CME
Common Pediatric Epilepsy Syndromes Jun T. Park, MD; Asim M. Shahid, MD; and Adham Jammoul, MD
Abstract Jun T. Park, MD, is an Assistant Professor of Pediatrics and Neurology, Division of Pediatric Epilepsy, Department of Pediatrics, Rainbow Babies and Children’s Hospital, Case Western Reserve University School of Medicine. Asim M. Shahid, MD, is an Assistant Professor of Pediatrics and Neurology, Division of Pediatric Epilepsy, Department of Pediatrics, Rainbow Babies and Children’s Hospital, Case Western Reserve University School of Medicine. Adham Jammoul, MD, is an Epilepsy Fellow, Department of Neurology, Neuroscience Instituite at University Hospitals, Case Western University School of Medicine. Address correspondence to Jun T. Park, MD, Division of Pediatric Epilepsy, 11100 Euclid Avenue, Mailstop 6009, Cleveland, OH 44106; email: [email protected]. Disclosure: The authors have no relevant financial relationships to disclose. doi: 10.3928/00904481-20150203-09
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Benign rolandic epilepsy (BRE), childhood idiopathic occipital epilepsy (CIOE), childhood absence epilepsy (CAE), and juvenile myoclonic epilepsy (JME) are some of the common epilepsy syndromes in the pediatric age group. Among the four, BRE is the most commonly encountered. BRE remits by age 16 years with many children requiring no treatment. Seizures in CAE also remit at the rate of approximately 80%; whereas, JME is considered a lifelong condition even with the use of antiepileptic drugs (AEDs). Neonates and infants may also present with seizures that are self-limited with no associated psychomotor disturbances. Benign familial neonatal convulsions caused by a channelopathy, and inherited in an autosomal dominant manner, have a favorable outcome with spontaneous resolution. Benign idiopathic neonatal seizures, also referred to as “fifth-day fits,” are an example of another epilepsy syndrome in infants that carries a good prognosis. BRE, CIOE, benign familial neonatal convulsions, benign idiopathic neonatal seizures, and benign myoclonic epilepsy in infancy are characterized as “benign” idiopathic age-related epilepsies as they have favorable implications, no structural brain abnormality, are sensitive to AEDs, have a high remission rate, and have no associated psychomotor disturbances. However, sometimes selected patients may have associated comorbidities such as cognitive and language delay for which the term “benign” may not be appropriate. [Pediatr Ann. 2015;44(2):e30-e35.]
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CME
E
pilepsy syndromes that are commonly encountered by a pediatric clinician are discussed chronologically from the neonatal period to adolescence in this article. Most of these childhood syndromes carry a good prognosis—contrary to popular opinion. In fact, several may not even necessitate treatment. The age of onset, nature of seizures, and family history may enable the pediatrician to come to a reasonable diagnosis. A pediatrician, in conjunction with the neurologist, may tailor a treatment plan that is appropriate for the child’s situation. Treatment options are presented in Table 1. BENIGN FAMILIAL NEONATAL CONVULSIONS Benign familial neonatal convulsion (BFNC), the first identified central nervous system channelopathy, is an autosomal dominant genetic epilepsy with a high penetrance rate of 85%. Seizures usually start within a few days of birth and almost invariably commence by age 2 months.1 Remission occurs on average by age 6 weeks (range, 1-6 months).1 The seizures of BFNC are short and occur in clusters. Seizures are characterized by apnea, generalized or focal tonic, or clonic convulsions. These newborns have normal psychomotor development during the epilepsy and after remission. Diagnosis is suspected in a normal newborn with spontaneous focal or generalized seizures occurring multiple times a day in the context of positive family history of neonatal seizures. Further evaluation with genetic testing should be done. Genetic mutations, microdeletions, or duplication involving potassium channel subunits (KCNQ2, KCNQ3) and nicotinic cholinergic receptor alpha 4 have been identified as a cause of BFNC.2 Mutations are most often seen in the potas-
PEDIATRIC ANNALS • Vol. 44, No. 2, 2015
sium channel subunit gene KCNQ2, which was previously mapped to the long arm of chromosome 20.3 Interictal electroencephalogram (EEG) may be abnormal but there are no characteristic diagnostic features. Because the seizures resolve spontaneously, treatment is controversial. Phenobarbital stops the seizures and can be tapered off after 4 weeks of “seizure freedom.”4 However, epilepsy develops later in approximately 16% of affected newborns. BENIGN IDIOPATHIC NEONATAL SEIZURES Benign idiopathic neonatal seizures (BINS) occur in otherwise healthy newborns without a family history of seizures. They are sometimes termed “fifth-day fits.” Diagnostic criteria include: (1) infants born after 39 weeks of gestation; (2) Apgar score of 9 or above at 5 minutes of life; (3) the presence of a seizure-free interval between birth and the onset of seizures; (4) clonic and/or apneic seizures; (5) negative workup for etiology; (6) a favorable neurological development; and (7) no seizures beyond the neonatal period.5 As the criteria indicate, the diagnosis of BINS is made retrospectively and only suspected at the time of presentation. As such, treatment is usually indicated initially. Seizures typically start on the fifth day of life in half of the patients, but can range between the first and seventh day of life.5 Seizure semiology is characterized by uni- or bilateral clonus and/or apnea with rare tonic seizures. Seizures in clusters often occur in increasing frequency, culminating in status epilepticus in 82% (63 of 77) of the patients in one study.5 As in BFNC, EEG findings vary with no certain diagnostic features. Unlike BFNC, etiology is unknown. Outcome is excellent with low rate of seizure recurrence.6
BENIGN MYOCLONIC EPILEPSY IN INFANCY Benign myoclonic epilepsy in infancy (BMEI) is a generalized idiopathic epilepsy, characterized by unprovoked and/or reflex seizures that appear between ages 4 months and 3 years in a previously healthy children. As the name of the syndrome implies, myoclonic seizures are the most commonly noted type of seizure in BMEI. The seizures are characterized by brief generalized myoclonic jerks, correlating with 3-4 Hz generalized spike-and-wave discharges on EEG.7 Some patients may have reflex seizures, in addition to BMEI, that are triggered by sudden unexpected visual, tactile, or auditory stimuli.7 Afebrile generalized tonic-clonic seizures and simple febrile seizures may precede the onset of BMEI.7 Interictal EEG is typically normal in awake and sleep state. The etiology is unknown; however, it is likely influenced by genetics. It has been shown in the long-term follow-up that some patients may develop other epilepsy syndromes after a seizure-free period.8 Levetiracetam may be the first choice to treat the myoclonic seizures in these patients. Valproic acid should be used with caution as fulminant hepatic failure may result in a patient with undiagnosed metabolic disease. BENIGN ROLANDIC EPILEPSY OR BENIGN EPILEPSY WITH CENTROTEMPORAL SPIKES Benign rolandic epilepsy (BRE) (or benign epilepsy with centro-temporal spikes) is the most common childhood idiopathic focal epilepsy. The “benign” nature is thought to be due to the absence of focal neurological deficits, sensitivity to antiepileptic drugs (AEDs), and spontaneous resolution by age 16 years. About 15% of children with epilepsy are affected with e31
CME TABLE 1.
