Approximately 10% develop subsequent nonfebrile seizures.
2. Benign idiopathic neonatal seizures (fifth-day fits).
Seizures occur on the fifth day of life without known cause and generally cease within 15 days. The neonate is neurologically normal, and prognosis is good with no seizure recurrence. Subsequent psychomotor development is normal.
3. Benign myoclonic epilepsy in infancy.
Age at onset is 4 months to 3 years, typically within the first year.
Clinical features. Brief, generalized myoclonic seizures usually involving the head and upper extremities occur several times daily in an otherwise normal child, usually with a family history of epilepsy.
EEG shows brief, generalized bursts of spike-polyspike wave activity.
Treatment. Valproic acid is the drug of choice. Clonazepam can be used if valproic acid is ineffective.
Prognosis. Response to treatment is good. Occasionally, some psychomotor delay and behavioral abnormalities may persist.
4.
Epilepsy with myoclonic astatic seizures (Doose syndrome).
9.
Generalized epilepsy with febrile seizures plus (GEFS+).
Autosomal dominant disorder manifesting with febrile seizures in children <1 year of age, which persist beyond 5 to 6 years, when nonfebrile seizures also occur. Family history of febrile seizures is necessary to the diagnosis. It has been linked to a number of gene loci (SCN1A, SCN1B, and GABRG2). With inherited missense mutations of SCN1A GEFS+ occurs, while de novo truncating mutations result in severe myoclonic epilesy of infancy (SMEI; Dravet’s syndrome).
B. Symptomatic or cryptogenic generalized epilepsy.
These disorders, which are listed in order of age of appearance, include generalized epilepsy syndromes secondary to known or suspected disorders of the CNS (symptomatic) or to disorders, the causes of which are hidden or occult (cryptogenic).
1. Infantile spasms (West’s syndrome, salaam seizures, and jackknife seizures).
Etiology. With the availability of newer neuroimaging techniques, only 10% to 15% of cases are cryptogenic. In symptomatic cases, there is evidence of previous brain damage (mental retardation, neurologic and radiologic evidence, or a known etiologic factor) (Table 38.1).
Age at onset. Onset occurs in infancy (peak 4 to 8 months).
Clinical features compose the triad of infantile spasms, mental retardation, and hypsarrhythmia. Infantile spasms occur in clusters, frequently during drowsiness and on awakening, characterized by brief nodding of the head associated with extension or flexion of the trunk, and often of the extremities. They occur rapidly, suggestive of a startle reaction. They can be flexor (salaam attacks), extensor, or most commonly, mixed spasms. They are almost always associated with arrested development.
EEG shows hypsarrhythmia—chaotic, high-amplitude, disorganized background with multifocal independent spike-and-wave discharges. Intravenous (IV) pyridoxine (vitamin B6) should be administered in a dose of 100 mg during the EEG to exclude pyridoxine-dependent infantile spasms.
Treatment.
Underlying conditions are managed as identified.
Adrenocorticotropic hormone (ACTH). Opinions vary regarding dosage and duration of ACTH therapy, ranging from high-dose therapy (150 IU/m2/day) to low-dose therapy (20 to 40 IU/day). We recommend starting at 40 to 80 units per day administered intramuscularly and continuing for 3 to 4 weeks, or for a shorter period if an early positive clinical response is observed. The dosage is then slowly decreased approximately 20% per week over 6 to 9 weeks. If seizures recur during withdrawal, the dosage should be increased to the previous effective level. ACTH therapy is initiated in the hospital under the guidance of a pediatric neurologist. Parents should be taught the injection technique with systematic rotation of the injection site.
Side effects of ACTH therapy are irritability, hyperglycemia, hypertension, sodium and water retention, potassium depletion, weight gain, gastric ulcers, occult gastrointestinal bleeding, suppression of the immune system, infection, congestive heart failure, and diabetic ketoacidosis.
Laboratory tests before initiation of ACTH therapy include baseline EEG, serum electrolytes, blood urea nitrogen (BUN), serum creatinine, glucose, urinalysis, CBC, chest radiograph, and tuberculin skin test.
Laboratory tests performed weekly during ACTH therapy include serum electrolytes, blood glucose, stool guaiac, and monitoring of weight and blood pressure.
Concomitant management. An antacid or a histamine H2 receptor antagonist (ranitidine) should be administered during ACTH therapy.
Alternative treatment.
Prednisone may be substituted when ACTH cannot be administered because parents cannot or will not learn to give injections. It is administered orally at 2 to 3 mg/kg/day for 3 to 4 weeks and gradually withdrawn in a schedule similar to ACTH withdrawal.
Other AEDs. Vigabatrin has the best response rates in patients with tuberous sclerosis. Valproic acid (usually at high therapeutic levels of 75 to 125 μg per ml), topiramate, zonisamide, and clonazepam have also been reported to be effective. Nitrazepam and clobazam have also been tried, but have not yet been approved in the United States.
