Diagnosis and Management of Childhood Epilepsy

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Diagnosis and Management of Childhood Epilepsy Abdullah Tolaymat, MD,a,b Anuranjita Nayak, MD,a,b James D. Geyer, MD,c,d Sydney K. Geyer, c,d and Paul R. Carney, MDa,b

Epilepsy is a relatively common neurologic disorder in children that has important implications for development, parents, and society. Making the correct diagnosis starts with an accurate and complete history that consequently leads to a directed diagnostic workup. This article outlines a diagnostic and management approach to pediatric seizures and epilepsy syndromes. Making the correct diagnosis of epilepsy or nonepileptic imitators allows the practitioner to prescribe appropriate therapy. Initial management for typical epileptic

syndromes and seizures and potential adverse effects are discussed. Alternative treatment options for pharmacologically resistant patients such as ketogenic diet, vagal nerve stimulation, and surgery are also discussed. While most children favorably respond to antiepileptic medications, early identification of medication failure is important to ensure optimal neurodevelopment.

Diagnostic Evaluation

ruling out epileptic seizures is vitally important because it prevents unnecessary and potentially dangerous tests and treatments. Understanding the disorder also reduces patient and family anxiety and stress. A complete history is usually all that is in most cases necessary to differentiate epileptic seizures from nonepileptic events in children. The constellation of symptoms, from the beginning to the end of the event, helps to confirm or refute a diagnosis of seizures. A sudden onset of symptoms may be shared between epileptic seizures and syncope, but the auras of seizures such as a funny mouth taste, smell, a sense of déjà vu, or upset-like feeling in stomach tend to be different from those associated with syncope. In syncope, typical symptoms consist of lightheadedness, dizziness, and visual loss as if a curtain was being pulled down. Uncontrollable motor activity during the event is more suggestive of an epileptic seizure. In non-epileptic seizures, witnesses may report that an activity can be stopped by an intervention. Postictal symptoms such as drowsiness or amnesia are also more suggestive of epileptic seizures. In general, a complex stereotyped clinical pattern with recurring features and evolution is a strong indicator of epileptic seizures. Although most childhood epilepsies occur with one stereotyped clinical pattern, some severe forms of epilepsy can present with multiple seizure manifestations. Furthermore, brief seizures may not manifest the full pattern seen in a longer seizure. Inpatient video-EEG sometimes assists with characterization of spells and helps to differentiate suspicious non-epileptic events from epileptic seizures. When spells are less

he appropriate management of childhood epilepsy begins with a clinical evaluation that precedes any therapeutic decisions.1 Four diagnostic questions help to determine the clinical management and prognosis as follows: (1) Seizure confirmation —“Are the described or witnessed events seizures?” (2) Seizure classification—“What is the likely neuroanatomical location for the seizure”? (3) Epilepsy classification—“What are the most likely causes or triggers for these seizures?” (4) Syndrome identification—“Do age of onset of the seizures, developmental milestones, neurological exam, EEG pattern, and/or brain imaging fit a typical pattern or syndrome?”

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Seizure Confirmation The initial step in evaluating a child with a possible seizure disorder is confirming that the events are actually seizures rather than another condition that might mimic seizures such as syncope, migraines, tics, sleep disorder, or behavioral events.1 Confirming or From the aDepartment of Pediatrics, University of Florida College of Medicine, Gainesville, FLbDepartment of Neurology, University of Florida College of Medicine, Gainesville, FLcAlabama Sleep Medicine, University of Alabama, Tuscaloosa, AL; and dAlabama Neurology and Sleep Medicine, Tuscaloosa, AL. Curr Probl Pediatr Adolesc Health Care 2015;45:3-17 1538-5442/$ - see front matter & 2015 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.cppeds.2014.12.002

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frequent, an ambulatory EEG can also assist in distinguishing a seizure disorder from a non-epileptic event.

Pediatric Epilepsy/Seizure Classification and Syndromes Seizure classification uses the International League Against Epilepsy's (ILAE) 1981 Clinical and Electrographic Classification of Epileptic Seizures.2,3 This classification approach uses clinical seizure symptoms and manifestations and between-seizure EEG to categorize epileptic events into three categories: partial (focal and local), generalized (convulsive or nonconvulsive), and unclassified.2,4 Partial seizures are further divided into simple, complex, and secondary generalized. Generalized seizures include absence, atypical absence, myoclonic, clonic, tonic, tonic– clonic, and atonic. The category of seizure is of importance when choosing the appropriate antiepileptic medication. In addition to the history and EEG, the physical examination and neuroimaging can be helpful in the classification of seizures and syndrome types. Classification of pediatric epilepsies also follows the ILAE Revised Classification of Epilepsies and Epileptic Syndromes.4 The etiologic categories include idiopathic, symptomatic, and cryptogenic. Structural brain imaging (CT and MRI) functional and metabolic imaging (functional MRI, position emission tomography, and single-photon emission tomography) can also assist with defining the cause. Additional studies aimed at epilepsy syndromic classification include genetic testing, metabolic, and histopathological studies. Recently, the ILAE Commission on Classification and Terminology has revised concepts, terminology, and approaches for classifying seizures and forms of epilepsy in an effort to offer a more clinically useful approach for management and treatment of epilepsy.4 This 2010 classification is largely multidimensional with determination of (1) epilepsy localization, (2) clinical seizure presentation, (3) etiology, and (4) inclusion of related medical conditions. Importantly, these four clinical items parallel the history and data review process during a typical evaluation. Also, this revised classification incorporates the ever-evolving knowledge about epilepsy and takes into account the age of onset as well as the electro-clinical syndromes by age.3 This is important since in most pediatric clinic offices, age of onset is obtainable and can be useful when considering the epilepsy classification in children.

