The (Potential) Problems with Generics in Epilepsy Carl Bazil MD, PhD Associate Professor of Clinical Neurology College of Physicians and Surgeons Columbia University.

In the past year or so, new generic equivalents have been approved for lamotrigine, topiramate, oxcarbazepine, and levetiracetam. While this is good news in that cost consciousness is always an issue in medicine, and generic equivalents usually offer substantial savings, there is still concern that epilepsy is a condition where more caution should be exercised.

The American Food and Drug Administration sets strict standards for the approval of generic equivalents. Each must be compared to the approved brand-name drug in normal volunteers to ensure that two measures, Area Under the Curve (AUC, a measure of total drug absorbed) and Cmax (the peak concentration) are comparable. To do this, single doses of the proposed generic are tested against the brand name drug. The 95% confidence interval for each of these measures must fall between 80 and 125% of the branded drug. Usually, that translates into an average variability of 3-5%. For most conditions, this would be an insignificant amount. Think of a headache: if a 600 mg generic ibuprofen actually delivers only 570 mg, that probably doesn’t translate into a major problem for the patient. At worst, the headache may last a bit longer, or another dose would be needed.

In epilepsy, there is a relatively narrow therapeutic window that must be maintained for extended periods of time. Too much, and the patient experiences toxicity. Too little, and a seizure may occur. So the consequences of a slight fall in delivered dose may be severe: a patient who was seizure free may have a sudden seizure, potentially resulting in injury, loss of driver’s license, or even death. Under most circumstances we wouldn’t expect a 5% change to cause this. However, there are other, at least theoretical reasons that that variability could be greater. First, generic equivalents are tested in normal volunteers. Epilepsy patients may have greater differences in absorption or metabolism due to their condition or to concurrently administered drugs. Second, generic agents are not tested against each other (only to the brand). As there are multiple, sometimes dozens, of approved generic manufacturers for each epilepsy drug, this results in increased potential for variability; each time the patient returns to the pharmacy, a generic equivalent from a different manufacturer may be dispensed. The roughly 5% variability compared to the brand could then become a 10% swing from one generic to another. A handful of states (including Hawaii and North Carolina) have limited changes in generic manufacturers dispensed to a given epilepsy patient. Several others (Florida, Kentucky, Maine, Maryland, Minnesota, Missouri, and Rhode Island) limit substitution for drugs , however the practice of substitution is still the norm.

How often do problems occur? We really don’t know. While most neurologists have anecdotes of a problem resulting from a generic switch – a sudden seizure in a previously controlled patient being most common – it is often difficult to prove it is due to the generic substitution. We all certainly see patients with unexplained seizures without a change in brand. There are a few cases where the time course and documented changes in levels make generic change the likely culprit but these are rare.

"What’s New on Epilepsy.com Professionals in May?"

Medication Management Joyce Cramer President, Epilepsy Therapy Project Associate Research Scientist, Yale University School of Medicine

Do you take your medication the way you expect your patients to take theirs?
Doctors are notoriously unreliable in following medical instructions, particularly taking medication. Healthcare professionals have the knowledge to understand the importance of preventive and symptomatic treatment; they know what health behaviors should be accomplished regularly (e.g., diet, exercise, medication); they understand the mechanisms of action and pharmacology of medications; they have the intelligence to plan and the self-regimentation to maintain a pattern of personal healthcare. True, but unrelated to actual behaviors. Of course, some healthcare professionals do follow the advice they give to patients, but not all. The Doctors’ Health Study revealed that a large proportion of doctors who volunteered for the study were not eligible for randomization because they were so poorly compliant with the dosing during the placebo run-in phase.

Kastrissios et al.¹ asked medical students to take Tic Tac candy pills for two weeks, in a BID or TID regimen. They discovered that only 2/3 of “doses” were taken as agreed, 47% of doses were taken at the prescribed frequency (BID or TID), and 29% were taken at the prescribed intervals (hours apart). The Physicians’ Health Study II was designed to assess the efficacy of vitamin C, vitamin E, beta-carotene, and a multivitamin in reducing cardiovascular risk. Doctors who enrolled were sent calendar packs containing placebos of all four of the study drugs. Of the 11,128 willing to participate, only 7,001 (63%) took the pills regularly during the baseline (placebo run-in phase) and said they wanted to continue with the study².

