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Thursday, February 16, 2012

Epilepsy

Author: Dr Tina Shih MD Neurologist UCSF  San Francisco, CA
2008-07-23

Epilepsy is a condition of recurrent seizures, which are defined as abnormal electrical activity in the brain that can cause a variety of involuntary behaviors, ranging from brief unresponsiveness to shaking of the limbs with loss of consciousness.

Written by Tina Shih, MD and Daniel Lowenstein, MD


Introduction

Epilepsy is a condition of recurrent seizures, which are defined as abnormal electrical activity in the brain that can cause a variety of involuntary behaviors, ranging from brief unresponsiveness to shaking of the limbs with loss of consciousness. Current treatments cannot cure the disease, but when paired with education, can allow most people with epilepsy to lead full and rewarding lives. This knol describes the condition, the seizures that characterize it, the populations it affects, and the available treatments.
 

What are seizures?

The brain is composed of cells called neurons. Using complex molecules and charged particles, these neurons communicate with one another on an electrical basis (see figure 1).

In normal circumstances, this electrical activity is balanced between states of excitation and inhibition and the activity is generally not synchronized (meaning the activity is “out of tempo”). During a seizure, however, the excitation becomes uncontrolled and there is a sudden surge of synchronized electrical activity.   One of the ways that the electrical activity of the brain can be measured is by using a device known as an electroencephalograph (EEG). During the EEG, metal disc-like electrodes are pasted to the scalp by a technologist and the person then lies quietly in bed for approximately 30 minutes.  Figure 2 shows what a seizure looks like when recorded by EEG. Note that the abnormal, overly synchronized electrical activity of the neurons creates large waves or “spikes” on the EEG.



The word “seizure” comes from the Latin “sacire”, which means “to take possession of.” During a seizure abnormal electrical activity “takes possession of” a region of the brain and depending on what area of the brain is involved, the person has different symptoms. If the abnormal electrical activity involves the area of the brain that controls movement, the person may have trembling or shaking of a limb or side of the body. If the abnormal electrical activity involves the area of the brain that processes visual information, the person may “see” flashing lights or complex images. Depending on the amount of brain involved, the person may lose awareness or consciousness.
 

Who is at risk for developing seizures?

Approximately 10% of people, at sometime in their life, will experience a seizure, with the majority being “provoked” or “triggered” seizures. Possible triggers include toxic substances (certain medications, alcohol or cocaine, to name a few), bleeding in the brain (from trauma or stroke), infections (e.g., viral or bacterial meningitis, encephalitis) and abnormalities in the person’s metabolic state (e.g., too little or too much blood sodium, too little or too much blood sugar). See Figure 3 for a pie chart of potential seizure triggers.[i]
 


What is epilepsy? Who is at risk for developing epilepsy?

Epilepsy is a condition of unprovoked, recurrent seizures (two or more) due to an underlying, often undiagnosed process.  There are a number of reasons for its occurrence.
  For example, some of the seizure triggers described above, such as bleeding and infection, can scar the brain; over time, this scar tissue becomes electrically unstable and excitable, thereby generating spontaneous seizures.  In other types of epilepsy, the area of excessively excitable tissue is due to a birth-related abnormality (e.g., “focal cortical dysplasia” which is a microscopic disorganization of the brain’s neurons).  In yet other types of epilepsy, the seizures are due to a genetic predisposition that affects the molecules that specifically control the excitability of neurons (the “ion channels” that control the movement of charged ions into or out of the neuron). Figure 4 lists commonly accepted epilepsy risk factors and the degree of risk associated with each factor.[ii] 
 

Diagnosis of seizures and epilepsy:


How is the diagnosis of “seizure” made?

There is often a delay between the onset of seizures and the diagnosis.  Frequently, in our practice, we meet people who have been experiencing seizures for sometime, but do not come to medical attention until someone witnesses the seizure or the seizures begin to interfere with daily life. 
The first step for the health care professional is to decide whether or not the spell(s) the person is experiencing are in fact seizures. See table 1A and table 1B for lists of other conditions that might be mistaken for seizures. Only after the diagnosis of seizure(s) is made does the health care professional then decide whether the criteria for a diagnosis of epilepsy have been met (at least two seizures, both unprovoked).