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Treatment Options Goals of Therapy The main goals of epilepsy therapy include complete seizure control, no adverse side effects, and optimal quality of life. Most childhood seizures can be successfully controlled with minimal antiepileptic drug (AED) adverse effects (Table 9). Children who fail treatment after adequate trials of two tolerated, appropriately chosen AEDs fall into the category of treatmentresistant epilepsy.5,6 For these children, clinicians may consider an evaluation for epilepsy surgery or treatment with the ketogenic diet or vagal nerve stimulation.

Indications for Treatment Following a first unprovoked seizure, the risk of a second seizure ranges from 3% to 55% over the next 2–5 years. The risk for seizure recurrence is higher in children with a known cause for the seizure, abnormal examination or brain MRI,7 and seizures during sleep, and an abnormal EEG with epileptiform discharges.8 Treating the first unprovoked seizure reduces the risk of recurrence but does not change the long-term prognosis.9,10 AED therapy is usually not started after the first unprovoked seizure, unless the risk of seizurerelated injury is very high. Following a second seizure, the risk of further seizures is between 80% and 90% within 2 years without treatment. For this reason, most clinicians will recommend treatment after the second seizure or after the first seizure in cases in which the risk for recurrent seizures is high.11

Selection of Anticonvulsant Medication The choice of the first AED is determined by the type of seizure disorder and patient-specific factors. Patientspecific factors include the type of seizure disorder, age, epilepsy syndrome, as well as co-morbidities, gender, and ability to swallow. In addition, the clinician must consider AED-specific factors including the efficacy of the drug in general as well as the efficacy of the drug for specific epilepsy syndrome or seizure class. Pharmacokinetics and idiosyncratic factors, teratogenicity, chronic toxicity, and carcinogenicity should also be considered when choosing an AED. The AED's drug toxicity and the child's disease characteristics are considered the most important feature when choosing an AED.12

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The potential success of a particular AED can be estimated based on the US Food and Drug Administration (FDA) indications, systematic reviews, and expert opinions. Results from use in adults may sometimes be used to predict the response in children.13 However, this approach may not apply to all pediatric epilepsy patients,14 and for this reason, AED selection should be individualized. The clinician should consider the strength of these three approaches when determining the best AED for a specific seizure type and individual child. Seizure frequency and severity may also play an important role in determining the best AED. AEDs that can be titrated quickly to therapeutic doses may be preferred especially when a child presents with prolonged generalized tonic–clonic seizures that occur daily. Age at onset and duration of the epileptic disorder may also provide insight into targeted AED treatment options.

are currently under development.18,19 Careful documentation of response to treatment is crucial since in approximately one-third to one-half of children with newly diagnosed epilepsy the first AED fails.6 By tracking the response to AEDs, the clinician can quickly respond by offering an alternative drug if the initial treatment fails. It is not uncommon that seizures follow a circadian pattern, especially in medically refractory generalized epilepsy.20 Seizures often follow a particular pattern or greater seizure susceptibility during particular times of the day or month.21,22 By tracking the diaries as well as the occurrence of seizures during an inpatient videoEEG study, the clinician may find when seizures are more likely to occur. Adjusting the timing and dosing of epilepsy medications around the circadian cycle may make certain AEDs more effective in treating seizures.22,23

Monitoring for Adverse Events

Medication Nonresponders

Most AEDs bring some level of risk for adverse events or side effects. The most common side effects are related to dosing. Dose-dependent side effects are most frequent during the first 4–8 weeks of therapy as the AED is titrated to its initial target dose. To reduce the risk of dose-dependent side effects, AEDs are usually increased slowly over several days to weeks depending on the individual drug. Gastrointestinal symptoms, such as nausea, are the most common side effects and can be resolved by slowing down the titration, taking the drug after meals, or changing the dosing schedule. Since adverse side effects can interfere with efficacy and compliance,15 it is good practice to have the parents complete a validated pediatric epilepsy side-effect questionnaire to help clinicians measure and follow medication side effects over time.16 At present, the only reliable biomarker that predicts idiosyncratic reactions associated with AEDs is HLA-B*1502, which helps to identify children of Asian backgrounds at risk for Stevens–Johnson syndrome from carbamazepine.17 Tracking response to AED treatment is extremely important in order to make informed decisions about dosing after the initial period. Paper dairies or online tracking tools, such as those found at www.epilepsy. com or www.seizuretracker.com, can be very useful to both the parent and the clinician. Portable wrist-worn seizure monitors that can track seizures in real-time and send information via a secure portal to the clinician

The vast majority of children will respond to the initial AED.6 The approach for selecting the second AED in cases of initial failure are the same as when choosing the first AED. As AEDs are added, the risk of adverse side effects without additional efficacy is not uncommon.24 In general, the risk of untoward side effects increases substantially when more than three AEDs are used simultaneously. Knowledge about AED drug–drug interactions is important, especially in enzyme-inducing and enzyme-inhibiting properties. In cases in which the child is not responding to the initial AED, the clinician should reassess why monotherapy failed in the first place. Reaffirming the diagnosis of epilepsy, an evaluation of non-epileptic seizures, nonadherence issues, and possible triggers may help to guide future management. A common cause for nonresponders is nonadherence. It is estimated that during the first 6 months of treatment after initial diagnosis, more than 50% of children with newly diagnosed epilepsy are noncompliant.25 Education about their condition, addressing bias to treatment, and access to follow-up may help to address nonadherence.

