New Hope for Children with Epilepsy

DOUGLAS R. NORDLI, JR, MD

aFall 2000

Epilepsy is  derived from the Greek verb meaning “to seize upon” and is synonymous with seizure disorder. A seizure is the manifestation of abnormal brain electrical activity that causes momentary alterations of behavior. Epilepsy may be caused by a variety of pathologic processes that interfere with normal brain function. In most cases, these processes cannot be precisely identified and the condition is referred to as idiopathic.

Seizures occur with a high rate in children, and epilepsy is one of the most common chronic conditions treated by pediatric neurologists. The cumulative incidence of epilepsy in the United States through age 24 years is 1.2%. Seizures occur more frequently in the first year of life, nearly five times as frequently as in adults up to the age of 65.

Recent work has shown that in the majority of children a single seizure is not a harbinger of epilepsy. Instead, these children have single isolated seizures that are the result of an acute disturbance of brain function rather than the manifestation of a persistent underlying pathologic process. A minority of children go on to have recurrent seizures of one or a variety of types, and these children may be properly considered to have epilepsy.

Of these children with epilepsy, 20% have an intractable condition, defined as a failure to respond to two well-chosen antiepileptic drugs. In addition to having uncontrolled seizures, these children are at increased risk for cognitive, behavioral, and psychiatric disturbances. Their care is complex, but recent advances offer many opportunities to alleviate seizures, markedly enhance their quality of life, or both. This requires sophisticated diagnostic testing procedures, unique therapeutic resources devoted to children, and a well-coordinated multidisciplinary approach.

Until recently, Chicago and its environs has had comparatively little in the way of this type of resource for children with epilepsy. Dr. Leon Epstein, director of neurology at Children’s Memorial Hospital, realized the need and made the development of Children’s Epilepsy Center a high priority. (Dr. Epstein’s efforts, along with those of the hospital’s leaders, including CEO Pat Magoon, laid the groundwork for the center. Also key was the foresight and generosity of the Woman’s Board, which provided much-needed financial support.)

ACCURATE DIAGNOSIS

The first step in the approach to the patient with intractable epilepsy is to accurately diagnose the nature of the problem. In order to better understand epilepsy and to improve its treatment a uniform system of classifying epileptic seizures was developed in 1964 by a special commission of the International League against Epilepsy; the system was revised in 1981.

Seizures were classified as either partial or generalized. Partial seizures arise from specific focal regions of the brain; generalized seizures are widespread at the onset. Partial seizures may be further divided into those in which consciousness is fully maintained (simple partial seizures) and those where consciousness is impaired or lost (complex partial seizures). Alteration of consciousness may occur as a result of extension of the seizure discharge to deeper limbic structures. Partial seizures may also evolve into generalized seizures (secondarily generalized seizures). In infants and young children it is difficult to accurately assess alteration of consciousness so rigid adherence to this classification scheme is not always possible.

A seizure is only one manifestation of the underlying brain disturbance, and a better understanding of the child’s condition can be gleaned from careful consideration of other factors including age of the child, results of physical examination, imaging studies, and electroencephalograms (EEGs). This information may be brought together to form an epilepsy syndrome diagnosis, which aids in the determination of prognosis and guides diagnostic studies. Knowledge of the proper epilepsy syndrome diagnosis allows the clinician, in conjunction with the child’s family, to make a rational decision whether to treat with antiepileptic medication and if so, what medication to use.

Accurate diagnosis of an epilepsy syndrome may be difficult for a variety of reasons. Health care professionals have usually not witnessed the seizure, but are relying upon descriptions from other observers, including parents, baby sitters, and siblings. These individuals are in a very distraught state at the sight of the child’s first few seizures. Parents are often more concerned about whether their child is breathing than subtle details of seizure semiology. Yet, it is the earliest and sometimes most subtle features of the seizure that allow accurate determination of its true nature. Clues to a focal or partial onset include auras, often of a vague or “indescribable” nature; deviation of the eyes to one side prior to generalization; unilateral fumbling movements of the hand (automatisms); asymmetric tonic postures (stiffening); or asymmetric clonus (rhythmic jerking). A mislabeling of the seizure type will point towards the wrong epilepsy syndrome.

In other circumstances, the seizure type and interictal brain wave (EEG) abnormalities do not agree. This is sometimes due to a sampling phenomenon. Routine EEGs may not demonstrate characteristic abnormalities in between the seizures, or may show findings only in certain times of the day. Light stages of sleep are provocative and will elicit epileptiform abnormalities: spikes and sharp waves.