Table 1A. Spells commonly mistaken for seizures in adults
Fainting spells
Transient ischemic attacks (stroke-like episodes)
Migraine headaches
Sleep disorders
Psychogenic nonepileptic seizures (spells that are frequently mistaken for epileptic seizures but are not caused by abnormal electrical activity in the brain)
Panic attacks
  Table 1B. Spells commonly mistaken for seizures in children
Breath-holding spells
Heartburn-related symptoms (Gastroesophageal reflux)
Tics and other movement disorders
Sleep disorders
Inattention/daydreaming
Because the person is often normal in between seizures, health care professionals rely heavily on the description of the event to make a diagnosis of seizures. And because the person experiencing the seizure often cannot remember details about the event, it is very helpful to interview witnesses to the seizure(s) or even better, have those witnesses present at the medical appointments. 

How is the diagnosis of “epilepsy” made?

Once the diagnosis of seizure(s) is made, the treating health care professional should attempt to exclude the possibility of an acute trigger (a factor that was present at the time of the seizure, but is no longer present) as the cause of the seizure. For example, if an individual experiences a seizure during alcohol intoxication or when he/she has a fever (also known as “febrile seizures”), usually, that individual is not at risk for developing spontaneously generated seizures and is only at risk for future seizures in the setting of the same trigger. After a reasonable determination that the seizure was not provoked, the diagnosis of “epilepsy” is then made.
  As part of the diagnostic process, the doctor may order some blood and/or urine tests (these are usually done only immediately after a seizure to look at blood sugar and sodium levels, kidney function, blood cell counts, and for the appearance of toxic substances in urine), an electroencephalogram (EEG) , and Magnetic Resonance Imaging (MRI, which is a test using a high-powered magnet to produce images) of the brain to help the doctor classify the type of epilepsy and identify any brain structural abnormalities which could be potential causes of epilepsy.
  If the diagnosis is unclear, the doctor may recommend a video/EEG to record the event concurrently on both video and EEG.  Video/EEG is considered the gold-standard test for the diagnosis of seizures.


Types of epileptic seizures


Primary generalized tonic-clonic seizure

Generalized tonic-clonic seizures, commonly referred to as “grand mal” seizures or “convulsions,” are due to synchronous abnormal electrical activity involving both hemispheres of the brain. There is symmetric stiffening and then shaking of the limbs and head position is usually mid-line.
 

Complex partial seizure

Complex partial seizures are due to abnormal electrical activity arising from one area of the brain, with spread to adjacent areas of the brain and/or regions of the brain responsible for memory function, so that the patient is often amnestic (lacking memory) for the seizure itself. Often, the person is unable to respond and appears “confused.”
 

Myoclonic seizure

Myoclonic seizures are like “hiccups” of the brain (actual hiccups are myoclonic muscular contractions of the diaphragm) and are due to very brief, split-second abnormal electrical activity involving either one region or several regions of the brain simultaneously. Some people call these “twitches” or “jerks.”
 

Atonic seizure

Atonic seizures, also known as “drop seizures,” are probably the most debilitating of all seizure types. They occur without warning and cause a person to suddenly become limp and fall dramatically to the ground, frequently injuring their face and/or head. Many of these individuals must wear helmets with face shields. These seizures usually occur in individuals with some form of developmental disability.
 

Secondarily generalized seizure

Secondarily generalized seizures are also known as “grand mal” seizures that start off as partial seizures, meaning that the abnormal electrical activity arises from one area of the brain, but then spreads to both hemispheres of the brain. The patient then has stiffness and shaking of all four limbs, but the appearance is often asymmetric. Sometimes the person’s head will strongly turn to one side and the shaking may start on one side of the body.


What to do in case of a seizure?

