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Seizure medications taken on a daily basis are the mainstay of treatment for any person with epilepsy. While the goal of treatment is to control seizures without side effects, and ideally one medicine if possible, this goal is not realistic for many people with LGS.

  • While medications can help, they rarely control seizures completely in LGS.
  • Usually more than one seizure medicine is needed to control the different types of seizures that are a main feature of LGS.
  • No comprehensive studies have been performed evaluating the effectiveness of a single medication as the first treatment of seizures in a child with LGS.
  • In the past, valproate or valproic acid had been considered the first medication to suggest for for treating LGS. Yet, from a practical point, often by the time a person has been diagnosed with LGS, a number of seizure medications may have been tried alone or in combinations with others. 
  • Now that medications specific for the treatment of seizures associated with LGS are available, treatment recommendations should be re-evaluated to consider trying one or more of these medicines in a child or adult with LGS. 
  • It’s also important to realize that some medications can worsen seizures associated with LGS and these medications should be removed or avoided.
  • Seizure medications in development provide hope to improve teatment options for people with LGS. 

Seizure medications that have been evaluated and approved for use in treating seizures associated with LGS include: felbamate, lamotrigine, topiramate, rufinamide, and clobazam. While many other seizure medications may be used in people with LGS, these medications are the only ones that have undergone the detailed testing as to how well they work and potential side effects in children and adults with LGS. Interestingly, how these medications work in the brain to control seizures is largely unknown.

The following information presents data from some of the initial research studies. After medications have been approved by the FDA, other studies are done to look at the benefits and safety of the medications over time.

Felbamate was approved by the FDA in 1993 for treatment of seizures with LGS and treatment of partial seizures.  When used for LGS, many people had a dramatic improvement in atonic (drop) seizures and convulsive seizures (tonic clonic), along with other seizure types.

  • In a randomized placebo-controlled study, 73 patients from age 4 to 36 years old with LGS were studied. People treated with LGS had a median (average) decrease in atonic seizures by 34% and a 19% decrease in total seizure frequency.
  • Common side effects include decreased appetite, difficulty falling asleep, and irritability. However, most of these can be managed.
  • Rarely, children may experience liver toxicity, and adolescents and adults may develop a toxicity in the bone marrow (blood forming elements in the body) resulting in serious and potentially fatal complications. These concerns have restricted the use of felbamate.
  • In children and adults who have drop or atonic seizures that don't respond to other therapies, felbamate still remains a good treatment option. As with all treatments, the physician and family should balance the potential benefits and risks of the medications with the risk of uncontrolled seizures.

Lamotrigine was the next medication to be thoroughly evaluated in LGS. It was approved by the FDA in 1998 to be used with other seizure medications in patients with LGS 2 years of age or older. This medication helps improve convulsive seizures, and may lead to improvements in behavior, coordination and speech as well.

  • In a randomized placebo-controlled study, 33% of patients treated with lamotrigine had an improvement in seizures by 50% or more.
  • Usually lamotrigine is tolerated well. Side effects include a risk for severe skin rashes including Stevens Johnson Syndrome, that seems to occur when the drug is started too quickly or at high doses. Rash is more likely in children who are also taking valproate. However, the risk of rash needs be balanced against the benefit of the combination of valproate and lamotrigine for treating seizures with LGS. When a person taking lamotrigine develops a rash, the family or caregiver should stop the medication and contact the physician immediately.
  • In people with LGS using lamotrigine and other seizure medications, there is also a risk for liver problems.
  • Lamotrigine has complicated drug interactions with other seizure medications. When it is used with valproate, it must be started at lower doses and more slowly than when used with enzyme inducing medications like phenytoin, carbamazepine, phenobartital or topiramate.
  • For most medicines, lamotrigine is started slowly and may take a while to reach an effective dose. Often it may take 8 to 12 weeks to obtain a full dose of this medication. This need to start lamotrigine slowly to avoid serious side effects can limit it’s usefulness in people who are having daily seizures, injuries, frequent clusters or seizure emergencies.  .

Topiramate was also found to be effective in treating convulsive seizures in Lennox-Gastaut Syndrome. The FDA approved the use of topiramate as add-on treatment in children 2 years of age and older with LGS.

