INTRODUCTION

Epilepsy is considered “resolved” for:

• People who have a type of epilepsy that the patient is expected to “outgrow”—and the patient is significantly older than the age that further seizures would be expected; or
• People who have remained seizure-free for the last 10 years, with no seizure medications for the last 5 years.

The term for a person who had epilepsy in the past and is no longer considered to have epilepsy is: “resolved epilepsy”. The ILAE used the word “resolved” rather than “in remission” or “cured” in order to send a clearer meaning. For example, “cured” indicates that the patient has no increased risk for seizures. Although patients who have, for example, gone > 10 years seizure free may have a very low risk for seizure activity, their risk may still be somewhat higher than the general population. It was thought that the word “resolved” conveyed a more precise description.

PATIENT STORY #1

A 22 year-old man has had three seizures in his life- at age 9, 10 and 14 years of age. Seizures consisted of facial twitching just prior to falling asleep. EEG at age 9 years showed spikes in a pattern consistent with Benign Epilepsy with Centrotemporal Spikes (BECTs). BECTs is an epilepsy syndrome that patients are expected to outgrow. At age 16 years he was tapered off his seizures medications. He has had no further seizures.

This patient would be considered to have his epilepsy resolved. This is because he is currently older than the age that seizures would be expected, given his type of epilepsy. He would be considered to have “outgrown” his epilepsy. Or, in the new terminology: his epilepsy is resolved.

PATIENT STORY #2

48 year-old male with the first seizure of his life at age 13 years. The initial seizure was a generalized tonic-clonic seizure. EEG was normal. No history of sleep deprivation or other triggers for seizures. No etiology was identified. He had a second generalized tonic-clonic seizure at age 14 years. He was started on a seizure medication. Because he had no further seizures, the seizure medication was tapered to off at age 17 years. He has had no further seizures.

This 48 year-old is currently a nurse working at a local hospital. He was recently filling out paperwork – he was asked if he had epilepsy. He wanted to be truthful. He decided to ask a Minnesota Epilepsy Group epileptologist if he had epilepsy or not. He really did not think he had epilepsy, since his last seizure was so many decades ago.

Our 48 year-old is exactly correct! His epilepsy is resolved. Based on the criteria above: he has remained seizure-free for the last 10 years, with no seizure medications for much greater than 5 years. As a matter of fact, his epilepsy was resolved a long time ago!

CONCLUSIONS

Patients who have not had seizures for many years may wonder if they still have epilepsy. The ILAE has provided the following criteria for epilepsy being resolved:

• People who have a type of epilepsy that the patient is expected to “outgrow”—and the patient is significantly older than the age that further seizures would be expected; or
• People who have remained seizure-free for the last 10 years, with no seizure medications for the last 5 years.

We are learning more and more about the natural history of seizures in people with epilepsy. In the past (before 1990), there was little data on what happens to patients with epilepsy over the course of their lives. The good news is that data in recent years suggests that a sizable percentage of patients will have long periods of seizure freedom off seizure medications. Further research is needed to better understand which individual patients will have their epilepsy resolve. Also, wouldn’t it be great if medications (used for a short time) or other treatments could be developed to substantially increase the percentage of patients with resolved epilepsy?

REFERENCES

Fisher RS. A practical clinical definition of epilepsy. Epilepsia 2014;55:475-482.
Kwan P, Sander JW. The natural history of epilepsy: an epidemiological view. J Neurol Neurosurg Psychiatry 2004;75:1376-1381.

The post Do I Still Have Epilepsy? appeared first on Minnesota Epilepsy Group.

The purpose of this article is to highlight a recent study which reviews the literature in tremendous detail in order to answer the following questions:

1) Does marijuana improve seizure control?
2) Is marijuana safe?

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3639568/pdf/i1535-7511-13-2-81.pdf

STUDY DESIGN
The authors did a very extensive review of the literature- in order to identify all papers that performed randomized control trials assessing marijuana in the treatment of epilepsy.

RESULTS
The study found: ” four randomized reports which included a total of 48 patients, each of which used cannabidiol as the treatment agent. (Cannabidiol is an important extract of marijuana). One report was an abstract, and another was a letter to the editor. Anti-epileptic drugs were continued in all. Details of randomisation were not included in any study. There was no investigation of whether control and treatment groups were the same or different. All the reports were low quality. ”

As far as seizure control, little information is provided: One study reported two of four treated patients becoming seizure free for 3 months. The other studies either reported no benefit, or the effect was not clearly stated.

CONCLUSIONS
“No reliable conclusions can be drawn at present regarding the efficacy of cannabinoids as a treatment for epilepsy. The dose of 200 to 300 mg daily of cannabidiol was safely administered to small numbers of patients, for generally short periods of time, and so the safety of long term cannabidiol treatment cannot be reliably assessed.”

Thus, at this time, there is a lack of scientific evidence to recommend marijuana for the treatment of epilepsy. To quote the American Epilepsy Society:

“The lack of information does not mean that marijuana is ineffective for epilepsy. It merely means that we do not know if marijuana is a safe and efficacious treatment for epilepsy. Healthcare professionals, patients, and caregivers are reminded that use of marijuana for epilepsy may not be advisable due to lack of information on safety and efficacy, and that, despite some states legalizing the use of medical marijuana, it is against Federal Law to possess or use marijuana.  In addition, little is known about the long term effects of using marijuana in infants and children, and chronic exposure during adolescence has been shown to have lasting negative effects on cognition and mood.  Such safety concerns coupled with a lack of evidence of efficacy in controlled studies result in a risk/benefit ratio that does not support use of marijuana for treatment of seizures at this time. The American Epilepsy Society is supportive of well-designed research to determine the safety and efficacy of marijuana in the treatment of epilepsy.”

https://www.aesnet.org/press-room/consensus-statements/marijuana-and-epilepsy

Please send in your comments on this important topic! Thank you!