Clinical Summary of Childhood Epilepsy Syndromes Epilepsy Syndromes
Age at Onset
Typical Clinical Symptoms
Cause
Prognosis
Suggested Treatment
BFNC
Days-2 months
Healthy newborn with apnea, generalized or focal tonic, or clonic seizures, and occur multiple times a day. Positive family history of neonatal seizure.
Genetic mutations
Remit
PHB or LVT
BINS
Fifth day of life
Healthy newborn with generalized or focal tonic or clonic seizures and/or apnea
Unknown
Remit
PHB or LVT
BMEI
4 months-3 years
Healthy infant/toddler with myoclonic jerks
Unknown
Remit
LVT
BRE
Adolescent
Healthy child with focal seizures in the morning that secondarily generalizes
Probably genetically influenced
Remit by age 16 years
LVT or OXC
EBOE
3-6 years
Prolonged emesis—mostly nocturnal and intact consciousness
Probably genetically influenced
Remit by age 16 years
LVT or OXC
LIOE
8-11 years
Visual hallucinations—brief and frequent. At times, postictal headache with migraine features.
Unknown
Excellent
LVT or OXC
CAE
4-10 years
Multiple staring episodes
Genetically influenced
Excellent remission rate
ETX
JME
13-15 years
Myoclonic jerks in the morning
Genetically influenced
Lifelong
VPA, LTG, or LVT
Abbreviations: BFNC, benign familial neonatal convulsions; BINS, benign idiopathic neonatal seizures; BMEI, benign myoclonic epilepsy in infancy; BRE, benign rolandic epilepsy; CAE, childhood absence epilepsy; EBOE, early-onset benign occipital epilepsy; ETX, ethosuximide; JME, juvenile myoclonic epilepsy; LIOE, late-onset idiopathic occipital epilepsy; LTG, lamotrigine; LVT, levetiracetam; OXC, oxcarbazepine; PHB, phenobarbital; VPA, valproate.
BRE, usually with onset between ages 7 and 9 years and before age 13 years. Seizures are usually 1-3 minutes long and status epilepticus is rare. The cardinal feature of BRE is focal seizures—such that consciousness is intact during the episode in more than half of all children. Focal seizures are characterized by unilateral facial pulling/twitching and paresthesia inside the mouth (30% of patients), oropharyngo-laryngeal symptoms (53%), speech arrest (40%), and hypersalivation (30%).9,10 Patients may try to talk and gesture purposefully during the initial stage of the seizure. Speech arrest often occurs due to dysarthria. Progression to a secondary e32
generalized tonic-clonic (GTC) seizure occurs in about half of the children.11 Uncommonly, long convulsions may be followed by Todds’s paresis. Family members may hear rhythmic “thumping” or “knocking” as the bed shakes during the secondary generalized tonicclonic phase. Three-quarters of the seizures occur during non-rapid eye moment (REM) sleep and drowsy state. EEG shows a classic pattern consisting of central-temporal spikes or polyspikes (CTS) uni- or bilaterally often activated by drowsiness or non-REM sleep.9 It is important to note that CTS are not specific to BRE, and may occur in other neurologic conditions. Brain
magnetic resonance imaging is normal except for incidental findings; therefore, neuroimaging is not needed in the presence of characteristic history and EEG findings. Very rarely, a patient with a focal brain lesion may present in a similar manner.12 No relation can be drawn between the seizure frequency and the frequency of interictal epileptiform discharges. These discharges also occur in 2%-3% of normal school-aged children, of whom about 8% develop BRE.11 EEG tracings normalize later than clinical remission. EEG may continue to be abnormal by the time seizures no longer occur. Clinical genetic studies suggest that the cause
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CME of BRE is, at least partially, genetically determined. However, additional acquired or environmental factors may contribute to the expression of BRE.13 Treatment is often not needed. Because the seizures are brief, occur mainly during sleep and interfere minimally with the daily activities, many clinicians opt not to treat. However, if the attacks are frequent and become generalized, short-term treatment may be necessary. With similar seizure burden and duration, no difference in social adjustment was found comparing children who were treated versus untreated.12 The prognosis is invariably excellent. Remission occurs within 2-4 years from onset and before age 16 years in most instances.9 Seizures disappear regardless of previous drug resistance to treatment, which may be present in up to 20% of patients.10 Moreover, development, social adaptation, and occupation of adults with a previous history of BRE was found to be normal.14 CHILDHOOD IDIOPATHIC OCCIPITAL EPILEPSY Early-Onset Benign Occipital Epilepsy (Panayiotopoulos Syndrome) Panayiotopoulos syndrome (PS) is a benign focal epilepsy that primarily occurs between ages 3 and 6 years.11 The clinical hallmark of PS is emesis (70%-80% of seizures).11 The seizures are mostly nocturnal and consciousness is retained. The duration of emesis is typically over 6 minutes, with around half lasting over 30 minutes. In 90% of patients, emesis is followed by eye deviation or opening (60%-80%), visual hallucinations, and generalized or hemi-convulsions.11 Two-thirds occur in sleep, during which time the frequency of EEG spikes are also increased. EEG shows predominantly occipital or multifocal spikes.9
