Epilepsy Talk

The Trouble with AEDs…  | February 19, 2023

At the very best, finding the right anti-epilepsy drug is a crap shoot. There’s always the hope that this one will do it.

Or maybe adjunct therapy will work. Or, sigh, the side-effects derail you and you’re on to the next.

Is asking for seizure control too much to ask?

The good news is that many newer AEDs are better tolerated than the older, standard AEDs. Although they, too, come with side-effects.

Newer AEDs often cause less sedation and require less monitoring than older drugs.

Although they are generally FDA-approved for use as add-ons to standard drugs that have failed to control seizures, they are often prescribed as single drugs.

Specific choices usually depend on your particular condition and the specific side-effects of the AED.

None has emerged as being superior to either standard or newer drugs.

All appear to offer some benefits, however, as with standard anti-seizure drugs, they all come with side-effects of their own.

But, until a cure for epilepsy is discovered, medical treatment is the only game in town. Unless you go for surgery or some of the newer intervention techniques.

So here’s the lineup of the most common AEDs, along with 4 exciting new meds.

Barbiturates: Phenobarbital (Luminal, Phenobaritone), is a barbiturate anticonvulsant.

And Primidone (Mysoline) is converted in the body to Phenobarbital with the same benefits and draw-backs.

It’s reported that Primidone is not as well-tolerated as Phenobarbital. In fact, some doctors believe that Primidone has no advantage over the other drug.

Uses: Barbiturates may be used to prevent Tonic Clonic Seizures (“Gran Mal”) or Partial Seizures. They are no longer typically used as first-line drugs, although they may be the initial drug prescribed for newborns and young children.

Side-Effects: Phenobarbital has fewer toxic effects on other parts of the body than most anti-epileptic drugs, and drug dependence is unusual, given the low doses.

However, because of the difficult side-effects, it’s less likely to be used over time than other drugs — including Phenytoin — another relatively inexpensive but effective drug.

Patients sometimes describe their state as “zombie-like,”with drowsiness, memory problems, coordination, hyperactivity (in children and the elderly), and depression (in some adults).

Note: Some controversy has arisen over studies indicating that children taking Phenobarbital score lower on intelligence tests, even for some months after going off the drug.

Brivaracetam (Briviact)

Uses: An antiepileptic drug (AED) indicated as adjunctive therapy in the treatment of partial-onset seizures in patients 16 years of age and older with epilepsy. Also known as a “cousin” of Keppra.

It may reduce excitatory neurotransmitter release and enhance synaptic depression during trains of high-frequency activity, such as is believed to occur during epileptic activity.

Side-Effects: Mood or behavior changes, anxiety, panic attacks, trouble sleeping, impulsiveness, irritability, agitation, hostility, aggressiveness, restlessness, hyperactivity (mentally or physically), depression.

Carbamazepine (Tegretol, Equetro, Carbatrol)

Uses: An effective anticonvulsant and specific analgesic when used alone or with other drugs.

Carbamazepine also has the added benefit of relieving depression and improving alertness.

An extended release form is available that allows twice-daily dosing rather than 3 times a day. A chewable form makes it easier for children to take.

This drug is used to prevent the following seizures or epilepsy syndromes: Partial Seizures, (people tend to tolerate this drug better than others, although responses differ), Tonic Clonic Seizures, Nocturnal Frontal Lobe Epilepsy.

Side-Effects: Double vision, headache, sleepiness, dizziness, and stomach upset. These usually subside after a week and can be reduced by slowly titrating up on the dose.

Some people experience visual disturbances, ringing in the ears, agitation, or odd movements when drug levels are at their peak. Water retention can be a problem in older people.

The extended-release form of Carbamazepine (Carbatrol) may help reduce these symptoms.

Serious side-effects are less common but can include: Risk of birth defects, (especially if it is taken during the first trimester of pregnancy).

Severe skin reactions, including toxic epidermal necrolysis and Stevens-Johnson Syndrome which can cause skin lesions, blisters, fever, itching, and other symptoms.

(People of Asian ancestry have a 10 times greater risk for skin reactions than other ethnicities. The FDA recommends that they get a blood test prior to starting the drug to determine if the gene variant is present that increases this risk.)

Sometimes Carbatrol can worsen Generalized Seizures.

Hormonal changes, particularly higher levels of male hormones in both men and women, pose some risk for sexual dysfunction over time.

A decrease in white blood cells occurs in about 10% of those taking the drug. (This is generally not serious unless infection accompanies it.) Other blood conditions can arise that are potentially dangerous.

