Update on Pediatric Epilepsy
The understanding of seizures and epilepsy has grown tremendously in the past decade, and many more treatment options have become available. Yet, pediatric epilepsy still remains a great challenge for clinicians to manage. This article describes how seizures and epilepsy are understood and classified today and how to approach the management of patients with seizures and updates the pediatrician on the newest approaches to epilepsy treatment.
Classification of seizures and epilepsy
The International League Against Epilepsy (ILAE) defines a seizure as “a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain” [1]. Diagnosis of seizures and epilepsy largely depends on being able to identify a seizure clinically. However, most seizures are not witnessed by medical professionals, and the diagnosis depends on a caregiver’s description.
Most seizures are characterized by unresponsiveness and eye opening. In fact, eye closure during a seizure is a sensitive indicator of pseudoseizure [2]. In addition, most patients who are having a seizure are unresponsive to painful stimuli. Parents of children with staring spells often say that the child does not respond to his or her name being called. This can be the case even with daydreaming. Parents are often asked to shake the child on the shoulder to see if they can abort the staring. If they cannot, it is more likely to be a seizure.
The ILAE has been working on a revision to the organization of seizures and epilepsy for many years. Their recent report has simplified the classification of seizures (Box 1) [3].
Box 1 Classification of seizures
Data from Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE commission on classification and terminology, 2005-2009. Epilepsia 2010;51(4):676–85.
It is to be noted that the term “focal” is used instead of “partial.” Focal seizures are no longer broken down into “complex partial” and “simple partial”. This terminology was thought to be confusing and misused. It is also to be noted that the use of simple and complex in terms of febrile seizures is completely unrelated to simple and complex partial seizures. Nevertheless, the commission recognizes that it is important to describe any alteration of consciousness as part of a seizure [3].
Absence seizures have been subcategorized further. A typical absence seizure involves an abrupt staring spell often accompanied by eyelid blinking and an abrupt return to responsiveness. There is no prodrome, no loss of tone, and no postictal phase. Often the children will be talking, then stop talking to stare into space for a few seconds, and then resume talking where they last left off. Atypical absence seizures are less abrupt; they last longer and can have postictal confusion. Myoclonic absence is an absence seizure with myoclonic jerks of the head, shoulders, and arms. Prominent eyelid myoclonus followed by absence seizure is also recognized as an absence subtype.
Myoclonic seizures are characterized by brief contractions of the whole body, or isolated parts of the body. A myoclonic jerk followed by the sudden loss of tone of the whole body is known as a myoclonic atonic seizure. Myoclonic atonic and myoclonic tonic seizures while a patient is standing can result in falls and injury.
Clonic seizure consists of rhythmic jerking of the body that can be asymmetric, even in a generalized clonic seizure. Tonic seizures involve sustained muscle contraction, and patients can appear to be in a decerebrate posture. A tonic-clonic seizure usually consists of a tonic phase in which the patient loses consciousness, falls to the ground, and is stiff for less than 30 seconds and then, a clonic phase in which the patient jerks all limbs for longer than 30 seconds, sometimes minutes. Tonic-clonic seizures have a postictal phase in which patients are lethargic and confused for up to an hour, or longer if sedative medications are given.
Focal seizures can consist of myoclonic jerks or can have tonic or clonic components. What distinguishes focal seizures is that they are thought to arise from one hemisphere. Sometimes this origin can be difficult to tell clinically. Also, focal seizures can just have sensory changes, or cognitive changes such as confusion, hallucinations, and staring. Both focal seizures and absence seizures can be described as staring spells, and it can be difficult to distinguish between them.
Infantile spasms are categorized as an “epileptic spasm.” It is unclear whether this type of seizure is focal or generalized, therefore, it has been categorized as “unknown.”
