Epilepsy Updates

Find information on current epilepsy issues such as new drugs, devices, research findings, and other topical issues.

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February 2008

AEDs and Bone Disorders

David G. Vossler, M.D.
Epilepsy Center at Washington Neuroscience Institute
Renton, Washington

The long-term use of some antiepileptic drugs (AEDs) may cause bone disorders. These can include short stature, abnormal teeth, and osteoporosis. Osteoporosis is a condition where the density of calcium in the bone is substantially decreased. This leaves bone protein and a smaller amount of calcium behind, and results in brittle bones which can break more easily. Bone fractures (especially, hip) are more common in people taking certain AEDs. A lesser degree of bone calcium loss is called osteopenia. This is basically a milder form of osteoporosis.

Older generation AEDs which speed up the liver’s metabolism, such as phenytoin and phenobarbital (and possibly carbamazepine), accelerate the breakdown of Vitamin D. Decreased serum Vitamin D reduces blood levels of calcium and phosphorus. These, in turn, result in the breakdown of bone to try to maintain the normal calcium blood levels. A major natural source of Vitamin D is your skin when it is exposed to sunlight. However, in northern areas where sunlight exposure is less, and with the use sunscreens in the summer to prevent the later development of skin cancer, many people may already have low or borderline in Vitamin D levels. AEDs can, in theory, worsen that problem.

A research study by Sato and colleagues in 2001 showed that bone mineral density (BMD) measurements in men and women with epilepsy was reduced an average of 14% with valproic acid/divalproex sodium and 13% with phenytoin compared to people not taking AEDs. Much less is known about whether bone disorders occur with the newer generation antiepileptic drugs approved in the United States since 1993: felbamate, gabapentin, lamotrigine, topriramate, tiagabine, levetiracetam, oxcarbazepine, zonisamide, and pregabalin.

Decreased calcium and phosphate mineral, and vitamin D, levels can sometimes be seen on blood tests that your doctor may order. Blood tests can also show elevated alkaline phosphatase and parathyroid hormone levels with AED use. Adults who have taken older generation AEDs should ask their doctors about getting blood levels or BMD tests. BMD is often measured using a DEXA (dual X-ray absorption) scan. Children may need fasting calcium, phosphate, alkaline phosphatase and parathyroid hormone blood tests done (BMD measurements are not useful in children because they are growing). If testing is abnormal, treatment with Vitamin D or calcium, and even prescription osteoporosis medication, may be needed to prevent fractures. You should ask your physician about this and also whether or not you should be taking a daily multivitamin or a supplement with Vitamin D and calcium.

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August 2007

Pregnancy and Women with Epilepsy
David G. Vossler, M.D.
Epilepsy Center at Washington Neuroscience Institute
Renton, Washington

Pregnancy is probably the most complex issue for women with epilepsy (WWE). One-half of 1% of all pregnancies occur in women with epilepsy. The pregnant WWE must balance the risks posed by seizures with the risks associated with antiepileptic drug (AED) exposure. Seizure frequency is increased in roughly one-third of women during pregnancy, but it remains the same in another third, and may actually decrease in another third.

A major concern is pregnancy complications. WWE whose seizures are poorly controlled have higher rates of toxemia, vaginal bleeding, premature labor, failure to progress in delivery, and cesarean section. The infants have higher death rates, decreased fetal growth and health, and a higher risk of intrauterine growth retardation. Well-treated patients, however, mostly have typical pregnancies and deliveries. Therefore, planning ahead for pregnancy with your health-care provider and keeping your seizures as well-controlled as possible with the proper medication are both extremely important.

A factor associated with an increase in seizure frequency as pregnancy progresses is changes in AED pharmacokinetics. Pharmacokinetics refers to how drugs move into, through, and out of the body. As pregnancy progresses, body volume, kidney drug clearance, or liver drug metabolism may increase, resulting in a decrease in the total AED blood levels. Total blood levels are only part of the story: A few AEDs, like phenytoin (Dilantin, Phenytek) and valproate (Depakote), are highly bound to blood proteins like albumin. Changes in protein binding during pregnancy can alter the ratio of the free blood level to the total blood level. It is the free level that accounts for the AEDs antiseizure benefits and side effects. Also, natural pregnancy hormone changes cause some AED levels, like lamotrigine (Lamictal), to fall to as low as 33% of normal in the third trimester. As a result of these various changes, neurologists often regularly monitor AED blood levels throughout pregnancy.