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Did you know that patients with epilepsy have a higher incidence of migraine headaches (and vice-versa!)? Patients are usually referred to our clinic for evaluation of their seizures. I will routinely ask patients about their headaches. If the patient has problematic headaches, treatment of the headaches may dramatically improve their quality of life.

It is not common, but sometimes an aura for a migraine can trigger a seizure. This shows the overlap in pathophysiology- between migraine and epilepsy.  The best thing for the patient is to treat the migraine and treat the seizure activity. Sometimes, one medication can treat both: “kill two birds with one stone!”

Some interesting/important points about migraine and epilepsy:

• Migraines can trigger seizures. Migraine triggered seizures are defined as seizures that occur within one hour of a migraine aura. The migraine aura is the warning that patients get before the headache gets severe- for example, patients may see flashing lights that slowly move across their visual fields. Patients may also have nausea that builds up over several minutes as their aura.
• Patient example: 28 year-old woman with a history of migraines and epilepsy for several years. The patient would note her migraine aura. This was a visual change—flashing lights that slowly moved from left to right across her visual field. The aura would become more intense over 10 minutes. Eventually, the symptoms could lead into a seizure (not always, but every few months)—patient would stare, lose contact, smack her lips and pick at her clothes. The seizure would last 60 seconds. She would then come out of the seizure. Although she would be mostly recovered, the patient would often be left with a headache. Headaches were often  a throbbing pain on one side of her head. Headaches were associated with nausea, light and sound would bother her. Headache would last for hours. Patient would often want to go lay down in a dark room.
• Migralepsy: this is the term for migraine-triggered seizure.
• Rates of migraine triggered seizures: In patients who have both epilepsy and migraine, migraine was noted to trigger seizures in 1.7-16% of patients.
• The prevalence of migraine in patients with epilepsy has been shown to be approximately 24%.
• Patients with epilepsy are 2.4 times more likely to be diagnosed with migraine (compared to the general population).
• 37%-51% of patients experience headaches after their seizures. These are called postictal headaches. These headaches can be as problematic as the seizures, for some patients.
• Mechanism of migraine and epilepsy:
  • Neurons are more active in both migraine and in epileptic seizures. A seizure, of course, is due to abnormal electrical activity coming from the brain. A migraine aura is due to  cortical spreading depression (CSD). CSD is a wave of electrical activity that slowly moves across the cerebral cortex. The abnormal electrical activity in a migraine aura moves more slowly than the typical spread of a seizure. One certainly can see how a migraine aura could trigger a seizure—the abnormal electricity of a migraine aura, in a patient with epilepsy, could trigger neuronal excitation and a seizure.
• Treatment can “kill two birds with one stone”.
  •  Certain medications can effectively treat both migraine headaches and epileptic seizures.
  • Such medications include topamax and depakote.
  • Possible reason that seizure medications work in migraine and epilepsy- similar mechanisms (both cause abnormal neuron excitation—see paragraph above).

REFERENCES

Forderreuther S, Henkel A, Noachtar S, Straube A. Headache associated with epileptic seizures: epidemiology and clinical characteristics. Headache 2002;42:649-55.

Haut SR, Fishman O, Lipton RB. Migraine, migralepsy and basilar migraine. In: Atlas of epilepsies. Edited by CP Panayiotopoulos.  Pp 629-637. Springer Verlag, London 2010.

Silberstein SD, Lipton RB, Haut S. Migraine. In: Epilepsy: A comprehensive textbook. Edited by Jerome Engel and Timothy Pedley. Pp 2733-2743. Lipppincott Williams & Wilkins, Philadelphia 2008.

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INTRODUCTION

A common question that we receive in clinic relates to the chance that a parent will “pass on” their epilepsy to their children. Also, if one child has epilepsy, will their brother or sister develop epilepsy? These are important questions. The answer is, of course, complicated. The answers to such questions must be tailored to the individual/family.

GENERAL FACTS ABOUT THE RISK OF DEVELOPING EPILEPSY:

• Remember: For the general population, the risk of developing epilepsy is approximately 1%. I always remind patients and families- even without a known family history of epilepsy or known genetic reason for epilepsy, any parent could have a child with epilepsy. Compare the 1% chance of epilepsy (for all people in the general population) to the higher risk groups described below.

• The risk of epilepsy is higher in the offspring of a mother with epilepsy compared to a father with epilepsy:
  • If mother has epilepsy, the risk of epilepsy in her children:
    • 2.9%-8.7%
  • If father has epilepsy, the risk of epilepsy in his children
    • 1.0%-3.6%

• If a parent has epilepsy, the risk of epilepsy in his or her daughter(s) is somewhat higher compared to the risk in son(s).

• If a parent develops epilepsy at a young age, the risk of epilepsy in his or her children is higher. An example may help clarify this: Let’s look at two fathers with epilepsy. Let’s compare the risk of these two fathers having a child with epilepsy. Father #1’s epilepsy began when he was 8 years old. Father #2’s epilepsy began at the age of 29 years of age. The father with the younger age of onset (Father #1) will have a higher risk of having a child/children with epilepsy
  • Parent with onset of epilepsy BEFORE the age of 20 years, risk of epilepsy in children:
    • 2.3%-6%
  • Parent with onset of epilepsy AFTERthe age of 20 years, risk of epilepsy in children
    • 1%-3.6%

• If a person has epilepsy, his or her sibling (brother or sister) is at higher risk of developing epilepsy. The younger the age of onset of epilepsy, the higher the risk that the sibling will develop epilepsy.
  • If  a patient develops epilepsy starting at age 0-9 years, the risk that the brother or sister will develop epilepsy:
    • 9.5%
  • If  a patient develops epilepsy starting at age 10-24 years, the risk that the brother or sister will develop epilepsy
    • 5.8%
  • If  a patient develops epilepsy starting after the age of 35 years, the risk that the brother or sister will develop epilepsy:
    • No increased risk