Classification of epilepsy
The epilepsies have a separate classification from seizures. For example, a patient has to have an absence seizure to have absence epilepsy, but patients with childhood absence epilepsy can have other types of seizures as well. Epilepsy describes a propensity for seizures because of an “enduring alteration in the brain” [1]. This alteration can be because of a known underlying structural cause, such as a remote encephalitis, or it can be because of a known epilepsy syndrome. The 1989 international classification of epilepsies categorized epilepsy syndromes as “idiopathic,” “symptomatic,” and “crytogenic” [4]. These terms have been abandoned because of their inaccuracy and inconsistency with new genetic and neuroscience knowledge. The commission now recognizes epilepsies called “electroclinical syndromes” (Box 2). These are a cluster of clinical symptoms and electroencephalographic (EEG) characteristics that appear at certain ages. In addition, there are “distinctive constellations,” which are also recognizable clusters of clinical symptoms but do not have the strong developmental component of the electroclinical syndromes.
Box 2 Electroclinical syndromes and other epilepsies (abbreviated)
Data from Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE commission on classification and terminology, 2005–2009. Epilepsia 2010;51(4):676–85.
It is beyond the scope of this article to describe every electroclinical syndrome, but the author describes a few of the syndromes in the other sections of this article.
Approach to seizures and epilepsy
Evaluation of a child with a seizure should always begin with an assessment of the cardiopulmonary status, including airway, breathing, and circulation. It is common during generalized tonic-clonic seizures for the patient to have increased secretions from the mouth, therefore it is recommended that unconscious seizure patients be placed lying on their side to allow secretions to escape and to prevent aspiration. Although it is not uncommon for parents of a child with seizures to request oxygen tanks to have at home, clinically significant hypoxia during a seizure is rare. Suctioning of the mouth can be helpful, especially in the hospital setting. The blood glucose level is frequently measured by paramedics in the field.
Besides an increase in respiratory secretions, other autonomic changes are frequently noted during a seizure. Most patients with complex partial seizure or generalized tonic-clonic seizures have tachycardia and hypertension. Changes in respiratory rate in either direction are frequent as well. In most seizure patients who have not been given antiepileptic medication, the cardiopulmonary changes are not severe enough to require resuscitation and mechanical ventilatory support. Other autonomic changes during a seizure can include flushing, pallor, sweating, bilateral pupillary dilation, abdominal pain, vomiting, and urinary incontinence [5].
Once it is established that the patient has stable cardiopulmonary status, the patient’s mental status should be assessed. Commonly, the patient is in a postictal state. If the patient had a generalized tonic-clonic seizure, the postictal state is characterized by the ceasing of limb movement, stupor or coma, and normalizing of the heart rate, blood pressure, and respiration. The length of the postictal period is related to the length of the seizure. Generalized tonic-clonic seizures lasting less than a few minutes are usually followed by a postictal stupor or coma of 5 to 30 minutes. The patient can remain depressed for longer, especially if given benzodiazepines to treat the seizure.
In rare cases, a patient who seems to be in the postictal state may be having nonconvulsive seizure activity. This situation is more likely if the original convulsive seizure was prolonged, meeting the definition for status epilepticus. The patient should be observed for normalization of vital signs and for gradual return of responsiveness. An EEG should be considered for patients who remain comatose. Status epilepticus is discussed in a separate section later.
After the patient is stabilized, a complete history and physical examination can be obtained. Questions and examination should be directed in an attempt to determine the cause of the seizure. Table 1 lists the common causes of seizures and the studies that can be done to help confirm the diagnosis.
Table 1 Common causes of seizures
| Cause of Seizure | Suggested Studies |
|---|---|
| Metabolic abnormalities: hypoglycemia or hyperglycemia, hyponatremia or hypernatremia, hypocalcemia or hypercalcemia, hypomagnesemia, uremia, liver failure, hyperammonemia | Basic chemistries, calcium and magnesium levels, liver function tests, ammonia levels |
| Infection: meningoencephalitis, sepsis, neurocysticercosis | Lumbar puncture, send cerebrospinal fluid for appropriate infectious titers/PCR, sepsis evaluation, head CT, MRI with gadolinium |
| Neoplasm, vascular malformation | Head CT, MRI with gadolinium |
| Trauma | Head CT |
| Inherited neurodegenerative disorder | Appropriate genetic testing |
| Toxic causes, drug withdrawal | Urine toxicology screen, ethanol levels, other specific drug tests |
| Perinatal stroke/asphyxia | Head CT, MRI |
| Congenital brain malformation | Head CT, MRI |
| Febrile seizure | Lumbar puncture in selected cases |
| Epilepsy | EEG, antiepileptic drug levels (to check for compliance) |
Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging; PCR, polymerase chain reaction.
