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!

The post Marijuana for the treatment of epilepsy appeared first on Minnesota Epilepsy Group.

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.

ARTICLE HIGHLIGHTS

• A seizure is a temporary change in the electrical activity of the brain. A seizure is an excess of electricity- like a power surge. This is what causes the symptoms of a seizure.
• When a first seizure occurs, a thorough evaluation is indicated. The evaluation often includes: 1) History and physical exam; 2) EEG; 3) MRI brain; and 4) blood work.
• Seizures can occur at any age—most commonly noted during early childhood and after the age of 60 years.
• In a patient who has had one seizure in their life and who is not started on a seizure medication, the risk of another seizure in the next two years is approximately 40-50%. Treatment with a seizure medication may reduce this chance by approximately half.
• The strongest predictors of seizure recurrence after the first seizure:
  • Abnormal EEG
  • Underlying condition that may make seizure activity more likely. Examples:
    • Birth related issues
    • Stroke
    • Head trauma
    • Brain tumor
• The decision to treat or not to treat a patient with a seizure medication after one seizure should be tailored to the individual patient’s clinical situation. Factors to consider:
  • Is the patient at high or low risk for another seizure?
  • Is the patient driving?
  • Risk of injury if patient has a seizure.
  • Possible adverse side effects of the seizure medication.
  • With a thorough and thoughtful approach, the optimal treatment plan can be provided.
    

INTRODUCTION

Patients and family are often absolutely shocked when seizure activity first occurs. The seizure itself may be very dramatic and frightening. The seizure could have resulted in injury. There are almost always a multitude of questions:

• What exactly is a seizure?
• Do I have epilepsy?
• What caused the seizure?
• How could this happen at my age?
• Will the seizure happen again?
• Do I need to go on a seizure medication?

The purpose of the article is to address the most commonly asked questions by patients with new onset seizures. A patient’s first seizure is one of the most frequent and most important consults that we see. Our experience tells us that education is extremely important and typically will significantly relieve stress in those who recently experienced their initial seizure.

What exactly is a seizure?

A seizure is a temporary change in the electrical activity of the brain. In the normal state, the cells on the surface o f the brain (the neurons) communicate and function by an organized flow of electricity. In a seizure, excessive electrical charge occurs—this excessive electricity results in abnormal brain activity. This abnormal activity will lead to the symptoms of the seizure.

An example will be useful to clarify this concept. As many people know, the right side of the brain controls the left side of the body. In the right front part of the brain, there is an area that controls left hand function. When I think, “move my left hand”, a smooth and organized flow of electricity occurs in the right front part of my brain—resulting in the movement of my left hand. Now imagine that a swarm of electrical activity is occurring in the right front part of my brain. Picture a major electrical power surge! The abnormal electrical activity would result in abnormal left hand movements. This would often result in jerking in my left hand. This is what a seizure is—abnormal electricity in the brain causing abnormal movements or other symptoms.

Now, let’s say the seizure activity in the above example became more widespread. Instead of being just in my right frontal region, it spread to involve my entire brain! You can imagine that if my whole brain was affected by excessive electrical activity, then the effects on my body would be dramatic- this could result in a “grand mal” seizure. A “grand mal” seizure is where a person collapses to the ground and has whole body shaking activity.

Do I have epilepsy?

Epilepsy is the tendency to have recurrent seizures. Using the most commonly used definition, having one seizure does not meet criteria for having epilepsy. In contrast, having 2 or more seizures in your life usually does meet criteria for epilepsy.

There can be exceptions where a patient may have two seizures in their life and not have epilepsy. The key is whether or not the seizures are provoked by a temporary condition. An example is a patient with diabetes who has their glucose drop to dangerously low levels. Such a patient could have two or more seizures and still not meet criteria for epilepsy—because the seizures were provoked. In contrast, patients with epilepsy have an underlying tendency to have recurrent seizures, even without any obvious provocation.