CHROMOSOME DISORDERS CONSISTENTLY ASSOCIATED WITH EPILEPSY

Some genetic neurologic conditions have seizures as a feature of their disorder. This may occur in all or nearly all patients with the genetic abnormality. It should be noted- these conditions are uncommon. Most patients with epilepsy do not have a specific chromosomal abnormality that the clinician can point to. The following is a list of two examples of chromosomal disorders in which patients typically develop seizures:

• Angelman Syndrome: Patients with this disorder have an abnormal chromosome 15. Patients have severe learning disabilities, tremor and poor coordination. The patient’s often have a happy appearance- they tend to smile and frequently laugh. Over 80% of patients will develop epilepsy.
• Ring Chromosome 20 Syndrome: Any person’s chromosomes can be looked at- with all the patients chromosomes laid out for analysis. The total number of chromosomes in a normal person is 46 chromosomes. The chromosomes can be laid out and a picture taken. If you have ever seen a chromosome picture, the chromosome looks like a little worm or a match stick. For patients with Ring Chromosome 20 Syndrome, chromosome 20 looks like a ring—instead of a straight stick, the chromosome has curled into a ring shape. This is abnormal. Patients with this disorder have poor concentration, impulsive behavior and sleep problems. Essentially all patients develop epilepsy at some point. Seizures usually occur out of sleep. Seizures are often associated with hallucinations.

COMPLEX  EPILEPSIES

Some patients, as noted in the above section, can have a single chromosome abnormality that can be clearly tested for and identified.  The single chromosome abnormality causes the neurologic disorder and epilepsy. This is (relatively!) straight forward. This is also relatively rare. A much more common scenario is that genetics plays a role in a patient developing epilepsy, but the cause and effect nature is not clearly understood and may be very complex. For example, some patients may have multiple genes that are abnormal, and it is the combination of these abnormalities that result in the epilepsy.

Let’s use mild head trauma as an example to help clarify some of these issues. Have you ever wondered why some people with mild head trauma develop epilepsy and some people do not? It is possible that there are people in the world who carry genes that predispose them to have seizures. But they may never develop epilepsy unless something happens to trigger the seizure activity. In our example, a person may have never developed epilepsy until he or she had the mild head trauma. Thus, it could be the combination of the genes and the mild head trauma that results in the epilepsy. If you could analyze 100 people who had the exact same mild head trauma, some of these patients may go on to develop epilepsy. The reason that some people develop epilepsy and some do not- may be related to differences in their genes!

(Please note: for many people, genetics may play only a minor role or no role whatsoever in their epilepsy. For example, people with head trauma may have no genetic predisposition to epilepsy. The trauma causes scarring in the brain and that is the whole cause of the epilepsy. The main point I want to make is that genetics may play a role in some patient’s epilepsy that may be surprising. The old thinking was that an injury to the brain like head trauma was the entire explanation for the cause of the epilepsy—and genetics had nothing to do with the seizures. The new thinking- genetics may play a role in some patients, even in cases of brain injury. This may be true even in adults.  As is often the case, the full story can be complicated!).

CONCLUSIONS

The information on genetics and epilepsy is progressing at a rapid pace. The research is absolutely fascinating!

If readers would like more information on this topic, let me know. For example, more information on the basics of genetics, DNA etc. Also, additional information on what genes to test for in patients with epilepsy may also be of interest.

References

Elmslie F. Genetic Counseling. In: Engel J, Pedley T, ed. Epilepsy: A comprehensive Textbook. Philadelphia: Lippincott Williams &Wilkins 2008: p. 211-215.

Goldman AM. Genes, seizures and epilepsy. Epilepsy.com

https://www.epilepsy.com/pdfs/Except_parent_art4.pdf

Zuberi S. Chromosome Disorders Associated with epileptic seizures. In: Panayiotopoulos CP, ed. Atlas of Epilepsies. London: Springer 2010: p. 121-127.

The post Facts on Genetics and Epilepsy appeared first on Minnesota Epilepsy Group.

• seizure control
• intellectual function  (measured by neuropsychological testing before and after surgery)

The study found that epilepsy surgery improved seizure control dramatically and many children were completely seizure-free.  Several studies have shown this and this was not unexpected.

Probably the most interesting finding in the study was that intellectual function appeared to improve after the surgery.  Isn’t that interesting- brain tissue was removed to control seizures.  Even with removing brain tissue, intellectual function improved!  IQ scores were noted to improve after greater than 6 years of follow-up.  Thus, the improvement was not noted immediately, but rather several years after the surgery.

The most important factor in improving IQ scores after surgery was stopping antiepileptic drugs.  I think this is important for patients and doctors to be aware of.  In our patient’s who have well controlled seizures after surgery, lowering or stopping medications certainly should be discussed thoroughly.

I thought pointing out the results of this study would be helpful for our readers.  This is further evidence that for those who are candidates for epilepsy surgery, the benefits may potentially outweigh the risks.  Thus, surgery is not just about improving seizure control.  Surgery may also lead to the added benefit of better intellectual function!

The entire article is available on-line (free!):

Skirrow C, et al. Long-term Intellectual Outcome After Temporal Lobe Surgery in Childhood. Neurology 2011;76:1330-1337.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3090063/pdf/znl1330.pdf

There is also a review of the article in Epilepsy Currents (free on-line!)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3220420/

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Neuropace

Approximately 30% of patients with epilepsy continue to have seizures despite trying several antiepileptic drugs (AEDs). This 30% of patients is considered to have intractable epilepsy. Some of these patients can have surgery for their seizures- this is where a surgeon removes a piece of brain tissue to remove the seizure focus. This type of surgery can be very helpful—in some cases, > 70% of patients would be expected to be seizure free.

So, what about the patients who do not respond to seizure medications and also are not resective surgery candidates? What do they do? Such patients may be considered for a device to treat their seizures. A device for epilepsy is something that is placed into a patient by a surgeon. The device is programmed to perform a function that stops seizures.