With an accurate history and physical examination, few to none of the studies in Table 1 will need to be performed acutely. Conversely, children with known epilepsy should still have investigations into the secondary causes of seizure, such as infection and trauma, if clinically warranted. The main piece of clinical information to obtain is to determine whether the child has returned to his or her baseline neurologic status. These children are only likely to need further studies on an outpatient basis. Children who remain lethargic after an appropriate postictal period need continued monitoring, possible admission, and further studies, such as lumbar puncture for viral encephalitis or subarachnoid hemorrhage or computed tomography of the head for subdural hematoma or hydrocephalus.
All children with a first-time afebrile seizure without an obvious secondary cause such as trauma should have an EEG [6]. EEG can be done as an outpatient if the patient is at the baseline neurologic status when presenting after the seizure. Antiepileptic drug therapy is generally not recommended after a first seizure, but this decision should be individualized [7]. There is no evidence that treating after the second seizure, as opposed to the first seizure, changes the long-term course or prognosis of the patient’s epilepsy.
Antiepileptic drugs
Medications are first line in the treatment of epilepsy. Once it is determined that a child has recurrent seizures, that is, epilepsy, initiating a daily medication in an attempt to prevent seizures is recommended. The choice of medication depends on many factors, including seizure type and syndrome, side effect profiles, forms of administration, drug interactions, underlying medical conditions, and cost.
There are many antiepileptic medications available in the United States. Tables 2 and 3 list the commonly used medications, the year they were made available in the United States, and a recommended dosing range. With the exception of bromide salts, many of the earliest seizure medications, such as phenobarbital and phenytoin, are still in clinical use today. Phenytoin was the first anticonvulsant to be screened through an animal model of epilepsy. Also called the electroshock model, the animal (a cat in the original experiment) was hooked up to mouth and scalp electrodes and given gradually increased electric current until a seizure occurred. The level of current was the cat’s seizure threshold. Then, the cat was premedicated with a test drug. If the drug increased the seizure threshold by an amount comparable to phenobarbital, it was considered for further testing as an anticonvulsant [8]. Drugs undergoing testing at present are screened with rodents through the “maximal electroshock model,” which uses principles similar to the original electroshock experiments in cats [9].
Table 2 Traditional antiepileptic medications
| Medication | Available in the United States | Recommended Dosing Ranges |
|---|---|---|
| Bromide | 19th century | Not currently used for seizures in the United States |
| Phenobarbital | 1912 | 3–5 mg/kg/d, qd to bid |
| Phenytoin | 1938 | 3–9 mg/kg/d, qd to bid |
| Acetazolamide | 1953 | 500–1000 mg/d, bid |
| Primidone | 1954 | Start 50 mg q hour, titrate slowly to 10–25 mg/kg/d tid, maximum 2 g/d |
| Ethosuximide | 1960 | 20 mg/kg/d to a maximum of 1.5 g/d, bid |
| Diazepam | 1963 | Recommended for status epilepticus, not daily prophylaxis |
| Carbamazepine | 1974 | Start 10 mg/kg/d, increase to 20–30 mg/kg/d, bid to tid |
| Clonazepam | 1975 | 0.05–0.2 mg/kg/d, bid |
| Valproic acid | 1978 | Start 10 mg/kg/d, increase to 20–60 mg/kg/d, bid |
Table 3 Newer antiepileptic medications
| Medication | Available in the United States | Recommended Dosing Ranges |
|---|---|---|
| Felbamate | 1993 | 15–45 mg/kg/d, tid |
| Lamotrigine | 1994 | Start 0.3 mg/kg/d, increase to 5–8 mg/kg/d, bid, lower if concurrent valproic acid |
| Fosphenytoin | 1996 | Same as phenytoin |
| Topiramate | 1996 | 1–9 mg/kg/d, bid |
| Levetiracetam | 1999 | 20–60 mg/kg/d, bid |
| Oxcarbazepine | 2000 | Start 15 mg/kg/d, increase to 30–60 mg/kg/d, bid |
| Zonisamide | 2000 | 100–600 mg/d, bid |
| Pregabalin | 2004 | 150–600 mg/d, bid |
| Rufinamide | 2008 | Start 10–15 mg/kg/d to a maximum of 50–60 mg/kg/d, bid |
| Vigabatrin | 2009 | 50–150 mg/kg/d, bid |
| Lacosamide | 2009 | Start 50 mg bid, increase to 100–200 mg bid |
In the early 1970s, the National Institutes for Neurologic Disorders and Stroke started the Anticonvulsant Drug Development program in an effort to screen many more drugs for potential anticonvulsant activity. Thousands of drugs have been screened through the maximal electroshock model as well as other animal models of epilepsy, such as the subcutaneous pentylenetetrazol and kindling models [8]. Drugs developed for the treatment of epilepsy by mass screening through animal models are not designed with a particular mechanism of action in mind. This is partly because not all the mechanisms of epilepsy are known. However, in examining the potential mechanisms of these drugs and potential mechanisms of the animal models in causing seizures and in studying the brains of people with epilepsy, our understanding of the development of epilepsy and the potential targets is rapidly growing.