First and foremost, do not panic. This is difficult in the setting of seeing a loved one or friend/colleague in the midst of a seizure, but in the majority of cases, seizures stop on their own and do not harm the person.
There was a recent survey concerning workplace stigma and epilepsy that found that individuals were fearful of working with a person with seizures mainly because they felt ill-equipped to help someone in the midst of a seizure[iii]. Therefore, it might be helpful to review this section with family members and close friends.
  1. Time the seizure. Be aware of how long the seizure is lasting. If the seizure appears to be lasting longer than five minutes, call 911. If the person doesn’t appear to be waking up after a seizure or improving with time, the seizure could still be continuing without shaking or trembling; call 911. If the person experiences a seizure, does not wake up, and then experiences a second seizure, call 911.
  2. Remove the person’s glasses or any objects that might harm him/her.
  3. Do not put anything in the person’s mouth. Contrary to a commonly held belief, a person cannot swallow his/her tongue. Instead, you risk damaging teeth or blocking the airway. Unfortunately, the person may bite his/her tongue, but the injury is temporary and will heal. 
  4. Do not roll the person on his/her side until the seizure is over. One study demonstrated a higher rate of shoulder dislocation in the hospital setting when nurses rolled patients on their side during a seizure.
  5. Do not hold the person down. This can cause tearing of ligaments and tendons or injury to joints.
  6. Do not administer medications or water by mouth until the person has fully recovered.
  7. Stay with the person until he/she has fully recovered.
  8. Check to see if the person has injured himself/herself during the seizure. If so, call 911.
For some individuals with frequent prolonged seizures or “clusters” of seizures, it is reasonable to discuss the possibility of treatment with rescue medications.
  Additionally, not every seizure, even unexpected ones, warrants a 911 call. For most individuals with chronic epilepsy, the seizure resolves and the person recovers spontaneously. An unwarranted 911 call could result in burdensome financial costs to the person with epilepsy or unnecessary and prolonged emergency room visits.


Safety and lifestyle issues for persons with epilepsy

The majority of individuals with epilepsy maintain lifestyles enriched with activity and experiences; however, it is also well-established that seizures may be associated with an increased risk of self-injury. These suggested guidelines should take into account the severity and frequency of the seizures. Please refer to the Epilepsy Foundation website  for more details.
1. Never swim alone
2. Take showers, not baths. Even a few inches of standing water can lead to a drowning accident for a person with epilepsy.
3. Avoid unrestricted heights. Avoid ladders, roof tops, and any other situation where a seizure may lead to a dangerous fall.
4. Use alcohol in moderation. If even a few sips of alcohol are associated with a worsening of your seizures, then you should probably abstain from alcohol completely. Generally, however, most adults with epilepsy are able to enjoy a glass of wine now and then.
5. Avoid operating heavy machinery, such as chain saws, lawn motors, and jet skis. Use common sense to assess risk: if you were to experience a seizure while operating a piece of machinery, what are the potential dangers?
6. Herbal medications: speak to your doctor before starting any herbal medication. Some herbal medications may be associated with an increased risk of seizures.


Treatment with medications

Unfortunately, no medication has been identified that prevents the development of epilepsy in someone who is likely to develop seizures later in life (for example, after severe head injury, individuals may have a 30-fold greater risk of developing epilepsy in comparison to the general population). Additionally, none of the anti-seizure medications “cure” an individual of their epilepsy. These medications merely reduce the risk of experiencing seizures in individuals with a propensity to have them.
For many, the decision to take daily medications is a straightforward one. They’ve experienced several seizures with loss of awareness, and they would like to reduce the risk of experiencing any further seizures. For others, however, especially those with a history of a single seizure or very rare seizures, the decision whether to start a chronic medication is difficult. Anti-seizure medications are not without potential side effects and many people are opposed to ingesting chemicals unless absolutely necessary. The decision whether to start chronic medications should be made jointly between the physician and the individual, after a discussion of the potential risks and benefits.  
 

Why might a doctor recommend medications?