People should be sure to inform the doctor if they have any sign of irregular heartbeats, sore throat, fever, easy bruising, or unusual bleeding.

Long-term therapy can also cause bone loss (osteoporosis) in women and men, and it’s best to take preventive Calcium and Vitamin D supplements.

Children are at higher risk for behavioral problems.

Note: Citrus fruit, especially grapefruit, can increase Carbamazepine’s side-effects and should be avoided.

Cenobamate (Xcopri)

Uses: Long-term use of Xcopri was safe and reduced seizures by more than 90% in adults with uncontrolled focal seizures, according to results of an open-label extension study published in Neurology.

Side-effects: The most common side effects of Xcopri include feeling sleepy and tired, dizziness, double vision, and headache.

Clobazam (Onfi)

Uses: A benzodiazepine which affects chemicals in the brain that may be unbalanced in people with anxiety.

Onfi is used in combination with other medications to treat seizures caused by Lennox-Gastaut syndrome, a severe form of childhood epilepsy that also causes developmental and behavior problems.

Side-Effects: Fever, drowsiness, sedation, constipation, aggressive behavior, lethargy, ataxia, drooling, and irritability.

Other side effects include: Urinary tract infection, pneumonia, cough, bronchitis, insomnia, fatigue, decreased appetite, and increased appetite.

Eslicarbazepine Acetate (Aptiom)

Uses: An anticonvulsant that works by decreasing nerve impulses that cause seizures and pain. It’s used as a monotherapy and adjunctive treatment for Partial-Onset seizures.

Side-Effects: Aptiom can reduce the sodium in your body to dangerously low levels, which can cause a life-threatening electrolyte imbalance.

Other less serious side effects include tremors, a disturbance of equilibrium, blurred vision, vertigo, nausea, ataxia, dizziness, headache, drowsiness, sedation, abnormal gait, fatigue, visual disturbance, weakness, and malaise.

If you develop a severe skin rash, speak with your doctor as soon as possible.

Also, Aptiom can make birth control pills less effective.

Clonazepam (Klonopin), Diazepam (Valium), Lorazepam (Ativan), Clorazepate (Tranxene), Alprazolam (Xanax) 

Uses: Clonazepam is recommended for Myoclonic and Atonic Seizures that can’t be controlled by other drugs. Also for Lennox-Gastaut Syndrome.

It may be useful in newborns when other drugs are ineffective.

Although Clonazepam can prevent Generalized or Partial Seizures, people generally develop a tolerance to the drug, and then seizures can recur.

Side-Effects: People who have had liver disease or acute angle glaucoma should not take Clonazepam. Also, those with lung problems should be cautious.

Clonazepam can be addictive, and abrupt withdrawal has been known to trigger Status Epilepticus.

Other side-effects include drowsiness, imbalance and staggering. Also, irritability, aggression, hyperactivity in children, weight gain, eye muscle problems, slurred speech, tremors, skin problems, and stomach problems.

Ethosuximide (Zarontin)

Uses: Ethosuximide (Zarontin) is used for Absence Seizures (“Petit Mal”) in children and adults when the person has experienced no other type of seizures.

Ethosuximide succeeds in abolishing Absence Seizures in 60% of patients and controls them in up to 90%.

Side-Effects: Dizziness, headache, somnolence, anorexia, diarrhea, GI upset, nausea, vomiting.

Methsuximide (Celontin), a drug similar to Ethosuximide, may be suitable as an add-on treatment for intractable epilepsy in children without causing serious or permanent side-effects.

Side-Effects: Stomach problems, dizziness, loss of coordination, and lethargy. In rare cases, it has caused severe and even fatal blood abnormalities.

Periodic blood counts are recommended.

Gabapentin (Neurontin)

Uses: An effective add-on drug for controlling Complex Partial Seizures plus Secondarily Generalized Partial Seizures and is approved for adults and children.

It has also been somewhat successful in people with Resistant Partial Epilepsy. It is not useful for Generalized Absence Seizures.

Side-Effects: Toxicity is low, but there are side-effects such as sleepiness, headache, fatigue, and dizziness. Some weight gain has been reported.

Children may experience hyperactivity or aggressive behavior.

Gabapentin has no significant interactive effects when taken with other drugs. Long-term adverse effects are still unknown.

Gabitril (Tiagabine)

Uses: Usedwith other epilepsy drugs to treat Partial and some Generalized Seizures in adults and children who are at least 12 years old.

Side-Effects: Dizziness, fatigue, weakness, irritability, anxiety, and confusion.