I wrote an article for www.epilepsy.com geared toward patients called: "The Titanic Impact of Medication Compliance on Epilepsy"³ to explain that seizures may be related to missed doses, inadequate scheduling, and other remediable factors. Forgetfulness remains the main reason people report for missed doses, not unexpected for people commonly having memory difficulties. Rather than expecting patients to accommodate to know how to take their medication, or to use dosing schedules that are not convenient, try to adjust the medication to what the patient will be able to accomplish.

Of course, it’s difficult to counsel patients on medication management unless you know a few methods to impart to patients. Watch for a new CME program next month with tips on how to teach patients approaches to taking their (essential) antiepileptic drugs.

Transition and Transfer: the rocky road from pediatric to adult epilepsy care Peter Camfield MD, FRCP(C) Professor of Pediatrics Dalhousie University Halifax, Nova Scotia, Canada Carol Camfield MD, FRCP(C) Professor of Pediatrics Dalhousie University Halifax, Nova Scotia, Canada

A wise senior child neurologist suggested to us that if we did our job properly in pediatric epilepsy there would be no one to pass along to our adult colleagues. We wish it were so simple! About 50% of epilepsy that begins in childhood persists into the adult years. In our experience, the two biggest groups are patients with mental handicap (with a variety of epilepsy syndromes) and patients with idiopathic generalized epilepsy, especially Juvenile Myoclonic Epilepsy. There are others with cryptogenic or symptomatic partial epilepsies whose disorder resembles the partial epilepsies of adulthood.

1. Dealing with the adolescent/youth with relatively normal intelligence.

It is not easy to successfully navigate adolescence with persistent epilepsy. The epilepsy adds special restraints – regular sleep hours, regular medication, no alcohol, and some restrictions on activities, especially driving, uncertainty about contraceptive efficacy for girls. Epilepsy is a hidden handicap that can only be understood by others if they are told about it. Yet, we know that more that 50% of US teenagers would not date someone with epilepsy and view epilepsy as a mental illness. So how would you develop the courage to tell others?

Pediatric epilepsy care is family focused. Adult epilepsy care tends to be focused on the individual. When you are child, your parents make sure that you don’t forget your medication and direct you to go to bed early. Your doctor concurs with this approach. When you are an adult, you learn that all this is your choice, but you may not understand the consequences of poor compliance or poor lifestyle choices. Your adult doctor may not seem to care as long as you understand the facts and make your choices.

Simple transfer from pediatric to adult is potentially brutal (1). The child, now adult, does not understand his/her illness well – much of the family instruction was years ago and directed to the parents. The adult epileptologist only has a case summary and is unlikely to really understand how much of a burden epilepsy is to an adolescent, even if the seizures are well controlled.

Transition from pediatric to adult care is conceptually more attractive. Transition means that the adolescent, family and adult epileptologist all learn the critical steps to allow the youth with epilepsy to be treated in the adult world. Transition is a process that takes time and needs to begin in the pediatric setting. The adolescent learns what they need to know to explain their disorder. They learn the names of the drugs, the doses, the side effects and what needs to be done to fill a prescription. They understand that they have epilepsy but are not “epileptic”. Transition for epilepsy care can take many forms but is virtually undescribed in peer-reviewed literature. Without any data to support our contention, we think that a transition clinic that is staffed by both adult and pediatric epilepsy specialists is needed. A number of joint adult/pediatric visits should take place until transfer to adult care is deemed appropriate. The family needs to see that the pediatric team is still involved and that communication with the adult team is complete. The adult team needs to understand at what stage this particular adolescent is in the process of becoming an adult and design a therapeutic approach that is appropriate. If the adolescent is still in the “invulnerable stage” (nothing bad can happen to me), then more family involvement is needed. The pediatric team needs to “back off” to allow the adolescent to take responsibility.