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Medication Discontinuation After 2 seizure-free years, most clinicians will recommend a trial of antiepileptic medication discontinuation. Medications can be gradually tapered over a

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6-week period. Only one medication at a time should be tapered. Before discontinuing medications, some clinicians may wish to assess the risk of seizure recurrent with a routine EEG. Considering the underlying etiology of syndrome should also be considered when discontinuing medications. For example, discontinuation could be deferred in the case of a child with a symptomatic generalized seizure disorder with an abnormal neurologic exam, EEG, and brain MRI. In contrast, a child who is developing normally and with a normal neurologic exam, EEG, and brain MRI is most likely to experience successful anticonvulsants wean without seizure recurrence.

Typical Childhood Epilepsies Febrile Seizures The most common seizure type in children includes febrile seizures. Epidemiological studies show that approximately 4% of children will have at least one febrile seizure by 7 years of age.26 In the United States, the prevalence of febrile seizures in African American children is 4.2% versus 3.5% in Caucasian children.26 Febrile seizures are convulsions induced by a fever in infants or young children. Febrile seizures are slightly more common in boys than in girls. While febrile seizures are usually benign, they are often “frightening and very upsetting” to parents. Depending on the duration, type, and number of seizures during a 24-h period, febrile seizures can be divided into simple and complex categories. According to the 1999 American Academy of Pediatrics Practice Parameter guideline, a

simple febrile seizure is a generalized seizure occurring in an infant or child between the ages of 6 months and 5 years, lasting less than 15 min and occurring only once in 24 h.27 The three critical elements of febrile seizures are shown in Table 1. Despite being such a common neurological disorder, the pathophysiology of febrile seizures is not known. Several features may interact resulting in a febrile seizure including immature brain development, fever, and genetic predisposition. Febrile seizures rarely occur before the age of 1–3 months, suggesting certain degree of myelination or network maturation is required for the clinical expression of febrile seizures. Since febrile seizures rarely occur after 5–6 years of age, there is a relationship between febrile seizures and brain maturation. Several studies have suggested that there is enhanced neuronal excitability during normal brain maturation.28 A number of factors can contribute to the increased excitability of the immature brain. The high input resistance helps the generation of action potentials and increases excitability results in the tendency of immature neurons to oscillate. In the early postnatal period, GABA exerts a paradoxical excitatory effect in all animal species including primates.29 The resulting lack of GABAergic inhibition increases excitability and can facilitate synchronicity.30 Also, fever is associated with cytokine release. This may increase the susceptibility to febrile seizures.31 Immune factors associated with fever may also modulate neuronal excitability. Genetic factors may play a role in febrile seizure susceptibility, but the mode of inheritance is unknown. These genetic factors may be either exacerbating or

TABLE 1. General characteristics of febrile seizures

Age at first seizure onset Typically between 6 months and 5 years Peak incidence at 18 months Febrile seizures occurring after 4 years account for 6–15% Febrile seizure occurring before 3 months or after 6 years are atypical, and the outcome of these febrile seizures may not be as benign as typical febrile seizures Temperature of the associated fever Both AAP and ILAE definitions did not provide a specific temperature criterion for its diagnosis An axillary temperature of either 438.51C or 437.81C as a simple cutoff level has been proposed as a component of the diagnosis of febrile seizures but is not required at present The majority of children with febrile seizures have rectal temperatures 41021F or 38.51C Most febrile seizures occur during the first day of fever There are no data to support the rate of temperature rise as being more important than the peak temperature achieved Seizures Most common type of febrile seizures are generalized seizures involving both sides of the body Simple partial seizures or complex partial seizures may occur with secondary generalization Partial-onset febrile seizures are usually less benign than generalized febrile seizures

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TABLE 2. Characteristics of simple and complex febrile seizures

Simple febrile seizures

Complex febrile seizures

Generalized tonic–clonic Duration less than 15 min Without recurrence within the next 24 h

Focal Duration more than 15 min Occurring in a cluster of 2 or more convulsions within 24 h

protective against febrile seizures. A positive family history for febrile seizures can be found in 25–40% of patients with febrile seizures, and the reported frequency in siblings of children with febrile seizures has ranged from 9% to 22%. The linkage on chromosomes 2q and 19q associated with the phenotype of febrile seizures, generalized epilepsy (tonic–clonic, absence, and myoclonic) shows evidence of sodium channel involvement. At least five genes have been identified as causal for epilepsy syndromes which include febrile seizures.32 This includes the unique syndrome of generalized epilepsy with febrile seizure plus (GEFSþ) which is caused in most cases by an autosomal dominant defect in cerebral voltage-gated sodium channels subunits (SCN1B, SCN1A, and SCN2A) or a defect in the γ2 subunit of the GABAA receptor.33 The most common genetic loci for febrile seizures include 8q13–q21, 19p, 2q23–24, 6q22–24, and 5q14– q15. Febrile seizures typically exclude seizures with fever in children who have previously had seizures unrelated to fever but do not exclude children with prior neurological impairment. Febrile seizures typically begin with the sudden contraction of muscles involving the face, trunk, arms, or legs on both sides of the body. The force of the muscle contraction may cause the child to emit an involuntary cry or moan. The seizures may be accompanied with loss of consciousness, tongue biting, urinary/bowel incontinence, fall, vomiting, and apnea, followed by postictal sleepiness, confusion, or feelings of fear. Depending on the duration, type, and number of seizures during a 24-h period, febrile seizures can be divided into simple and complex categories (Table 2). Simple febrile seizures are relatively brief lasting less than 10–15 min. Complex febrile seizures are characterized by one of the following features: prolonged duration lasting more than 10–15 min, focal, or with multiple recurrences within a 24-h period. In the context of febrile illness in a neurologically abnormal child, seizures are still considered simple or complex according to the above criteria. Although children who have preexisting neurological abnormalities are more