In a prospective study comparing a traditional antiepileptic drug with a newer antiepileptic drug, there was no significant difference in the seizure remission rate after either drug was given in subjects who completed the study [10]. There are not many trials of head-to-head comparisons between seizure medications, but generally, increased efficacy has not been seen with the newer agents. Always, one-third of patients do not respond to one or more seizure drugs, and these patients are labeled refractory. Generally, however, the newer antiepileptics have a more tolerable side-effect profile.
Medication choice based on seizure type and syndrome
After phenytoin became widely used, it was noted that it did not prevent petit mal seizures very well. Since then, further evidence has demonstrated that phenytoin and carbamazepine, as well as several other drugs, seem to worsen seizures in patients who have an idiopathic generalized epilepsy [11]. These drugs, considered narrow spectrum (Box 3), should be reserved for patients with focal and/or secondarily generalized seizures. They should be avoided in patients with idiopathic or primary generalized epilepsy, which are age-related epilepsy syndromes characterized by generalized spike-and-wave discharges on the EEG, such as childhood absence epilepsy and juvenile myoclonic epilepsy (JME).
Conversely, most of the other antiepileptic drugs as listed in Tables 2 and 3 are considered broad spectrum and therefore have been shown to work against a variety of seizure types. Some exceptions include ethosuximide, which is regarded as first-line treatment for typical absence seizures, but not enough evidence exists to use it for partial seizures.
Medication choice based on potential toxicity
There are many different antiepileptic medications that have the potential to be effective for any particular patient. Often, choices are narrowed down to avoid certain toxicities. For example, many neurologists would not use valproic acid in women of childbearing age because of the association of valproic acid with polycystic ovary disease, obesity, and hyperandrogenism [12].
Box 4 lists some prominent and unique side effects and toxicities of the antiepileptic drugs. The author has not listed headache, dizziness, nausea, abdominal pain, or sedation because these side effects have been reported for every anticonvulsant.
Box 4 Unique side effects and toxicities of antiepileptic medications
The newest antiepileptics
The newest antiepileptics to be approved by the US Food and Drug Administration (FDA) are rufinamide, lacosamide, and vigabatrin. Vigabatrin is discussed in the section on “Infantile Spasms.”
Rufinamide, like many other antiepileptics, affects sodium channels, and in in vitro studies of cultured neurons, this drug has prolonged the inactivated state of the channel. In a randomized, double-blind, placebo-controlled study for Lennox-Gastaut syndrome (LGS), adjunct therapy with rufinamide was found to reduce the number of drop attacks (which can be the most disabling seizure type in LGS) by 42.5% [13]. In the same study, rufinamide also demonstrated a 32.7% decrease in the total seizure frequency over 28 days compared with the 11.7% decrease for placebo. These results are comparable to those of clinical trials for other drugs tried for LGS, namely topiramate, lamotrigine, and felbamate [14]. Based on these results, the FDA approved rufinamide in November 2008 for the treatment of LGS in patients aged 4 years or older. Rufinamide has also been tried in older children and adults with partial-onset seizures showing modest efficacy [14].