“Do I have epilepsy?” is a very common question at our clinic. This question is even asked by patients who have had epilepsy for many years. Often times, patients are feeling stressed about the diagnosis of epilepsy. A clear description of what epilepsy is all about can be very helpful for patients to better understand the diagnosis. A clear explanation may significantly relieve stress. We will often review the many different types of epilepsy. Patients can develop epilepsy at any age. Patients with epilepsy run the gamut in terms of physical and mental abilities. Judges, doctors, writers, musicians, artists, teachers have patients with epilepsy in their ranks.

What caused the seizure?

This is an extremely important question. The doctor’s job is to do the detective work to answer this question as accurately as possible. Identifiable causes of seizures are typically due to conditions that disrupt the normal flow of electricity in the brain. Conditions such as head-trauma, stroke and infection can cause scarring on the brain. This will disrupt the wiring between the brain’s cells (neurons). This will in turn cause the potential for abnormal electrical charge from those cells. Excessive electrical charge from neurons can produce seizures.

The most common cause of epilepsy that begins in childhood is birth related issues. In adults, stroke is the most common reason to develop epilepsy. Stroke accounts for just over 10% of new-onset epilepsy and approximately one-third of cases with an identified cause. Brain tumors (approximately 6%) and Alzheimer’s Disease/other dementias (approximately 7%) are other common causes. Depending on where you live in the world, infection may be a very common, if not the most common, cause of epilepsy.

The arrow marks an area of stroke. This is a potential area where seizures could start.

Certain conditions, if they apply to you, can dramatically increase your risk of seizures. For example, a penetrating head injury, such as a bullet piercing the brain, can increase the risk of developing epilepsy 500 times (compared to the general population). In those patients with encephalitis (a severe brain infection), > 20% of patients may develop epilepsy (Neurology Asia 2008 Misra).

Despite extensive work-up, including history, physical examination, EEG, MRI and blood testing, a large percentage of patients still do not have an identified cause for their seizures. This is in some ways reassuring—at least the patient does not have a stroke, tumor or other life-threatening illness. On the other hand, the patient and family are often very frustrated about not getting answers. Most large epidemiologic studies report that the cause of a patient’s epilepsy is unknown in greater than 50-60% of cases. As brain imaging and other technologies improve, it is hoped that the “unknown” category shrinks to as close to zero as possible. One area of very hot research is in the genetics of epilepsy—this may explain a big part of the “unknowns.”

How can this happen at my age?

Seizures can start at any age. This is a surprising fact for most people learning about epilepsy. Even more surprising is that the highest incidence of epilepsy is in the older population (after age 60, 70 and beyond). Most people think of seizures beginning in early childhood. This is a very common time for new-onset seizures. When a 30 year-old man suddenly has his first seizure of his life out of the blue—the patient is usually shocked that seizure activity could strike him. A review of epidemiological data supports that seizures can occur at any age, but the incidence is relatively lower during early adulthood. After age 60 years, the incidence of seizures increases dramatically as conditions such as stroke and tumor become more common.

Will the seizure happen again?

This is a very important and often emotionally charged question. When someone has had their first seizure, there is typically great concern about having more seizures. The patient may have real concerns about loss of control. This can be frustrating and anxiety provoking! An effective way to address the patient’s fears is to provide accurate information about what the literature says in regards to seizure recurrence. Also, it is important to have the information tailored to the patient’s specific clinical situation.

When a patient has had a single seizure, the chance of having more seizure activity in the next two years ranges from 24% to greater than 60%. This is a very wide range! The doctor’s job is to carefully analyze the patient’s case and determine the patient’s individual risk. There have been excellent studies which help guide the clinician (FIRST study, MESS study). For most patients, it can be determined if they are at low risk of seizure recurrence (approximately 24%), intermediate risk (approximately 40%) or high risk (>60%). The evaluation to determine an individual patient’s risk of seizures typically includes a thorough history and physical examination, an EEG and an MRI of the brain. Further testing may be considered, depending on the patient’s situation.