1. Risk of seizure recurrence and safety issues: Population-based research suggests that after a single unprovoked seizure (one where no trigger could be identified that incited the seizure), there is a 35% chance of experiencing a second seizure in the next five years.[iv]  After two unprovoked seizures, the risk of experiencing further seizures doubles. And because many seizures are associated with loss of awareness or loss of consciousness, there is the potential for self-injury during seizures, prompting many physicians to advocate treatment.
2. Driving: Many states require that an individual be seizure-free for some period of time on a stable dose of anti-seizure medication in order to apply for a medically suspended driver’s license, especially if one is applying less than a year after the initial seizure (see the Epilepsy Foundation website for the regulations in your state). In some states, if an individual chooses to be without medication, the department of motor vehicles may require that individual to be seizure-free for 6-12 months. The required time period of seizure-freedom is often shorter if one is taking anti-seizure medications. 
3. Sudden unexpected death in epilepsy (SUDEP): This phenomenon, during which a person with known epilepsy is suddenly found dead, possibly after experiencing a seizure, is uncommon and poorly understood. For adults with recent onset of seizures, the risk of SUDEP is about 1 in 3500 per year. For adults with chronic epilepsy, the risk is higher, about 1 in 1000 per year.[v] The risk of SUDEP has been demonstrated to be extremely rare in children. It is generally believed that control of seizures may lessen the chance of SUDEP. 
4. Status epilepticus: Most seizures stop on their own and the majority of seizures terminate within five minutes. Occasionally, however, seizures do not self-terminate and this neurological emergency is called “status epilepticus.” There is ample evidence that generalized convulsive (“grand mal”) seizures lasting longer than 30 minutes can cause brain damage. Some physicians may advocate treatment with medications to reduce the risk of status epilepticus, especially if there is a history of prolonged seizures.


Chronic daily anti-seizure medications

There are over 15 commonly prescribed anti-seizure medications in the United States. Nine new
medications and seven new formulations of already available medications were introduced in the United States in the last 15 years. Choosing which anti-seizure medication is not easy. It is important that the physician takes into account the type of epilepsy and reviews the potential side effects.
Many patients ask, “What is the most effective anti-seizure medication?” The truth is that we don’t know. Few head-to-head research trials comparing anti-seizure medications have been performed.  Additionally, the response of any individual patient to a medication is unpredictable. Even though there are no clear guidelines, many of us who care for patients with epilepsy have certain biases, based on our accumulated experience and judgment. Tables 2a and 2b merely reflect our opinion and are not based on any scientific evidence.

Table 2a: Common anti-seizure medications used in the treatment of partial seizures (with or without loss of awareness) and secondarily generalized seizures (“grand mal” seizures that start in one region of the brain)

Table 2b: Common anti-seizure medications used in the treatment of primary generalized tonic-clonic seizures (“grand mal seizures” starting in both hemispheres of the brain simultaneously and synchronously)

In these tables, we have ranked certain medications based on effectiveness, which we have designated to mean “control of seizures” (1-10 with “1”being poor control of seizures and “10” being outstanding control of seizures) , and on tolerability, which we have interpreted to mean “relative freedom from unbearable side effects” (1-10, with “1” being intolerable and “10” being easy-to-tolerate). Because the choice of a particular anti-seizure medication is based on the type of seizures that an individual is habitually experiencing, the tables are organized in that fashion, separating partial seizures and secondarily generalized seizures (which are seizures that appear to involve both hemispheres of the brain at the same time, but start from one area of the brain) from generalized seizures (seizures that start in both hemispheres at the same time). The medications listed in the generalized seizures table are considered “broad-spectrum” medications, meaning that they can be used for any type of epilepsy. Some of the medications listed in the partial seizures table can only be used in partial epilepsy and may worsen some of the generalized epilepsies.