Patients who are taking rufinamide are often on other antiepileptics and may have failed several antiepileptics previously. Rufinamide has minimal drug-drug interactions, but, like many other drugs, its level can be decreased by cytochrome P450 inducing seizure medications such as phenobarbital, carbamazepine, and phenytoin. The concurrent administration of valproic acid can increase levels of rufinamide; therefore, caution should be taken when starting rufinamide on patients who are already taking valproic acid. Generally, the starting dose should be lowered and the titration much slower.
The main side effect in the author’s experience has been somnolence, and this is alleviated by a slower titration. In addition, one can consider lowering the dose of other sedating antiepileptics such as topiramate. The author recommends starting rufinamide at 10 to 15 mg/kg/d divided twice daily. The dose is doubled after one week to 20 to 30 mg/kg/d. If there is no improvement, the dose is further increased by 10 to 15 mg/kg/d weekly until a maximum of 50 to 60 mg/kg/d.
At present, rufinamide is available in 200-mg and 400-mg tablets, which are scored and can be cut in half. In addition, the tablets can be crushed for administration through gastrostomy tubes. The manufacturer has applied to the FDA for approval of an oral suspension 40 mg/mL in the summer of 2010.
In 2009, lacosamide was approved for the adjunctive treatment of partial seizures in adults. In a double-blind placebo-controlled trial in which patients were randomized to 4 arms of different dosing (200 mg, 400 mg, 600 mg, and placebo), there was a median reduction of 40% in the 400-mg and 600-mg groups compared with 10% in the placebo group [15]. There were dose-related adverse events that included dizziness, nausea, fatigue, ataxia, headache, diplopia, and nystagmus. Because of these side effects, the clinical recommendation is to start at 50 mg twice daily and increase the dose weekly by 100 mg to a target dose of 200 to 400 mg. The author reports that an even slower titration, 50 mg per week, is better tolerated.
There are not enough data on the efficacy of lacosamide in younger populations. It is approved for patients aged 17 years and older. As with other antiepileptics, it will likely find a place in the treatment of pediatric epilepsy. Advantages of lacosamide include low drug-drug interactions and an intravenous (IV) formulation, with a 1:1 oral to IV substitution.
Infantile spasms
Infantile spasms were first described in the medical literature in 1941 by Dr William James West, whose infant son had a peculiar seizure disorder consisting of rapid flexor jerks [16]. It has since been learned that infantile spasms are associated with a specific EEG pattern called hypsarrhythmia and that infantile spasms can occur in older children. The new ILAE revised terminology has categorized infantile spasms under the term epileptic spasms, and it is unknown whether these seizures are generalized or focal [3].
The triad of infantile spasms, developmental regression or arrest, and hypsarrhythmia is now known as the West syndrome. The possible underlying cause should be searched when an infant presents with this triad of symptoms. Secondary causes of seizures as described in Table 1 should be investigated. A thorough physical examination looking for neurocutaneous and other genetic syndromes should be done. A brain magnetic resonance imaging (MRI) is helpful to look for cerebral malformations, evidence of prior hypoxic-ischemic injury, trauma, or infection. An underlying cause is found in about two-thirds of patients with West syndrome.
The treatment of infantile spasms has been controversial, but adrenocorticotropin and oral steroids showed particularly efficacy when they were tried in the midtwentieth century. Recently, the Infantile Spasms Working Group established recommended guidelines for the treatment of infantile spasms in the United States [17]. Adrenocorticotropic hormone (ACTH) is recommended as first-line treatment based on prospective randomized controlled trials. However, the optimal dose and duration of the treatment is unclear. The side effects of ACTH are severe and worse at high doses. Patients need to be carefully monitored for signs of infection, hyperglycemia, cardiomyopathy, electrolyte abnormalities, and hypertension. There are published protocols for a high-dose and a low-dose ACTH regimen. The high-dose regimen starts at 150 IU/m2 per day in 2 divided doses for 1 week and a careful taper over 10 weeks total. The lower-dose schedule starts at 40 IU/d total, and increases to 60 to 80 IU/d if there is no response after 2 weeks at 40 IU. Because response to ACTH is generally seen after 1 to 2 weeks, it is recommended to taper the dosage after 2 weeks if it has not been effective [18].
