Eric   Kossoff

Tough seizures: 
        When the first anticonvulsant fails 

 Children with epilepsy can usually achieve seizure control,         but not always with the first medication prescribed. General pediatricians         can learn from a child neurologist's approach to this problem.       

Your patient, a 6-year-old girl with infrequent generalized               tonic-clonic convulsions but "staring and nonresponsive spells"               multiple times each day, continues to have events despite high doses               of carbamazepine. When you increase the dose even further she becomes               ataxic and sedated. What should you do next?

Another patient, a 15-year-old girl with seizures for the past               year, continues to have events despite high doses of valproic acid.               All her events happen in the early morning on the school bus and               have never been witnessed by her parents. Her electroencephalogram               (EEG) has been normal three times and a magnetic resonance imaging               (MRI) scan done the week before was also normal. What is your next               step?

Last, a 9-year-old boy with daily seizures has not responded               to high doses of carbamazepine that you have prescribed. His parents               describe focal jerking of his left side with all seizures, and an               EEG shows right temporal sharp waves consistently. An MRI scan is               normal. How should he be treated now?

"We believe your child has epilepsy." Very little in pediatrics can be         as terrifying to parents as that statement, often said after a child has         had two or more seizures.

 The term "epilepsy" invokes thoughts         of loss of control over all body functions and unpredictability. For thousands         of years, patients with seizures were seen as demonically possessed. Over         the past 150 years, however, the emergence of both the EEG and anticonvulsants         has revolutionized our understanding of epilepsy and our ability to treat         it. The growth in the number of available anticonvulsants, including a         dramatic increase in options during the past decade (Figure 1), has enabled         most children with epilepsy to obtain seizure control without any interference         in normal home and school functions.       

 Despite so many options, the decision to start anticonvulsant therapy         remains a complicated one. After a single, unprovoked, nonfebrile seizure,         the risk of recurrence is approximately 30%.

 Once a second         seizure occurs, the risk of a third seizure more than doublesto         70%.

 However, even with this increase in incidence and even         after two seizures, many variablesincluding patient compliance,         severity and frequency of seizures, epilepsy syndrome if present, and,         of course, parental preferenceinfluence the decision to treat.       

 The choice of many parents to defer use of an anticonvulsant is an understandable         one. All anticonvulsants can cause side effects, both modest (sedation,         rash, ataxia) and severe (Stevens-Johnson syndrome, hepatotoxicity). The         ability to drive a motor vehicle safely is a consideration in the decision         to use an anticonvulsant in an adolescent, but it is not an issue with         a child. In addition, most children are well supervised, especially when         bathing or swimming although pediatricians should still remind parents         of the need for close supervision because of the possibility of another         seizure. Moreover, seizures, while bothersome and occasionally prolonged,         do not cause brain damage or learning disability.

 When anticonvulsant therapy is started, most children respond to the         first agent chosen. In adults, approximately 50% respond to the first         drug with total seizure control, 90% of whom do so with only a modest         dosage.

 Child neurologists often pick anticonvulsants based         on the child's age, seizure type (generalized vs. partial), side effect         profile, and epilepsy syndrome if known (for example, absence, benign         rolandic, juvenile myoclonic epilepsy). The EEG can be very influential         in this regard.

 Frequently, children can be tapered off         medication after several years without seizures, as many will "outgrow"         their seizures. That is especially true with certain epilepsy syndromes,         such as benign rolandic and absence epilepsy.       

 A small percentage of children with epilepsy are described as "intractable."         The definition of this varies: from failure to respond to one drug to         failure to respond to multiple agents.

 Pediatricians are certainly         capable of managing children who have had only a few seizures, especially         if they have responded successfully to the first anticonvulsant prescribed.         If, however, a child begins to have breakthrough seizureseven after         doses of the antiepileptic drug have been maximizedthe primary care         pediatrician should refer the patient to a child neurologist or epileptologist.         The experience and training of these subspecialists can be invaluable         in the decision-making process.       

