What is epilepsy?
Dr. James White, Minnesota Epilepsy Group

Lessening the burden of epilepsy.
Dr. James White, Minnesota Epilepsy Group

How epilepsy is treated.
Dr. James White, Minnesota Epilepsy Group

Pregnancy and epilepsy.
Dr. Julie Hanna, Minnesota Epilepsy Group

Visit www.allinahealth.org/epilepsy for more info.

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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.

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.

The post Hormones and Seizures in Women with Epilepsy appeared first on Minnesota Epilepsy Group.

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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Despite a proven track record, it is typically many years from the time the patient starts having seizures to the time they finally have epilepsy surgery. Studies suggest that patients are finally referred for epilepsy surgery after 20 years of seizure activity. There is mounting data that performing epilepsy surgery sooner rather later may be helpful. Surely, it does not take 20 years to see if 2 or 3 seizure medications are going to control the seizures! Please note- if a patient has not had his or her seizures controlled after trying 2 AEDs, the chances of having AEDs completely control the seizures is quite low. That is why epilepsy surgery is considered in those who have tried 2 AEDs.

Of course, epilepsy surgery has risks. Remember, the surgery involves having the surgeon remove a piece of the skull and removing a piece of brain tissue. This brain tissue is the area of the brain that the seizures were starting. By removing this abnormal tissue, the seizures can be controlled. Risks include stroke, infection or memory problems. With careful evaluation, these risks can be minimized.

A recent article has been published entitled “Early Surgical Therapy for Drug-Resistant Temporal Lobe Epilepsy.” (Engel, JAMA, 2012). The goal of the study was to compare: 1) epilepsy surgery to 2) continued AED therapy without epilepsy surgery. The study looked at the effect of surgery on seizure control and the effect on quality of life. The patients in the study had tried 2 AEDs and were still having seizures. The seizures had to be disabling for no more than 2 consecutive years. This is important—this is the “early” part of the study. Rather than waiting for many many years, the study sought to evaluate those who had seizures for only a short period of time (< 2 years).

A total of 38 patients (18 men and 20 women) with temporal lobe epilepsy were included in the study. 15 patients were randomized to the surgery group and 23 patients were randomized to the medical group (medical group – treated with AED only, did not have surgery). It should be noted, the surgery patients did continue their AEDs.

Results:

• Surgery group: 11 of 15 patients were seizure free.
• Medical group: 0 of 23 patients were seizure free. (P < 0.001)
• Quality of life scores were better in the surgery group, but the findings did not reach statistical significance (p=0.08).
• Surgery group adverse events: 1 patient had a postoperative stroke. Neurologic symptoms resolved.
• Medical group adverse events: 3 patients went into status epilepticus (prolonged and potentially dangerous seizure activity).

The authors concluded that early surgery is superior to AED treatment alone for controlling seizures in patients with temporal lobe epilepsy. This study clearly supports the idea that you should not wait years and years for surgery. If a patient is not responding to AEDs, then surgery should be considered sooner rather than later.

The study suggested that quality of life was also better in the surgery group, but the small number of patients resulted in a non-significant finding. It should be noted that the study was stopped early because it was a challenge to recruit patients that met the inclusion criteria. The actual study had a total of 38 patients—the goal was 200. Because of the small numbers, the results need to be interpreted with appropriate caution.

This study supports the recommendation of the American Academy of Neurology: if a patient’s seizures are not controlled by 2 AEDs, then evaluation for possible epilepsy surgery should be considered. This should happen sooner rather than later!

REFERENCES

Engel J, McDermott M, Wiebe S, et al. Early surgical therapy for drug-resistant temporal lobe epilepsy. JAMA 2012;307:922-930.

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ARTICLE HIGHLIGHTS

• Stem cell therapy for epilepsy is a possible treatment option in the future.
• Stem cell therapy may prove useful for:
  • Improving seizure control
  • Improving memory issues
  • Stem cell therapy is not yet approved for the treatment of epilepsy- the safety and effectiveness of such treatment has to be thoroughly studied and approved by the FDA.