2. Dealing with the adolescent/youth with mental handicap

The situation is quite different when the adolescent/youth has mental handicap. It is worth remembering that possibly 50% of epilepsy that starts in childhood and persists into adulthood is accompanied by mental handicap. Now parents and guardians must have an ongoing supervisory role. But, how much is too much and how much is too little?

Pediatric epilepsy specialists should have a fairly good understanding of how much independent judgment by these special adolescents is possible. This is likely more difficult for the adult neurologist. And where do the parents fit in? Suddenly, the individual focused adult health care system breaks down because the patients with mental handicap cannot represent themselves completely.

Parents have many years of trust in the pediatric system and need to be convinced that the adult system is equally nurturing, but it rarely is. They know when things are not going well but they may not know what to do about these issues in the adult system. Eventually the parents will need to surrender this responsibility to someone else – a guardian or an institution. So, the transition is more for the parents than the patient. The adult physician has few models and little experience in this arena. We often hear from our adult colleagues that they like children but could not deal with parents. If the child is mentally handicapped, there is no escape from the parents. In our experience, parents of a mentally handicapped adolescent with longstanding epilepsy are often very reluctant to take adult neurology advice – a new drug or consideration of an operation is threatening. They have come to accept a status quo that may not be acceptable in the eyes of the adult team.

Pediatric epileptologists also are giving up years of continual medical care for the patient and a long-standing friendship and bond with the family. Helping them cope over time is one of the main joys of pediatrics – and to lose this connection is hard. There is a transition for the pediatric epilepsy specialist also!

We are aware of few publications about transition and epilepsy. One paper describes a very personal transfer of care – the pediatric epileptologist and the adult epileptologist met together once with the family (2). There was no outcome measure – just a description of the process. Another paper describes an epilepsy adolescent clinic and some of the changes in medical prescriptions (3). Frankly, the literature in other chronic diseases of childhood is not much better. We know that in youth with diabetes and asthma often the transfer does not take place properly and the young adult may go without medical care for many critical years. Family physicians have not been very involved in the child’s care and in the eyes of the family are generally not significant contributors to ongoing care. For youth with epilepsy that persists into adulthood, we know that the social outcome, even for those with normal intelligence, is unsatisfactory in 30-50%. We know that for those with serious mental handicap and persistent seizures, adult neurology visits are relatively rare and newer medications are typically not prescribed. In summary, the epilepsy community handles transition or transfer of care poorly.

What needs to happen? Every centre needs to identify one or more adult epileptologists who are willing to participate in a structured transition clinic. Willingness must mean not just the prescription of medication but also major efforts at education, social integration and rehabilitation. Obviously, such an approach does not guarantee success, but it should be better than what we are currently doing.

References

1. Warnell P. The transition experience of epilepsy patients/families: results of a telephone survey. Axone. 1998;20:31-3.
2. Appleton RE. Appleton RE. Transition from paediatric clinic to the adult service. J R Soc Med. 2001;94:554.
3. Smith PE, Myson V, Gibbon F. A teenager epilepsy clinic: observational study. Eur J Neurol. 2002;9:373-6.

Epilepsy.com/Professionals Announcements from Joseph I. Sirven, MD, Editor-in-Chief

Happy Fourth of July!!

In the nonfiction book entitled, ”Mountains beyond Mountains,” Tracy Kidder tells the amazing story of Dr. Paul Farmer the famed infectious disease specialist from Harvard Medical School and his work in caring for the poor of Haiti. In a memorable aphorism, Dr. Farmer states that “medicine is a social science and politics is nothing but medicine on a larger scale. Medical education does not exist to provide students with a way of making a living but to ensure the health of the community. Physicians are the natural attorneys of the sick and social problems should largely be solved by them.” In the spirit of this message, during the month of March, epilepsy.com Professionals will focus on the concept of how the physician can best help our patients with psychosocial issues which are such a significant burden of disease. In four separate interviews on Hallway Conversations we explore the theme of how best to support our patients in dealing with the obstacles that epilepsy has placed in front of them.