Currently, there are three devices for epilepsy that are commonly discussed. Only one is FDA approved—this is the Vagus Nerve Stimulator. The other two (Deep Brain Stimulator and Neuropace) are not fully FDA approved. At this time, the Vagus Nerve Stimulator can be ordered by your clinicians. Deep Brain Stimulator and Neuropace are not fully FDA approved and are thus not available to the general public.

A brief description of each of these three devices may be of interest:

Vagus Nerve Stimulator (VNS):

• How it works: A battery is placed under the skin on the left side of the chest. A wire goes from this battery to the vagus nerve—this is a large nerve in the neck. Thus, the patient has two areas of surgery- 1) the skin on the left side of the chest and 2) the left side of the neck to attach wires to the vagus nerve. No brain surgery is done. The vagus nerve has connections to the brain—in a widespread manner. The battery produces electrical charge that is transmitted to the vagus nerve. This electrical stimulation is then transmitted to the brain. The device is often programmed to stimulate for 30 seconds and then be off for 5 minutes. This stimulation goes on like clockwork: 30 seconds on/5 minutes off. By stimulating the vagus nerve, which then stimulates the brain, the seizure potential is changed for the better- seizure control can be improved!

Deep Brain Stimulator:

• How it works: Small probes are placed deep in the brain. This requires surgery that involves going through the skull and brain tissue. The probes are programmed to delivery electricity to areas deep in the brain. By stimulating this area, the brain activity changes in a good way- seizure activity can be reduced. Like the Vagus Nerve Stimulator, the Deep Brain Stimulator is programmed to stimulate at a pre-programmed set time. For those who love neuroanatomy, the deep brain area is called the anterior nucleus of the thalamus.

Neuropace:

• How it works: Electrodes are placed on the surface of the brain. This involves brain surgery-a piece of skull is opened to place these electrodes. The electrodes are very sophisticated- they are attached to a computer system that allows the detection of seizure activity. Imagine this- the electrodes are placed directly over the part of the brain where seizures are coming from. When a patient has a seizure, the electrodes can detect this activity. The electrodes are then programmed to delivery electricity to the brain. The electricity from the electrodes zaps the brain—and the seizure activity is stopped!

The three devices described in this article can reduce the frequency and intensity of seizure activity, but they are not expected to stop seizures completely. Obviously, this is important for patients to know. For example, the devices are not expected to stop seizures to the point where patients can drive. Placing one of the above devices may help patients reduce seizure medications. This may help with side effects.  The devices would not be expected to produce the well known seizure medication side effects, such as feeling sleepy, dizzy, poor coordination (you know—feeling like you are drugged!).

Each device has its own side effects. When a patient has surgery, infection and stroke are always discussed. Fortunately, the procedures do have a very good safety records.

I will plan on going into more detail about these devices in a future article. I will review the risks and benefits in more detail.

Please comment, ask questions.

For more information:

• VNS
• Deep Brain Stimulator
• Neuropace

The post Devices for Epilepsy appeared first on Minnesota Epilepsy Group.

For most patients, changing from brand to generic AEDs does not cause problems. This is because, again, the FDA mandates that the brand and generic AED be very close, in terms of their function and metabolism. The way the studies are usually done are to compare the generics to the brand. To clarify: assume we have generic medication A, generic medication B and generic medication C.  Currently, each of these medications are compared to the brand seizure medication- to make sure the metabolism of the drugs are very similar.

ILLUSTRATION 1: To illustrate how studies are usually done (FDA required):

GENERIC A compared to BRAND SEIZURE MED

GENERIC B compared to BRAND SEIZURE MED

GENERIC C compared to BRAND SEIZURE MED

A recent article (Krauss 2011) was published that compared the metabolism of different generic AEDs. Thus, they compared blood levels of generic medication A to generic medication B to generic medication C.

ILLUSTRATION 2: To illustrate how this study was done:

GENERIC A compared to GENERIC B compared to GENERIC C

Remember, usually the generic medications are compared to the brand, as required by the FDA (see Illustration 1, above). This study did something that the FDA does not require—it compared the metabolism of the different generic AEDs to one another (see Illustration 2, above). What they found was that for some patients, the differences between the various generic formulations was significant.

This study did not determine if the variability in blood levels caused problems- such as seizures. That will be left to another study. What the study suggests is that switching from one generic AED to another generic AED may result in significant increases or decreases in AED levels- for a small percentage of patients. It is thought that some patients may have seizure activity due to this fluctuation, although the percentage of patients is likely not high.

As our readers may well know, a pharmacy can switch from one generic AED to another. There can be more than 10 different generic AED manufacturers for a given seizure medication. A patient may be getting a peach colored pill that is shaped like a diamond one month, then the patient is switched to a white round pill. This may be due to changing the manufacturer. Thus, the study I describe in this article is important—it demonstrates that levels can fluctuate significantly in a small percentage of patients- when patients are switched from one generic AED to another.

The message of this article is NOT- stop taking generic seizure meds. Rather, the message is – understand that there may be some risk in changing from one generic AED to another. This is a risk that can be discussed between a patient and their clinician. It is important and complex!

For more information on the brand vs generic seizure medication debate, see our article on this website:

What to take: Brand vs generic seizure medications?

https://www.mnepilepsyhudson.org/education/featured-topics/what-to-take-brand-vs-generic-seizure-medications/

REFERENCES

The reference for the above described study:

Krauss GL, Caffo B, Chang YT, Hendrix CW, Chuang K. Assessing bioequivalence of generic antiepilepsy drugs. Ann Neurol 2011;70:221-228.

The article is reviewed in Epilepsy Currents.

Gidal BE. Generic antiepileptic drugs: How good is good enough? Epilepsy Currents 2012;12:32-34.

You can review the Epilepsy Currents article at:

https://www.aesnet.org/files/dmfile/epcu-12-1-32ClinicalCommentaryGidal.pdf

The post Switching From One Generic Seizure Medication To Another appeared first on Minnesota Epilepsy Group.