In a minority of children, even multiple recordings fail to capture these characteristic markers of an epileptogenic susceptibility. Even when these abnormalities are captured, their interpretation may be difficult owing to the age of the patient. The organization of normal and abnormal features of the EEG is highly dependent upon the child’s age. Very young children have less synchronization of activity between the two sides of the brain and cannot manifest generalized discharges. Generalized paroxysmal discharges, like generalized spike-wave discharges, are the hallmark of a generalized epilepsy. Instead of manifesting these discharges, the EEGs in children with a generalized form of epilepsy will often show focal or multifocal abnormalities early in life. The absence of generalized spikes can create confusion as to the true identity of the epilepsy.

DIAGNOSTIC ADVANCES

Closed circuit television/electroencephalographic (CCTV/ EEG) recording in a specially equipped inpatient unit is the procedure of choice to aid in these circumstances. Monitoring is very valuable because the paroxysmal spell in question is recorded, not just the EEG in between the events. This allows unambiguous documentation of non-epileptic events, corrects erroneous epilepsy syndrome diagnoses, and localizes the source of ictal activity. The ability to establish precise electrical-clinical correlations and localize epileptogenic foci for resective surgery has been responsible for the proliferation of specialized monitoring units around the world.

Children’s Memorial Hospital has recently installed a four-bed, state-of-the-art CCTV/EEG unit. Unlike most units where the patient’s image is recorded on a VHS tape, Children’s unit is completely digitized so that the patient’s image is recorded directly on a computer hard drive and later edited so that selective samples are “burned” onto a CD. The concurrent EEG is also digitized, which allows reconstruction of the data in many different formats or montages. Digitization of both the video and EEG information facilitates review, allowing the electroencephalographer to analyze every minute of the patient’s study and to focus on the relevant portions. Digital images can be rapidly edited, manipulated, stored, and retrieved. This is critical because the emphasis in intensive monitoring is on the paroxysmal behavioral events not interictal activity.

The diagnostic yield using this approach is 80%, and the need for it is prodigious. Children’s unit was projected to record 40 patients in the first year; instead it has recorded more than 100 patients in the first four months of operation and is on-target to surpass estimates of its fifth-year productivity in the first year. Clearly, families in the Chicago area have acutely needed the technology.

Accordingly, when the unit moves to its permanent location on the third floor of the hospital, revised plans call for a total of eight CCTV/EEG units, two of which will be dedicated to neonatal recordings. Coordinating these efforts are Dr. Kent Kelley of the epilepsy center, Dr. Mark Wainwright of neurology, and neonatology division head Dr. Robin Steinhorn. Dr. Wainwright, also recruited by Dr. Epstein, is keenly interested in neuroprotection, which is particularly relevant to neonates suffering from asphyxia.

IMAGING ADVANCES

Like skull films, CT is now nearly obsolete when MRI is available. The main reason for this is that the lesions seen in children with epilepsy are often subtle and relate more to mild disturbances of cortical formation than to gross destructive lesions with mass effect. In addition, CT scans are prone to bone artifact from the middle cranial fossa and orbital apices, thereby obscuring large portions of the most epileptogenic portions of the brain: the temporal and inferior frontal lobes. CT is limited to the axial plane unless the patient is laboriously re-positioned or computer-assisted reconstructed images are generated, and some subtle abnormalities, to be appreciated, must be viewed in the proper plane.

Reconstructed CT images lack the clarity and definition of MRI sagittal or coronal images. In contrast to the CT, there are many different sequences to use with MR imaging, allowing one to customize the MR to the clinical problem. These sequences reveal abnormalities that often appear isodense on CT. Finally, CT requires ionizing radiation with all of its inherent concerns. Even in emergency room visits, CT should play little or no role in the evaluation of the child with new onset epilepsy.

For all these reasons, MRI is the neuroimage of choice for children with seizures. Standard T1, T2 weighted and proton density images allow detection of various focal lesions in both surgical and non-surgical candidates, but coronal images through the temporal lobe, orthogonal to the axis of the hippocampi, can provide additional helpful information, particularly with regard to the mesial temporal lobe structures. High resolution axial inversion recovery sequences markedly aid the detection of cortical malformations like cortical dysplasia. Children’s neuroradiology department, under the direction of Dr. Sharon Byrd, uses all of these specialized sequences and MR spectroscopy in the evaluation of children with intractable epilepsy.

Concomitant with the arrival of the epilepsy center, Children’s neuroradiology department has added functional MRI to the list of available scanning techniques for children with epilepsy. Neuropsychologist Dr. Frank Zelko has developed a series of protocols to identify speech areas and is refining protocols that may isolate other cognitive functions. This procedure takes advantage of small changes in the blood oxygen concentration during normal brain activities to image the critical areas involved in certain tasks like hand movement, speech, and visual processing. This information can be superimposed upon the brain image to localize the area and to determine its relationship to the epileptogenic cortex. This is an invaluable aid in surgical planning and with other advances will likely supplant the need for invasive recording electrodes.