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Prognosis is excellent as in BRE with no evidence that long-term prognosis is worse in untreated patients. The majority of patients have less than 10 seizures in total, and an AED may not be indicated.15 One-tenth of children with PS have BRE or develop it later before all seizures remit by ages 15-16 years. As in BRE, the cause is probably genetically determined. Late-Onset Idiopathic Occipital Epilepsy This is a relatively rare form of pure occipital epilepsy, which accounts for about 2%-7% of benign childhood focal seizures with the mean age of onset between 8 and 11 years.10 Seizures are occipital in origin and primarily manifest as elementary or formed (patients can delineate the nature of the object that they “see”) visual hallucinations, sudden blindness, or both. The seizures are brief, frequent, and diurnal.11,16 These may be followed by hemi-sensory, motor signs or unresponsiveness. Approximately one-third of the patients can have severe postictal, prolonged headache— at times associated with nausea or vomiting with additional migrainous features.10 In fact, 19% of the patients have a family history of migraine headaches.10 The headache occurs immediately or within 10 minutes after visual hallucinations. Consciousness is intact during the visual hallucinations or blindness. The majority of the untreated patients experience visual seizures that range in frequency from several per day to a couple monthly. However, seizure propagation to convulsions is less frequent. Interictal EEG is normal; however, unilateral or bilateral, synchronous or asynchronous, spikewave complexes occur only with the eyes closed. Visual fixation suppresses the discharges, even in complete darkness as long as the patient can visually fixate on an object, such as a dot of red
light.17 The clinical course is considered benign. CHILDHOOD ABSENCE EPILEPSY Absence seizures are usually brief in duration (4-20 seconds), but can occur frequently (10 to ≥100 per day) with abrupt onset/offset associated with impaired consciousness. Immediately after the seizure the child resumes pre-absence activity. Age of onset is 4-10 years with peak incidence at 5-6 years. Prevalence is 8%-15% of all childhood epilepsies.18 Impairment of consciousness as characterized by loss of awareness, unresponsiveness, and behavioral arrest is an essential feature of childhood absence epilepsy (CAE). About twothirds of these children have associated repeated blinking, lip smacking, picking/rubbing, head retropulsion, trunk arching, or twitching of the eyelids, eyebrows, or mouth. Some slumping of posture can be seen due to decreased axial muscle tone, but falls due to atonia do not occur. Pallor is common, but urinary incontinence is exceptional.18 About one-third of the children have at least one GTC.19 In 83% of the patients, seizures are induced by unnatural hyperventilation and not associated with physiologic hyperventilation.18 Differential diagnosis includes inattention or daydreaming. Ictal EEG of CAE is easily recognized. It is characterized by high-amplitude, bisynchronous, and symmetric discharges of rhythmic 3 Hz “spikeand-slow” wave complexes that start and end abruptly (Figure 1). Interictally, paroxysmal activity consisting of fragments of generalized spike-wave discharges can be seen in up to 92% of patients. EEG abnormalities may persist into adulthood after resolution of seizures. Neuropsychological studies have demonstrated that, at the time of diagnosis, these children have behavioral e33
CME withdrawal.23 Absence seizures remit within 2-5 years from the onset. A favorable prognostic sign is prompt seizure control with an appropriate AED therapy.
Figure 1. Ictal discharges in childhood absence epilepsy showing a 5-year-old patient who stopped hyperventilating due to 3 Hz spike-and-wave discharges. She had no memory of the word given to her during the induced-absence seizure.
Figure 2. Interictal discharges in juvenile myoclonic epilepsy showing an 18-year-old female with diffuse polyspikes lasting approximately 1 second with no clinical signs.