Lacosamide (Vimpat)

Uses: Lacosamide is a unique medication for individuals with uncontrolled Partial-Onset Seizures.

Its primary advantages include the fact that it has no drug interactions, is dosed twice a day, and is effective.

The drug appears to work in a manner similar yet distinct to Phenytoin and Carbamazepine.

Lacosamide has an IV formulation, therefore it might be useful in emergency situations; but again, it has not been approved for use in this condition.

Side-Effects: Dizziness, headache, nausea or vomiting. Also, double vision, fatigue, memory and mood problems.

In rare cases, Lacosamide may affect internal organs, blood counts or heart rhythm, but these potentially serious side-effects are infrequent.

Lamotrigine (Lamictal)

Uses: Approved as add-on therapy for Partial Seizures, and Generalized Seizures associated with Lennox-Gastaut Syndrome.

Lamotrigine is also approved as add-on therapy for treatment of Primary Generalized Tonic-Clonic (PGTC) Seizures, in children aged 2 years and older, plus older adults.

It can be used as a single drug treatment (monotherapy) for adults with Partial Seizures.

Birth control pills lower blood levels of Lamotrigine.

Side-Effects: Common side-effects include dizziness, headache, blurred or double vision, lack of coordination, sleepiness, nausea, vomiting, insomnia, and rash.

Although most cases of rash are mild, in rare cases the rash can become Stevens-Johnson Syndrome, which is extremely dangerous.

The risk increases if the drug is started at too high a dose or if the patient is also taking Valproate. (Serious rash is more common in young children who take the drug than it is in adults.)

The rash is most likely to develop within the first 8 weeks of treatment.

Be sure to immediately notify your doctor if you develop a rash, even if it is mild.

Levetiracetam (Keppra)

Uses: This drug is approved as add-on therapy for Partial Onset Seizures in adults and children ages 4 years and older, Myoclonic Seizures in adults and adolescents ages 12 years and older who have Juvenile Myoclonic Epilepsy, Primary Generalized Tonic-Clonic Seizures in adults and children ages 6 years and older who have Idiopathic Generalized Epilepsy.

Levetiracetam appears to have fewer drug interactions than other anti-epileptic drugs and may be particularly useful for older patients.

Side-Effects:The most famous of these is “Keppra Rage” as well as severe aggression, irritability, anxiety, depression, and thoughts of suicide.

On the other side of the coin, you may experience sleepiness and fatigue, muscle weakness and coordination difficulties, headache, flu symptoms, dizziness, possible risk of a reduced white blood cell count, and a higher rate of infections.

Caution is advised for patients with kidney dysfunction.

Oxcarbazepine (Trileptal) — similar to Phenytoin and Carbamazepine but generally has fewer side-effects.

Uses: Approved as single therapy or add-on therapy for Partial Seizures in adults and for children ages 4 years and older.

Side-Effects: Stevens-Johnson Syndrome and toxic epidermal necrolysis. These skin reactions cause a severe rash that can be life-threatening.

Rash and fever may also be a sign of multi-organ hypersensitivity, another serious side-effect associated with this drug.

Oxcarbazepine can also reduce sodium levels. Make sure you have the sodium level in your blood checked regularly.

This drug can also reduce the effectiveness of birth control pills. Women who take Oxcarbazepine may need to use a different type of contraceptive.

Phenobarbital (Luminal)

Uses: This old-timer is very inexpensive and effective in a single daily dose.

Side-Effects: Sedation, thinking/memory problems and depression. Phenobarbital can also cause long-term bone problems.

It’s mildly addictive and requires slow withdrawal. And it is not suitable for pregnant mothers, because there is a significant rate of birth defects.

Phenytoin (Dilantin)

Uses: Phenytoin is effective for adults who have the following seizures or conditions: Tonic Clonic Seizures, Partial Seizures, Status Epilepticus, and it can be effective for people with head injuries who are at high risk for seizures.

This drug is not useful for the following seizures: Absence Seizures, Myoclonic Seizures, Atonic Seizures.

Side-Effects: The most dangerous is the risk of Stevens-Johnson Syndrome, a potentially life-threatening rash. Also, some people may develop a toxic response to normal doses, resulting in a coma.

Others, such as those with alcoholism, may require higher doses to achieve benefits.

Using Phenytoin in combination with newer add-on drugs can allow lower doses and may reduce some of the risks.

Other side-effects may include: Bone loss (from long-term use), gum disease, peripheral neuropathy, excess body hair, eruptions and coarsening of the skin. Also, weight loss, staggering, lethargy, nausea, depression, eye-muscle problems, and anemia.