NEW MEDICATIONS

There has been a flurry of drug development in recent years that has resulted in the successful introduction of a number of new agents: fosphenytoin (Cerebryx), felba-mate (Felbatal), gabapentin (Neurontin), rectal diazepam (Diastat), lamotrigine (Lamictal), sustained release forms of carbamazepine (Carbatrol, Tegretol XR), topiramate (Topamax), intravenous valproate (Depacon), tiagabine (Gabatril), oxcarbazepine (Trileptal), zonisamide (Zonegram), and leviteracetam (Keppra).

These agents aid treatment in several different ways and complement the older antiepileptic medications. Some offer pharomokinetic advantages allowing BID dosage, others introduce new means of delivery, including rectal and intravenous administration. Recently the pharmacy committee expanded the approved use of two of these—rectal diazepam and fosphenytoin—to include all areas of the hospital. Several drugs have novel mechanisms of action, and early experience indicates that they help children who are refractory to older agents. Many of the new drugs have improved side effect profiles compared to their older counterparts. Several of the newer medications cause less sedative, behavioral, and cognitive problems.

Far more children with seizures are overtreated with multiple ineffective agents than undertreated with appropriate ones. Therapy should always begin with a single drug, even in children with more than one seizure type. If the first agent is ineffective, or produces unacceptable side effects, then a second drug should be added with a clear plan of weaning the first. If not, it is very easy for the child with difficult-to-control epilepsy to ultimately be on three or more medications. This rarely helps seizure control, but pharmocodynamic interactions intensify the cumulative toxicity on the central nervous system.

The pediatrician bears a special responsibility for helping the child and family adjust to living with a chronic disorder. Drug, surgical and diet treatments are important, but these are clearly only one aspect of what must be a comprehensive therapeutic approach. The pediatrician is the best person to coordinate and advocate for the child’s overall health and too often gets pushed to the side as the complexity of the evaluation and treatment builds in children with intractable epilepsy. One challenge for the epilepsy center is to see that this does not happen. Good communication with referring physicians is a key aspect and focus of the center. (At Children’s Memorial, much of this essential communication in the epilepsy center is directed by office coordinator Clara Samaniego.)

DIET

The ketogenic diet was first introduced in 1921 when the only effective antiepileptic medications were phenobarbital and bromides. It is remarkable that scores of years and dozens of new drugs later, the diet still has a role in the management of children with intractable epilepsy. It works against all seizure types, but is most effective in treating epilepsies with myoclonic seizures and is more useful in younger years when the brain’s ability to extract ketone bodies is higher. The necessary restrictions are stringent, but the diet can be well-tolerated and easily maintained once families understand its principles.

The mechanism of the anticonvulsant action of the ketogenic diet probably relates to the formation of increased cerebral energy reserves. Stable and sustained ketosis seems to be the most important factor. Consequently, skilled dietitians such as Jill Reynolds at Children’s are instrumental in providing variety and palatability to the diet. It is important to recall that the diet may have adverse effects, including serious, potentially, life-threatening complications.

Dietary therapy is begun in the hospital to allow strict supervision of the initial phase of treatment. The parents should be closely involved in food preparation and the testing of urine for ketone bodies. After 24 hours of fasting, the child is place on a high-fat diet in which the ratio of fats to carbohydrates and protein combined is 3:1. Daily caloric requirements are initially estimated at 75 to 80 kcal/kg. Of this total, protein must be present in an amount that will ensure growth, usually 1.5 g/kg/d. Supplemental B and C vitamins, calcium, and iron are necessary because the diet is deficient in these requirements, but preparations without carbohydrates must be selected. We also give 10,000 IU of vitamin D each week. The ratio of fats to non-fats may be increased to 4:1 and beyond if inadequate ketone body production is noted. Anticonvulsant drugs may be reduced or eliminated entirely if the diet is effective.

SURGERY

A subset of children with intractable epilepsy will not respond to any of the above treatments, and surgery represents their only chance of cure. Surgical treatment should be considered early in children with medically intractable epilepsy, deteriorating cognition, or diseases that are notoriously catastrophic. We consider seizures medically intractable if children are incapable of living a normal life as a result of seizures or their treatment. We require evidence of two to three appropriate antiepileptic drugs trials pushed to maximally tolerated doses. This typically takes only six months to a year to establish and allows time for the natural history of the disorder to declare itself. Prompt referral to a comprehensive epilepsy center facilitates the evaluation, which begins with a CCTV/EEG study. The study is used to determine the seizure type and epilepsy syndrome. If the child suffers from a localization-related epilepsy, then the findings often help to indicate the epileptogenic region and target the region of interest for specialized MR images. In certain cases, functional imaging will determine the relationship between the epileptic cortex and various regions subserving critical brain functions.