disorders in addition to cognitive 25% (17 of 69) and linguistic difficulties 43% (29 of 69).20 Cognitive impairment, in particular, involves attention and executive functions21 as well as verbal and visuospatial memory regardless of seizure control. Additional studies suggest increased prevalence of attention-deficit/ hyperactivity disorder in children with CAE.15 Seizures usually respond well to ethosuximide, valproate, and lae34
motrigine. Studies indicate that ethosuximide is the optimal initial monotherapy for CAE due to its efficacy in controlling seizure in 70%22 of patients and fewer cognitive side effects. However, ethosuximide does not treat convulsions; thus, an add-on therapy or an alternative AED needs to be considered in cases where convulsions coexist. Prognosis is excellent for remission of seizures (56%-84%) and AED
JUVENILE MYOCLONIC EPILEPSY Juvenile myoclonic epilepsy (JME), also a genetically mediated generalized epilepsy, comprises 5%10% of all epilepsy syndromes, and peaks in early adolescence between ages 13 and 15 years.19 Multiple seizure types may be present in a patient. Seizures typically occur after awakening in the mornings. Patients often complain of suddenly dropping objects, morning clumsiness, or jitters, which are, in fact, myoclonic seizures. Patients have myoclonic jerks (97%), GTC seizures (79%), absence seizures (33%), or all three types (21%).19 Sleep deprivation and fatigue are the most common precipitating factors. Other precipitants may be alcohol, flashing lights, mental stress, strong emotions, anxiety, and menstruation. Ictal EEG is characterized by a generalized spike-and-wave pattern at 4-6 Hz that last between 1 and 20 seconds (Figure 2). Interictal EEG may show generalized spike/polyspike and wave complexes or focal abnormalities (>50% of patients).24 Photic stimulation during EEG may induce an electrographic seizure in up to onehalf of patients—termed photoconvulsive response.19 The mechanism and pathophysiology of JME are not yet clear. Major genes only account for a few cases, and most cases appear to involve multifactorial or complex inheritance.25 Seizures are sensitive to valproate, rendering at least 80% of patients seizure free. Valproate may not be a drug of choice for an adolescent girl due to, among other risks, its teratogenic effect on the fetus. JME is thought to
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CME be a lifelong condition as attempts to wean AEDs almost-always fails.19 CONCLUSION Pediatricians are often the first to encounter children with epilepsy syndromes. Being familiar with typical clinical presentations may help triage and manage these patients upon presentation in primary care settings. In addition, unnecessary work-up and morbidities may be avoided. Recognition of the benign nature of some of these entities would go a long way in alleviating the fear of families as the term “epilepsy” often conjures up notions of lifelong treatment with a significant impact on day-to-day life. REFERENCES 1. Herlenius E, Heron SE, Grinton BE, et al. SCN2A mutations and benign familial neonatal-infantile seizures: the phenotypic spectrum. Epilepsia. 2007;48:1138-1142. 2. Singh NA, Westenskow P, Charlier C, et al. KCNQ2 and KCNQ3 potassium channel genes in benign familial neonatal convulsions: Expansion of the functional and mutation spectrum. Brain. 2003;126:27262737. 3. Biervert C, Steinlein OK. Structural and mutational analysis of KCNQ2, the major gene locus for benign familial neonatal convulsions. Hum Genet. 1999;104:234240. 4. Zonana J, Silvey K, Strimling B. Familial
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neonatal and infantile seizures: an autosomal-dominant disorder. Am J Med Genet. 1984;18:455-459. 5. Plouin P. Benign neonatal convulsions (familial and non-familial). In: Roger J, Dravet C, Bureau M. Derifuss FE, Wolf P, eds. Epileptic Syndromes in Infancy, Childhood and Adolescence. London: John Libbgey Eurotext; 1985:2-11. 6. Miles DK, Holmes GL. Benign neonatal seizures. J Clin Neurophysiol. 1990;7:369379. 7. Dravet C, Bureau M. The benign myoclonic epilepsy of infancy. Rev Electroencephalogr Neurophysiol Clin. 1981;11:438-444. 8. Capovilla G, Beccaria F, Gambardella A, et al. Photosensitive benign myoclonic epilepsy in infancy. Epilepsia. 2007;48:96100. 9. Panayiotopoulos CP. Benign childhood partial epilepsies: benign childhood seizure susceptibility syndromes [editorial]. J Neurol Neurosurg Psychiatr. 1993;56:2-5. 10. Panayiotopoulos CP. Typical absence seizure and their treatment. Arch Dis Child. 1999;81:351-355. 11. Panayiotopoulos CP, Michael M. Benign childhood focal epilepsies: assessment of established and newly recognized syndromes. Brain. 2008;131:2264-2286. 12. Ambrosetto G, Tassinari CA. Antiepileptic drug treatment of benign childhood epilepsy with rolandic spikes: is it necessary? Epilepsia. 1990;31:802-805. 13. Vears DF, Tsai MH, Sadleir LG, et al. Clinical genetic studies in benign childhood epilepsy with centrotemporal spikes. Epilepsia. 2012;53:319-324. 14. Loiseau P, Pestre M, Dartigues JF, et al. Long-term prognosis in two forms of childhood epilepsy: typical absence seizures and epilepsy with rolandic (centrotemporal)
EEG foci. Ann Neurol. 1983;13:642-648. 15. Nolan MA, Redobaldo MA, Lah S, et al. Memory function in childhood epilepsy syndromes. J Paediatr Child Health. 2004;40:20-27. 16. Auvin S, Pandit F, De Bellecize J, et al. Benign myoclonic epilepsy in infants: electroclinical features and long-term follow-up of 34 patients. Epilepsia. 2006;47:387-393. 17. Panayiotopoulos CP. Inhibitory effect of central vision on occipital lobe seizures. Neurology. 1981;31:1330-1333. 18. Sadleir LG, Farrell K, Smith S, et al. Electroclinical features of absence seizures in childhood absence epilepsy. Neurology. 2006;67:413-418. 19. Panayiotopoulos CP. Obeid T, Tahan AR. Juvenile myoclonic epilepsy: a 5-year prospective study. Epilepsia. 1994;35:285296. 20. Caplan R, Siddarth P, Stahl L, et al. Childhood absence epilepsy: behavioral, cognitive, and linguistic comorbidities. Epilepsia. 2008;49:1838-1846. 21. Pavone P, Bianchini R, Trifiletti RR, Incorpora G, Pavone A, Parano E. Neuropsychological assessment in children with absence epilepsy. Neurology. 2001;56:1047-1051. 22. Matricardi S, Verrotti A, Chiarellil F, et al. Current advances in childhood absence epilepsy. Pediatr Neurol. 2014;50(3):205-212. 23. Callenbach PM, Bouma PA, Geerts AT, et al. Long-term outcome of childhood absence epilepsy: Dutch study of epilepsy in childhood. Epilepsy Res. 2009;83:249-256. 24. Janz D. Epilepsy with impulsive petit mal (juvenile myoclonic epilepsy). Acta Neurol Scand. 1985;72:449-459. 25. Zifkin B, Andermann E, Andermann F. Mechanisms, genetics, and pathogenesis of juvenile myoclonic epilepsy. Current Opin Neurol. 2005;18:147-153.