"Thoughts of Spring"

Spring has begun as evident by longer days, warmer temperatures, and the desire to put the long cold winter behind us. Summer is drawing near. More people are outside playing, walking, driving and enjoying the best of the outdoors. Our thoughts often turn to spring cleaning and personal renewal. For some people, this time of year is marked by looking for a fresh start; finding a novel approach to dealing with situations at hand. In individuals with epilepsy or their families, their attention is diverted to “What can I do to improve my seizure control?” or “How can I join the rest of world in their pursuit of happiness?” At Epilepsy.com/Professionals, we have some answers to these questions.

As we start the year with a new US President, we now know that one of Mr. Obama’s main agenda items is healthcare reform. Thus, as we greet the month of February, a healthcare debate will begin in earnest on the many changes likely to occur in the coming months and years which may have a significant impact on the way in which healthcare is delivered. Regardless of whatever health system modifications are implemented, there will be an increased emphasis on quality and its measurement and how to deliver medical care at a lower cost.

Risks and Benefits of Epilepsy Surgery: Are We Missing A Boat?

Orrin Devinsky, MD
Dept of Neurology
NYU Langone School of Medicine

Medical disciplines are celebrated for their successes, defined by their challenges and haunted by their failures. Epilepsy surgery, a long and deep partnership between neurosurgery and neurology, has pockets of progress punctuating a field with little movement. Advances in neuroimaging and neurophysiology/invasive electrode monitoring have expanded the diagnostic arsenal. Novel stimulation and direct-to-brain drug delivery paradigms form an exciting pipeline to future therapies. Yet, it is frustrating to review Penfield’s outcomes from 50 years ago and wonder just how far we have come.

Unilateral temporal lobe epilepsy and extratemporal lobe epilepsy due to localized lesions are the success stories of epilepsy surgery, with seizure-free rates over 60%. In highly selected groups (e.g., patients with mesial temporal sclerosis on their non-dominant side and concordant seizure onsets), seizure-free rates exceed 80%. Among the estimated 500,000 US and 10,000,000 worldwide cases of medically refractory partial epilepsy, less than a third have unilateral temporal lobe epilepsy or extratemporal epilepsy with well-circumscribed lesions. What about the other two-thirds?

The past decade documents some improved outcomes that largely reflect improved patient selection. But improved outcome for who? And for the two-thirds who are not offered surgery, is it really better patient selection? Perhaps the goal should be to seek a lower percentage of seizure-free outcomes. Our target population should be widened, away from the “sweet center” of unilateral temporal lobe and extratemporal cases with localized lesions, to include those who are less likely to achieve seizure freedom.

The field of epilepsy surgery focuses on seizure-free outcome as the marker of success. But have we ignored palliation, the opportunity to improve quality of life through a reduction of seizure frequency and medication burden. For the approximately majority of patients with medically refractory partial epilepsy who are “not good candidates for epilepsy surgery”, we need to deeply reconsider our definition of “good candidate”. How did we come to decide that seizure freedom was synonymous with surgical success?

Epilepsy surgery shares with cerebral tumor and other neurosurgeries, a spectrum of disease substrates and a range of respective acceptable outcomes. These outcomes range from permanent alleviation of the disease to palliation or prolongation of the time to recurrence of the disease process. What all of these therapies share is the intention to improve the patient’s quality of life. Yet epilepsy surgery, unlike tumor surgery, is perceived as failing unless seizures are completely controlled. Our current demands for epilepsy surgery success restricts patient selection, being analogous to restricting tumor surgery to only benign or low-grade tumors. Evaluating success based solely on seizure resolution may deny therapy to patients who may gain worthwhile improvement otherwise. As epilepsy surgery becomes better refined are patients being excluded from consideration?