Epilepsy surgery is functional neurosurgery, where the goal is not to remove a life-threatening lesion, but ultimately to improve the quality of the patient’s life. Children in whom surgery is considered must have a reasonable expectation either of seizure elimination or substantially fewer disabling seizures that translates into improved quality of life. There should be minimal risk of losing neurological function.

A very accurate knowledge of the location of the lesion, its relationship to eloquent cortex, the psycho-social circumstances, and the functional integrity of the remaining cortex helps to determine the potential risks and benefits of the procedure. Detailed neuropsychological, nursing, psychiatric and social work assessments are necessary. These findings are reviewed at a weekly case conference with members of the comprehensive team. Children’s neurosurgical division, headed by Dr. David McLone, is already one of the most prestigious services in the country and one of the busiest. Epilepsy surgery, under the direction of Dr. John Grant, adds another important service to the division. In cases in which tumors are producing seizures, the epilepsy center assists the brain tumor center, and Dr. Tadanori Tomita in mapping out the epileptogenic and eloquent cortical areas.

Focal cortical resection is the most common procedure performed in children with intractable epilepsy with or without a demonstrable lesion. If a lesion is evident on imaging studies, good results may be obtained by removing the lesion, sometimes with a small amount of adjacent tissue. Many of the anterior temporal lobectomies performed in children with uncontrolled partial seizures have been for tumors or cerebral dysgenesis; mesial temporal sclerosis is less often an indication for temporal lobectomy in children than in older adolescents and adults. Intraoperative electrocorticography may help define the margins for functional resections; somatosensory evoked potentials and electrical stimulation of the cortex are used to map vital sensorimotor and language areas. In children older than five or six years, preoperative intracarotid amobarbital (Wada test) is used to anesthetize each hemisphere selectively to determine language dominance and memory competence.

Hemispherectomy is indicated for children with seizures arising from multiple regions of a hemisphere that is severely dysfunctional. These children typically have a hemiparesis that is most marked in the hand and, often, have hemiatrophy as well. Most have hemisensory loss and visual field defects. In such patients, neurological function is not noticeably worsened by hemispherectomy. Causes of these severe unilateral epilepsy syndromes include epilepsia partialis continua (Rasmussen’s syndrome), hemimegalencephaly, and large porencephalic lesions resulting from strokes that occurred in infancy. In a large series from the Montreal Neurological Institute, 82% of patients became seizure-free, and none lost the ability to walk.

Another surgical procedure used in children with intractable epilepsy is corpus callosotomy, which is a palliative, not curative, procedure. The indication for this procedure is largely restricted to children with severe astatic and secondarily generalized seizures that result in frequent self-injury. Most children have a static epileptic encephalopathy (e.g., Lennox-Gastaut syndrome). Typically, the anterior two-thirds of the corpus callosum is sectioned first; the callosotomy is completed only if seizure control remains unsatisfactory.

Vagal nerve stimulators, introduced recently at Children’s by Dr. C. Stack and Dr. John Grant, are another possible option for palliative treatment. Implanted in a child’s chest, they periodically send an electrical current to the vagal nerve in the neck. The stimulus ascends to the brain and influences the cerebral cortex in such a manner that the seizure threshold is temporarily raised. In one pediatric study, six of 16 children experienced a greater than 50% reduction in seizure frequency during the tenth to twelfth month of treatment with vagus nerve stimulation. More pediatric controlled trials are needed to fully assess the efficacy and safety of this treatment.

OTHER CHALLENGES

Children with epilepsy face many challenges. Usually, the seizures themselves receive the most attention from parents and health care professionals, and these become the focus of office visits and communication between the physician and the family. Sadly, other very important coexistent problems get short shrift, and children are unintentionally left to deal with these vexing issues independently. Ironically, long-term studies have indicated that the vast majority of children enter into seizure remission, but these other issues, including schooling difficulties, attention problems, behavioral disorders, psychiatric conditions, and deficient self-esteem likely contribute to a profound effect on the individual’s ability to achieve their lifetime goals. Indeed, children with epilepsy are two to four times less likely to finish secondary education, marry, have children, and be employed.

A comprehensive approach to the child with epilepsy can improve these dire statistics by attending to these important co-morbid factors. To do this properly requires a team of professional, dedicated individuals with unique skills and perspectives on normal child growth and development. The comprehensive epilepsy center has a dedicated social worker, Sarah Mass, and a pediatric nurse practitioner, Christine Corns, to aid in these critical aspects.

We firmly believe that these challenges can be best addressed in a facility dedicated exclusively to the care of children, like Children’s Memorial Hospital.

Copyright © 2008 by Children’s Memorial Hospital. All rights reserved.