Vigabatrin has also been found to be effective for infantile spasms. There is evidence that it works better in patients who have infantile spasms secondary to tuberous sclerosis [19]. As with ACTH, the optimal dose of vigabatrin is not known, although most recommend starting at 50 mg/kg/d, divided twice daily, and titrating up to 100 to 150 mg/kg/d. The use of vigabatrin has been limited because of 2 serious adverse effects: intramyelinic edema and irreversible visual field defects. Edema in the myelin sheaths has been observed in rats given vigabatrin, but not in primates. In infants given vigabatrin for infantile spasm, MRI T2 signal abnormalities have appeared that seem to be dose related and have resolved after treatment is discontinued [20]. It is unclear whether these transient MRI changes are related to intramyelinic edema seen in rats.
Visual field defects were first reported in 1997 [21]. Usually the defects are bilateral and concentric. Further studies have demonstrated retinal injury in the cone system [20]. The pathophysiology of retinal injury is unclear, but up to 40% of patients who have taken vigabatrin are affected, with adults being more affected than children. Because of this adverse effect, the use of vigabatrin is restricted only to physicians who have registered with a program that includes frequent ophthalmologic screening for patients prescribed vigabatrin.
Example case in the management of pediatric epilepsy
Henry is a healthy 13-year-old boy who presents in the pediatric emergency department with a generalized seizure. He had just woken up and was getting dressed when his mother heard a loud bang. She ran into his room and found him lying on his bedroom floor shaking. His eyes were rolled back in his head, and he was unresponsive when she called his name. Paramedics were called, and Henry stopped shaking by the time they arrived. A rapid glucose test showed glucose levels of 120 mg/dL. Henry was groggy but responsive to pain. He woke up further in the ambulance and was awake by the time he was in the pediatric emergency department.
On examination, Henry is afebrile with stable vital signs. He has a scalp hematoma on the back of his head. Henry remembers riding in the ambulance and waking up in his room, but nothing in between. The result of neurologic examination is normal.
On further questioning, Henry and his parents state that over the past few months he has been having brief body jerks. The jerks usually occur in the morning, and he has dropped things from his hands before.
Discussion
As with all acute seizure presentations, once the child is stabilized, an investigation into the cause of the seizure is begun. Because Henry is a previously healthy boy who is neurologically normal and is on no medications, a metabolic condition is not suspected. A urine toxicology screen is sent, and the result is negative. There is minimal suspicion for drug exposure. Because Henry is at his baseline mental status and afebrile, suspicion for meningitis or encephalitis is low. There are no focal neurologic signs, so emergent neuroimaging is not required.
This seems to be a first unprovoked seizure; however, the history of brief body jerks is concerning for myoclonic type seizure. Henry’s age and presentation could fit the electroclinical syndrome of JME. An EEG is recommended to look for 4- to 6-Hz spike and polyspike and wave discharges that are bilateral and symmetric, and classic, for JME. JME is considered a primary generalized epilepsy, therefore the patient should not be placed on narrow-spectrum antiepileptic medications such as phenytoin or carbamazepine. Valproic acid is considered the drug of choice for JME, although if Henry was a girl, another drug might be considered because of the possible increased risk of polycystic ovarian syndrome associated with valproic acid.
If one were confident that the body jerks were seizures, then it would be reasonable to start Henry on valproic acid right away. If Henry weighs 50 kg, the reasonable starting dose of valproic acid is 250 mg administered orally twice daily. It would also be reasonable to wait until the EEG is performed before starting medication.
Status epilepticus
The author has emphasized that the child should be stabilized before investigations are made into the cause of the seizure; however, in status epilepticus, treatment of the seizure, determination of the precipitating cause, and treatment of the cause (if possible) should be done simultaneously. The Epilepsy Foundation of America Working Group on Status Epilepticus has defined status epilepticus as longer than 30 minutes of either continuous seizure activity or 2 or more sequential seizures without full recovery of consciousness between the seizures [22]; however, any continuous seizure should be treated as status epilepticus because there is evidence that the more prolonged a seizure the more difficult it is to control [23].
As stated earlier, seizure management first includes management of the airway. Because metabolic derangements can be rapidly treated, and because seizures caused by metabolic abnormalities are resistant to antiepileptic medication, the level of glucose and electrolytes should be measured right away. An IV line should be placed, but if this proves difficult, medication can be given via the rectum.