In completely healthy women without epilepsy, major birth malformations (teratogenesis) occur in roughly 2-3% of infants. Research studies have variably estimated that major malformations affect 3.5-6% of infants born to mothers with epilepsy; minor abnormalities affect 6-20%. From 1996-2005 the U.K. Epilepsy and Pregnancy Register (UKEPR) studied 237 WWE untreated during pregnancy and found a major malformation rate of 3.5%. Major malformations include cleft palate/lip, spina bifida, and congenital heart disease. Minor abnormalities include wide-spaced eyes, epicanthal folds, nasal growth deficiency, abnormal ears, low hairline, distal finger and toe development, small fingernails, and others. Some conditions causing epilepsy, such as tuberous sclerosis and malformations of cortical development, are associated an increased risk of defects.

All of the older AEDs are associated with an increased risk of birth defects. The North American AED Pregnancy Registry (NAPR) has reported that the major malformation rate in babies born to WWE taking one of the older AEDs was 6.5% for phenobarbital and 10.7% for valproate (NAPR report, Winter 2006). There is evidence that the use of more than one AED, and higher doses of either valproate or lamotrigine, increase the risk of congenital malformations (UKEPR 2006, and NAPR 2006). For the newer AEDs (ones approved by the FDA since 1993) some data are emerging. For lamotrigine, the NAPR and several other international registries are estimating a major malformation rate around 2.9%, with a mild increase in cleft lip and cleft palate in some, but not all, registries.

Data presented at the April 2007 American Academy of Neurology annual meeting by Dr. Kimford Meador and the Neurodevelopmental Effects of AED (NEAD) group showed that at age 2 years, children exposed in the womb to valproic acid had significantly lower scores on the Mental Developmental Index compared to children exposed to carbamazepine, lamotrigine, or phenytoin. The negative impact of valproate was related to the dose. Further information on the long-term effects of AEDs on the intelligence of children will come from this important ongoing study.

Folic acid 2 - 4 mg/day and one prenatal vitamin per day are recommended before and during pregnancy, to reduce the risk of congenital malformations. A high-level detailed ultrasound and a “quad screen” blood test are often recommended during weeks 16-20 of pregnancy. Close monitoring of AED blood levels during pregnancy can be important because generalized tonic-clonic seizures can cause physical injury or asphyxia to the fetus or miscarriage.

Another risk to infants with older AEDs like phenytoin is decreases in vitamin K levels in mother and baby. This can lead to serious hemorrhages in infants. In Washington State, infants do receive an intramuscular injection of vitamin K. However, it is recommended that vitamin K 10 mg/day should be taken orally during the last 1-4 weeks of pregnancy with older AEDs. This may be less of an issue with newer AEDs. Practice parameters have been published by the American Academy of Neurology (Epilepsia 1998;39:1226-31).

All of the older antiepileptic drugs, and some of the newer antiepileptic drugs, cross into breast milk to some degree. Some of them, such as primidone (Mysoline), cross extensively over into breast milk. A physician should be consulted about whether or not nursing should occur, but in most cases nursing is usually recommended for infants already exposed to the AED in the womb.

In summary, much is known about pregnancy in epilepsy. However, much still needs to be learned, especially with the newest medications. Planning ahead for pregnancy can greatly reduce the risk of many of the risks and adverse outcomes listed above. For example, it may be possible to change from riskier medications, such as valproate, to other less risky ones. Also, working with your health-care provider, it may be possible to get seizures under better control before becoming pregnant. Once you are pregnant, careful frequent consultations with knowledgeable health-care professionals to monitor your seizures and AEDs, run needed tests, and ensure you get the proper vitamins and good general care can help the vast majority of WWE have successful, safe pregnancies and healthy babies.

These are general guidelines that should not be taken as specific advice, for women with epilepsy. Please consult your physicians about all of these issues. These points are made for discussion only, and to encourage further research and investigation into these issues.