Rescue medications

Some individuals with chronic epilepsy experience predictable clusters of repetitive seizures (several seizures over a short period of time) or experience a seizure much longer in duration than his/her typical seizures. In such circumstances, a medication that works quickly to shorten the duration of a seizure or prevent further seizures that day may be of benefit. These medications are known as “rescue” or “abortive” medications and are generally of the “benzodiazepine” class of medications. The only FDA-approved medication for this purpose is rectal diazepam gel (brand-name Diastat ®). However, because rectal administration can be inconvenient and many patients have an aversion to this form of administration, there is a dire need for a safe, FDA-approved, easy-to-administer rescue medication. At the UCSF Epilepsy Center, we routinely prescribe oral lorazepam, intranasal (in the nose), midazolam, and buccal (in the area between cheek and gum) midazolam for this purpose, although none of these formulations is FDA-approved for this indication. We advise you to speak to your physician to determine whether “rescue medications” are appropriate.


Treatment with epilepsy surgery

For individuals who cannot attain full seizure control with medications, epilepsy surgery should be considered.  The evaluation begins with a referral to an epilepsy center (go to the National Association of Epilepsy Centers website for the nearest location.). The goal of the evaluation is to identify the region of the brain responsible for the seizures and determine if it is safe to remove that brain region.
Testing usually involves

Other tests might include
For some individuals with hard-to-control seizures, surgical treatment may be vastly superior to best medical therapy, as demonstrated in a randomized, controlled trial performed in Canada.[vi]



Treatment with the vagus nerve stimulator (VNS)

Epilepsy specialists generally consider implantation of the vagus nerve stimulator (VNS) if resective epilepsy surgery is not possible (for example, seizures are coming from multiple areas of the brain), and seizures are not fully controlled despite best medical therapy. VNS almost never completely controls an individual’s seizures, but it may reduce how often the person experiences seizures, as well as the duration or the severity of the seizures. The results are at best equivalent to adding another anti-seizure medication. In its favor, VNS is associated with side effects different from anti-seizure medications. For an individual who is already nearly intoxicated from multiple anti-seizure medications, VNS potentially allows for additional treatment without worsening medication side effects.

Treatment with ketogenic diet

Developed in the 1920s, the ketogenic diet has experienced a “comeback” in the past 20 years; however, there are few individuals who have the will-power to maintain the diet, and generally it is administered by parents/caregivers for children with severe epilepsy not responsive to medications. The diet in practice requires a very strict regimen low in calories, starch, and sugar – and high in fat. The process begins with a period of fasting (to attain “ketosis”). All food must be carefully weighed and the urine must be closely monitored (a dipstick is placed in the urine to measure the urine ketones).  A typical meal may consist of the following: ¾ ounce of ham, ¾ ounce of apple sauce, 2 tablespoons of heavy cream, 2 tablespoons of butter. The long-term effects of such a diet are unknown. A mistake in the diet could result in a loss of “ketosis” and a loss of seizure control.
 

Epilepsy in special populations


Women
There are several issues unique to women with epilepsy.

1. Family planning: Some seizure medications can reduce the effectiveness of birth control pills or other hormonal contraceptives. Additionally, hormonal contraceptives may reduce the blood levels of certain anti-seizure medications. It is imperative to review one’s medication regimen with a physician before starting hormonal contraceptives.
2. Anti-seizure medications and pregnancy: Anti-seizure medications are associated with an increased risk (estimated to be around two times the general population’s risk) of major birth defects in fetuses of women with epilepsy. Certain medications have been associated with higher risks, but the information is insufficient to recommend any one medication.  The goals of prenatal planning are the following (all of these goals are to be achieved before becoming pregnant):

a. Reduce the number of anti-seizure medications (preferably one medication) but still maintain control of convulsive seizures and seizures associated with a high risk of self-injury.
b. Decrease the total dosage of anti-seizure medications, but still maintain seizure control.
c. For some anti-seizure medications, it is helpful to send blood tests to determine the level of anti-seizure medications in the blood stream before becoming pregnant.  Metabolism of anti-seizure medications may change during pregnancy and blood levels will have to be closely monitored.
d. Supplement with folic acid and prenatal multivitamins.
3. Menstrual-cycle related seizures: Some women notice that their seizures are worse around the time of ovulation (mid-cycle) or three days before their menstrual period or the first three days of menstrual flow. It is helpful to keep a diary detailing the dates of seizures and the dates of your menstrual period and review this with your doctor.