ARTICLE HIGHLIGHTS

• The North American Antiepileptic Drug Pregnancy Registry recently reported its important new findings (Hernandez-Diaz, 2012).
• The report compares the frequency of major malformations in the developing fetus in women taking an antiepileptic drug (AED) during their pregnancy. New and older AEDs are analyzed. Major malformations are serious medical problems that the fetus can develop during early development in the womb.
• What is really important about this study: it describes the risks/safety of using the newer AEDs during pregnancy.
• The study provides information about the relative risk/safety during pregnancy of 11 of the most commonly used AEDs. It looks at older AEDs, such as Dilantin and Depakote, and newer AED, such as Lamictal and Keppra. Prior to this study, there was not enough information available to say, with hardly any degree of confidence, which of the newer AEDs are the safest. This study describes a relatively large number of women exposed to AEDs during their pregnancies in order to compare the rates of problems with the fetal development- for both old and the new AEDs.
• The study indicates that some of the newer AEDs may be safer during pregnancy than some of the older AEDs. Some of the relatively safer new AEDs:
  • Lamictal (generic = lamotrigine)
  • Keppra (generic = levetiracetam)
• Depakote (generic= valproate) was associated with a 9.3% prevalence of major malformations- significantly higher than the relatively safer AEDs.
• Take a look at the Table below—it lists the 11 AEDs and each AED’s prevalence of major malformations. A very valuable Table for clinicians and patients!
• The website for the pregnancy registry:www.aedpregnancyregistry.org

INTRODUCTION

In 1963, one of the earliest reports describing a problem with fetal development in a woman taking an antiepileptic drug (AED) was published. The report described that the woman was taking mephenytoin, a medication similar to Dilantin, throughout her pregnancy. The child was found to have a low IQ, cleft palate, speech problems and a small head. Since that early report, it is clear that AEDs can be associated with an increased risk of medical problems with the developing fetus.

While seizure medications can cause problems for the developing baby, not taking seizure medications may result in more problems- a real double edged sword! Remember, intense seizures, especially generalized tonic-clonic seizures (= grand mal seizures) can result in serious problems for developing fetus. For most women with epilepsy, the safest strategy for their developing baby is to take a seizure medication.

In the old days, women with epilepsy were discouraged by some clinicians from going through a pregnancy—because of concerns about having a medically handicapped child. The latest data suggests that it is quite safe for the overwhelming number of women with epilepsy to consider pregnancy. Although the risk of having a medical problem may be higher than the general population, the increased risk may not be all that high and the majority of women with epilepsy can deliver healthy children. See the Table below for more details.

So, which AED should a woman take during her pregnancy? This is an extremely important question. The North American Antiepileptic Drug Pregnancy Registry recently reported its important new findings. These findings will be of great help in this important decision making process. The report compares the frequency of major malformations in the developing fetus in women taking an antiepileptic drug (AED) during their pregnancy. New and older AEDs are analyzed. Major malformations are serious medical problems that the fetus can develop during early development in the womb. Examples of major fetal malformations include cleft palate, spina-bifida and heart valve defects.

What is really important about this study: it compares the risk/safety of taking older and the newer AEDs during pregnancy. The study provides information for clinicians about the relative safety during pregnancy of 11 of the most commonly used AEDs. Prior to this study, there was not enough information available to say, with hardly any confidence, which of the newer AEDs is the safest. Past studies had too few women exposed to the newer AEDs to make conclusions. I am sure it makes sense-you need a large number of women exposed to an AED during their pregnancy to see what the problems are. You also need to compare women taking AEDs to controls (women going through their pregnancy not taking AEDs). This way, you can study what the problems are. That is why the North American Pregnancy Registry report is so important. This study describes a relatively large number of women exposed to AEDs during their pregnancies in order to compare the rates of problems with the fetal development- for both old and the new AEDs.

The study evaluated women from 1997 through 2011. 7,370 women were enrolled in the study. 4,899 women were taking only one seizure medication. The women taking only one AED are an important group—because they are only on one AED, it is easier to determine what problems are the result of the seizure medication. In contrast, if a woman is on three AEDs (Depakote, Dilantin and Keppra, for example), then it is harder to determine which AED is causing an identified problem. The study describes the rates of fetal malformations in women taking only one AED. These women are compared to controls (women not taking AEDs).

The following table summarizes some of the key findings (based on Table from North American Antiepileptic Drug Pregnancy Registry Spring 2012 newsletter). This is a great Table!:

www.aedpregnancyregistry.org

Take-away points:

• Lamictal and Keppra appear to be safer, compared to some of the older AEDs (Depakote and Phenobarbital).
• Depakote has a relatively higher rate of major malformations (9.3%). This does not mean that women should never take Depakote during pregnancy. Rather, other AEDs should be considered first, and Depakote should only be used if it is clearly needed for seizure control.
• Topamax (a newer AED) was associated with a higher risk of cleft lip.
• You may have noticed that Zonegran had no reported malformations. It should be noted, only 90 women were on Zonegran – this is too few patients to make a determination on the safety of Zonegran. More study is needed!
• Please note- in the controls (women not taking AEDs) , 1.1% of patients had malformations.

CONCLUSIONS

The results of this study will be helpful as the clinician and patient consider going through a pregnancy on an AED. We encourage women with epilepsy who are considering pregnancy to have a detailed discussion with their healthcare provider—to optimally plan the pregnancy. The results from the North American Antiepileptic Drug Pregnancy Registry are a great addition to the literature (see their newsletter:www.aedpregnancyregistry.org for more information). The results of other pregnancy registries are going to be reported in the near future—and will further add to our understanding of this complicated and important topic!

REFERENCES

Hernandez-Diaz S, Smith CR, Shen A, et al. Comparative safety of antiepileptic drugs during pregnancy. Neurology 2012;78:1692-1699.

Mullers-Kupper vM. Embryopathy during pregnancy caused by taking anticonvulsants. Acta Paeddopsychiatr 1963;30:401-405.

