This is Your Brain on Drugs: The Effects, Reactions and Risks of Taking Antiepileptic Medication

Among the 200,000 Americans diagnosed with epilepsy each year, more than two-thirds control their seizures with medication. A century ago, that wasn’t an option. Before 1912, when phenobarbital became the first drug to suppress seizures without severe side effects, epilepsy was a problem without a solution.

In 1974, the Anticonvulsant Drug Development Program at the National Institutes of Health got off to an extremely slow start. After releasing their final first-generation antiepileptic drugs, 15 years passed with no new therapies. But in 1993, felbamate and gabapentin were introduced, followed by other second-generation drugs. Within a few years, the number of AEDs had doubled.

Today, patients can take advantage of these broader treatment options, and work with their physicians to determine which AEDs suit them best. Gregory L. Barkley, M.D., past chair of the Epilepsy Foundation’s professional advisory board, states patients’ goals clearly: “First, to become seizure-free; and second, to be free of side effects.”

People who take AEDs, should understand what these drugs do – and be sure they’re working for them, not against them.

How AEDs Affect Your Brain

Your doctor has probably explained how seizures occur: Nerve cells in your brain conduct electrical currents. Cells that are chemically or physically unstable may become too active, conduct too much electricity, and activate all the nearby nerves. If you picture a single fire cracker being set off in a fireworks factory, you’ll get the picture. First a small explosion goes off, then a few neighboring fire crackers explode, then an ever-spreading wave of activity races through the entire factory.

AEDs influence several chemical processes by which nerve cells communicate: sodium currents, GABA effects and calcium channels.

Sodium currents: When a nerve cell conducts electrical current, sodium ions (Na ) enter through the cell membrane via pores that open and close very quickly. If this happens in a controlled way, a sequence of nerve cells can conduct messages from your brain to make you flex your biceps, blink your eye or secrete saliva. But in epilepsy, nerve cells act like the fire crackers in the factory – spreading activity in many directions at once, with few limits or controls. The first antiepileptic medications slowed this process by attaching to the pores as they closed. Instead of reopening quickly, the pores were forced to take a “time-out” before letting in more sodium. By reducing the overwhelming sodium entry that makes cells fire out of control, these drugs limited cells to normal activity levels and prevented seizures.

GABA effects: Gamma amino-butyric acid (GABA) is a chemical released by some nerve cells to talk to the next cell in their circuit. GABA has a calming effect – when cell No. 1 secretes GABA, cell No. 2 becomes calmer and less active. In our fireworks factory, GABA is like a high level of humidity: the firecrackers become “damped down,” less likely to ignite and explode. Scientists have found several ways to increase or prolong the effects of GABA in the brain. AEDs similar to GABA have the same calming effect on nerve cells. Other medications slow down GABA recycling – until cell No. 1 vacuums GABA up for re-use, cell No. 2 is unlikely to fire. Other drugs block the enzymes designed to chop GABA into small, non-functioning pieces. If GABA stays in one piece and in contact with cell No. 2, its calming effect continues.

Calcium channel blockers: A third way to inactivate nerve cells involves channels that let calcium ions (Ca ) enter the cells. In nerve cells programmed to stimulate the central nervous system, blocking calcium channels slows things down. Back to the firecrackers – blocking the calcium channels is like removing the fuses. The cells can fire, but it’s harder to get them started. Calcium channel blockers are also prescribed for heart problems; they decrease irregular activity in the heart and its conduction system.

AEDs – Actions and Reactions

Drug interactions: Think of your liver as a chemical processing plant. It tears apart drug molecules, reducing them to small pieces that your kidneys or intestines excrete. The liver reacts to increased levels of a drug by making more enzymes to break it down. A chemist would say that a drug “induces” the liver to make more of the enzymes that break it down. This is one way a person develops drug resistance.

Phenobarbital. One of the oddest effects of phenobarbital is how it stimulates the liver in a very non-specific way. When you take phenobarbital with other medications, many drug levels decrease. Does phenobarbital cancel out their effects? Not directly. But phenobarbital induces the liver to secrete more enzymes – a broad “increase production” order. These enzymes digest the other drugs and remove them from your blood faster. When you take phenobarbital – or when you forget to take it – you affect the blood levels of other drugs in your body.

Phenytoin. Phenytoin is effective within a very narrow dosage range. Low doses have practically no effect on seizures. But a patient who doubles their normal dose risks drug toxicity – seizures may even get worse. To make things more interesting, let’s add phenobarbital to the picture. Although phenobarbital decreases blood levels of most AEDs, its effect on phenytoin is “unpredictable.” According to the 2002 edition of Antiepileptic Drugs (eds. Levy, Mattson, Meldrum, & Perucca), taking phenobarbital may cause an increase, a decrease, or no change at all in phenytoin levels. Upsetting the balance between these drugs could either lower seizure control or cause drug toxicity – either one increases the risk of seizures.