An increase in seizures can occur as a result of high doses. There is an increased risk for birth defects and in rare cases, liver damage may develop.

People should definitely take preventive Calcium and Vitamin D supplements and exercise regularly to improve bone mass.

Pregabalin (Lyrica) — similar to Gabapentin

Uses: Approved as add-on therapy to treat Partial-Onset Seizures in adults with epilepsy. In clinical trials, half of the patients who received Pregabalin experienced a 50% reduction in seizure frequency.

Side-Effects: Dizziness, sleepiness, dry mouth, swelling in hands and feet, blurred vision, weight gain, and trouble concentrating.

Tiagabine (Gabitril) has properties similar to Phenytoin and Carbamazepine, and is also showing promise.

Uses: When added to treatment with another anti-epileptic drug,Tiagabine is sometimes effective in reducing Partial Seizures in children older than 12 years.

It seems to work better in controlling Partial Seizures in adults, either alone or when used with another antiepileptic medicine.

It is not helpful in reducing other types of seizures, such as Primary Generalized Seizures or seizures in children who have Lennox-Gastaut Syndrome.

Side-Effects: Evidence has reported some significant side-effects with its use, including dizziness, fatigue, agitation, and tremor.

At least one study suggested that it has more adverse effects than Lamotrigine and is not as well tolerated.

In February 2005, the FDA issued a warning advising that Tiagabine may cause seizures in patients without epilepsy.

It is only approved for use with other anti-epilepsy medicines to treat Partial Seizures in adults and children 12 years and older.

Topiramate (Topamax)

Uses:Topiramate is similar to Phenytoin and Carbamazepine and is effective and safe for a wide variety of seizures in adults and children.

It is approved as add-on therapy for patients 2 years and older with Generalized Tonic-Clonic Seizures, Partial-Onset Seizures, or seizures associated with Lennox-Gastaut Syndrome.

It is also approved as single drug therapy.

Side-Effects: Most side-effects are mild to moderate and can be reduced or even prevented by titrating up gradually on your dosage.

Serious side-effects may include glaucoma, decreased sweating, increased body temperature, kidney stones, sleepiness, dizziness, confusion, and trouble concentrating.

You should immediately notify your doctor if you have blurred vision or eye pain.

Topiramate may have fewer interactions with oral contraceptives than other AEDs.

Valproate (Depakene, Valproic Acid) and its delayed release form, Divalproex Sodium (Depakote), are anticonvulsants.

Valproate is the most widely prescribed anti-epileptic drug worldwide.

Uses: The first choice for patients with Generalized Seizures and is used to prevent nearly all other major seizures as well.

Side-Effects: These drugs have a number of side-effects that vary depending on dosage and duration.

Stomach and intestinal problems, which are experienced by nearly half of patients after starting the drugs may still occur after several years of use.

Divalproex Sodium (Depakote) has a lower risk for these side-effects than Valproate (Depakene).

Increased appetite with significant weight gain often becomes a problem and can be a major reason for noncompliance, particularly in young people.

Other side-effects include: Hand tremors, irritability, and hyperactivity in children. Temporary hair thinning and hair loss.Taking Zinc and Selenium supplements may help reduce the effect.

Young girls may develop secondary male characteristics, and premenopausal women are at increased risk for menstrual irregularities and polycystic ovaries, due to elevated male hormones. The effects are reversible.

(These side-effects also appear in women using other anti-epileptic drugs, but the risk from Valproate appears to be higher.)

Studies have reported symptoms of Parkinson’s Disease preceded by hearing loss in people who have taken it for more than a year, but they were reversible when the drug was withdrawn.

Valproate poses a higher risk for serious birth defects than many other AEDs. These birth defects include skull and limb deformities, in addition to brain, heart, and lung problems.

Women of child-bearing age should use a different type of anti-epilepsy drug than Valproate. If it is used, it should be prescribed at the lowest possible dose.

Cases of pancreatitis, a serious and even life-threatening inflammation in the pancreas, have been reported in children and adults taking Valproate. (It is still very rare, however.)

Valproate and Divalproex Sodium are not usually recommended for young children because of an unusual, but potentially fatal, toxic effect on the liver.

This very rare effect is most likely to affect children under 2 years of age who have birth defects and are taking more than one anti-seizure drug.

Some doctors recommend monitoring blood levels for liver function once prior to administering Valproate or Divalproex Sodium, monthly during the first 6 months, and then periodically after that.