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likely to suffer from complex febrile seizures and are more likely to develop subsequent epilepsy, they can still have simple febrile seizures. If the febrile seizure lasts longer than 30 min without full recovery between seizures, it is classified as febrile status epilepticus. Febrile status epilepticus accounts for approximately 5% of all febrile seizures (Table 2). Risk factors for a first febrile convulsion have been studied in comparison with age-matched febrile and afebrile controls.34 The risk of a first febrile seizure is about 30% if a child has two or more of the following independent risk factors listed in Table 3. It may be reasonable to offer anticipatory guidance (familiarization with febrile seizures, first aid, and types of management) to families at high risk (Table 3). The initial workup of a febrile seizure should include a thorough history from a reliable witness and a careful pediatric and neurological examination. Meningitis, encephalitis, accidental poisoning, trauma or abuse, electrolyte imbalance, and acute symptomatic seizures must be excluded first. Examination for evidence of meningitis, underlying neurological deficit, asymmetry, or stigmata of a neurocutaneous or metabolic disorder and signs of developmental delay are important. If the cause of fever can be identified and the child presents no disturbance of consciousness, it is usually not necessary to obtain further laboratory evaluation. Febrile seizures are now known to be benign, and less than 3% of children will later develop epilepsy. Therefore, febrile seizures can be viewed as a syndrome of reactive seizures and not as a true epileptic syndrome (Table 4). The management of febrile seizures should focus on seizure first aid, fever control, and parental counseling. Febrile seizures are usually brief and self-limited, with no treatment necessary in most cases. When a seizure occurs, the child should be placed on his/her side on a protected surface and observed carefully. If the seizure lasts longer than 10 min, intravenous diazepam or rectal diazepam should be given to halt the seizure. If the convulsion is prolonged, the child's airway should be kept clear and oxygenation maintained. In the rare event that seizures continue after the initial treatment with diazepam, a diagnosis of febrile status epilepticus TABLE 3. Risk factors for first febrile seizures

A first- or second-degree relative with febrile seizures Delayed neonatal discharge of greater than 28 days of age Parental report of slow development Day care attendance

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TABLE 4. Evaluation of febrile seizures

Lab studies Routine laboratory studies usually are not indicated unless they are performed as part of a search for the source of a fever. Serum electrolytes (particularly sodium), glucose, blood urea nitrogen, calcium, and phosphorus levels should be reserved for children for whom there is a reasonable suspicion that one or more may be abnormal. Patients with febrile seizures have an incidence of bacteremia similar to patients with fever alone, therefore, blood cultures and complete blood count are not routinely necessary. Imaging studies Neuroimaging should not be performed in the routine evaluation of child with a first simple febrile seizure. A CT or MRI should be performed only when an underlying structural lesion is suspected. A CT or MRI should be considered in patients with complex febrile seizures. Neuroimaging might be considered when the child has significant focal neurological abnormalities, developmental abnormalities, neurocutaneous lesions, or abnormal head size. EEG An EEG should not be routinely performed in the evaluation of a neurologically healthy child with a first simple febrile seizure. Lumbar puncture According to the 2011 AAP updated guidelines for febrile seizures evaluation, lumbar puncture must be done in cases highly suspicious for meningitis, and it is also recommended for child aged 6–12 months with a simple febrile seizure if the immunization status is unknown or insufficient for Hib or S. pneumoniae. It is also an option for a child with a febrile seizure who has had previous antibiotic therapy, since such treatment can mask meningeal signs. The incidence of meningitis in children with first seizures associated with fever is 2–5%. Patients who have a first-time febrile seizure and do not have a rapidly improving mental status should be evaluated for meningitis. Risk factors for meningitis in patients presenting with seizure and fever include the following:  a physician visit within 48 h;  seizure activity at the time of arrival in the ED;  focal seizure, suspicious physical examination findings (e.g., rash and petechiae), cyanosis, hypotension, or grunting; and  abnormal neurological examination.

should be made, and the standard status epilepticus treatment protocol is indicated. Optimal management of status epilepticus requires admission to a pediatric hospital. About one-third of all children with a first febrile seizure experience recurrent seizures. Recurrent febrile seizures occur in about 30–40% of patients, usually within a year of the first seizure.35 Predictors of recurrence include age, family history, and duration of illness, and temperature at the time of the seizure. Risk factors can be combined to provide a useful prediction scheme. The recurrence risk for patients with none of the four risk factors (age less than 18 months, family history of febrile seizures, low temperature at the time of the seizure, and short duration of illness) was 4%, with one factor 23%, with two 32%, with three 62%, and with all four 76%. Patients with all four risk factors have greater than 70% chance of recurrence. Patients with no risk factors have less than a 20% chance of recurrence. Febrile seizures are now known to be benign, and only 2–3% of children will later develop epilepsy.26 The risk of epilepsy following a simple febrile seizure is about 2% and following a complex febrile seizure still only 5–10%. Therefore, febrile seizures can be viewed as a syndrome of reactive seizures and not as a

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true epileptic syndrome. Approximately 15% of children with epilepsy have one or more preceding febrile seizures, regardless of the cause of the epilepsy.36 This observation suggests that the tendency for febrile seizure occurrence plays an important role in the creation of an individual person's seizure threshold. However, there is no evidence that one or multiple febrile seizures cause epilepsy.