Phenytoin also interacts with alcohol. Chronic alcohol use decreases phenytoin levels, but occasional alcohol intake may increase phenytoin levels. So, should you avoid phenytoin altogether? Not at all, but you should be aware of drug interactions to prevent problems.

AEDs and alcohol: Alcohol and phenobarbital have a special relationship. Both depress the central nervous system, so people are warned not to “drive or operate heavy equipment” while taking barbiturates and especially “avoid alcohol ingestion.” Despite its tendency to “increase production,” phenobarbitaldecreases the activity of alcohol dehydrogenase (ADH), an enzyme that digests alcohol. A person combining phenobarbital with alcohol is not only taking two depressants, but the alcohol burns off very slowly. As a result, people become drunk more easily. And when high doses of phenobarbital are combined with rapid alcohol intake, coma or even death can result.

To drink or not to drink. This brings us to the often-heard question: Should a person on AEDs drink alcohol at all? For some people, even a tiny amount of alcohol increases their chances of seizure activity. Most studies conclude that adults can have one or two drinks a day without affecting seizures or AED blood levels. However, Barkley explains that “while you’re drinking, alcohol suppresses seizures. But as it washes out of your system, it becomes a ‘pro-convulsant,’ acting like other substances that cause withdrawal seizures. This often occurs 12 to 24 hours after drinking. Alcohol is always a risk factor for patients with epilepsy.”

Three or more alcoholic drinks a day definitely decreases seizure control – an effect lasting up to 72 hours after the drinks. Because seizures or convulsions frequently occur during drug withdrawal (even in people who are normally seizure-free) the prospects for seizure-prone people are not good.

Withdrawal: When your body adapts to a drug, it strikes a compromise. For example, when alcohol binds to GABA-receptors it enhances the calming effects of GABA. Cells produce less GABA during chronic alcohol use, since a little bit goes a long way. But in alcohol withdrawal, GABA nerve cells are on their own again. Until GABA production returns to normal, a person feels anxious, fidgety, nauseated – unable to calm down. Every type of withdrawal is different, but the common factor is a set of body functions that depend on the presence of a drug – and then the drug is pulled away from them. Many people only achieve seizure control with AEDs. Abrupt withdrawal can cause seizures, often with a rebound effect that makes them more severe than ever.

Adding insult to injury: Besides the direct effects of alcohol, seizure risks are increased by related social patterns:

Josh G., a 23- year-old college graduate,is healthy, handsome and starting his first professional job in sales. Last summer he was best man in his brother’s wedding and really had been looking forward to it. He had been diagnosed with partial complex seizures at 16, after a minor concussion following a car accident. When Josh had several seizures in three months, his family doctor referred him to an epilepsy specialist. He achieved nearly-complete management with medication and had experienced only two seizures, both mild, since finishing college.

The week of the wedding, Josh conscientiously maintained a regular schedule to avoid any problems. The night before the wedding, he attended his brother’s bachelor party, had several drinks (without getting noticeably drunk) and came back home around 3 a.m. He realized the next morning that he’d skipped his bedtime medications, but took his regular doses before dressing for the wedding. The day progressed well until the reception when he suddenly felt uneasy. Josh recognized the symptoms in time to reach the hotel lobby before passing out. It was his first seizure in 10 months.

“Josh” is a composite patient drawn to highlight several challenges to seizure control:

  • Emotional excitement, even of a positive kind;

  • Use of alcohol. Having three drinks was pushing the limits, especially with the other factors present at the same time;

  • Lack of sleep or irregular sleep patterns. This effect on seizures is well established; doctors ask new patients to “pull an all-nighter” before an EEG to increase their chances of recording seizure activity;

  • Irregular or missed medication. Abrupt withdrawal from AEDs often causes breakthrough seizures. Even one missed dose is risky, especially for medications taken once a day

In his book, A Guide to Understanding and Living with Epilepsy, Orrin Devinsky, M.D., director of the New York University Comprehensive Epilepsy Center and a current member of the Epilepsy Foundation’s board of directors, chose Missed Medication for the first topic in his chapter entitled “Seizure-provoking factors.” Why? Because, in his expert opinion, missed medication “is the most common cause of ‘breakthrough’ seizures.” Most epilepsy specialists agree.

SUDEP – trying to explain the “unexplained”

Although “Josh” didn’t feel lucky at the time, his seizure was only one mishap in an otherwise wonderful day. The outcome could have been more serious.

