INTRACTABLE PEDIATRIC EPILEPSY
When seizures are not well controlled with a single standard antiepileptic drug (AED), there can be several reasons:
(1) The epileptic condition has not been appropriately classified, resulting in the use of an AED that does not provide
optimal seizure control.
(2) The epileptic condition has been accurately classified and the choice of AED is appropriate, but the AED has not been
increased to achieve full therapeutic effect. Some patients can tolerate supratherapeutic blood levels without side effects.
(3) The problem is not an epileptic condition but rather a paroxysmal movement disorder, psychogenic seizure, sleep disorder,
or other nonepileptic condition. Antiepileptic drugs do not provide relief and some may even exacerbate the underlying condition.
(4) The patient has a medically refractory seizure disorder.
A comprehensive epilepsy program is the best place to refer a child and family for a seizure disorder that is not easily
controlled with AEDs. A comprehensive epilepsy program recognizes that a child with medically intractable epilepsy and their
families have complex and diverse problems that cannot be solved by a single person or physician. The problems are not just
medical, they are also emotional, developmental, educational, social, psychological, economic, and marital.
In a comprehensive epilepsy program, a multidisciplinary team approach is utilized with coordinated services of Pediatric
Neurology, Child Psychiatry, Pediatric Neurosurgery, Pediatric Neuropsychology, Speech and Language, Electroencephalography,
Neuroradiology and Nuclear Medicine. Child Psychiatry is available to assist families with difficult psychiatric and behavioral
problems associated with epilepsy. Clinical nurse specialists can assist with the coordination of the patient services, often
acting as care coordinators. They also provide needed education to families about epilepsy, antiepileptic medications and
their side effects, driving regulations, and safety considerations. Pharmacists can obtain antiepileptic drug histories from
patients, answer questions about antiepileptic medications, provide tapering schedules and initiation schedules for antiepileptic
drugs to parents, and assist physicians with questions they might have about specific drugs and their interactions with other
medications. Social workers are also a critical part of the team , providing families with avenues for financial assistance,
helping families with the myriad of insurance forms that they so often face, assisting and advocating for school and educational
issues, providing adjustment counseling and support to child and families, assisting families with lodging and meals during
the child's evaluation, and assisting with transitional services from hospital to home environment. In addition, networking
is an essential part of the program. Parents are put in touch with other families with similar histories.
In any comprehensive epilepsy program, appropriate classification of a paroxysmal event is the crucial first step in the
evaluation of a child with poorly controlled seizures. Often, the history will provide the most pertinent information. If
the classification is incorrect and the reported seizure is nonepileptic (such as a motor tic, paroxysmal movement disorder,
confusional migraine, or breath-holding spell), discontinuation of the AED may be all that is necessary .
If the event is felt to be a seizure disorder, the history combined with interictal EEG may lead to the diagnosis and the
initiation of the appropriate AED. Sometimes, a short inpatient evaluation using EEG monitoring with video telemetry is necessary
to properly classify the event. Inpatient EEG monitoring may be suggested, therefore, for the following reasons:
(1) Differentiation of epileptic seizures from pseudoseizures, movement disorders, breath holding spells, or sleep disorders
(2) Classification of seizure type according to the International Classification System, resulting in an adjustment in
AEDs
(3) Determination of seizure frequency in order to determine efficacy of AED therapy or to determine the role of subtle
seizure activity in behavioral problems, developmental delays, and /or educational difficulties.
(4) Electrographic recognition of specific epileptic syndromes, some of which may not require AED therapy.
The principles of AED management, as discussed in previously, are utilized. If the standard AEDs have been ineffective,
one of the new FDA approved drugs may be used, alone or as adjunctive therapy as discussed earlier in this article. Comprehensive
epilepsy programs also have investigational drug studies.
Most children who have epilepsy, if their seizures are appropriately classified and the proper AED has been selected, are
seizure free and lead fairly normal lives. The goal in most children is to achieve a seizure free state. The prevailing theory
is that, at least with the non-benign localization related epilepsies, recurrent seizures result in stimulation of aberrant
synaptic connections that result in the continuation of the epileptic condition. Recurrent seizures may sometimes stimulate
additional epileptogenic foci--the kindling theory.
There are a small, but significant, number of children whose epileptic condition is intractable despite appropriate classification
and AED selection. These children do not do well developmentally due to the prevailing epileptic encephalopathy. These children
should be referred to a comprehensive epilepsy program for consideration of epilepsy surgery.
PEDIATRIC EPILEPSY SURGERY
The chances of antiepileptic medication controlling epilepsy rapidly decreases with successive trials of antiepileptic
medication. Specifically, if a patient has been tried on two separate antiepileptic drugs without seizure control, the chances
of a third medication working is less than 10 percent. This has prompted epileptologists to look for new avenues of therapy.