Benign Neonatal Convulsions Onset is usually during the first week of life. For this reason, this benign newborn seizure type of often called fifth-day fits. Characteristically, benign neonatal seizures debuting during the first week of life are usually focal and have the potential to migrate from one region to another, and they could be generalized, and often accompanied by apneas.37 Apnea may occur with the clonic activity or be the sole manifestation of the seizure. Generalized seizures are less common, and tonic seizures are rare. In general, prognosis is excellent, and subsequent seizures after the newborn period rarely recur. The newborn exam, development, EEG, and brain MRI are usually normal. There is usually no family history of similar seizures.

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Benign Familial Neonatal Convulsions Onset of this seizure type is typically in the first few weeks of life.37 There is often a family history of neonatal seizures, and it is sometimes the key for diagnosis. Benign familial neonatal seizures (BFNSs) are brief but very frequent and difficult to control pharmacologically.38 A voltage-gated potassium channel mutations specifically KCNQ2 and KCNQ3 mutations are responsible for BFNS.39 Electroencephalography at onset shows a burst suppression pattern or multifocal epileptiform activity, but interictally it can be normal. Early MRI of the brain shows characteristic hyperintensities in the basal ganglia and thalamus that later resolve.39 Prognosis is good as most resolve during infancy, but 10–16% of patients develop epilepsy later in life. This condition can be treated with anticonvulsants. Oxcarbazepine is initiated at an initial dose of 20 mg/kg/ day and then titrated to 40 mg/kg/day, which can be later discontinued when the child becomes seizure free and the EEG normalizes.

Generalized Epilepsy With Febrile Seizures Plus Such seizures can be of any class, including generalized tonic–clonic, atonic, myoclonic, absence, or even complex partial. In this subclass of febrile seizures, seizures persist beyond the age of 6 years. There is usually a family history of seizures, and multiple genetic mutations are associated with this syndrome. Inheritance in most cases is autosomal dominant causing defect in cerebral voltage-gated sodium channels subunits (SCN1B, SCN1A, and SCN2A) or a defect in the γ2 subunit of the GABAA receptor.34 Valproate, lamotrigine, levetiracetam, or topiramate may be used for non-febrile generalized seizures, if these are frequent. Prognosis is usually good, but 30% of cases progress to more severe epilepsy.40,41

Myoclonic Astatic Epilepsy (Doose Syndrome) This is a rare generalized seizure disorder.37 The child is developmentally normal until the seizures start.42 They usually have multiple seizure types, the most common of which being the myoclonic astatic type, where there is a jerk followed by a sudden fall forward. More than half of patients have brief absence seizures often together with myoclonic jerks, facial myoclonus, and atonic manifestations. Atonic and

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absence seizures are frequent and sometimes many occur each day. An EEG is helpful in distinguishing this from Lennox–Gestaut syndrome.

Absence Seizures An absence seizure is the most common childhood benign seizure disorder.43 This type of seizures typically begin between 4 and 10 years of age characterized by sudden pauses in behavior, staring, and eye flicker, lasting between 10 and 20 s several times per day. Absence seizures typically have no preceding aura or prodromal, and there is no postictal confusion. The EEG pattern consists of a 3-Hz spike-and-wave complex (Fig).44 Hyperventilation sometimes triggers an absence seizure. The juvenile onset subtype of absence is different from the more common childhood onset absence in that it has onset around puberty. Tonic–clonic seizures are more common in this type, and these frequently occur early in the morning when the child awakens. Absence seizures usually resolve over time by age 10– 20 years. Atypical absence epilepsy usually occurs in children who are neurologically or developmentally abnormal. The juvenile onset type usually persists to adulthood. Ethosuximide is the most effective drug with complete seizure control in about 80%. Lamotrigine and valproate are effective alternatives. Carbamazepine may worsen the seizures and cause absence status.

Juvenile Myoclonic Epilepsy Juvenile myoclonic epilepsy (JME) is a chronic seizure disorder associated with juvenile myoclonic epilepsy. JME seizures typically have no preceding aura but may have a prodromal period of early morning myoclonus, and these myoclonic jerks are brief and bilateral but not always symmetric, flexor jerks of the extremities, which may be repetitive. Consciousness is not impaired so the patient is aware of the jerking movement. Seizures are precipitated by sleep deprivation, alcohol ingestion, flickering light, and awakening from sleep. The seizures may consist of generalized tonic–clonic activity; however, absence seizures may also occur. The postictal phase is variable depending on the seizure type.43 The age of onset of juvenile myoclonic epilepsy is typically 10–20 years. EEG in JME shows bilateral, generalized polyspike-and-wave discharges of 3.5–6 Hz.44 Patients are usually developmentally and neurologically normal.45 The Figure shows typical epileptiform pattern in a teenager with JME.

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Fig. Typical electroencephalographic pattern in a teenager with juvenile myoclonic epilepsy.

Valproic acid, levetiracetam, and lamotrigine are widely used for JME; however, lamotrigine may lead to worsening of the myoclonic jerks, so a small dose of clonazepam can be considered as an adjunctive agent to lamotrigine in this case. Patient with JME are usually developmentally and neurologically normal, but this condition may require lifelong treatment, as JME patients are less likely to outgrow their epilepsy compared to the other types of generalized epilepsies, which tend to have somewhat better prognosis

background is often slow, and the seizures typically generalized.43 Table 5 lists examples of the most common progressive myoclonic epilepsies. The medical treatment of progressive myoclonic epilepsy is usually successful early in the disease course, but as the disease progresses, the medications become less effective and seizures become refractory so different antiepileptic combinations may fail. Prognosis is usually poor, and progressive developmental delay is likely.