INTRODUCTION

There are many exciting areas in epilepsy research. One topic of great interest is the use of stem cells to treat seizures. Although stem cell research related to epilepsy is in its early stages, preliminary data would suggest promise for this treatment option. The writing of this article has been prompted by several people in clinic and on our Facebook page asking for information on stem cell therapy for epilepsy. The goals of this article are to: 1) provide a basic understanding of stem cell therapy; and 2) to review stem cell therapy in epilepsy.

WHAT IS A STEM CELL? HOW DO STEM CELLS STOP SEIZURES?

When an organism (a human, mouse, etc) is developing, the organism will start as a single fertilized cell. This cell will begin dividing. As the cells divide, groups of cells are programmed to form parts of the body- heart, lungs, skin and brain, for example. These early dividing cells are called stem cells. Stem cells are cells that have the ability to develop into a wide variety of cell types. Some stem cells have the potential to become any cell type in the body. Cell types include muscle cells, skin cells or brain cells, such as neurons. In addition, stem cells have the special ability to renew themselves for long periods of time.

It has been shown that stem cells can be transplanted into the brain and produce functioning neurons. One strategy for the use of stem cells in neurological conditions is to transplant stem cells into abnormally functioning brain tissue—this will allow the stem cells to develop into normally functioning brain cells and produce normal brain function.

Illustrative case: Consider a patient with a small area of scarring in her left temporal lobe. Her seizures are coming from that area of scarring. This area of scarring has very abnormally functioning neurons. Properly functioning neurons are supposed to have a nice normal flow of electricity, from one neuron to the next. In our patient’s area of scarring, the neurons are electrically abnormal—the electrical charge is way too high. This abnormal electrical activity can lead to spreading electrical charge that results in a seizure (see our article “What is a seizure?” for details). Now, imagine that you could place stem cells in her brain in the area of scarring. This would result in relatively normal cells replacing the abnormal cells. Instead of excessive electrical activity, you would have normal electrical activity. Because the neurons are now functioning properly and not causing excessive electricity, the seizures are stopped! That is the hope of how stem cells could work.

TYPES OF STEM CELLS

Photo credit: digitalart @ freedigitalphotos.net

Embryonic stem cells: Cells derived from embryos. An embryo is defined as a young animal (human, mouse, etc), early in the stages of development within the womb.

Adult stem cells: The study of adult stem cells for clinical use has been prompted for several reasons, including the ethical issues related to the use of embryonic stem cells. In 2006/2007, researchers identified conditions that would allow some specialized adult skin cells to be “reprogrammed” into stem cells. This is almost like turning the clock back in time—adult cells are reverted to an early stage in cell development—the stem cell. The stem cell could then be used to create a variety of different types of cells (heart cells, brain cells, etc).

This discovery leads to a great hope! Imagine this futuristic treatment plan: 1) patients could have some of their own skin cells removed; 2) skin cells are reverted to stem cells; 3) these stem cells are placed into the patient’s brain – they become normally functioning brain cells and replace the neurons that caused seizures; 4) seizures are stopped! Obviously, this is not reality at this time—but the potential is very exciting!

POSSIBLE WAYS THAT STEM CELLS COULD HELP PEOPLE WITH EPILEPSY (Shetty, Stem Cells, 2007):