Epilepsy surgery has existed since the late nineteenth century. Wilder Penfield (1891-1976) was a neurosurgeon who dedicated
his career to the study of epilepsy and focal cortical resections. His early operations for epilepsy were based on the study
of the clinical seizure pattern extended by cortical mapping and stimulation, as well as recognition of the importance of
scar tissue from trauma or infection in creating an epileptogenic focus. Penfield performed the first temporal lobectomy for
epilepsy. His seminal research in epilepsy and epilepsy surgery has greatly enhanced our ability to surgically treat patients
with intractable seizures. However it has only been in the last fifteen years that epilepsy surgery has become the standard
of care for some epileptic conditions in adults.
In children, more and more physicians are recognizing that medically intractable childhood epilepsy can also be treatable
by epilepsy surgery. It is best conducted at a center with years of experience and with a multidisciplinary team approach.
Surgery should be considered in the following cases:
1. Failure of standard AED therapy, i.e., medical intractability. This doesn't require two years of treatment or a trial
of all of the standard AEDs. Pediatric epileptologists are in the process of redefining medical intractability in children.
Specifically, catastrophic seizure disorders, such as can be produced by Sturge-Weber syndrome and hemimegalencephaly, require
early intervention. Continuation of the epileptic encephalopathy induced by these conditions results in significant morbidity.
2. Seizures severe enough or frequent enough to interfere with quality of life.
3. Lack of suitable investigational drugs.
4. Absence of diffuse neurodegenerative process. Tuberous sclerosis is an exception. Some patients with tuberous sclerosis
have a highly epileptogenic CNS tuber that can be surgically resected.
5. Developmental decline in the face of intractable seizures.
6. Localized or lateralized epileptogenic focus by EEG, MRI scan or PET scan. A generalized seizure disorder (infantile
spasms as an example), however, may not preclude surgical intervention.
Children require special consideration when being considered for epilepsy surgery. The nature of children's seizure disorders
is different than adults. They have benign seizure disorders as well as catastrophic seizure disorders. It is crucial to separate
out the benign seizure disorders. In addition, the effects of intractable seizures are more costly and detrimental. We know
that intractable epilepsy produces an "epileptic storm" that has long term consequences in the developing brain, including
deficits in learning, memory, and behavior. The early months of infancy are a time of rapid brain development with neuronal
reorganization and synaptic arborization. Windows of developmental opportunity are missed if surgery is delayed and an epileptic
encephalopathy is allowed to persist. The psychological sequelae of intractable epilepsy are also significant, including low
self esteem, poor academic performance, and severe behavioral disturbances. These problems are probably the result of a combination
of factors - the underlying CNS abnormality, the repetitive seizures, and the AEDs used to treat the epilepsy. Therefore,
in children, whose potential for recovery from surgery is excellent, early prompt intervention with epilepsy surgery is crucial,
particularly with the catastrophic seizure disorders.
The most common brain disorders that may be treatable by cortical resection include:
1. Infantile Spasms 2. Sturge-Weber Syndrome 3. Hemimegalencephaly 4. Congenital porencephalic cyst 5. Rasmussen's encephalitis
6. Focal cortical dysplasias 7. Temporal lobe abnormalities
As described earlier in the text, there is a subset of patients with intractable infantile spasms who have an underlying
focal cortical dysplasia that acts as the generator for the hypsarrhythmia EEG pattern and clinical infantile spasms. Preliminary
data suggest that surgical removal of this abnormality results in the cessation of the seizures and an improvement in developmental
outcome.
Sturge Weber syndrome is characterized by venous angiomatosis of the leptomeninges over one hemisphere with ipsilateral
facial angiomatosis, resulting in the "port wine stain" on the face. The prognosis is variable, being better in unihemispheric
lesions. At its worst, however, it produces progressive hemiparesis, cognitive impairments, and intractable seizures. When
Sturge-Weber syndrome follows this course, early hemispherectomy in the first few years of life results in resolution of the
seizures. The neurologic deficits produced by hemispherectomy include permanent field cuts and hemiparesis. However, when
compared with the known deterioration that occurs without surgery, these deficits are tolerable. Some children are cognitively
normal after surgery.
In the same vein, hemimegalencephaly and congenital porencephalic cysts accompanied by intractable seizures are best treated
by hemispherectomy. Rasmussen's encephalitis, characterized by progressive hemiparesis, epilepsia partialis continua, and
cognitive impairments, has also been treated with hemispherectomy. Recent studies have suggested that autoimmune mechanisms
play a role in the pathogenesis of Rasmussen's encephalitis. Specifically, autoantibodies acting as GluR3 agonists may activate
an "excitotoxic cascade" resulting in tissue injury and inflammation. Initial trials of plasmapheresis and intravenous gammaglobulin
were encouraging but long term efficacy has not yet been demonstrate. Nonetheless, future research may provide us with a medical
therapy rather than a surgical option for this disorder.
A patient with intractable seizures who has a focal temporal lobe abnormality should have a temporal lobectomy along with
amygdalohippocampectomy. Examples would include (1) mesial temporal sclerosis, (2) hippocampal atrophy, (3) ganglioglioma
or other tumor in the temporal lobe, (4) focal cortical dysplasias in the temporal lobe. Extratemporal focal cortical dysplasias
or tumors are more common in children than adults. Stereotactic lesionectomies have been reported to render patients seizure
free in 50-60%. In one study from our center, involving children and adults, stereotactic lesionectomy alone resulted in a
significant reduction in seizures (>90%) in approximately 75%. If the surrounding epileptogenic zone is removed as well,
using electrocorticography, the success rate has been reported to be as high as 90%. Some patients with tuberous sclerosis
have one highly epileptogenic tuber that can be surgically excised with a marked improvement in seizure control.