Who are these patients with refractory partial epilepsy whose seizures are frequent enough to restrict their lives, who have tried and failed multiple antiepileptic drugs and drug combinations; who live with ongoing seizures and side effects? For many, epilepsy is a progressive disorder, with deteriorating cognitive and behavioral function, increased rates of suicide and sudden unexplained death (SUDEP). Memory, attention, mental processing speed, executive and language functions, and social skills can all decline over the years of seizures pounding on the brain. Depression, anxiety disorders, psychosis all become more frequent with chronic epilepsy. Perhaps most startling are the rates of SUDEP. Among patients with refractory epilepsy who are considering surgery, the yearly rate of SUDEP is between 0.5 and .9%. Over a decade, that is a 5-9 rate. That does not include deaths from drowning, driving, accidents, and other causes. We need to re-examine the benefits as well as the risks of the status quo.

Epilepsy surgery is definitely not for everyone with refractory partial epilepsy. Many patients have multiple or widespread foci that overlap with functional cortex. Surgery could leave a permanent deficit without any benefit. Yet some patients with two or even three seizure foci can benefit when one or two main foci are resected. Seizure frequency and severity may be reduced by 50% or more. Hardly a cure, but a better place. And for some, potentially life-saving. Our challenge is to increase the frequency of seizure free outcomes, but also help patients who cannot currently achieve seizure freedom.

The field of epilepsy surgery needs to move beyond the myopic focus on seizures. Yes, well designed studies have examined deficits in naming and short-term verbal memory after dominant temporal resections. Yet, what do we know about real life executive and social functions after frontal lobe resections? Not much. More recent studies have addressed employment, quality of life, and mood. However, we have ignored or avoided questions that Penfield raised a half century ago concerning the epileptic substrate that he believed caused adverse inter ictal effects.

Nociferous cortex is defined as dysfunctional epileptogenic tissue that fails to perform its normal functions and impairs the function of other brain areas. Penfield and Jasper introduced the concept of nociferous cortex in describing the dramatic behavioral improvements after hemispherectomy in an aggressive boy: “Among patients who have large areas of abnormality in one hemisphere, abnormal behavior may appear, together with advancing mental retardation. The behavioral abnormality is often a more important complaint than the seizures themselves. Radical complete excision may correct the abnormal behavior, stop the seizures, and allow improvement in the patient’s mental state.” How do we systematically identify both deficits and improvements after epilepsy surgery? What can we do to predict postoperative cognitive and behavior changes before surgery? Restricted epileptogenic foci can be nociferous. For example, non-dominant anterior temporal lobectomy can improve verbal memory. Temporal lobectomy can improve metabolic functions ipsilateral and contralateral to the seizure focus, cortically and subcortically. Preoperative depression and anxiety often resolve after ATL.

Excellent surgical centers may improve outcomes through diagnostic and therapeutic advances as well as more restrictive patient selection. We must address the problems faced by those epilepsy patients who do not meet the more rigorous selection criteria. As epilepsy surgery becomes better refined are patients that would benefit from surgery being excluded from consideration?

Make sure to check out our other new offerings during the month of June on Epilepsy.com Professionals

Hallway Conversations will highlight new devices for epilepsy therapy during the month of June:

Medical Errors in Epilepsy — Redemption Joseph I. Sirven, M.D. Editor-in-Chief, Epilepsy.com/Professionals

Recently I had the opportunity of attending an institutional Medical Grand Rounds on a rather provocative topic. The lecture entitled” Medical Redemption” consisted primarily of physicians telling stories of medical errors that they had committed in the presence of patients who had been the subject of these errors. The point was to examine the issue of medical errors from two vantage points; physician and patient. If I had been a malpractice attorney, I would be in a state of disbelief and shock to witness an open discussion of one of the most emotionally fraught and legally complicated topics that can confront a medical professional. As I listened to their stories, I was struck by a few observations. Physicians who committed the errors were riddled with guilt out of proportion to the patients’ expressions of anger over the error. Patients seemed to be forgiving even when the consequences of the error were quite serious and long-lasting. Admitting the error appeared to relieve the patient and physician from the burden of anger and guilt respectively. It seemed that the old dictum that “It isn’t the crime that creates problems, but it’s the cover up” seemed to be a reality in the field of medical errors at least from my perspective as an attendee.