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Common Pediatric Epilepsy Syndromes Jun T. Park, MD; Asim M. Shahid, MD; and Adham Jammoul, MD
Abstract Jun T. Park, MD, is an Assistant Professor of Pediatrics and Neurology, Division of Pediatric Epilepsy, Department of Pediatrics, Rainbow Babies and Children’s Hospital, Case Western Reserve University School of Medicine. Asim M. Shahid, MD, is an Assistant Professor of Pediatrics and Neurology, Division of Pediatric Epilepsy, Department of Pediatrics, Rainbow Babies and Children’s Hospital, Case Western Reserve University School of Medicine. Adham Jammoul, MD, is an Epilepsy Fellow, Department of Neurology, Neuroscience Instituite at University Hospitals, Case Western University School of Medicine. Address correspondence to Jun T. Park, MD, Division of Pediatric Epilepsy, 11100 Euclid Avenue, Mailstop 6009, Cleveland, OH 44106; email: [email protected]. Disclosure: The authors have no relevant financial relationships to disclose. doi: 10.3928/00904481-20150203-09
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Benign rolandic epilepsy (BRE), childhood idiopathic occipital epilepsy (CIOE), childhood absence epilepsy (CAE), and juvenile myoclonic epilepsy (JME) are some of the common epilepsy syndromes in the pediatric age group. Among the four, BRE is the most commonly encountered. BRE remits by age 16 years with many children requiring no treatment. Seizures in CAE also remit at the rate of approximately 80%; whereas, JME is considered a lifelong condition even with the use of antiepileptic drugs (AEDs). Neonates and infants may also present with seizures that are self-limited with no associated psychomotor disturbances. Benign familial neonatal convulsions caused by a channelopathy, and inherited in an autosomal dominant manner, have a favorable outcome with spontaneous resolution. Benign idiopathic neonatal seizures, also referred to as “fifth-day fits,” are an example of another epilepsy syndrome in infants that carries a good prognosis. BRE, CIOE, benign familial neonatal convulsions, benign idiopathic neonatal seizures, and benign myoclonic epilepsy in infancy are characterized as “benign” idiopathic age-related epilepsies as they have favorable implications, no structural brain abnormality, are sensitive to AEDs, have a high remission rate, and have no associated psychomotor disturbances. However, sometimes selected patients may have associated comorbidities such as cognitive and language delay for which the term “benign” may not be appropriate. [Pediatr Ann. 2015;44(2):e30-e35.]
e30
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CME
E
pilepsy syndromes that are commonly encountered by a pediatric clinician are discussed chronologically from the neonatal period to adolescence in this article. Most of these childhood syndromes carry a good prognosis—contrary to popular opinion. In fact, several may not even necessitate treatment. The age of onset, nature of seizures, and family history may enable the pediatrician to come to a reasonable diagnosis. A pediatrician, in conjunction with the neurologist, may tailor a treatment plan that is appropriate for the child’s situation. Treatment options are presented in Table 1. BENIGN FAMILIAL NEONATAL CONVULSIONS Benign familial neonatal convulsion (BFNC), the first identified central nervous system channelopathy, is an autosomal dominant genetic epilepsy with a high penetrance rate of 85%. Seizures usually start within a few days of birth and almost invariably commence by age 2 months.1 Remission occurs on average by age 6 weeks (range, 1-6 months).1 The seizures of BFNC are short and occur in clusters. Seizures are characterized by apnea, generalized or focal tonic, or clonic convulsions. These newborns have normal psychomotor development during the epilepsy and after remission. Diagnosis is suspected in a normal newborn with spontaneous focal or generalized seizures occurring multiple times a day in the context of positive family history of neonatal seizures. Further evaluation with genetic testing should be done. Genetic mutations, microdeletions, or duplication involving potassium channel subunits (KCNQ2, KCNQ3) and nicotinic cholinergic receptor alpha 4 have been identified as a cause of BFNC.2 Mutations are most often seen in the potas-
PEDIATRIC ANNALS • Vol. 44, No. 2, 2015
sium channel subunit gene KCNQ2, which was previously mapped to the long arm of chromosome 20.3 Interictal electroencephalogram (EEG) may be abnormal but there are no characteristic diagnostic features. Because the seizures resolve spontaneously, treatment is controversial. Phenobarbital stops the seizures and can be tapered off after 4 weeks of “seizure freedom.”4 However, epilepsy develops later in approximately 16% of affected newborns. BENIGN IDIOPATHIC NEONATAL SEIZURES Benign idiopathic neonatal seizures (BINS) occur in otherwise healthy newborns without a family history of seizures. They are sometimes termed “fifth-day fits.” Diagnostic criteria include: (1) infants born after 39 weeks of gestation; (2) Apgar score of 9 or above at 5 minutes of life; (3) the presence of a seizure-free interval between birth and the onset of seizures; (4) clonic and/or apneic seizures; (5) negative workup for etiology; (6) a favorable neurological development; and (7) no seizures beyond the neonatal period.5 As the criteria indicate, the diagnosis of BINS is made retrospectively and only suspected at the time of presentation. As such, treatment is usually indicated initially. Seizures typically start on the fifth day of life in half of the patients, but can range between the first and seventh day of life.5 Seizure semiology is characterized by uni- or bilateral clonus and/or apnea with rare tonic seizures. Seizures in clusters often occur in increasing frequency, culminating in status epilepticus in 82% (63 of 77) of the patients in one study.5 As in BFNC, EEG findings vary with no certain diagnostic features. Unlike BFNC, etiology is unknown. Outcome is excellent with low rate of seizure recurrence.6
BENIGN MYOCLONIC EPILEPSY IN INFANCY Benign myoclonic epilepsy in infancy (BMEI) is a generalized idiopathic epilepsy, characterized by unprovoked and/or reflex seizures that appear between ages 4 months and 3 years in a previously healthy children. As the name of the syndrome implies, myoclonic seizures are the most commonly noted type of seizure in BMEI. The seizures are characterized by brief generalized myoclonic jerks, correlating with 3-4 Hz generalized spike-and-wave discharges on EEG.7 Some patients may have reflex seizures, in addition to BMEI, that are triggered by sudden unexpected visual, tactile, or auditory stimuli.7 Afebrile generalized tonic-clonic seizures and simple febrile seizures may precede the onset of BMEI.7 Interictal EEG is typically normal in awake and sleep state. The etiology is unknown; however, it is likely influenced by genetics. It has been shown in the long-term follow-up that some patients may develop other epilepsy syndromes after a seizure-free period.8 Levetiracetam may be the first choice to treat the myoclonic seizures in these patients. Valproic acid should be used with caution as fulminant hepatic failure may result in a patient with undiagnosed metabolic disease. BENIGN ROLANDIC EPILEPSY OR BENIGN EPILEPSY WITH CENTROTEMPORAL SPIKES Benign rolandic epilepsy (BRE) (or benign epilepsy with centro-temporal spikes) is the most common childhood idiopathic focal epilepsy. The “benign” nature is thought to be due to the absence of focal neurological deficits, sensitivity to antiepileptic drugs (AEDs), and spontaneous resolution by age 16 years. About 15% of children with epilepsy are affected with e31
CME TABLE 1.