• Replace neurons that are lost or dysfunctional- to stop seizures: It has been shown that patients with chronic epilepsy can have a reduced number of neurons in the area where their seizures originate (= the seizure focus). Also, the neurons in the region of the seizure focus may not function correctly – for example, they may be overly electrically active. This abnormally high electrical activity is what can produce seizure activity. Stem cells could be transplanted into the area of the seizure focus and replace the lost or abnormal neurons. The stem cells could be programmed to become normally functioning neurons. By replacing the abnormal function with the normal function, the potential for seizure activity could be potentially erased. This method to use stem cells is similar to the example described above (see above section: Illustrative case).
• Replace neurons that are lost or dysfunctional- to help memory: Some patients with epilepsy have memory complaints. There are a multitude of possible reasons for people with seizures to have memory issues- medication side effects, seizure activity, and mood problems are commonly identified causes. Some patients have memory problems related to losing neurons or  dysfunctional neurons in the area of the seizure focus. By replacing the lost or dysfunctional neurons with normally functioning neurons derived from stem cells, memory problems could be potentially significantly improved.
• Transplant stem cells that have the ability to produce a chemical to stop seizures: Stem cells can be programmed to become neurons that produce a neurotransmitter called GABA. This is a chemical which can stop the overly active neuronal function that can produce seizures. GABA results in inhibition of neurons (opposes the excitation of dysfunctional neurons). If stem cell derived neurons could produce a high quantity of GABA and were placed in the area where seizures started (seizure focus), the seizures could be stopped before they started!

SAFETY ISSUES AND STEM CELLS (Naegele, Neuropharmacology, 2010)

There are several challenges that need to be worked out before stem cell therapy will be widely considered as safe:

• Stem cells can lead to the development of tumors. As noted above, stem cells have the ability to renew themselves for a long-term. This is a good thing- by continuously dividing, stem cells can produce a supply of new cells for therapy. An important negative- the long-term dividing process can lead to the development of tumors, in some cases. This issue is being studied. This issue needs to be considered safe before widespread clinical use will be possible.
• Stem cells can lead to rejection by the body’s defense system. When stem cells are placed into the brain, there is the potential for the body’s immune system to have a reaction to the stem cells- as if the stem cells are an infection that the body needs to get rid of. This can lead to the stem cells being cleared away by the body’s immune system. Obviously, the stem cells will not be able to provide therapy if this occurs. Again, this issue is being studied.

CAN CLINICIANS PRESCRIBE STEM CELL THERAPY FOR EPILEPSY NOW?

The answer is no. Essentially all the research on stem cell therapy for epilepsy has been carried out in animal models (rodents, for example). There are currently no FDA approved stem cell therapies for epilepsy. In the coming years, large scale human studies using stem cell therapy for the treatment of epilepsy will hopefully be carried out. Such studies will look at the safety and effectiveness of such treatment. These studies will be necessary to obtain FDA approval- so that patients can receive stem cell therapy in the clinic setting. An important question is- when will stem cell therapy be approved by the FDA? The answer to this question is unknown, although experts in the field are hopeful for significant advances in the next 10 years.

CONCLUSIONS

Stem cell therapy is a promising treatment for patients with epilepsy. More studies need to be performed to determine the safety and effectiveness of this treatment. Hopefully, in the not too distant future, stem cell therapy could be offered as a treatment for our patients.

References

Naegele J, Maisano Xu, Yang Jia, Royston S, Ribeiro E. Recent advancements in stem cell and gene therapies for neurological disorders and intractable epilepsy. Neuropharmacology 2010;58:855-864.

Riban V, Fitzsimons HL, During MJ. Gene therapy in epilepsy. Epilepsia 2009;50:24-32.

Shetty AK, Hattiangady B. Concise review:prospects of stem cell therapy for temporal lobe epilepsy. Stem Cells 2007;25:2396-2407.

Stem Cell Information: NIH resource for stem cell research https://stemcells.nih.gov

The post The Latest Stem Cell Therapy and Epilepsy appeared first on Minnesota Epilepsy Group.

Epilepsy Society App
by The National Society for Epilepsy

Features:

• Seizure diary
• Seizure facts
• Medication information
• Recovery guide

Download for iPhone
Download for Android

My Epilepsy Diary
by Epilepsy.com

Features:

• Seizure diary
• Medication tracking
• Text/email reminders
• Print reports

Download for iPhone

Track It
by Seizuretracker.com

Features:

• Seizure logging
• Record seizures with video
• Integration with Youtube
• Graphical reports and statistics

Download for iPhone

The Track It app is an extension of the online seizure logging website seizuretracker.com .  It’s free and you can use it online or with the app.

Know about a good epilepsy app?  Lets us know about it in the comments.

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