Treatment of status epilepticus begins with a benzodiazepine, such as lorazepam, 0.1 mg/kg of which is given via a slow IV push (0.75 mg/min). The drug should be given a few minutes to take effect. If the seizure does not stop, another dose should be given. If there is no IV access, diazepam, 0.3 mg/kg, can be given intrarectally.
If the patient is still having a seizure, fosphenytoin (or phenytoin) is recommended at 20 mg/kg [24]. At this point, the seizure has been continuing for 20 minutes or more. The recommended drugs vary by institution. If the patient is known to be taking valproic acid, a 20-mg/kg load of valproic acid can be given. Another 10 mg/kg of fosphenytoin can be given. Phenobarbital, 10 to 20 mg/kg, can be given, but caution must be taken to observe for respiratory compromise. Often, patients require intubation and mechanical ventilation at this point because they are no longer protecting their airway. Once patients are intubated, IV anesthesia can be administered with a midazolam or propofol drip [24].
Nonmedication epilepsy treatment options
Nonmedication epilepsy treatment options include the ketogenic diet, vagus nerve stimulation (VNS), and epilepsy surgery.
The ketogenic diet
The ketogenic diet, which was reviewed in the previous issue of this journal, is a high-fat low-carbohydrate diet used to treat epilepsy. The goal of the diet is to mimic the metabolic changes of starvation because fasting has been noted since biblical times to reduce the number of seizures in epileptics. The ketogenic diet was developed in the 1920s, but its use decreased as phenytoin and other antiepileptic medications were developed and marketed. In the past 15 years, however, due in part to the efforts of patients and families for whom the standard antiepileptic drugs have not been effective, awareness and use of the ketogenic diet has been increasing.
The classic ketogenic diet has a 4:1 ratio of grams of fats to grams of protein and carbohydrate. For the diet to be effective, a dietician must work with the family to carefully calculate everything that the child ingests. Other diets, such as the modified Atkins diet and the low glycemic index treatment, which are less strict because they have higher amounts of protein and carbohydrate, have been tried and show results similar to the ketogenic diet in small uncontrolled trials [25].
The ketogenic diet is generally started in conjunction with the antiepileptic medications that the child is already taking. There are a few inherited metabolic conditions in which the ketogenic diet would be started as first-line therapy, including glucose transporter 1 (GLUT-1) deficiency and pyruvate dehydrogenase deficiency, and a few conditions in which the ketogenic diet would be absolutely contraindicated, such as primary carnitine deficiency, fatty acid oxidation disorders, and pyruvate carboxylase deficiency. Screening for these conditions should be done before initiating the diet [26].
There are several cohort studies, mostly retrospective, showing efficacy of the ketogenic diet in patients who were already refractory to multiple medication regimens [27]. In a combined analysis of the outcome data in 2000, more than half of the patients had a greater than 50% reduction in seizure frequency, which is a frequently used outcome measure in medication trials [27]. In 2008, the first randomized controlled trial of the ketogenic diet was published [28]. In this study, 145 children were randomized to the diet or no diet for 3 months. On intention-to-treat analysis, 38% of the diet group had a greater than 50% reduction in seizures compared with 6% of the control group (P<.001). Around 7% of the diet group had a greater than 90% reduction in seizures compared with none in the control group (P<.05).
Patients who are on the ketogenic diet need to be closely monitored, both for compliance as well as for side effects. Effectiveness does depend on ketone production, so parents are taught to monitor urine ketone levels. Constipation is the most common side effect of the ketogenic diet, and this can be managed with the usual fiber, stool softeners, and increased fluid regimen. Also, the addition of medium chain triglyceride oil to improve ketosis can help with the constipation because of its laxative properties [29]. Other side effects include vitamin and mineral deficiencies (supplementation is required), kidney stones, and lipid elevation [30].
An international consensus guideline recommends that patients remain on the ketogenic diet for at least 3.5 months before tapering because of inefficacy [31]. If the diet does result in a significant reduction in the seizure frequency, the recommendation is to remain on the diet for 2 years [31]. There is limited information about the long-term use of the ketogenic diet. In a retrospective study of almost 600 children, 12% became seizure free after 2 years on the diet and most of these patients were medication free. However, 13% of these patients eventually had seizure recurrence at a median of 2.4 years after discontinuing the diet. Most of the patients were able to regain seizure control after resuming the diet [32].