The North American Antiepileptic Drug Pregnancy Registry Spring Newsletter: www.aedpregnancyregistry.org

Yerby MS, Battino D, Montouris GD. General principles: teratogenicity of antiepileptic drugs. In: Engel J, Pedley T, ed. Epilepsy: a comprehensive textbook. Philadelphia: LWW; p. 1213-1224.

LATEST UPDATE: 5/23/2012

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ARTICLE HIGHLIGHTS

• Catamenial epilepsy is a condition in which seizures increase around the time of a woman’s period.
• The change in seizure frequency noted around the time of the period appears to be due to hormonal changes.
• Estrogen tends to increase seizure activity
• Progesterone tends to reduce seizure activity.
• As women go through the changes in their hormones during their lifetime, seizure frequency can also change. During perimenopause, there is a tendency for women to have an increase in seizure activity. During menopause, there is a trend towards improved seizure control. These patterns are noted more often in women with catamenial epilepsy.
• There are medication options currently available for the treatment of catamenial epilepsy.

INTRODUCTION

Women with epilepsy will often note an increase in their seizures around the time of their periods (Penovich, 2008). It is not unusual for the patient herself to bring this observation up to the doctor. The increase in seizure activity correlates with changes in hormones that occurs during the menstrual cycle. The worsening in seizure control can best be documented on a calendar: the patient’s periods can be charted along with the seizures. A clear clustering of seizures may be noted in close association with the periods. The medical term for an exacerbation of seizures around the menstrual cycle is catamenial epilepsy (Penovich 2008, Herzog 2008). I should stress-this is a common phenomenon! Approximately one-third of women with inadequately controlled seizures meet criteria for catamenial epilepsy (Herzog, 2008). The purpose of this article is to explore how hormones can change seizure activity in women with epilepsy.

EXAMPLE CASE

32 year-old woman with history of seizures since 13 years of age. Her typical seizures are described as follows: She has an aura- it is a rising sensation in her stomach. It is a combination of mild nausea and fear. This will last for a few seconds. She then loses contact. She stares and is unresponsive. She will pick at her clothes and grab at people or items that are in front of her. Seizures last for 30 seconds. Frequency of seizures was 3 per month.

The patient pointed out to her doctor that her seizures seemed to occur around the time of her period. The patient ended up keeping a careful calendar for 5 months- charting the days of her period and the days of her seizures. Just like clock-work, her seizures occurred over a 2 day span, consistently two days before her period started. She was diagnosed with catamenial epilepsy.

The patient was started on progesterone therapy. Progesterone was given 10 days before her period started and was then tapered to off four days into her period. Thus, she was on progesterone for 14 days and off progesterone for 14 days. The progesterone was allowed to build-up in her system before the increase in her seizures was expected (seizures were expected to increase 2 days before her period started).

The patient had an excellent response. Her seizure frequency was reduced by 60%.

ESTROGEN AND PROGESTERONE

Estrogen and progesterone are two important hormones that change during the course of a menstrual cycle as well as during a woman’s lifetime. During the approximately 28 day cycle, the fluctuations in estrogen and progesterone can be quite dramatic. For example, around ovulation (mid-cycle), estrogen level may be quite high. During puberty, perimenopause and menopause, there are major changes in the relative levels of estrogen and progesterone. There is robust research in both human and animal models which support the following basic concepts:

• Estrogen tends to increase seizures.
• Progesterone tends to reduce seizures.

It has been observed that when estrogen levels are high, seizure activity tends to cluster. In contrast, progesterone is being studied as a possible treatment for seizures (see below).

SEIZURES AND THE MENSTRUAL CYCLE

During the typical 28 day menstrual cycle, there are variations in the relative levels of estrogen and progesterone. At times, the levels of estrogen are much higher compared to the levels of progesterone. It is when estrogen is relatively high that seizure activity is most likely to occur. There are three times during the menstrual cycle that hormonally triggered seizures are most likely (Herzog, 2008):

1. Around the time of ovulation (between days 10 to 15 of menstrual cycle).
2. Around the time of the period (between three days before and three days after the period starts).
3. During second half of menstrual cycle (between days 18 of cycle through three days after period starts).

It is during these three times that women with catamenial epilepsy will notice an increase in their seizures.

LIFETIME CHANGES IN SEIZURES: FROM PUBERTY TO MENOPAUSE

A very common question we receive in clinic is: What will happen to my seizures when I hit menopause? Another common question is: Did puberty trigger my daughter’s seizures? These are great questions. Research to answer these questions is ongoing. There is information currently available to guide patients on these important issues.

Puberty

As everyone knows, puberty is a time of dramatic hormonal changes! The adolescent physical appearance, emotions and thinking are all undergoing remarkable changes. Mood changes can fluctuate in remarkable ways. Given all the hormonal activity, it is not surprising that some girls experience changes in their seizures during puberty. Certain types of epilepsy are more likely to start during puberty (for example, Juvenile Myoclonic Epilepsy).

Pregnancy

Of course- pregnancy includes remarkable changes in hormones! These changes have many important effects. Pregnancy in women with epilepsy is such an important topic, I will plan on writing a separate article on this topic. Keep on the look-out for the article!

Perimenopause/menopause

Perimenopause is the time in a woman’s life where her menstrual cycle is shifting- from regular cycles to toward permanent infertility. Perimenopause is characterized by erratic fluctuations in hormones.  Estrogen levels can often be quite high during this perimenopause period.  For some women with epilepsy, seizures can become much more frequent as they go through perimenopause.  This is thought to be due to the high levels of estrogen.

When women enter menopause, hormone levels are characterized by low and stable estrogen levels.  During menopause, women with epilepsy often have a reduction in the frequency of her seizures. Thus, women with epilepsy often will often have an increase in the frequency of seizures during perimenopause, and a reduction in seizures during menopause.  This pattern is more frequently noted in those women who have a history of catamenial epilepsy (Harden, 1999).