EEG is one of the most effective tools to determine a patient’s likelihood of more seizures. Abnormalities on EEG, especially discharges know as sharp-wave or spike-wave discharges, would indicate a relatively higher risk of seizure recurrence. When a patient has an EEG, each electrode picks up the electrical activity from the brain. A normal EEG brain wave looks like a smooth squiggly line. Sharp-waves or spike-wave discharges are sudden, brief, sharply contoured discharges that typically last for less than one second. Sharp-waves and spike-waves are due to very brief abnormal electrical charge from the brain. It should make sense that if a brain is firing abnormal electrical charge represented as sharp-waves or spike-waves, the brain has a higher likelihood to produce seizures. Studies show that sharp-waves and spike-waves are indeed associated with higher risk of seizures.

Another important factor in determining a patient’s risk of seizure activity is whether or not the patient has an underlying condition which would make having seizures more likely. Many of these conditions can be identified by detailed history taking and performing an MRI of the brain. The patient should be asked whether they have a history of:  infection of the brain (meningitis), stroke, head-trauma, dementia, brain tumor or family history of seizures/other neurological conditions. Such underlying conditions can significantly increase the chances of having seizures. The patient should also be asked about whether they were awake or asleep at the time of their first seizure. Patient’s who experience their first seizure out of sleep appear to be at double the risk of seizure recurrence, compared to those who had their first seizure while awake.

There are some clinical factors which are possibly, but not definitely, associated with an increased risk of seizures. The data is just too inconclusive. These factors include: 1) history of seizure activity in the setting of fever as a young child; and 2) age of initial seizure.

Table- Patients followed after first seizure in their life. The chance of having a second seizure in 2 years (Berg, Neurology, 1991):

*Underlying condition: A condition which could make seizures more likely. Examples: brain, tumor, stroke, head trauma and dementia.

Do I need to go on a seizure medication?

“To treat” or “not to treat”? A key question after a patient has their first seizure. This is a very important question and requires a thorough evaluation to arrive at the best recommendation. There are several critical issues to consider:

• What is the chance for further seizures?
• Would another seizure cause serious injury?
• What are the negative consequences of taking a seizure medication?

In a patient who has had one seizure in their life and who is not started on a seizure medication, the risk of another seizure in the next two years is approximately 40-50%. Treatment with a seizure medication may reduce this chance by approximately half. Approximately two-thirds of seizure recurrences are within 6 months of the initial seizure. Seizure medications are typically recommended for patients at high risk of having further seizures. Patients with highly abnormal EEGs or with an underlying condition such as stroke, brain infection would be considered at high risk and a seizure medication is typically prescribed.  Such patients may have a greater than 50% chance of having a seizure within two years. In addition, patients who have had two seizures have an approximately 70% chance of further seizure activity. Such patients usually are recommended for treatment.

The decision to start a seizure medication is actually more complicated in those with a single seizure and no abnormalities found on work-up. Such patients would have a normal exam, normal EEG and normal MRI of the brain. Such a patient would be at relatively low risk for seizure recurrence. Some patients take the approach that they want to do anything they can to reduce the chance of seizure activity and very much want to try a seizure medication. In contrast, some patients take the view that the seizures may never happen again, so they may prefer no medications. Some people just do not want to take medications, period!

In addition to considering the likelihood of seizure recurrence, other important issues need to be considered. Lifestyle is important to consider when evaluating a patient after their first seizure. Medication treatment may be recommended in those with work activity or hobbies that could be dangerous if they were to have a seizure. Those who drive for a living, work at heights or around dangerous machinery, usually want to take whatever steps possible to prevent seizures. We have seen the close calls or tragically serious injuries that can occur to patients who have seizures at the wrong time in dangerous work environments. Even those patients who simply drive to and from work may be very appropriately concerned about seizures. A seizure behind the wheel of a car can have terrible consequences. The need to drive as safely as possible prompts many adults to take seizure medications.

While some lifestyle factors may lead to the starting of a seizure medication, other life circumstances may prompt the decision to not take a seizure medication. For example, women who are considering pregnancy and who at very low risk for seizure activity may choose to not take a seizure medication. A child’s potential for learning should also be considered. The risk of adversely affecting a child’s learning potential with seizure medication side effects needs to be weighed in the decision to treat or not. In children who are at low risk for seizures, it may be very reasonable to not start a seizure medication.