  • A randomized placebo-controlled study of 98 people with LGS from over 1 year to less than 30 years old showed an improvement in seizure severity for people treated with topirmate compared to those treated with placebo. Also, 33% of patients treated with topiramate had an improvement in major seizures by at least 50%.  
  • This medication may make a person sleepy and lower appetite and weight. Some people notice that that they have more difficulty talking smoothly or finding the right words. Language and other developmental aspects should be monitored in a child starting this medication.
  • Topiramate may also cause decreased sweating. As a result, a person can get overheated without realizing it. This can make it very difficult for the child to play outside when it is warm. This occurs more often in infants and young children and less often in adolescents and adults. Appropriate precautions should be discussed with the health care team. 
  • Topiramate occasionally leads to kidney stones, which can be quite painful and increase seizure frequency in people who may not be able to report the pain correctly.  Very rarely topiramate can lead to glaucoma, producing eye pain or a change in vision (decreased ability to see items at a distance).
  • Topiramate is similar to lamotrigine when it is started – people tolerate it better with less side effects when it is started slowly at low doses.

Rufinamide was approved in the U.S as add on treatment of seizures associated with LGS in 2011 for people 4 years of age and older. This drug is effective in treating atonic seizures (drop attacks) and convulsive seizures. Rufinamide does not appear to worsen other seizure types. A recent study showed benefit for partial seizures.

  • A randomized placebo-controlled study found that people taking rufinamide had a median (average) decrease in total seizure frequency by 32.7% and a decrease in major seizures by 42.5%.
  • Common side effects include sleepiness, nausea or vomiting. These can be helped by starting the medicine slowly.
  • Rarely, a serious rash may occur on this medication. Like with any medication, if a rash occurs during the first several weeks or months on this medication, the neurologists’ office should be contacted immediately.

Clobazam, a benzodiazepine, was approved in 2011 by the FDA for add-on treatment of seizures associated with LGS in people 2 years of age and older. While some other benzodiazepine medications have been used in people with LGS before this, Clobazam is the only one that has undergone extensive testing for this type of epilepsy. It appears better tolerated than clonazepam, and the helpful effects may wear off less often than with other benzodiazepines.

  • A randomized placebo-controlled study showed that weekly rates of drop or atonic seizures declined from 14.2% in people taking a placebo or inactive drug to between 41% and 68 % of baseline in patients taking 3 different dosage strengths of clobazam.
  • Common side effects include sleepiness or changes in behavior and mood. If these side effects occur, they are usually noted within the first weeks.

Valproate can be helpful against multiple seizure types seen in a child with LGS. 

  • In general, valproate is well tolerated, but some children may have stomach upset, sedation, or increased appetite.
  • Rarely, especially in children below age 2 years, valproate may cause serious liver problems, potentially resulting in death. In light of this rare side effect, if valproate is used in young children, parents must know the symptoms of potential liver toxicity and call the doctor as soon as any problems are seen.
  • Some people may chose not to use this in a child with LGS, especially if there are concerns about metabolic problems associated with the LGS. Underlying metabolic problems could increase the risk for serious liver problems in a child.

Clonazepam is also from the benzodiazepine family and has been used to treat LGS, yet has not been approved by the FDA for this purpose. This is primarily helpful for the convulsive and myoclonic seizures.

  • Some side effects may include behavioral symptoms, like increased activity and changes in mood, or sleepiness, drooling or problems with motor coordination.
  • The effectiveness of benzodiazepines like clonazepam can decrease over time when it is taken on a daily basis, making this primarily useful for short-term seizure control.
    • While tolerance is possible with any benzodiazepine, so far it seems to be less of a problem with the use of clobazam. 

Other medications have been less well studied but have been used in treating children, adolescents and adults with LGS. These medications include ethosuximide, vigabatrin, zonisamide, and levetiracetam.

Medicine that can worsen seizures: Some medications may worsen the frequency or severity of seizures. While this happens rarely, it’s important to know which medicines can help or worsen your seizures, especially if a person has multiple types of seizures.  The reason for seizure worsening is not fully known. Additionally, while a medicine can worsen some one type of seizure, it may be very helpful for another. Thus, each medication must be carefully evaluated for its overall benefit. If seizures worsen, the medication may need to be adjusted or withdrawn.  Managing seizure medications in a person with LGS requires carefully choosing and tailoring medication plans to each person to increase seizure control and limit side effects. 

For more information:

Authored by: Patricia O. Shafer RN, MN | Elaine Kiriakopoulos MD, MSc | Joseph I. Sirven, MD on 11/2014
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