Progressive Myoclonic Epilepsy

Infantile Spasms

This family of progressive myoclonic epilepsies (PME) also known as the progressive myoclonic epilepsies consists of a number of loosely related epileptic encephalopathy. These epilepsy subtypes are quite rare and have complex presentations and diagnostic findings. Tonic–clonic, tonic, or myoclonic seizures; progressive mental deterioration; cerebellar ataxia; or involuntary movements are different presentations for this group of disorders. Most of these disorders are genetically based, though sporadic cases have occurred in some cases. The EEG associated with these disorders is variable. The

The seizures associated with infantile spasms or West's syndrome consist of jack-knifing movements

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TABLE 5. Examples of progressive myoclonic epilepsies

Unverricht–Lundborg disease (baltic myoclonus) Myoclonic epilepsy and ragged red fibers (MERRF) Lafora's disease Neuronal ceroid lipofuscinosis (NCL) (also known as Batten's disease) Sialidosis Noninfantile Gaucher's disease Late infantile and juvenile GM2 gangliosidosis Juvenile neuroaxonal atrophy Dentatorubral-pallidoluysian atrophy

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and myoclonus, typically begins between 3 months and 3 years of age and can occur in clusters shortly after waking.46 The EEG consists of a hypsarrhythmia pattern with bursts of asynchronous slow waves, spikes, and sharp waves alternating with a suppressed EEG.47 The clinical features of West's syndrome include infantile spasms and mental retardation, which varies according to the etiology of the spasms. As the child grows, the spasms subside by 2 years of age, and the EEG also changes. An underlying etiology is often identified, including tuberous sclerosis, a history of hypoxic ischemic encephalopathy, and other forms of cerebral insults. More than one-third are idiopathic, and some of this group with prior normal development has a good prognosis of becoming seizure free. However, the majority of children with an identifiable etiology proceed to have motor and cognitive delay. Treatment with ACTH, oral steroids, or vigabatrin is standard practice by most clinicians.48

Lennox–Gastaut Syndrome Lennox–Gastaut syndrome (LGS) is chronic generalized seizure disorder associated with multiple seizure types, delayed development, abnormal neurologic exam, and abnormal EEG and brain MRI.49 LGS typically begins between 1 and 10 years of age. The seizures are typically refractory to medication. Medications such as valproic acid, lamotrigine, rufinamide, or topiramate may prove helpful. Surgical procedures like the vagal nerve stimulator, corpus callosotomy, and high-fat diet (ketogenic diet) usually provide better seizure control and should be considered when antiepileptic medications fail.

Dravet Syndrome Dravet syndrome is a rare disorder associated with SCN1A (α-1 subunit of the neuronal voltage-gated sodium channel) gene mutation.50 A normally developing child develops either partial-onset or generalized clonic seizures. The initial seizures are commonly diagnosed as febrile seizures because they usually occur in association with fever, immunization, or infection. Over time, seizures progress and become more frequent, prolonged, and occur both with and without fever. Myoclonic jerks appear by 2–5 years of age and eventually worsen becoming refractory to antiepileptic treatment.

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Developmental regression along with ataxia appears. Initially the EEG is normal, but eventually generalized spike–wave complexes are seen. The brain MRI may show lower volume and hippocampal sclerosis later on. Valproic acid, clobazam, and stiripentol may help these seizures, while lamotrigine and carbamazepine worsen seizures. Up to 20% of children die mainly due to uncontrolled prolonged seizures or sudden unexpected death in epilepsy, also known as SUDEP.51,52 Phase 3 clinical studies are underway to test to safety and efficacy of cannabidiol.

Partial Seizures—Localization-Related Epilepsy Jacksonian motor seizures are simple partial seizures with no alteration of consciousness. These seizures begin with tonic contractions of the face, fingers, or feet and transforms into clonic movements, which march to other muscle groups on the ipsilateral hemibody. There is no alteration in consciousness, but postictal aphasia may occur if the primary epileptogenic zone involves the dominant hemisphere. Simple partial seizures may involve autonomic functions including apnea, chest pain, cyanosis, flushing, emesis, and sensory, motor, or psychic functions.

Benign Rolandic Epilepsy Benign childhood epilepsy with centrotemporal spikes or Benign Rolandic epilepsy is a common self-limited benign seizure disorder, which usually begins between ages 5 and 10 years. Benign Rolandic epilepsy is transmitted in an autosomal dominant pattern with variable penetrance.44 The clinical features include a single nocturnal seizure with clonic movement of the mouth accompanied by gurgling sounds. Secondary generalization is common while alteration of consciousness, auras, and postictal confusion are rare. The seizures usually resolve by age 16 years and typically have little effect on adult life.53

Temporal Lobe Epilepsy Temporal lobe epilepsy accounts for approximately 70% of partial seizures in adults. In pediatrics, temporal lobe epilepsy can occur in young children, but in general, seizures are first observed in adolescents. A prior history of febrile seizures or head trauma is common. Auras are also common, but not universal and include an array of findings, such as déjà vu, funny 11

taste, or a rising upper gastric sensation similar to the dip felt on a roller coaster. During the seizure, oral or motor automatisms, alteration of consciousness, head and eye deviation, contralateral twitching, or tonic–clonic movements and posturing are common. The EEG often shows temporal area spikes or focal slowing, and brain imaging may show hippocampal atrophy or signal changes. The frequency of aura types by location and auras types is found in Tables 6 and 7, respectively.