TREATMENT OF CATEMENIAL EPILEPSY

There are several treatment options for catemanial epilepsy. Some of the options include:

• Natural progesterone lozenges ( a hormone)
• Acetazolemide (a diuretic)
• Clobazam (a benzodiazepine, effects GABA receptor)
• Ganaxolone ( a steroid, effects GABA receptor)

Data on progesterone was presented at the most recent American Epilepsy Society Meeting (Herzog et al, December 2011). A randomized, double-blind, placebo controlled multicenter trial was described. Progesterone was noted to be an effective treatment for selected women with catamenial epilepsy. It appeared that the more frequent a patient’s seizures are around their periods, the better the response to progesterone.

A suggested treatment strategy is to give progesterone for 14 days of the menstrual cycle (Herzog 2008, Pennell 2009). Thus, the patient may be on progesterone for 14 days and then off for14 days. The progesterone is started several days before the period starts and before the seizures are expected to occur. This allows the progesterone to buildup in the body. The progesterone is then continued a few days into the period, and then tapered to off. It is hoped that the higher progesterone will stop the seizures!

Progesterone has side effects—sedation, mood changes, bloating, weight gain, breast tenderness and other side effects. These need to be considered—a thorough discussion between the patient and clinician is important. Also, natural progesterone appears to have better efficacy than synthetic progesterone. In order to obtain natural progesterone, ordering from a compounding pharmacy may be necessary.

Conclusions:

Hormones can play an important role in seizures in women with epilepsy.  Increasing levels of estrogen tends to increase seizures, while higher levels of progesterone tends to reduce seizures. Women who have an increase in their seizures related to their periods may be diagnosed with catamenial epilepsy. This is a surprisingly common condition, noted in one-third of woman with intractable epilepsy. In order to determine if a person has catamenial epilepsy, careful tracking of seizures and periods on a calendar is needed. Treatments that are relatively specific for hormone triggered seizures exist and appear to be effective. Clinicians can currently prescribe such treatments. Research is ongoing to develop better treatments for this important condition.

REFERENCES:

Harden CL, Pulver MC, Ravdin L, et al. The effect of menopause and perimenopause on the course of epilepsy. Epilepsia 1999;40:1402.

Herzog AG. Progesterone therapy in women with epilepsy: A 3-year follow-up . Neurology 1999;52:1917.

Herzog A. Catamenial epilepsy:Definition, prevalence, pathophysiology and treatment. Seizure 2008;17:151-159.

Herzog AG, Fowler JM, Massaro JM, et al. Progesterone therapy for women with epilepsy:results of the phase 3 NIH progesterone trial. Presented at the American Epilepsy Society Meeting, December 2012.

Pennell PB. Hormonal aspects of epilepsy. Neurol Clin 2009;27:1-25.

Penovich PE, Helmers S. Catamenial Epilepsy. International Review of Neurobiology 2008;83:79-90.

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ARTICLE HIGHLIGHTS

• Sudden unexpected death in epilepsy (SUDEP) can be defined as: 1) a patient with epilepsy unexpectedly dies; 2) no cause of death is identified at autopsy.
• Early death rates are higher in patients with epilepsy compared to the general population. Most early deaths in patients with epilepsy are due to the underlying disorder, such as a brain tumor or stroke, and not due directly to the epilepsy.
• Seizure related accidents can result in death in patients with epilepsy. Motor vehicle accidents or drowning are tragic examples.
• SUDEP occurs more often in patients with poorly controlled seizures. Sudden death rates in patients with frequent generalized tonic-clonic seizures are higher compared to the general population.
• Risk factors for SUDEP include: frequent and severe seizures, intellectual disabilities, brain lesions such as stroke or tumor.
• Recommendations to prevent SUDEP:
  • Educate patient and families.
  • Optimize seizure control.

• Most patients with epilepsy are expected to live long full lives, especially if seizures are well controlled and the patient is otherwise in good health!

INTRODUCTION

Epilepsy doctors are being encouraged to discuss a topic with patients and families that is very difficult, emotional and important. The topic is sudden unexpected death in epilepsy (SUDEP).

SUDEP can be defined as:

• A patient with epilepsy who dies unexpectedly.
• No cause for death is found at autopsy.

ILLUSTRATIVE CASE

24 year-old male who had a history of uncontrolled seizures since infancy. Seizure types included generalized tonic-clonic seizures (= grand mal seizures) and tonic seizures (brief stiffening seizures). The patient had intellectual disabilities. He was able to work stocking shelves at a local grocery store. He enjoyed bowling and watching movies.  He was very social- he loved going to stimulating events such as parties or to the state fair. He smiled and laughed easily. Other than epilepsy and intellectual limitations, he was healthy. One day, he became ill and vomited up his seizure medications. He went to sleep early that night. Tragically, he was found dead in bed the next morning. There was evidence of a seizure—he had bitten his tongue and was incontinent of urine. An autopsy was performed. A medical cause for the death was not identified. The death certificate indicated cause of death: sudden unexpected death in epilepsy.

INCIDENCE AND RISK FACTORS FOR SUDEP

Fortunately, SUDEP is an uncommon occurrence. However, it is a tragedy that does occur, and families are far too often unprepared. Families who have lost a loved one have expressed great disappointment in having never been told about this well documented phenomena. Families consistently indicate that if they had been educated about SUDEP, they would have been better prepared for the tragedy. Health care providers need to discuss this important issue with patients and families. Although death is not easy to talk about, it clearly is an important conversation to have.

It should be noted that patients with epilepsy do have a greater risk of early death compared to the general population. The increased risk is usually not directly related to the seizures, but rather to the underlying cause of the epilepsy. For example, patients with brain tumors and epilepsy usually die from the tumor, not from the epilepsy. Although the incidence is not high, some patients can die more directly from their seizures- for example due to drowning, crashing a motor vehicle or very prolonged and intense seizure activity (= status epilepticus).

It should be stressed that patients who do not have an underlying disorder that will shorten their life (such as a tumor or stroke, for example) can be expected to live a full life span. As noted above, accidental injuries are more common in certain patients with epilepsy- thus appropriate precautions should be taken to keep a patient safe—for living a long and full life.