Clinical Summary of Childhood Epilepsy Syndromes Epilepsy Syndromes
Age at Onset
Typical Clinical Symptoms
Cause
Prognosis
Suggested Treatment
BFNC
Days-2 months
Healthy newborn with apnea, generalized or focal tonic, or clonic seizures, and occur multiple times a day. Positive family history of neonatal seizure.
Genetic mutations
Remit
PHB or LVT
BINS
Fifth day of life
Healthy newborn with generalized or focal tonic or clonic seizures and/or apnea
Unknown
Remit
PHB or LVT
BMEI
4 months-3 years
Healthy infant/toddler with myoclonic jerks
Unknown
Remit
LVT
BRE
Adolescent
Healthy child with focal seizures in the morning that secondarily generalizes
Probably genetically influenced
Remit by age 16 years
LVT or OXC
EBOE
3-6 years
Prolonged emesis—mostly nocturnal and intact consciousness
Probably genetically influenced
Remit by age 16 years
LVT or OXC
LIOE
8-11 years
Visual hallucinations—brief and frequent. At times, postictal headache with migraine features.
Unknown
Excellent
LVT or OXC
CAE
4-10 years
Multiple staring episodes
Genetically influenced
Excellent remission rate
ETX
JME
13-15 years
Myoclonic jerks in the morning
Genetically influenced
Lifelong
VPA, LTG, or LVT
Abbreviations: BFNC, benign familial neonatal convulsions; BINS, benign idiopathic neonatal seizures; BMEI, benign myoclonic epilepsy in infancy; BRE, benign rolandic epilepsy; CAE, childhood absence epilepsy; EBOE, early-onset benign occipital epilepsy; ETX, ethosuximide; JME, juvenile myoclonic epilepsy; LIOE, late-onset idiopathic occipital epilepsy; LTG, lamotrigine; LVT, levetiracetam; OXC, oxcarbazepine; PHB, phenobarbital; VPA, valproate.
BRE, usually with onset between ages 7 and 9 years and before age 13 years. Seizures are usually 1-3 minutes long and status epilepticus is rare. The cardinal feature of BRE is focal seizures—such that consciousness is intact during the episode in more than half of all children. Focal seizures are characterized by unilateral facial pulling/twitching and paresthesia inside the mouth (30% of patients), oropharyngo-laryngeal symptoms (53%), speech arrest (40%), and hypersalivation (30%).9,10 Patients may try to talk and gesture purposefully during the initial stage of the seizure. Speech arrest often occurs due to dysarthria. Progression to a secondary e32
generalized tonic-clonic (GTC) seizure occurs in about half of the children.11 Uncommonly, long convulsions may be followed by Todds’s paresis. Family members may hear rhythmic “thumping” or “knocking” as the bed shakes during the secondary generalized tonicclonic phase. Three-quarters of the seizures occur during non-rapid eye moment (REM) sleep and drowsy state. EEG shows a classic pattern consisting of central-temporal spikes or polyspikes (CTS) uni- or bilaterally often activated by drowsiness or non-REM sleep.9 It is important to note that CTS are not specific to BRE, and may occur in other neurologic conditions. Brain
magnetic resonance imaging is normal except for incidental findings; therefore, neuroimaging is not needed in the presence of characteristic history and EEG findings. Very rarely, a patient with a focal brain lesion may present in a similar manner.12 No relation can be drawn between the seizure frequency and the frequency of interictal epileptiform discharges. These discharges also occur in 2%-3% of normal school-aged children, of whom about 8% develop BRE.11 EEG tracings normalize later than clinical remission. EEG may continue to be abnormal by the time seizures no longer occur. Clinical genetic studies suggest that the cause
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CME of BRE is, at least partially, genetically determined. However, additional acquired or environmental factors may contribute to the expression of BRE.13 Treatment is often not needed. Because the seizures are brief, occur mainly during sleep and interfere minimally with the daily activities, many clinicians opt not to treat. However, if the attacks are frequent and become generalized, short-term treatment may be necessary. With similar seizure burden and duration, no difference in social adjustment was found comparing children who were treated versus untreated.12 The prognosis is invariably excellent. Remission occurs within 2-4 years from onset and before age 16 years in most instances.9 Seizures disappear regardless of previous drug resistance to treatment, which may be present in up to 20% of patients.10 Moreover, development, social adaptation, and occupation of adults with a previous history of BRE was found to be normal.14 CHILDHOOD IDIOPATHIC OCCIPITAL EPILEPSY Early-Onset Benign Occipital Epilepsy (Panayiotopoulos Syndrome) Panayiotopoulos syndrome (PS) is a benign focal epilepsy that primarily occurs between ages 3 and 6 years.11 The clinical hallmark of PS is emesis (70%-80% of seizures).11 The seizures are mostly nocturnal and consciousness is retained. The duration of emesis is typically over 6 minutes, with around half lasting over 30 minutes. In 90% of patients, emesis is followed by eye deviation or opening (60%-80%), visual hallucinations, and generalized or hemi-convulsions.11 Two-thirds occur in sleep, during which time the frequency of EEG spikes are also increased. EEG shows predominantly occipital or multifocal spikes.9