Excisional surgery of the region of cortical abnormality defined at EEG, MRI, and positron emission tomography (PET) is being performed on children with infantile spasms intractable to medical therapy, but only in specialized centers. Further studies are needed to determine which patients may benefit from surgery and whether long-term development is significantly improved after surgical intervention.
Prognosis. West’s syndrome has a high morbidity, with a 90% incidence of mental retardation. From 25% to 50% of cases evolve into Lennox-Gastaut’s syndrome (LGS), infantile spasms transforming to other seizure types (GTCS, myoclonic, and tonic seizures) over subsequent years. Favorable prognostic indicators are as follows:
Cryptogenic spasms have a better prognosis than symptomatic cases.
Normal development and neurologic examination before the onset of spasms.
Short duration of seizures before control.
TABLE 38.1 Causes of Secondary Generalized Epilepsy Syndromes (Infantile Spasms and LGS) | ||||||||||
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2. Lennox-Gastaut’s syndrome.
Etiology. A large number of patients have a history of infantile spasms. About 10% to 40% of cases are cryptogenic. In 60% to 90% of symptomatic cases, a specific cause, usually perinatal insult, is found (Table 38.1).
Age at onset is 1 to 8 years of age, with peak between 3 and 5 years.
Clinical features are seizures of multiple types, typically tonic, atypical absence, atonic,
and myoclonic seizures but also GTCS, and partial seizures. Seizures are often frequent and intractable to medical treatment. Most patients have cognitive dysfunction.
EEG shows slow background activity, generalized, bisynchronous, 2 to 2.5 Hz spike-slow-wave discharges activated by sleep, generalized paroxysmal fast spike activity (10 Hz), and other multifocal epileptiform abnormalities.
Treatment.
AEDs. Valproic acid is effective against all the different types of seizures associated with LGS. However, these seizures often are intractable, and valproic acid may have to be used in combination with other AEDs. Ethosuximide, lamotrigine, and topiramate have successfully demonstrated efficacy as adjunctive therapy in LGS. Zonisamide and levetiracetam have also been reported to be effective. Felbamate, though effective, is infrequently used because of severe side effects such as aplastic anemia and acute liver failure. Phenytoin and phenobarbital may be helpful in controlling the associated GTCS. Benzodiazepines (clonazepam, nitrazepam, and clobazam) can be used, but may be associated with side effects of decreased alertness and drowsiness, which are associated with increased seizure frequency. IV diazepam or lorazepam may induce tonic seizures, and carbamazepine can exacerbate absence seizures.
Ketogenic diet may be effective for patients with otherwise intractable seizures. Benefits include fewer seizures, less drowsiness, and fewer concomitant AEDs.
ACTH has been found to be effective in the treatment of some patients.
Psychological support for the child and family. A prescription for protective helmets to prevent head injuries in patients with drop attacks is helpful.
Surgical procedures such as corpus callosotomy, hemispherectomy, and rarely resection of a localized lesion have been tried with variable results. Vagal nerve stimulation is also effective with at least 50% reduction in seizure frequency in follow-up periods as long as 5 years.
3. Symptomatic seizures.
Myoclonic seizures are difficult to differentiate from nonepileptic myoclonus. However, characteristic epileptiform discharges associated with myoclonic jerks in myoclonic epilepsy help differentiate the two.
Early myoclonic encephalopathy. Multiple causes include inborn errors of metab olism such as nonketotic hyperglycinemia, methymalonic academia, and proprionic academia. Early myoclonic encephalopathy is characterized by the onset of medically intractable myoclonic seizures and partial seizures in early infancy before 3 months of age, burst suppression on EEG, and very poor prognosis including profound neu rologic impairment or death in the first year of life.
Early infantile epileptic encephalopathy (Ohtahara’s syndrome) is character ized by an early onset of tonic spasms within the first few months of life, which are medically intractable. Myoclonic seizures are rare. The suppression-burst pattern on the EEG is present during waking and sleep states. MRI demonstrates severe developmental anomalies such as hemimegalencephaly, porencephaly, and Aicardi’s syndrome. The prognosis is very poor.
SMEI (Dravet’s syndrome) represents 3% to 5% of all epilepsies starting in the first year of life. The disorder begins in the first year of life as febrile seizures, fol lowed by myoclonic seizures, atypical absences, and convulsive seizures between 1 and 4 years of age. The child is initially normal, but cognition becomes progres sively impaired. EEG shows generalized spike and polyspike-slow-wave activity, focal or multifocal spikes. Photosensitivity is seen in 40%. Lamotrigine may induce worsening of seizures. The seizures are medically intractable, but may respond to valprioc acid, topiramate, and clobazam. Stiripentol has also proved to be effective. A link between SMEI and GEFS+ has been identified in several families. De novo truncating mutations of the SCN1A gene on chromosome 2p24 in coding for the neuronal voltage-gated sodium channel α1 subunit have been found in SMEI.