Elderly
Age is an independent risk factor for developing epilepsy and an individual 75 years or older has four times the risk of developing epilepsy in comparison to a 20 year old.  Unfortunately, little is known about anti-seizure medications in the elderly. We suspect that medication doses must be adjusted for the elderly because of decreased kidney and liver function. Additionally, elderly individuals often have other medical conditions and are taking multiple medications in addition to their anti-seizure medications. This increases the risk of complications due to drug-drug interactions.

Children
Treating epilepsy in children also requires special expertise for several different reasons.
1. Learning and development: Treatment of epilepsy must take into account the developing brain and the effects of seizures and medication on learning and the achievement of developmental milestones.
2. Age-dependent epilepsies: Some types of epilepsy begin in childhood and may be associated with a strong chance of going away later in life. Other types of epilepsy have a better prognosis if treated effectively at their onset.  It is therefore extremely important that accurate diagnosis is made quickly and the patient and family receive adequate counseling about prognosis.  
 3. Concurrent conditions: Autism, attention deficit/hyperactivity disorder, developmental delay, cerebral palsy and many other neurological conditions are often associated with epilepsy. Effective treatment of seizures must also incorporate attention to such additional conditions.  

 


Future directions

Despite recent advances in epilepsy drug development and epilepsy surgery, there are still many people who suffer from uncontrolled seizures. We believe that in order to find new therapies and new medications, we must better understand the disease itself. One direction is the study of the genes that are involved in seizures and epilepsy. We are part of a team of scientists who are participating in the Epilepsy Phenome/Genome Project (EPGP) which is funded by the National Institutes of Health (NIH). To learn more about this project and to see if you, a family member, or someone else you know may be eligible to participate, please go to http://www.epgp.org for more information.


Links to other websites:


www.ninds.nih.gov/disorders/epilepsy/epilepsy.htm
www.epilepsyfoundation.org
www.epilepsy.com
www.naec-epilepsy.org
www.aedpregnancyregistry.org
www.cureepilepsy.org
www.aesnet.org
www.epilepsyconsortium.org  
www.epgp.org

 


Books about epilepsy

Carl Bazil.  Living well with epilepsy and other seizure disorders: an expert explains what you really need to know.
John M. Freeman, Eileen P.G. Vining and Diana J. Pillas.  Seizures and epilepsy in childhood: a guide (Johns Hopkins press health book).
Orrin Devinsky.  Epilepsy: patient and family guide.
Stacey Chillemmi and Blanca Vasquez.  Epilepsy and pregnancy. 
Elaine Willey.  Epilepsy: A Cleveland Clinic guide. 
Andrew Wilner.  Epilepsy: 199 answers.  

[i] Annegers JF, Hauser WA, Lee JR-J, Rocca WA. The incidence of acute symptomatic seizures in Rochester, Minnesota: 1935-1984. Epilepsia 1995;36:327-333
[ii] Hauser WA. Incidence and Prevalence in Epilepsy: A Comprehensive Textbook, ed J.Engel, Jr. and T.A. Pedley. Lippincott-Raven Publishers, Philadelphia, 1997.
[iii] Harden CL, Kossoy A, Vera S, Nikolov B. Reaction to epilepsy in the workplace. Epilepsia. 2004 Sep;45(9):1134-40.
[iv] Hauser WA, Rich SS, Lee JR, Annegers JF, Anderson VE. Risk of recurrent seizures after two unprovoked seizures. N Engl J Med. 1998 Feb 12;338(7):429-34
[v] Tomson T, Walczak T, Sillanpaa M, Sander JW. Sudden unexpected death in epilepsy: a review of incidence and risk factors. Epilepsia. 2005;46 Suppl 11:54-61. Review.

[vi] Wiebe S, Blume WT, Girvin JP, Eliasziw M; Effectiveness and Efficiency of Surgery for Temporal Lobe Epilepsy Study Group. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med. 2001 Aug 2;345(5):311-8.