This led me to wonder about my own medical errors over time in the care of patients with epilepsy. I have personally never seen any literature or been privy to nonconfidential conversations of specific instances of medical errors as it pertains to epilepsy management. Attorneys often counsel that admitting a mistake publicly has legal implications and therefore the topic is somewhat taboo. However, we are certain that it occurs. Attendance at any hospital morbidity and mortality conference can confirm it. I too can profess to having committed a medical error which I have had to address with a patient and I have been personally forgiven by the patient. However, I was lucky as there were no long lasting untoward effects as the result of the error. Nevertheless, errors have consequences and oftentimes the patient will look for their care elsewhere after such an admission.

So how often do medical errors occur in the US? In November 1999, the Institute of Medicine issued a report entitled “To Err is Human; Building a Safer Health System” addressed this issue and the statistics were staggering. The authors found that as many as 44,000 to 98,000 people died in hospitals every year as a result of medical errors. By using the conservative estimate of the extent of the problem, medical errors would actually rank as the eighth leading cause of death in the United States, higher than motor vehicle accidents, breast cancer, and HIV. 7,000 people a year are estimated to die from medical errors. Errors are not restricted to hospitals but they occur in any healthcare settings such as physician offices, nursing homes, pharmacies, urgent care centers and care delivered in the home. The costs of these errors are in the billions of dollars.

To date there are no estimates that delineate the extent or cost of medical errors in the field of epilepsy. However, one can make an educated guess based on several papers that have courageously addressed the allied topic of complications as a result of specialized epilepsy care. Most notable are those from Noe and colleagues, reporting 21% of epilepsy monitoring units had some type of adverse event and from Hamer and colleagues, reporting the complication rate from invasive EEG monitoring. However these are complications that may be expected and would not be considered an error based on the definitions from the Institute of Medicine. Therefore the extent of the problem in epilepsy is not known.

So how should physicians address medical errors when caring for patients with epilepsy? If one accidentally overdoses a patient with extra anti-epileptic medication which results in toxicity or an unusual complication, does the physician or healthcare professional take the blame? Does one call the patient? How will the patient/physician relationship be altered as a result of this admission and can it ever really recover? The answers to these questions are not known, but intuitively honesty appears to be the best policy with regards to one’s admission of errors when they occur. More study is clearly needed for the best approach.

So as I sat in the audience anonymously in a cavernous auditorium listening to patient and physician stories, I was struck by how fragile the patient/physician relationship really is. The same trust issues that typify a partnership, a marriage, a friendship are the same ones involved in the relationship between physician and patient. One has to be honest, open and caring with regards to how information is presented. Communication is essential and yes legal counsel is sometimes needed. I suspect the issue of medical errors will remain an unspoken issue but it is important to understand how difficult the issue is for both patient and physician.

References:

1. Institute of Medicine. To err is Human, Building a safer Healthcare system. 1999. National Academy Press.
   http://books.nap.edu/html/to_err_is_human/reportbrief.pdf
   Accessed September 29. 2009.
2. Noe K, Drazkowski J. Safety of Long-Term Monitoring for Evaluation of Epilepsy. Mayo Clinic Proceedings 2009:84(6): 495-500.
3. Hamer H, Morris H, Mascha E, Karafa M, Bingaman W, Bej R and colleagues Complications of invasive video-EEG monitoring with subdural grid electrodes. Neurology 2002; 58; 97-103

My Epilepsy Diary - Why You Should Recommend it to Your Patients Joseph I. Sirven, M.D. Editor-in-Chief, Epilepsy.com/Professionals

Do your patients frequently forget to take their medications? When your patients recall past seizures, do you believe that critical details may be missing? Do you wish you could analyze the effectiveness of your patients’ treatment plans using trend data over the long term?