 A neurologist who is asked to evaluate a child with epilepsy after the         first medication has failed should, before anything else, confirm three         things: that the child in fact has 

chosen makes sense based on the individual child and his or her seizures;         and, last, that the anticonvulsant actually 

 An algorithm         for approaching these patients is presented in Figure 2.       

 It is always prudent for the specialist         to confirm that the child actually has epilepsy. It is not uncommon for         a child who has been on medications for several years to be referred to         a child epileptologist from a primary care provider or even a child neurologist,         only for the epileptologist to discover that the reason the drugs have         not worked is because the child does not have epilepsy! The differential         diagnosis for nonepileptic seizures is large and varies somewhat depending         on the child's age (Table 1). Repeatedly normal EEGs, events not witnessed         by health professionals or parents, and consistent triggers for events         (such as sleep or stress) should raise a red flag for a nonepileptic cause.         In many cases, anticonvulsants can actually worsen the patient's conditionas         with sleep myoclonus, breath-holding, staring spells, and syncope, for         exampleprimarily because of their sedative side effects.       

Major nonepileptic causes of seizure-like events

 There is no substitute for a detailed history in potential nonepilepsy         situations. Nonetheless, combination video-EEG monitoring over a prolonged         period, though expensive, is often necessary to make the diagnosis. These         children may require several days of monitoring in the hospital after         medications have been withdrawn to "capture" events. At the least, families         can try to video record an event; many families have access to a portable         camcorder. A picture is worth a thousand words, as the saying goes, but         a videotape can be worth a million. Have the parents send a videotape         to your office.       

 Assuming the child is         indeed having seizures, the choice of anticonvulsant should be carefully         evaluated. Does the child have an epilepsy syndrome that was missed? Benign         rolandic epilepsy (nocturnal seizures, often starting in the face unilaterally,         with central-temporal spike waves on EEG) is often exquisitely sensitive         to carbamazepine and less so to other anticonvulsants. Absence epilepsy         (formerly known as petit mal) usually responds to ethosuximide or valproic         acid but may be worsened by carbamazepine.

 Table 2 lists         special indications for the various anticonvulsants.     

Is the seizure more likely to be generalized (entire brain involved at         onset) or partial (one part of the brain)? An initially normal EEG may         lead a neurologist to choose a partial epilepsy agent, because most cases         of generalized epilepsy have an abnormal interictal (between seizures)         EEG. Not all anticonvulsants are equally effective in treating the different         epilepsy types, however, and an anticonvulsant can occasionally make another         type of seizure pattern worse.       

 One of the most common histories         provided to child epileptologists is that the child failed multiple anticonvulsants.         However, a detailed drug history reveals that some of these agents were         tried for only several days and discontinued because of perceived side         effects or lack of efficacy. Most anticonvulsants need several weeks to         show their effectiveness.       

 Another common mistake is considering a drug a failure if the serum         level is in the therapeutic range but there is no seizure control. Because         therapeutic levels were established based on limited data for 95% of adults         in initial clinical trials who had obtained seizure control, the usefulness         of a level is limited. Levels can, however, be useful for measuring compliance         or as a general marker for determining the serum level at which control         was obtained in that individual child. Anticonvulsants should be titrated         up to the level required for seizure control, not just to a "therapeutic"         level; the occurrence of side effects should serve as the limiting factor.         No agent should be discarded as failed until the dose has been maximized.         Each child has a unique metabolism and may require double or even triple         the recommended dose per kilogram of body weight to achieve seizure control.       

 As with any medical condition, adherence can be an issue. Children or         adolescents responsible for taking their own medications should be specifically         asked, occasionally with their parents out of the examining room, if they         are actually taking their medicine. Obviously, no anticonvulsant will         work if it is not taken.       

 In cases where patients are nonadherent, are side effects the major         reason? Sometimes an anticonvulsant can make a child seizure free but         the cost to the child's well- being can make it intolerable. If so, a         change may be in orderas in the case of an overweight adolescent         female who experienced a 20 lb weight gain and hair thinning after being         placed on valproic acid. All anticonvulsants, especially the older agents,         have predictable, often dose-dependent, side effects, which are listed         in Table 2.       