Vagus nerve stimulator
VNS was approved by the FDA in 1997 as adjunctive treatment or partial epilepsy in patients aged 12 years and older. It was also approved in 2005 for treatment-resistant depression and is currently undergoing clinical trials for chronic pain, migraine, and even Alzheimer disease.
It is unclear how the vagus nerve stimulator works, but its wide applicability as listed earlier, reinforces the fact that connections from the vagus nerve project widely to the forebrain. Studies in dogs demonstrated attenuation of experimentally induced seizures [33]. Based on these animal studies, a VNS therapy system was developed using a pacemakerlike pulse generator.
The generator is implanted subcutaneously in the upper left part of the chest, and bipolar leads are tunneled up the neck and attached to the left vagus nerve. The left vagus nerve is used because it has fewer sinoatrial fibers than the right vagus nerve. The generator provides intermittent electric stimulation at programmable preset intervals. For example, the device can be set to 30 seconds of “on time” and 5 minutes of “off time.” During the 30 seconds of on time, electric current is delivered at a certain preset frequency and pulse width. The VNS runs continuously 24 hours, 7 days a week, turning on every 5 minutes until the settings are changed or until the battery runs out. At typical stimulation settings, the battery lasts 7 to 10 years [34].
The VNS system also comes with a small strong magnet that can be worn on the patient’s wrist. The magnet activates the stimulator and provides a current that is usually set higher and longer than the baseline current that is given around the clock. This on-demand stimulus is meant to interrupt or shorten an ongoing seizure. Usually, the magnet is used by a caregiver because the patient does not have the capacity to use it during a seizure.
Physicians can check the device and change the settings with a programming wand that is connected to a hand-held computer. The wand is placed over the generator on the patient’s chest and can detect signals through clothing. The physician can set the proportion of on time to off time (known as the duty cycle) as well as change the current, frequency, and pulse width. The device does not allow high-enough settings that could lead to severe pain and nerve damage [35].
The vagus nerve stimulator was tested in 2 double-blind clinical trials in which patients were randomized to receive high-stimulation versus low-stimulation parameters. Both studies showed a reduction in seizure frequency by half in about 30% of subjects in the high-stimulation group [36,37]. Patients on VNS followed up for 12 months continued to show improvements, with additional patients demonstrating a significant reduction in seizure frequency [38].
Similar to the ketogenic diet, vagus nerve stimulator therapy is recommended for patients who have failed traditional antiepileptic medication treatments (usually at least two drugs). Contraindications for VNS implantation include prior left cervical vagotomy and underlying cardiac or pulmonary disease. Side effects include changes in voice, cough, and dyspnea. These side effects are generally mild, well tolerated, and stimulation dependent. Therefore, the settings can be lowered if the side effects are intolerable. Surgical problems such as wound infections, fluid accumulation at the generator site, and unilateral vocal cord paralysis are very rare.
Epilepsy surgery
A detailed discussion of epilepsy surgery is beyond the scope of this article. Generally, referrals for surgery are made after it is determined that a child has a focal epilepsy and is not responding to antiepileptic medications. Also, it is recommended that patients who have a resectable epileptogenic lesion should be referred to surgery before VNS or ketogenic diet therapy [31,39]. Medical centers with expertise in epilepsy surgery have the capability with prolonged video EEG monitoring and PET scanning to detect small epileptogenic foci, such as cortical dysplasias, that may be amenable for surgical removal.
Summary
Seizures and epilepsy in children remain challenging to manage. Newer classification reflects the more sophisticated understanding of the genetic, anatomic, and neurophysiologic bases of seizures and epilepsy syndromes. Seizure management includes knowledge of emergency procedures and awareness of a broad differential diagnosis. Epilepsy management requires knowledge of the numerous electroclinical syndromes and high familiarity with the many drugs that are available. Although many patients remain refractory, with rapid advances in elucidating the animal models of epilepsy, it is to be hoped that drug mechanisms and nonmedication treatment options will free more patients from their seizures.
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