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Prognosis is excellent as in BRE with no evidence that long-term prognosis is worse in untreated patients. The majority of patients have less than 10 seizures in total, and an AED may not be indicated.15 One-tenth of children with PS have BRE or develop it later before all seizures remit by ages 15-16 years. As in BRE, the cause is probably genetically determined. Late-Onset Idiopathic Occipital Epilepsy This is a relatively rare form of pure occipital epilepsy, which accounts for about 2%-7% of benign childhood focal seizures with the mean age of onset between 8 and 11 years.10 Seizures are occipital in origin and primarily manifest as elementary or formed (patients can delineate the nature of the object that they “see”) visual hallucinations, sudden blindness, or both. The seizures are brief, frequent, and diurnal.11,16 These may be followed by hemi-sensory, motor signs or unresponsiveness. Approximately one-third of the patients can have severe postictal, prolonged headache— at times associated with nausea or vomiting with additional migrainous features.10 In fact, 19% of the patients have a family history of migraine headaches.10 The headache occurs immediately or within 10 minutes after visual hallucinations. Consciousness is intact during the visual hallucinations or blindness. The majority of the untreated patients experience visual seizures that range in frequency from several per day to a couple monthly. However, seizure propagation to convulsions is less frequent. Interictal EEG is normal; however, unilateral or bilateral, synchronous or asynchronous, spikewave complexes occur only with the eyes closed. Visual fixation suppresses the discharges, even in complete darkness as long as the patient can visually fixate on an object, such as a dot of red
light.17 The clinical course is considered benign. CHILDHOOD ABSENCE EPILEPSY Absence seizures are usually brief in duration (4-20 seconds), but can occur frequently (10 to ≥100 per day) with abrupt onset/offset associated with impaired consciousness. Immediately after the seizure the child resumes pre-absence activity. Age of onset is 4-10 years with peak incidence at 5-6 years. Prevalence is 8%-15% of all childhood epilepsies.18 Impairment of consciousness as characterized by loss of awareness, unresponsiveness, and behavioral arrest is an essential feature of childhood absence epilepsy (CAE). About twothirds of these children have associated repeated blinking, lip smacking, picking/rubbing, head retropulsion, trunk arching, or twitching of the eyelids, eyebrows, or mouth. Some slumping of posture can be seen due to decreased axial muscle tone, but falls due to atonia do not occur. Pallor is common, but urinary incontinence is exceptional.18 About one-third of the children have at least one GTC.19 In 83% of the patients, seizures are induced by unnatural hyperventilation and not associated with physiologic hyperventilation.18 Differential diagnosis includes inattention or daydreaming. Ictal EEG of CAE is easily recognized. It is characterized by high-amplitude, bisynchronous, and symmetric discharges of rhythmic 3 Hz “spikeand-slow” wave complexes that start and end abruptly (Figure 1). Interictally, paroxysmal activity consisting of fragments of generalized spike-wave discharges can be seen in up to 92% of patients. EEG abnormalities may persist into adulthood after resolution of seizures. Neuropsychological studies have demonstrated that, at the time of diagnosis, these children have behavioral e33
CME withdrawal.23 Absence seizures remit within 2-5 years from the onset. A favorable prognostic sign is prompt seizure control with an appropriate AED therapy.
Figure 1. Ictal discharges in childhood absence epilepsy showing a 5-year-old patient who stopped hyperventilating due to 3 Hz spike-and-wave discharges. She had no memory of the word given to her during the induced-absence seizure.
Figure 2. Interictal discharges in juvenile myoclonic epilepsy showing an 18-year-old female with diffuse polyspikes lasting approximately 1 second with no clinical signs.