The pre-surgical evaluation in children with intractable seizures relies heavily on the identification of appropriate candidates,
a multidisciplinary team approach, and the confluence of historical, EEG, MRI, PET (positron emission tomography), and SPECT
(single proton emission computerized tomography) data in order to properly localize the epileptogenic focus (94). In children,
as in adults, the computerized prolonged EEG monitoring with video telemetry which captures the ictal and interictal events
must be intelligently interpreted along with MRI scan or PET/SPECT data in identifying the epileptogenic focus for surgical
resection. As an example, in patients with infantile spasms, the ictal EEG usually shows a generalized burst of polyspike
activity followed by a marked attenuation in the background. Interictally, the EEG usually shows multifocal spikes. As mentioned
above, there is a certain subset of these patients who have underlying focal cortical dysplasias, which act as focal generators
for the generalized, multifocal epileptogenic disturbances. The MRI scan can, with application of new techniques, identify
the underlying focal cortical dysplasia . The PET scan classically shows hypometabolism of the dysplastic/epileptogenic region
interictally. In some cases, a retrospective analysis of the EEG data shows one or both of the following patterns: (1) the
most active epileptogenic focus is located in the region of the focal cortical dysplasia and/or (2) nonepileptiform background
asymmetries exist in the area of focal dysplasia. In these patients with focally generated infantile spasms, the identification
of an area of structurally abnormal cortex is critical. Preliminary data suggest that resection of the zone of cortical abnormality,
utilizing PET scan data combined with electrocorticography, results in cessation of the infantile spasms and improvement in
developmental outcome.
Similarly, in a patient with intractable localization related epilepsy, an identifiable structural lesion on MRI scan is
as good as, or better than, the results of prolonged EEG monitoring. Other functional studies may add to the evidence that
the identified structural lesion is the source of the epileptogenic activity. These functional studies include:
(1) FDG - PET will show hypometabolism interictally/hypermetabolism ictally in the epileptogenic region (2) SPECT - Preliminary
studies with ictal SPECT indicate that it can help identify the focal onset of seizures. Ictal hyperperfusion occurs at the
site of the epileptic focus (98). (3) Cortical evoked potentials - they are reduced in the abnormal hemisphere. (4) Sodium
thiopental test will often show a paucity of beta activity in the affected area. At times, particularly if there is a discrepancy
in the data or if there is no one specific anatomic lesion on the MRI scan, invasive monitoring with electrode strips or depth
electrodes may be necessary in order to properly identify the epileptogenic focus. The golden rule is "Never ignore the lesion".
In our experience, a lesionectomy even in the face of widespread EEG abnormalities, will produce a dramatic improvement in
seizure control. The lesionectomy obviates the need for invasive monitoring.
Once the epileptogenic focus is identified, an assessment must be made as to whether surgery might result in significant,
unacceptable neurologic deficits. In our pediatric series, lesionectomies performed in areas of eloquent cortex have not resulted
in significant neurologic deficit. Children also have a remarkable capacity to recover from epilepsy surgery, especially children
less than six years of age. Hemispherectomies performed in the first few years of life will result in a functional hemiparesis,
not hemiplegia, with the only significant neurological deficit being poor hand function and visual field deficits. Additionally,
electrocorticography with awake stimulation can help predict the neurologic deficits and avoid unacceptable risks. Older patients
(greater than 8 years old) with intractable localization-related epilepsy who undergo epilepsy surgery often will have an
intracarotid sodium amytal test (Wada test) prior to surgery. This test was designed to chemically ablate one hemisphere selectively
in order to identify if the ipsilateral hemisphere is speech dominant and if the contralateral hemisphere supports functional
memory. A failed Wada test may prompt the surgeon to do a modified surgical procedure, electrocorticography during surgery,
or no surgery.
In summary, epilepsy surgery offers new hope for children and adolescents with medically refractory epilepsy. Surgery offers
the prospect of (1) control of seizures, (2) prevention of further brain injury induced by the epileptogenic abnormality and
repetitive seizures, (3) prevention of the psychological sequelae of intractable epilepsy, and (4) improvement in overall
quality of life. In a prospective study of 100 children with medically intractable complex partial seizures, 33% continued
to have seizures and were dependent on outside care; 33% continued to have seizures but were capable of living independently;
30% had significant psychiatric disabilities.
Pediatric epilepsy surgery must be conducted in centers with experience in this area. A multidisciplinary team approach
provides the coordination of care and support for families that is critically needed during this time. The ramifications of
intractable epilepsy are far-reaching - including psychological disturbances in the child, poor learning with inadequate school
performance, financial burdens to the family, insurance problems, and parental guilt. A multidisciplinary team approach helps
the family unit cope with the consequences of intractable epilepsy and guides the family unit through the surgery and postoperative
adjustment phase into a better future.