TABLE 7. Aura types

Psychical auras

Illusion

Hallucination

Memory Vision

Déjà vu, jamais vu, and strangeness Macropsia, micropsia, near, far, and blurred Advancing, receding, louder, softer, and clearer Depersonalization and remoteness Standstill, rushing, and slowing

Flashbacks Objects, faces, and scenes Voices and music

Sound Self-image Time

Autoscopy

Parietal Lobe Epilepsy Frontal Lobe Epilepsy Frontal lobe epilepsy accounts for  20% of partial seizures. A prodrome is rare. Auras are unusual. The seizures typically consist of combinations of behavior alteration and automatisms of very brief duration. Frontal seizures often have atypical presentations and vary widely depending on the region of the frontal lobe from which the seizures arise. Postictal confusion is rare. The characteristic of frontal lobe seizures by region of onset is listed in Table 8.

Occipital Lobe Epilepsy Occipital lobe epilepsy is rare, accounting for less than 10% of partial seizures. Prodromes are rare with occipital lobe seizures, and auras are unusual. As with the frontal lobe seizures, the seizure characteristics are dependent on the area of the occipital lobe involved. When the striate cortex is involved, there are typically elemental visual hallucinations. Involvement of the lateral occipital lobe results in twinkling, pulsing lights. Seizures arising from the temporo-occipital are usually associated with formed visual hallucinations. TABLE 6. Frequency of aura types by location

Aura type

Temporal (%)

Frontal (%)

Occipital (%)

Somatosensory Epigastric Cephalic General Psychical Visual Auditory Olfactory Gustatory Vertiginous None

5 50 5 10 15 10 10 10 10 10 15

15 15 15 15 5 5 0 0 0 2 40

0 5 5 5 15 50 0 10 10 0 5

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Parietal lobe seizures are also relatively uncommon. They may be seen as simple partial seizures, but they will often propagate. The initial features can include contralateral paresthesia, contralateral pain, ideomotor apraxia, and limb movement sensations. As the seizure progresses and propagates, asymmetric tonic posturing and automatisms may develop.

Landau–Kleffner Syndrome Landau–Kleffner syndrome (LKS) is a rare, invariably progressive, idiopathic-acquired aphasia related to a focal epileptic disturbance in the area of the brain responsible for verbal processing.54 The syndrome typically begins between ages 3 and 10 years with normally acquired language abilities. The child then develops a verbal auditory agnosia and infrequent nocturnal partial or secondarily generalized seizures. Verbal auditory agnosia is particular to LKS and manifests itself primarily in the inability to recognize or differentiate between sounds. It is not a defect of the ear or “hearing” but a neurological inability of the brain to process sound meaning. LKS has a pathognomonic EEG pattern consisting of high-voltage multifocal spikes predominating in the temporal lobes.44 Treatment is usually with valproic acid and benzodiazepines, intravenous γ-globulins, and surgery with variable success.55 The outcome for language and cognitive function depends in part on how early the syndrome is recognized and treated, but over two-third of children with LKS are left with significant language or behavioral deficits.

Epilepsy and Seizures Management Seizure management can be achieved either pharmacologically which is preferred and more efficacious or by nonpharmacologic measures such as resective surgery or ketogenic diet.

Curr Probl Pediatr Adolesc Health Care, January 2015

TABLE 8. Characteristics of frontal lobe seizures by region of onset

Orbitofrontal—blinking or staring and complex automatisms Dorsolateral frontal—tonic eye and head contraversion and simple partial Anteromedial frontal—somatosensory aura, tonic posture, contralateral eye and head version, and frequent generalization Frontopolar—loss of tone and rapid generalization Cingular—“psychotic” appearance, facial expressions of fear and anger, and amnesia Opercular/insular—seizures include gustatory sensation and salivation and complex seizures include gagging, swallowing, chewing, amnesia, and genital manipulation Supplementary motor area—simple motor seizure, vocalizes, somatosensory aura, contralateral tonic posture, tonic eye, and head contraversion

Pharmacological Treatment Options Monotherapy is desirable because it decreases the likelihood of adverse effects and avoids drug interactions, which tend to happen sometimes with polypharmacy. In general, recommendations are to start anti-seizure therapy with a single drug, and most children with epilepsy achieve complete seizure control with monotherapy when using the correct drug for the seizure type. When using more than one drug, it is recommended to change only one drug at a time, because it is impossible to determine which drug is responsible for a beneficial

or an adverse effect if we make several changes simultaneously. The less frequent the doses are, the more compliance rate will be achieved. Table 9 summarizes the most commonly used antiepileptic medications with FDA-recommended doses, therapeutic serum level ranges, and their most common side effects.

Nonpharmacologic Treatment Options Children with antiepileptic medication-resistant epilepsy or ongoing seizures with focal abnormality should be considered for epilepsy surgery. The steps

TABLE 9. Most commonly used antiepileptic drugs

Drug

Pediatric dose (mg/kg/day)

T1/2 (h)

Protein Metabolism binding (%)

Therapeutic Side effects level (mcg/mL)

Carbamazepine

10–30

12–17

75

Hepatic

4–12

Clobazam

36–42

80–90

Hepatic

Ethosuximide

2 years (0.5–1), 2–16 years: 5–40 15–40

Diplopia, ataxia, hyponatremia, rash, liver dysfunction, and dyscrasias Rare rash, sleepiness, tolerance, and ataxia

18–40

0

Hepatic

40–100

Felbamate

45–60

20

25

30–100

Gabapentin Lacosamide Lamotrigine

30–100 200–400 1–15

5–7 13 24

0 15 55

50% Hepatic and 50% renal Renal Renal Hepatic

Levetiracetam Oxcarbazepine

20–60 15–45

6–8 9

o10 40

5–50

Nausea, lethargy, headache, rash, and nephritic syndrome Bone marrow failure (1/3000), liver failure, weight loss, GI symptoms, and rash Dizziness, fatigue, ataxia, somnolence, and rash Syncope, dizziness, and PR interval prolongation Rash, Stevens–Johnson syndrome, diplopia, ataxia, and headache Dizziness, sleepiness, headache, and irritability Sleepiness, dizziness, ataxia, and rash