 Fluctuations in the anticonvulsant serum level are a potentially amenable         variable that can be adjusted to make an agent more efficacious and enhance         compliance. Twice daily dosing is much more convenient for families than         dosing three or four times a day. Although the half-life of many agents         is six to eight hours, seizures in children with uncomplicated epilepsy         can often be controlled with bid dosingtid or qid dosing is rarely         necessary. A child with a history of seizure exacerbations before a dose         is due to be given, however, should be switched to more frequent dosing         or to an extended-release formulation (available for carbamazepine, phenytoin,         and valproic acid) before the anticonvulsant is considered to have failed.       

 Once an anticonvulsant has been tried and deemed ineffective, the decision         to either add a second agent or to make a substitution is not clear-cut.         If the dosage of the first agent was escalated but seizure control was         not achieved or intolerable side effects developed, that drug should without         question be discontinued and a new drug substituted. Polypharmacy has         its share of problems, including the increased risk of drug interactions         (for example, the combination of valproic acid and lamotrigine causes         rash; carbamazepine decreases levels of many other anticonvulsants), side         effects, and teratogenicity.

 It is certainly tempting simply         to continue to add drugs when a child is having persistent seizures, but         it can be counterproductive in the long run. In a recent consensus guideline         of epilepsy experts, approximately 90% thought that a second attempt at         monotherapy (substitution) was preferable to add-on therapy.

         Even after a second drug failed, physician preference for trying a third         agent or for using a combination of therapies was about equal.

 When a child has some positive response to the first medication but         is experiencing the "law of diminishing returns," it might be beneficial         to continue the drug at a dose that does not cause side effects and add         a second agent for combined effect. A recent study in adults showed a         slightly higher chance of improvement in seizure control, without a worsening         of side effects, by adding a second agent (26% seizure free) compared         with making a substitution (17%).

 When adding a second drug,         it may be preferable to use an agent from a class whose mechanism of action         is different from that of the original medication (Table 3).

         Specifically, using the combination of a sodium channel blocker and a         drug with more than one mechanism of action may be idealsuch as         lamotrigine and valproic acid, or carbamazepine and topiramate.

         In addition, certain drug combinations, such as lamotrigine and valproic         acid, have a synergistic effect, making their sum greater than their parts.       

The decision to slowly increase the dose of a new drug to a standard         level before tapering the initial drug, rather than tapering it immediately,         is a matter of style not science. Even if the first agent did not seem         to have benefit, suddenly tapering it without having another anticonvulsant         on board may precipitate an increase in seizures. Slowly tapering medications         over four to six weeks seems to be the ideal.       

 Once the decision to try a new agent is made, the number of choices         available can seem overwhelming. Over the past decade, the number of available         anticonvulsants has doubled. This growth has both improved the options         for children with epilepsy and made deciding which anticonvulsant to use         more difficult.

 Older anticonvulsants, such as phenobarbital, carbamazepine, valproic         acid, and phenytoin, have been used for decades, are well-studied, and         can often be considerably less expensive than newer agents. They come         in multiple formulations, including extended-release preparations, capsule         sprinkles, chewable tablets, oral suspensions, and even intravenous solutions.         For these reasons, most neurologists use these older drugs as first-line         medications. On the other hand, many of the newer agents, such as gabapentin,         oxcarbazepine, and lamotrigine, have fewer side effects and fewer drug         interactions, and may have additional benefits for pain and migraine.

 In one large study, approximately 50% of patients became seizure free         with the first anticonvulsant chosen. But, when the drug failed, only         11% became seizure free (without intolerable side effects) with a second         agent.

 With such discouraging results, the physician always         needs to consider in the back of his or her mind whether a child who fails         the first agent is potentially a candidate for surgery. Epilepsy surgery         can range from relatively small resections such as lesionectomy to larger         operations such as temporal lobectomies and hemispherectomies. Recent         evidence in adults suggests that, after one year, surgery is superior         to medical management when an epileptic focus is located in the temporal         lobes.