The rate of sudden death in the general population < 45 years of age is estimated at 0.05-0.1/1000 person-years of follow-up (Nashef, 2008) . In comparison, patients with epilepsy whose seizures are not controlled have been found to have SUDEP rates of 1-6/1000 patient years of follow-up. If you compare these numbers, you can see that patients with poorly controlled seizures have several times the risk of sudden death, compared to the general population. The more severe the seizures, the higher the incidence of SUDEP. For example, studies have demonstrated that patients who continue having seizures despite several seizure medication trials and who even fail epilepsy surgery are at relatively higher risk of SUDEP (4.5-6/1000 patient years of follow-up). Interestingly, epilepsy surgery, if it controls the seizures, appears to be effective at reducing the risk of SUDEP. Patients who have had epilepsy surgery have been followed long-term (Stavern, Epilepsy Res, 2005). Those who are seizure free after the surgery have the same incidence of sudden death as the general population.

Several studies have looked at clinical variables that are associated with a higher risk for SUDEP (Nashef, 2008/Walczak, Neurology, 2001). A summary of important clinical characteristics associated with SUDEP:

• Severe epilepsy
• Frequent generalized tonic-clonic seizures (= grand mal seizures)
• Abnormal EEG
• Male gender
• Intellectual disabilities
• Alcohol abuse
• Brain lesions (tumor, stroke, other)
• Not being compliant with seizure medications
• Being on multiple seizure medications

WHAT CAUSES SUDEP?

Patients who have died of SUDEP typically are found in bed. In one study evaluating 135 SUDEP patients, two thirds of patients died while in bed (Langan, JNNP, 2000). The patient had typically gone to sleep the night before, with no issues to forewarn of the impending tragedy. How exactly the death occurs is currently an area of active research. Patients may be found with evidence of having an intense seizure- for example, tongue bite or urine incontinence may be noted. Although most SUDEP cases are not witnessed, when SUDEP is seen, seizure activity has often been described to occur at the time of the death. It is known that intense seizure activity can disrupt respiratory function and cause cardiac arrhythmias. Most experts suspect that intense seizure activity triggers cardiac or respiratory arrest—which then results in the death of the patient. Causes other than seizure activity have been postulated. For example, cardiac arrhythmias due the affects of seizure medications or due to brain pathology have been suggested.

RECENT ARTICLE SUPPORTS: BETTER SEIZURE CONTROL, LESS CHANCE FOR SUDEP

A recent article examined all SUDEP cases in a large number of randomised antiepileptic drug (AED) studies (Ryvlin, Lancet Neurol, 2011). What the authors did was a thorough review of the literature to find essentially all randomised AED studies that met their inclusion criteria. They found 112 studies that met their criteria. The authors then reviewed each of these studies to see if any patients in the study died of SUDEP. They identified 20 cases of SUDEP out of all these studies. Remember, patients can die during the course of a drug study. Sometimes, they may get in a car accident. Some may have a heart attack. Some patients may die of SUDEP. If a patient has died during a drug study, the reason for the death is reported.

The authors analyzed all the patients who died of SUDEP. They compared the SUDEP rate in those: 1) patients who were treated with the study AED to 2) those patients on placebo. As you may know, most AED drug trials are designed as follows: One group of patients has the study AED added to their current AEDs. The frequency of their seizures and side effects are studied. This study group is compared to a group of patients who have a placebo added to their current AEDs (basically, a sugar pill). By comparing the groups, you can tell if the AED is effective at improving seizure control and if side effects are a problem.

The results of the study were striking (Spencer, Epilepsy Currents, 2012). Treatment with the add on AED (study drug) reduced the incidence of SUDEP more than 7 times, compared to treatment with a placebo. This study provides arguably the best evidence to date the concept that improving seizure control may be helpful in reducing the incidence of SUDEP.

CONCLUSIONS

Early death rates are higher in patients with epilepsy compared to the general population. Most early deaths in patients with epilepsy are due to the underlying disorder, such as a brain tumor or stroke, and not due directly to the epilepsy. However, patients with epilepsy are at higher risk of death due to SUDEP. Although uncommon, SUDEP is a true tragedy, because it can strike patients who are young and otherwise in good health except for their seizures. There are many unanswered questions about SUDEP: 1) what is the cause of SUDEP?; 2) who is at greatest risk? 3) what is the best way to prevent SUDEP?

The current thinking on SUDEP is that patients and families should be educated about SUDEP. Also, the best possible seizure control should be pursued—poorly controlled intense seizures is probably the most important risk factor for SUDEP.

Although this article has reviewed the important topic of early death in patients with epilepsy, it should be stressed that most patients with epilepsy are expected to live long full lives, especially if seizures are well controlled and the patient is otherwise in good health!

REFERENCES

Langan Y, Nashef L, Sander JW. Sudden unexpected death in epilepsy: a series of witnessed deaths. J Neurol Neurosurg Psychiatry 2000;68:211-213.

Sperling M. Sudden unexplained death in epilepsy. Epilepsy Currents 2001;1:21-23.

Nashef L, Tomson T. Sudden death in epilepsy. In: Engel J, Pedley T, editors. Epilepsy: A comprehensive textbook. Philadelphia: Lippincott Williams & Wilkins; 2008: 1991-1998.

Ryvlin P, Cucherat M, Rheims S. Risk of sudden unexpected death in epilepsy in patients given adjuctive antiepileptic treatment for refractory seizures: a meta-analysis of placebo-controlled ranomised trials. Lancet Neurol 2011; 10:961-968.

Spencer D. SUDEP: Sudden unexpected death in epilepsy on placebo? Epilepsy Currents 2012;12:51-52.

Stavern K, Guldvog B. Long-term survival after epilepsy surgery compared with matched epilepsy controls and the general population. Epilepsy Research 2005;63:67-75.

Walczak TS, Leppik IE, D’Amelio M, et al. Incidence and risk factors in sudden unexpected death in epilepsy: a prospective cohort study. Neurology 2001;56:519-525.

LINKS

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