4–20 3–20

Perampanel Phenobarbital Phenytoin/ fosphenytoin Primidone Rufinamide

2–6 4–8

105 55–140 7–42

95 50 90

Primarily renal 73% Hepatic and 23% renal Hepatic Hepatic Hepatic

5–20 10–45

6–20 6–10

30 34

Hepatic Hepatic

4–12 NA

Tiagabine

0.25–1.25

4–9

95

Hepatic

5–70

Topiramate

5–25

8–30

15

3–25

Valproate

20–60

6–16

80–95

75% Renal and 25% hepatic Hepatic

Vigabatrin Zonisamide

40–100 4–10

9 50–70

0 35

Renal Renal

NA 10–30

Curr Probl PediatrAdolesc Health Care, January 2015

15–40 10–20

50–100

Hostility, ataxia, vertigo, and falls Sedation, irritability, rash, and liver induction Ataxia, rash, sedation, neuropathy, gingival hyperplasia, and hirsutism Sedation, irritability, rash, and impotence QT interval shortening, hypersensitivity, headache, sleepiness, and dizziness Dizziness, somnolence, tremor, and gait difficulty Somnolence, confusion, paresthesias, cognitive disturbance, and anorexia Nausea, tremor, weight gain, hair loss, and hepatic toxicity Vision loss, tremor, fatigue, and weight gain Rash, renal stone, and cross sensitivity with sulfa drugs

13

in the presurgical evaluation of pediatric epilepsy surgery candidates are aimed at identifying the seizure focus and eloquent brain areas. In addition to a detailed history and physical examination, video-EEG and brain MRI studies are done to assess candidacy. Additional studies such as neuropsychological testing, high-resolution MRI of the brain, ictal single-photon emission computed tomography, positron emission tomography/magnetoencephalography/functional MRI, and Wada testing may be obtained as well. The epilepsy presurgical evaluation is followed by an interdisciplinary patient management conference where candidacy for surgery and surgical intervention is discussed, including the need for invasive monitoring and mapping. In general, seizure freedom after surgery ranges from 60% to 70%.56 Children undergoing temporal lobe resections have better outcomes than extratemporal lobe resections. Also, specific pathologies such as benign tumors have better outcomes than malformations of cortical development.57 The vagus nerve stimulator (VNS) is sometimes indicated in pediatric patients over 12 years of age with medication-resistant epilepsy who do not qualify for epilepsy surgery.58 Children with LGS, LKS, and epileptic encephalopathies where medication has failed are the best candidates. VNS consists of an implanted device that provides continuous retrograde stimulation to the left vagus nerve. In addition, on-demand stimulation can be used to activate the stimulator by simply swiping a magnet over the implanted generator.

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VNS has been shown to decrease seizure frequency by 50% in at least one-quarter of children with implanted devices.59 Although the VNS is well-tolerated in most children, the most common reported adverse side effects have included coughing, hoarseness, throat pain, and shortness of breath. The ketogenic diet should be considered in children who do not respond to antiepileptic medications, not surgical candidates, or where surgery has failed.60 The main goal of this diet is to reduce the amount of carbohydrate intake and increase the caloric intake through fat, and increasing ketogenesis. In most ketogenic-diet regimens, the ratio of fat to protein and carbohydrate is usually 3:1 or 4:1. In recent years, a low glycemic index diet or Atkins-type diet has been introduced as a way to improve adherence without compromising the therapeutic benefits.61 Specific epileptic syndromes including Dravet syndrome, Rett syndrome, myoclonic epilepsy, tuberous sclerosis, and infantile spasms may be particularly responsive to the ketogenic diet.62 Prior to initiation of the ketogenic diet, an evaluation for metabolic conditions such as carnitine deficiency or beta-oxidation defects, pyruvate carboxylase deficiency, and porphyria must be assessed as the ketogenic diet may exacerbate each of these disorders.61 Timely and accurate identification of seizures and factors can weigh positively for children with specific epileptic syndromes. Since seizures can be distressing for the child, parents, and primary care provider, it is reassuring to know that most seizures disorders have a

Curr Probl Pediatr Adolesc Health Care, January 2015

positive outcome. For those who have a more serious pediatric epilepsy, optimal management and a favorable outcome will rely in part on patient-specific factors, education, and access to pharmacological and nonpharmacological treatments.

Example Case A 6-year-old boy presented with frequent staring spells, which started 2 months ago. They are now occurring several times a day, lasting between 10 and 20 s. During each spell, he will suddenly stare, stop talking, and remain still. Sometime his eyes roll upward and his lids will flicker. He does not remember the events. After each spell, he immediately returns to his baseline. Development is normal, and birth history is unremarkable. He is an A/B student. His neurologic exam is normal. A routine EEG showed generalized 3Hz spike-and-wave complexes. Hyperventilation provoked a generalized absence seizure associated with the generalized discharges. Childhood typical absence epilepsy was diagnosed, and he was started on ethosuximide. Within 3 weeks, he became seizure free. Over the next 4 months, he exhibited rare breakthrough seizures. His drug levels were measured, and his medication dose was adjusted as his weight increased. After a 2-year period, he became seizure free, the EEG was normal, and the medication was tapered and discontinued with no further seizures.

Comment This case illustrates a common clinical presentation and diagnostic evaluation. The choice of medication was based on his seizure type, EEG classification, and epilepsy syndrome. The decision to taper the medication was based on a 2-year seizure-free period and risk for further seizures. EEG showing typical 3-Hz spike-and-wave complexes during an absence seizure.

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