 The study found that 58% of these surgical patients         were seizure free at one year, compared with 8% in the medical group.         Evidence from children and even infants is equally strong, with approximately         60% seizure free with surgery.

 Surgery should be strongly considered when several drugs have failed,         there is a single epileptogenic focus, and that focus is located in a         functionally silent cortex. Most epilepsy experts consider surgery after         three antiepileptic drugs tried as monotherapy or at least one combination         trial has failed.

 Resection of an epileptogenic focus can         save a child from years of medications with potential side effects and         can be curative rather than solely suppress seizures. New neuroimaging         technologies and surgical techniques have improved outcomes in even the         most difficult cases.       

 The following options should be reserved for children with intractable         epilepsy who do not have a clear structural lesion amenable to surgical         resection.       

 is a high fat, adequate protein, low carbohydrate         diet that has been used for the treatment of intractable childhood epilepsy         since the 1920s.

 The diet mimics the biochemical changes         associated with starvation that have been well-documented to reduce seizures.

         Typical meals include eggs, bacon, heavy cream, tuna, and mayonnaise,         without breads and sugars and only limited fruits and vegetables. Calories         and fluids are carefully measured by weighing foods. Urine ketones are         checked frequently to monitor efficacy. The ketogenic diet was used less         often from 1940 to 1990 than previously because of the increased availability         of anticonvulsants such as phenytoin and carbamazepine, but it has reemerged         recently as a viable therapeutic option.

 Although difficult         to adhere to, the diet can result in a more than 50% reduction in seizures         in half of children with epilepsy that is hard to control.

Well-established         side effects include constipation, limited weight gain, and kidney stones         (5%).       

 With VNS, approved for use in         1997, a small metal device is surgically implanted in the chest and wires         are connected to the vagus nerve, which is then electrically stimulated         periodically. It is postulated that this stimulation then travels toward         the thalamus, causing a desynchronization of seizure discharges and thereby         preventing seizures. VNS also has the benefit of allowing patients to         abort seizures by holding a magnet over the device to induce stimulation.         Although expensive, VNS has been shown to be efficacious for refractory         epilepsy in children.

 Side effects include periodic voice         hoarseness.       

 As with any complex disorder in a pediatric patient, having a well-educated         parent is a definite advantage. There are many books and World Wide Web         resources available for parents and children to read, with easy-to-understand         information (see "

For patients and their parents: Resources         about epilepsy

"). In addition, the Epilepsy Foundation, through         its local chapters, will advocate for children with mild to severe epilepsy         who are having difficulty with school or any other issue.       

 With many new anticonvulsants (and nonpharmacologic therapies) available,         a majority of children with epilepsy can have seizure control without         compromising quality of life. Key points to remember in caring for children         with this condition are listed in the box on the left.       

 The author gratefully acknowledges the assistance               of Dr. Eileen P. Vining, Dr. John M. Freeman, and Heather D. Hladky,               RN, in editing this manuscript before submission.            

1.	Commission on epidemiology and         prognosis, International League Against Epilepsy: Guidelines for epidemiologic         studies on epilepsy. 

 	2.	Shinnar S, Berg AT, O'Dell C, et al: Predictors         of multiple seizures in a cohort of children prospectively followed from         the time of their first unprovoked seizure. 

 	3.	Hauser WA, Rich SS, Annegers JF, et al:         Seizure recurrence after a first unprovoked seizure: An extended follow-up.         

 	4.	Musico M, Beghi E, Solari A, et al, for         the First Seizure Trial Group (FIRST Group): Treatment of first tonic-clonic         seizure does not improve the prognosis of epilepsy. 

 	5.	Shinnar S, Berg AT: Does antiepileptic         drug therapy prevent the development of "chronic" epilepsy? 

 	6.	Kwan P, Brodie MJ: Effectiveness of first         antiepileptic drug. 

 	7.	Shinnar S, Berg AT, Moshe SL, et al: The         risk of seizure recurrence following a first unprovoked afebrile seizure         in childhood: An extended follow-up. 