Symptomatic myoclonic epilepsy is associated with specific progressive neurologic diseases such as Lafora’s disease, Baltic myoclonus (Unverricht-Lundborg’s disease), neuronal ceroid lipofuscinosis (Batten’s disease), sialidosis, mitochondrial encephalomyopathy, and Ramsey-Hunt’s syndrome.
III. EPILEPSIES AND SYNDROMES UNDETERMINED WHETHER FOCAL OR GENERALIZED
A. Neonatal seizures.
Seizures occur most frequently in the neonatal period than at any other time in childhood, with an incidence of 1.5 to 5.5 per 1,000 live births.
1. Clinical features.
Neonatal seizures (occurring between birth and 2 months) are more fragmentary than are seizures among older children. GTCS do not occur in neonates. Common causes are outlined in Table 38.2. Neonatal seizures are classified as follows:
Seizures associated with electrographic signatures include focal and multifo cal clonic seizures, focal tonic seizures, generalized myoclonic seizures, and rarely, apnea. These seizures usually are associated with focal structural lesions (infarction or hemorrhage), infection, or metabolic abnormalities (hypoglycemia or hypocalcemia).
Seizures not associated with electrographic signatures include generalized tonic seizures, focal and multifocal myoclonic seizures, and subtle seizures (oral-buccallingual movements, bicycling movements, and some rhythmic ocular movements such as horizontal eye deviation). These seizures usually are observed among lethar gic, comatose neonates with poor prognoses, such as those with severe hypoxic isch emic encephalopathy.
2. Evaluation.
Neonatal seizures should be managed in a neonatal intensive care unit by experienced personnel, including a pediatric neurologist and a neonatologist.
History and examination. History of maternal illness, infection, or drug and alco hol abuse during pregnancy should be obtained. Family history of neonatal seizures is suggestive of BFNC. Evaluation of the skin, anterior fontanel, and neurologic and ophthalmologic examinations should be performed. Presence of skin rash and chorioretinitis may suggest toxoplasmosis.
Laboratory data include CBC, serum glucose, electrolytes, BUN, serum creatinine, liver function tests, magnesium, calcium, phosphate, ammonia, lactate, pyruvate, biotinidase, lumbar puncture (LP) to rule out CNS infection and subarachnoid hemorrhage (SAH), titres for toxoplasmosis, rubella, cytomegalovirus, herpes, and HIV (toxoplas mosis, other agents, rubella, cytomegalovirus, herpes [TORCH]), and Venereal Disease Research Laboratory. Additional studies such as plasma amino acids and very-longchain fatty acids, urinalysis for amino acids and organic acids, CSF lactate, and neu rotransmitters may be indicated if metabolic disorders are suspected. Ultrasonography of the head at bedside to rule out intracranial hemorrhage and a non-contrast-enhanced CT or MRI of the head can be performed when the neonate’s condition is stable. EEG is useful for the diagnosis of subclinical seizures and assessment of prognosis. EEGs with low voltage, burst-suppression or isoelectric patterns suggest poor prognosis.
3. Treatment.
Management of underlying cause such as CNS infection or specific metabolic abnormality (hypoglycemia, hypocalcemia, or hypomagnesemia).
Phenobarbital, the initial drug of choice is administered IV as a loading dose of 20 mg per kg followed by additional 5 to 10 mg per kg boluses as required to
achieve serum levels between 20 and 40 μg per ml and to control clinical seizures. Maintenance dose of 3 to 4 mg/kg/day given twice a day is usually sufficient because phenobarbital has a relatively long half-life in neonates. Cardiorespiratory monitoring is important because IV administration can be associated with respiratory depression and hypotension.
Phenytoin is added if a phenobarbital level of 40 mg per ml is not sufficient to control seizures. An IV loading dose of 20 mg per kg results in serum levels ranging from 15 to 20 μg per ml, followed by a maintenance dose of 3 to 4 mg/kg/day given twice a day. Phenytoin is infused slowly with cardiac monitoring, because it can cause cardiac arrhythmias and hypotension. It is alkalotic and may lead to local venous thrombosis or tissue irritation. Use of fosphenytoin reduces these risks.
Benzodiazepines are third-line treatments. Lorazepam 0.05 to 0.1 mg per kg administered IV enters the brain rapidly, being effective in <5 minutes. Being less lipophilic, it does not redistribute from the brain as rapidly as does diazepam, the duration of action being 6 to 24 hours. Lorazepam is less likely to produce respira tory depression or hypotension than diazepam.
Pyridoxine (100 mg IV) administered during EEG monitoring stops seizures and nor malizes the EEG within minutes in the rare patient with pyridoxine-dependent seizures.