Children with epilepsy who take Valproic Acid may eventually develop some problems in the kidney, although they are generally not significant.

Symptoms of Toxic Side-Effects in Liver or Pancreas: Take careful note of abdominal pain, nausea or vomiting, loss of appetite, lethargy, acute confusion, water retention, easy bruising, and yellowish skin coloring.

Zonisamide (Zonegran)

Uses: A unique drug that blocks sodium and calcium channels and may have nerve-protecting properties.

It’s approved as add-on therapy for adults with Partial Seizures, and studies indicate it’s often effective against Infantile Spasms (West Syndrome) and Myoclonic Seizures.

Side-Effects: Increases the risk for kidney stones, which can be reduced with increased fluid intake and citrate.

It has also been associated with reduced sweating and a sudden rise in body temperature, especially in hot weather. Children are especially at risk for this side-effect, which can be serious. (The drug has not been approved for children.)

Other side-effects tend to decrease over time and include dizziness, forgetfulness, headache, weight loss, and nausea.

Less Commonly Used AEDs

Felbamate (Felbatol)

Uses: An effective anti-seizure drug. However, after reports of deaths from a serious blood condition known as aplastic anemia or from liver failure, Felbamate is recommended only under certain circumstances.

Side-effects: They include severe epilepsy, such as Lennox-Gastaut Syndrome or as monotherapy for Partial Seizures in adults when other drugs fail.

Vigabatrin (Sabril) is a chemical called Gamma-Vinyl GABA. 

Uses: It was designed to increase the brain levels of the enzyme that inhibits seizure activity.

Side-effects: It is generally prescribed in the U.S. only in certain cases, such as in low doses for patients with Lennox-Gastaut Syndrome.

Overseas, it is also used for Partial Seizures and as first-line therapy in children with Infantile Spasms (West Syndrome).

Between 10-30% of people on long-term treatment have developed irreversible visual disturbances, including reductions in acuity and color vision.

Men are at higher risk for this side-effect than are women.

Further studies are needed to determine the extent and severity of this complication, particularly in children.

There is a slight risk for depression or psychosis when Vigabatrin is used as add-on therapy, and particularly if the drug is administered too quickly.

These risks are far lower if the drug is used as sole therapy.

Newer Drugs:

Ethotoin (Peganone)

Uses: Alone or in combination with other medications for the control of Tonic-Clonic (Grand Mal) and Complex Partial (Psychomotor) seizures in adults and children.

Side-Effects: You should not use this medication if you have liver disease or a blood cell disorder. Unusual bleeding, weakness, and infection can occur.

Fycompa (Perampanel)

Uses: Adjunctive treatment for Partial-Onset Seizures with or without Secondarily Generalized Seizures in patients with epilepsy age 12 and older.

Side-Effects: Dizziness, sleepiness, fatigue, irritability, falls, nausea, problems with muscle coordination, problems walking normally, vertigo and weight gain.

Serious or life-threatening psychiatric (mental) problems were also seen more frequently in patients treated with Fycompa.

Rufinamide (Banzel)

Uses: An add-on treatment for children age 4 and older and adults with the Lennox-Gastaut Syndrome. This syndrome can include seizure types such as Atonic (drop) Seizures, Tonic (stiffening) Seizures, Myoclonic (brief jerking) Seizures, or Absence (staring) Seizures, as well as Partial Seizures.

Side-Effects: Do NOT use Rufinamide if you have or a family member has a history of certain heart problems, or you have severe liver problems.

Sudden or worsened depression, anxiousness, restlessness, irritable behavior or panic attacks are a possibility.

Older AEDs: Some older but less effective drugs may still play a role against epilepsy.

Acetazolamide (Diamox) It is sometimes used against common types of seizures, but patients quickly develop a tolerance for it.

It still may be useful when drug interactions are a problem, when a rapid effect is required, or when an additional drug is needed for a short time.

Trimethadione (Tridione) is effective for Absence Seizures, but has very serious side-effects, and its use is severely limited.

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Resources:

http://www.webmd.com/epilepsy/medications-treat-seizures

https://www.medicinenet.com/what_are_the_side_effects_of_antiepileptic_drugs/article.htm#what_are_the_side_effects_of_antiepileptic_drugs

https://www.drugs.com/condition/epilepsy.html

https://www.epilepsy.com/medications/brivaracetam

http://www.drugs.com/fycompa.html

http://www.drugs.com/mtm/peganone.html

http://www.drugs.com/cdi/rufinamide.html

https://www.drugs.com/aptiom.html

https://www.drugs.com/onfi.html

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