 	8.	Hirtz D, Ashwal S, Berg A, et al: Practice         parameter: Evaluating a first nonfebrile seizure in children: Report of         the quality standards subcommittee of the American Academy of Neurology,         The Child Neurology Society, and The American Epilepsy Society. 

 	9.	Crumrine PK: Antiepileptic drug selection         in pediatric epilepsy. 

 	10.	Guerrini R, Belmonte A, Genton P: Antiepileptic         drug-induced worsening of seizures in children. 

 	11.	Ferrendeli JA: Pharmacology of antiepileptic         drug polypharmacy. 

 	12.	Karceski S, Morrell M, Carpenter D: The         expert consensus guideline series: Treatment of epilepsy. 

 	13.	Kwan P, Brodie MJ: Epilepsy after the         first drug fails: Substitution or add-on? 

 	14.	Pellock JM, Appleton R: Use of new antiepileptic         drugs in the treatment of childhood epilepsy. 

 	15.	Cutrer FM, Silberstein SD, Mathew NT,         et al: Antiepileptic drugs in migraine, cluster headache, and mood disorders.         

 	16.	 Mellegers MA, Furlan AD, Mailis A: Gabapentin         for neuropathic pain: Systematic review of controlled and uncontrolled         literature. 

 	17.	Kwan P, Brodie MJ: Early identification         of refractory epilepsy. 

 	18.	Wiebe S, Blume WT, Girvin JP, et al:         A randomized, controlled trial of surgery for temporal-lobe epilepsy.         

 	19.	Saneto RP, Wyllie E: Epilepsy surgery         in infants. 

 	20.	Swink TD, Vining EPG, Freeman JM: The         ketogenic diet: 1997. 

 	21.	Lennox WG: Ketogenic diet in treatment         of epilepsy. 

 	22.	Geyelin HR: Fasting as a method for treating         epilepsy. 

 	23.	Lefevre F, Aronson N: Ketogenic diet         for the treatment of refractory epilepsy in children: A systematic review         of efficacy. 

 	24.	Freeman JM, Vining EPG, Pillas DJ, et         al: The efficacy of the ketogenic diet-1998: A prospective evaluation         of intervention in 150 children. 

 25. Valencia I, Holder DL, Helmers SL, et al: Vagal         nerve stimulation in pediatric epilepsy: A review. 

DR. KOSSOFF is assistant professor, neurology and pediatrics, The         Johns Hopkins Hospital, Baltimore, Md.

 Based on the description of her events, this 6-year-old         girl may have absence seizures. An EEG reveals three-per-second spike-and-wave         discharges diffusely. You discontinue carbamazepine and begin valproic         acid. Within two weeks, her staring spells vanish.       

The 15-year-old girl with events on the bus is         brought in for video EEG monitoring. During her admission she has two         events of full body tremors with apparent nonresponsiveness despite a         normal waking EEG. These events are thought to be nonepileptic (pseudoseizures).         Her valproic acid is discontinued and she is referred for psychological         evaluation and therapy.       

The 9-year-old boy with stereotyped left focal         seizures and right temporal abnormalities is admitted for video-EEG monitoring.         His carbamazepine is tapered and he has four seizures, all of which originate         from the right midtemporal lobe. His carbamazepine is restarted and lamotrigine         is initiated. Further investigation (including positron emission tomography         scan, magnetic resonance spectroscopy, and subdural grid electrode implantation)         is considered, given that he is a potential surgical candidate if lamotrigine         and, perhaps, a third agent fail.       

For patients and their parents: Resources about epilepsy       

Articles

Children with epilepsy can usually achieve seizure control, but not always with the first medication prescribed. General pediatricians can learn from a child neurologist&s approach to this problem.

Eric Kossoff

Articles

Tough seizures: When the first anticonvulsant fails