During discussions about starting a seizure medication, families often want to know if a seizure medication will prevent the development of epilepsy. The short answer is: NO. Seizure medications will suppress the symptoms of seizure activity. They can reduce the frequency and severity of seizures. But long-term studies indicate that after several years of follow-up (for example, 5 years or longer), those who are treated after their first seizure, when compared to those who delayed treatment, were equally likely to have a second seizure (and thus meet criteria for epilepsy).

An example may help clarify this complicated concept. If a patient has a brain infection, then treatment with an antibiotic will eradicate the infection. The antibiotic can be stopped after a few days, and the infection does not come back. Thus, the antibiotic was a true cure for the infection. In contrast, a seizure medication is not a cure for epilepsy. Rather, it suppresses the symptom of seizure activity- making seizures less frequent and less intense. The development of epilepsy comes down to the patient’s underlying predisposition. If the patient is predisposed to have recurrent seizures, then they will go on to develop epilepsy, and, unfortunately, starting a seizure medication does not prevent that. Research is ongoing attempting to discover ways to truly cure epilepsy. That goal remains in the future.

Although seizure medications can be very useful to improve seizure control, the patient and the doctor need to consider the negative effects of seizure medications. Approximately one-third of patients taking seizure medications report side effects. Dizziness, sleepiness and cognitive problems could adversely affect a patient’s quality of life. There can be serious reactions to seizure medications, such as liver or bone marrow impairment. Long-term problems, such as bone density loss, should also be discussed. Thus, even though many patients who have their first seizure may benefit from starting a seizure medication, the risks and benefits of starting a medication needs to be carefully weighed.

CONCLUSIONS

Experiencing the first seizure in your life can be very stressful. Education for the patient is critical. The decision to start a seizure medication should be carefully weighed and tailored to the patient’s individual clinical situation. Patients with abnormalities on EEG or MRI may be at higher risk of having recurrent seizures. If pertinent, driving needs to be discussed in detail. Also, the pros and cons of seizure medications needs to addressed. With a thorough and thoughtful approach, the optimal treatment plan can be provided.

REFERENCES

Banerjee P, Hauser A. Incidence and Prevalence. In: Engel J, Pedley T, editors. Epilepsy: A comprehensive textbook. Philadelphia: Lippincott Williams & Wilkins; 2008: 45-56.

Beghi E, Berg A, Shinnar S, Hauser A. Treatment of single and infrequent seizures. . In: Engel J, Pedley T, editors. Epilepsy: A comprehensive textbook. Philadelphia: Lippincott Williams & Wilkins; 2008: 1327-1333.

PHOTO CREDITS

Picture of electricity in brain: Better Health Research 1.24.2011

MRI brain picture: Theuniversityhospital.com

The post Information on New Onset Seizure Activity appeared first on Minnesota Epilepsy Group.

The brand vs generic antiepileptic drug (AED) controversy remains a hot debate in the epilepsy community. Generic AEDs are often much less expensive for patients compared to brand AEDs.  However, brand AEDs may provide more reliable seizure medication levels which could potentially reduce side effects and improve seizure control. We recommend that decisions about whether to use a brand or generic AED should be tailored to the individual patient’s clinical situation. The use of brand AEDs may be preferable in certain high risk groups. Examples of higher risk groups include: 1) patients with significant risk for prolonged and dangerous seizures; 2) pregnant patients; and 3) patients with well controlled seizures who are driving.

INTRODUCTION

In the last few years, several generic alternatives for antiepileptic drugs (AED) have become available on the market. A major and often heated debate has ensued—to treat patients with generic AEDs to save money or to demand brand only AEDs to ensure optimal seizure control and side effect profile. Proponents of both sides of the argument have data to support their respective positions. At this time, the brand vs generic debate remains very controversial. The arguments can be summarized as follows:

PRO BRAND AED ARGUMENT

• Consistent manufacturer: When a patient is taking a brand AED, they are receiving medication from the same manufacturer. In contrast, each AED can have many (often > 10) manufacturers. This can lead to a different appearing pill when a patient goes to the pharmacy to pick-up their medications. More importantly, the various generic formulations may have slight differences compared to brand AED for absorption into the body and metabolism from the body. These differences could lead to side effects (AED levels shoot-up too high) or seizures (AED levels drop too low).
• Risk of seizures: For some patients, even one break-through seizure can be a disaster. Patients with very difficult to control seizures may go into convulsive status epilepticus (prolonged seizure activity that can be life-threatening). Patients who are pregnant could have seizures that result in injury to a fetus. Many patients with well controlled seizures are driving- a single seizure while driving could result in serious injury or death to the patient or others on the road. These issues need to be considered when deciding about taking the brand vs generic AED.
• Evidence from the literature: There is some evidence in the literature suggesting that changing from the brand to the generic formulation of an AED can result in seizure activity. For example, a retrospective study (Zachary 2009) reviewed seizure related emergency/urgent care utilization (emergency room visits and hospitalizations). They compared those who had been switched from brand to generic AEDs vs those who remained on the brand AED. Patients who were switched to generic AEDs were significantly more likely to use emergency/urgent medical care (11.3% of generic AED patients vs 6.2% of controls). Although this is not clear proof, the study does support the concept that switching to a generic AED may result in an increased risk of serious break-through seizures.
• Overall costs: Although generic AEDs are cheaper compared to brand AEDs, there is an argument that the overall costs (cost of medication, clinic visits, emergency room visits, and hospitalizations) are less expensive with the brand compared to the generic AED.  For example, a pharmacoeconomic study (Lelorier 2008) indicated that the savings associated with switching to a generic AED were offset by higher costs due to increased utilization of medical services (clinic visits, emergency room visits and hospitalizations).

PRO GENERIC AED ARGUMENT

• Generic AEDs are cheaper: Generic AEDs are often dramatically less expensive compared to brand AEDs. The difference can be several hundred dollars a month difference. Financial realities can create a situation in which a patient can only afford the generic AED.
• No significant differences between brand and generic AEDs: The FDA mandates that the brand and generic AEDs are extremely close in terms of how they are metabolized. There are strict criteria for bioequivalence. The FDA definition of bioequivalence is: “The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.” The bottom-line is that brand and generic AEDs are very similar in how they work and how they are cleared from the body. For example, it has been shown that the average plasma AED concentration differs between the brand and generic AED by no more than 5-7% (Perucca 2006). This small difference is usually not considered clinically significant.
• Potential cost savings: Generic AEDs can significantly reduce the overall medication related health-care costs. It has been estimated that laws which mandate generic medication use could reduce the cost of prescribed medications by 10-15%. This could translate into a $14 billion reduced expenditure on medications.
• No definitive proof that brand is better: The evidence that seizure control worsens or side effects occur as a direct result of changing from brand to generic AED are not conclusive.

CONCLUSIONS

The brand vs generic AED debate is complicated. Generic medications may be significantly less expensive than brand AEDs. However, there is some evidence that brand AEDs may provide moretreatment to the individual patient. For some patients, break through seizures could be potentially dangerous—brand AEDs may be preferable in such patients.

If you have questions about this important topic, please post a comment.

To schedule a visit at the Minnesota Epilepsy Group Hudson clinic, please call 715-377-1616.

REFERENCES

Gidal B, Tomson T. Debate: Substitution of generic drugs in epilepsy: Is there cause for concern? Epilepsia 2008;49(Suppl. 9): 56-62.

Lelorier J, Duh MS, Paradis P, et al. Economic impact of generic substitution of lamotrigine: projected costs in the US using findings in a Canadian setting. Current Med Res Opin 2008;24:1069-1081.

Perucca E, Albani F, Capovilla G, et al. Recommendations of the Italian League Against Epilepsy work group on generic products of antiepileptic drugs. Epilepsia 47(Suppl. 5):16-20.

Privitera M. Generic Antiepileptic drugs: current controversies and future directions. Epilepsy Currents 2008;8:113-117.

Zachary WM, Doan QD, Clewell JD, Smith BJ. Case-control analysis of ambulance, emergency room or inpatient hospital events for epilepsy and antiepileptic drug formulation changes. Epilepsia 2009;50:493-500.

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