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July 2007

Dense Array EEG & Epilepsy
Mark D. Holmes MD
Professor, Department of Neurology
Regional Epilepsy Center
University of Washington, Seattle WA

The evaluation of a person with epilepsy requires a thorough assessment, including a detailed clinical examination, and use of several laboratory studies, especially brain magnetic resonance imaging (MRI), and, depending upon circumstances, neuropsychological testing, and a variety of hematologic and biochemical assays. However, the single most important laboratory study in understanding the nature of the seizure disorder in the affected patient remains, more than 70 after its invention, the electroencephalogram (EEG), The EEG records the electrical activity of the brain, and discloses the abnormal electrical patterns which are the hallmarks of the fundamental disturbance in epilepsy. Regardless of this critical role, standard EEG nevertheless has some severe limitations. One of these is that typically only 16-21 electrodes are applied to the scalp in conventional recordings, a practice that leads to relatively large distances between the recording electrodes. This, in turn, results in the long-held observation that localization of abnormal findings from standard EEG is usually very poor.

Recent and rapid technological advances are changing the current state of affairs, and leading to an expanded role for the EEG in the understanding of epilepsy and epileptic circuits. One of these advances is the capability to record from the scalp with a “dense array” of 256 EEG electrodes. With reduced interelectrode distances, spatial resolution is markedly improved, and approaches the mininum distance required to maximize the spatial information that can be extracted from scalp recordings. Furthermore, the 256 channel electrode net that is utilized in dense array recordings covers portions of the face and neck (in contrast to conventional EEG) and in this manner allows "sampling" of electrical activity from portions of the undersurface, or basal, brain regions. This capability is important, since seizures often originate in these regions. Dense array EEG recording is used in conjunction with sophisticated methods of EEG source analysis, mathematical tools that assist in determining where in the brain abnormal electrical patterns originate. Source analysis is used with realistic models of the head and brain in order to obtain accurate results. Dense array EEG recordings are possible for either short-term 1-2 hour recordings, or when required, for continuous longterm EEG video monitoring.

At the University of Washington Regional Epilepsy Center dense array EEG is being used to study patients with a variety of epilepsy syndromes. These studies are leading, in some cases, to novel insights into the cerebral cortical networks activated during epileptic discharges One study, for example, that examined patients with typical absence seizures, often regarded as prototypic generalized seizures, suggests that "generalized" seizures are not truly generalized. Rather, only restricted brain regions appear to be activated at the onset and during the propagation of the seizure. Cortical areas preferentially involved in absence include parts of the frontal lobe. Similarly, in a series of patients with juvenile myoclonic epilepsy (JME), a common generalized epilepsy syndrome in adults, highly restricted cortical areas are also found to be active during discharges, which usually include parts of the frontal and temporal lobes. In the future, knowledge of the pathologic neuronal circuitry in medically refractory generalized seizures may lead to novel approaches to treatment.

A major research focus at the Regional Epilepsy Center employs continuous longterm EEG-video monitoring using dense array EEG in order to capture seizures in medically intractable patients who are potential candidates for epilepsy surgery. To date, we have successfully monitored over 40 subjects for periods of 24-96 hours and have recorded clinical seizures in nearly all. Our goal is to compare the results of seizure onset and propagation, as predicted by dense array EEG, to standard methods of evaluation, including invasive EEG monitoring. The outcome in one case of a subject with refractory epilepsy forms the basis of optimism that dense array EEG recordings of partial seizures may, at least in some cases, accurately predict seizure onsets. In this patient, standard EEG recordings disclosed widespread, poorly localized interictal discharges and conventional longterm monitoring disclosed seizures that could not be localized. Prior to invasive EEG recordings, dense array EEG studies captured a clinical seizure and source analysis disclosed that the attack originated from left posterior inferior occipital cortex. This prediction was confirmed precisely on subsequent invasive recordings. The resection was carried out based on the results of the intracranial studies and the individual has been seizure-free nearly 30 months after the operation. To date, dense array EEG predictions of seizure onset have been confirmed, based on comparison with subsequent intracranial EEG recordings, in eight of ten patients. We anticipate that dense array EEG may one day reduce the need for invasive EEG recordings, and at the very least, help guide the placement of intracranial electrodes.

In the near future, work with dense array EEG will co-register an individual patient’s own MRI to the electrographic data. Research with this technology also includes investigations of EEG features unique to seizure onsets, and some investigators believe that recordings with up to 1000 EEG electrodes will be made in the future to extract the maximum possible information from scalp recordings. We may anticipate that the outcome of this research will be ever increasing accuracy in determining the nature and location of epileptic discharges in the brain using a safe and noninvasive technique.