Sudden Unexplained Death in Epilepsy (SUDEP) is a problem that physicians rarely discuss with their patients. Because AEDs control seizures in over two-thirds of patients, epilepsy is generally regarded as a chronic but controllable disorder – much like diabetes. With proper medication and a sensible lifestyle, most people with seizure disorders achieve a high quality of life with few limitations. Yet, SUDEP is of great concern to epilepsy specialists, especially because it is, by definition, “unexplained.”

A Mayo Clinic study reviewed the medical records of people diagnosed with epilepsy between 1935 and 1994. Adding together the total years covered by the patients’ records, slightly more than one case of SUDEP occurred in every 3,000 patient-years. Yet, rare as it is, sudden unexplained death occurs 24 times more frequently in people with epilepsy than in the general population.

Risk factors for SUDEP include generalized tonic-clonic seizures and treatment with more than two AEDs. SUDEP is more frequently identified as causing death in patients age 15 to 44 than in older epilepsy patients – possibly because deaths of older patients were attributed to heart disease. Low levels of therapeutic drugs are sometimes considered risk factors for SUDEP. But the bottom line is the occurrence of tonic-clonic seizures: Whatever increases their frequency or severity increases the risk of SUDEP.

Mark Spitz, M.D., is a neurologist and director of the University of Colorado Epilepsy Center. Like many other epilepsy specialists, he believes the “unexplained” deaths involve the heart or lungs.

“During generalized tonic-clonic (grand mal) seizures, a lot of adrenaline is released,” Spitz said. “This can cause irregular heart rhythms.” The hearts of many people who die from SUDEP have contraction band necrosis, which is a sign of heart injury.

“At the University of Washington, physicians recorded the echocardiograms of two adults during grand mal seizures and found that parts of their hearts weren’t contracting normally,” Spitz continued. “Several days later, their heart motion was OK. But, at least in the short term, a seizure can cause heart damage, and a damaged heart is more likely to develop fatal rhythms. The danger isn’t from too fast a heart rate, but when the heart rate becomes too slow.”

A slow heart rate is associated with some seizures, especially as they start, although fast heart rates are more common.

Spitz also notes that body fluids become more acidic during seizures. “In generalized tonic-clonic seizures, lactic acid builds up from all the muscle contractions. In fact, the body’s pH [a measure of acidity] drops from 7.4 to only 7.0, and people with a low pH – from any cause – are more likely to develop an irregular heartbeat.”

A third factor in SUDEP may be fluid collecting in the lungs, a condition called pulmonary edema. Adrenaline released during a seizure increases blood pressure in the lungs, forcing fluid out of the capillaries and into the lung tissue. Heavier lungs, containing excess fluid, are frequently found in victims of SUDEP.

A tragic sudden unexplained death occurred in fall 2005 in Steamboat Springs, Colo. Adele Dombrowski, a 17-year-old high school senior, died in her sleep from “cardiopulmonary arrest consistent with a grand mal seizure.” Blood analysis showed that alcohol wasn’t a factor, and no drugs – including AEDs – were found in her body. Adele took her epilepsy medications only intermittently.

Spitz knows personally of four other patients in the past year who died under similar circumstances: most recently, a 36-year old man who, typically, wasn’t taking his AEDs.

How can SUDEP be prevented? How can physicians – or patients – prevent a problem whose cause is “unexplained?”

“Take your meds!” Spitz said.

And for the doctors, Spitz said, “Don’t be afraid to discuss it with your patients.”

Barkley supports this advice, and emphasizes, “The most important factor in SUDEP is the occurrence of tonic-clonic seizures. The number of medications may reflect how intractable the seizures are. But to prevent SUDEP, you must control the occurrence of seizures.”

Achieving your personal goals with AEDs

Patients with epilepsy try to ignore it, but ignoring epilepsy is like ignoring a swarm of mosquitoes at camp. Who is more in control: the person who pretends they aren’t there (and goes home covered with mosquito bites), or the person who comes prepared with bug spray and mosquito netting?

Barkley advises epilepsy patients to take charge of their lives. “If you’re dissatisfied with the way AEDs manage your seizures, don’t ignore the problem. Talk with your doctor about alternatives. See a specialist. Find out about experimental treatments, new drugs, changes in lifestyle. Maybe you’re a candidate for an implanted device or for surgery. If you have trouble talking with your doctor, find a different doctor!”

After thousands of years as a problem without a solution, epilepsy now has many treatment alternatives. It’s up to each person to choose the one that serves them best.

Editor’s note: Jacquelyn Beals, Ph.D., was formerly on the research faculty in the Department of Anesthesiology at the University of Virginia School of Medicine and is currently a full-time science writer/editor.

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The mission of the Epilepsy Foundation is to lead the fight to overcome the challenges of living with epilepsy and to accelerate therapies to stop seizures, find cures, and save lives.

 
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