disorders in addition to cognitive 25% (17 of 69) and linguistic difficulties 43% (29 of 69).20 Cognitive impairment, in particular, involves attention and executive functions21 as well as verbal and visuospatial memory regardless of seizure control. Additional studies suggest increased prevalence of attention-deficit/ hyperactivity disorder in children with CAE.15 Seizures usually respond well to ethosuximide, valproate, and lae34
motrigine. Studies indicate that ethosuximide is the optimal initial monotherapy for CAE due to its efficacy in controlling seizure in 70%22 of patients and fewer cognitive side effects. However, ethosuximide does not treat convulsions; thus, an add-on therapy or an alternative AED needs to be considered in cases where convulsions coexist. Prognosis is excellent for remission of seizures (56%-84%) and AED
JUVENILE MYOCLONIC EPILEPSY Juvenile myoclonic epilepsy (JME), also a genetically mediated generalized epilepsy, comprises 5%10% of all epilepsy syndromes, and peaks in early adolescence between ages 13 and 15 years.19 Multiple seizure types may be present in a patient. Seizures typically occur after awakening in the mornings. Patients often complain of suddenly dropping objects, morning clumsiness, or jitters, which are, in fact, myoclonic seizures. Patients have myoclonic jerks (97%), GTC seizures (79%), absence seizures (33%), or all three types (21%).19 Sleep deprivation and fatigue are the most common precipitating factors. Other precipitants may be alcohol, flashing lights, mental stress, strong emotions, anxiety, and menstruation. Ictal EEG is characterized by a generalized spike-and-wave pattern at 4-6 Hz that last between 1 and 20 seconds (Figure 2). Interictal EEG may show generalized spike/polyspike and wave complexes or focal abnormalities (>50% of patients).24 Photic stimulation during EEG may induce an electrographic seizure in up to onehalf of patients—termed photoconvulsive response.19 The mechanism and pathophysiology of JME are not yet clear. Major genes only account for a few cases, and most cases appear to involve multifactorial or complex inheritance.25 Seizures are sensitive to valproate, rendering at least 80% of patients seizure free. Valproate may not be a drug of choice for an adolescent girl due to, among other risks, its teratogenic effect on the fetus. JME is thought to
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CME be a lifelong condition as attempts to wean AEDs almost-always fails.19 CONCLUSION Pediatricians are often the first to encounter children with epilepsy syndromes. Being familiar with typical clinical presentations may help triage and manage these patients upon presentation in primary care settings. In addition, unnecessary work-up and morbidities may be avoided. Recognition of the benign nature of some of these entities would go a long way in alleviating the fear of families as the term “epilepsy” often conjures up notions of lifelong treatment with a significant impact on day-to-day life. REFERENCES 1. Herlenius E, Heron SE, Grinton BE, et al. SCN2A mutations and benign familial neonatal-infantile seizures: the phenotypic spectrum. Epilepsia. 2007;48:1138-1142. 2. Singh NA, Westenskow P, Charlier C, et al. KCNQ2 and KCNQ3 potassium channel genes in benign familial neonatal convulsions: Expansion of the functional and mutation spectrum. Brain. 2003;126:27262737. 3. Biervert C, Steinlein OK. Structural and mutational analysis of KCNQ2, the major gene locus for benign familial neonatal convulsions. Hum Genet. 1999;104:234240. 4. Zonana J, Silvey K, Strimling B. Familial
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neonatal and infantile seizures: an autosomal-dominant disorder. Am J Med Genet. 1984;18:455-459. 5. Plouin P. Benign neonatal convulsions (familial and non-familial). In: Roger J, Dravet C, Bureau M. Derifuss FE, Wolf P, eds. Epileptic Syndromes in Infancy, Childhood and Adolescence. London: John Libbgey Eurotext; 1985:2-11. 6. Miles DK, Holmes GL. Benign neonatal seizures. J Clin Neurophysiol. 1990;7:369379. 7. Dravet C, Bureau M. The benign myoclonic epilepsy of infancy. Rev Electroencephalogr Neurophysiol Clin. 1981;11:438-444. 8. Capovilla G, Beccaria F, Gambardella A, et al. Photosensitive benign myoclonic epilepsy in infancy. Epilepsia. 2007;48:96100. 9. Panayiotopoulos CP. Benign childhood partial epilepsies: benign childhood seizure susceptibility syndromes [editorial]. J Neurol Neurosurg Psychiatr. 1993;56:2-5. 10. Panayiotopoulos CP. Typical absence seizure and their treatment. Arch Dis Child. 1999;81:351-355. 11. Panayiotopoulos CP, Michael M. Benign childhood focal epilepsies: assessment of established and newly recognized syndromes. Brain. 2008;131:2264-2286. 12. Ambrosetto G, Tassinari CA. Antiepileptic drug treatment of benign childhood epilepsy with rolandic spikes: is it necessary? Epilepsia. 1990;31:802-805. 13. Vears DF, Tsai MH, Sadleir LG, et al. Clinical genetic studies in benign childhood epilepsy with centrotemporal spikes. Epilepsia. 2012;53:319-324. 14. Loiseau P, Pestre M, Dartigues JF, et al. Long-term prognosis in two forms of childhood epilepsy: typical absence seizures and epilepsy with rolandic (centrotemporal)
EEG foci. Ann Neurol. 1983;13:642-648. 15. Nolan MA, Redobaldo MA, Lah S, et al. Memory function in childhood epilepsy syndromes. J Paediatr Child Health. 2004;40:20-27. 16. Auvin S, Pandit F, De Bellecize J, et al. Benign myoclonic epilepsy in infants: electroclinical features and long-term follow-up of 34 patients. Epilepsia. 2006;47:387-393. 17. Panayiotopoulos CP. Inhibitory effect of central vision on occipital lobe seizures. Neurology. 1981;31:1330-1333. 18. Sadleir LG, Farrell K, Smith S, et al. Electroclinical features of absence seizures in childhood absence epilepsy. Neurology. 2006;67:413-418. 19. Panayiotopoulos CP. Obeid T, Tahan AR. Juvenile myoclonic epilepsy: a 5-year prospective study. Epilepsia. 1994;35:285296. 20. Caplan R, Siddarth P, Stahl L, et al. Childhood absence epilepsy: behavioral, cognitive, and linguistic comorbidities. Epilepsia. 2008;49:1838-1846. 21. Pavone P, Bianchini R, Trifiletti RR, Incorpora G, Pavone A, Parano E. Neuropsychological assessment in children with absence epilepsy. Neurology. 2001;56:1047-1051. 22. Matricardi S, Verrotti A, Chiarellil F, et al. Current advances in childhood absence epilepsy. Pediatr Neurol. 2014;50(3):205-212. 23. Callenbach PM, Bouma PA, Geerts AT, et al. Long-term outcome of childhood absence epilepsy: Dutch study of epilepsy in childhood. Epilepsy Res. 2009;83:249-256. 24. Janz D. Epilepsy with impulsive petit mal (juvenile myoclonic epilepsy). Acta Neurol Scand. 1985;72:449-459. 25. Zifkin B, Andermann E, Andermann F. Mechanisms, genetics, and pathogenesis of juvenile myoclonic epilepsy. Current Opin Neurol. 2005;18:147-153.
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