Epilepsy: How Genetic Testing Enables More Precise Diagnosis and Targeted Therapy

Paolicchi, Juliann M., MA, MD
Professor, Clinical Pediatrics and Neurology
Weill Cornell Medical Center
New York, NY
Also by this Author 

About a third of epilepsy patients do not respond to therapy, despite a thorough work-up and extensive testing.1 Genetic testing of these patients can identify specific syndromes and provide a basis for more effective treatment.

Dr. Juliann Paolicchi, Professor,Clinical Pediatrics and Neurology, Weill Cornell Medical Center, discusses the importance of timely genetic testing to direct treatment, reduce the risk of inappropriate therapy and help avoid unnecessary procedures.

The Diagnostic Challenge

The first challenge with epilepsy, says Dr. Paolicchi, is the diagnosis – determining whether or not a seizure patient has, in fact, epilepsy. “This is usually achieved by taking a thorough history of how the patient presented and following up as necessary with detailed EEG testing, which then determines how much additional testing is needed. If the patient has a relatively benign epilepsy syndrome or a relatively straightforward presentation, that may be all that is necessary. Patients who have ‘generalized’ epilepsy, epilepsy that comes from all over the brain at once, may not need further MRI or neuroradiographic testing, if they are otherwise neurologically normal.  The patient with partial, or focal, seizures, most often needs further neuroradiographic testing.” 

“A good portion of patients, close to 50%, will be well controlled on the first medication,” continues Dr. Paolicchi. “Unfortunately, if the first medication is not effective, there's only about an 11% chance that the second medication will be effective. After that, the odds of success fall drastically and the percentage of patients who are controlled fully, who are seizure-free, on the third or subsequent medication, is less than 4%.1 So, there are about a third of patients who continue to have seizures despite good diagnosis, good testing, and a good choice of medication. For this category of patients we have additional questions to resolve. Why do they have their epilepsy? Is there an underlying syndrome? Is there more that we need to diagnose? Is there something besides medicines, or are there more specific medicines, that we need to consider in their treatment? This is the point at which we consider genetic testing.”

Role of Genetic Testing

“Patients who do not have a partial focus, whose neuroradiology has not shown a specific lesion, who may have seizures from multiple parts of the brain at once, and for whom we don’t yet have an explanation, are certainly candidates for genetic testing,” notes Dr. Paolicchi. “In addition, we used to believe that patients with a lesion didn’t need additional testing, but with the availability of newer genetic information, we found that many of the focal epilepsies that cause abnormalities in the brain itself, especially in the way the brain is formed, can have a genetic basis. This has been shown by data coming from earlier studies as well as newer genetic studies, especially the Epilepsy Phenome/Genome Project (EPGP study)2 and the Human Epilepsy Project (HEP study)3. Therefore, brain malformations are a new category of epilepsy syndromes that, in the past, we did not even consider for genetic testing but which could also have a genetic basis.”

A Step-wise Approach to Testing

The selection of genetic tests follows a step-wise approach, explains Dr. Paolicchi.

“The first line of testing is usually a chromosomal microarray (CMA), which provides an analysis of microdeletions and duplications, as well as structural abnormalities of the chromosomes, such as translocations. In the past, we used to get chromosome analysis or, karyotypes, but these are now less indicated, unless the patient seems to have one of the chromosomal syndromes. It’s a first line of genetic testing, utilized for very specific kinds of examination, for example, if the patient condition could be consistent with Down Syndrome.”

If we feel that the patient's characteristics fit a set pattern - it looks like a specific genetic epilepsy syndrome, like severe myoclonic epilepsy of infancy or Dravet Syndrome - we might go straight to a genetic panel screening for Dravet Syndrome and other related syndromes. If not, we might go through the CMA step, and if that's not revealing, or the findings are nonspecific, we will usually then proceed to more comprehensive genetic testing. In general, we'll go first to one of the epilepsy genetic panels as they are capable of surveying for multiple genetic epilepsy syndromes.” 

If there is still no definitive answer at this point there is one further step, which is to move to whole genome, or whole exome, sequencing to look for any possible putative gene in a particular patient. “Our approach is guided by what we believe will answer our question most expeditiously and least expensively.”

Helping Guide Appropriate Therapy

Identifying a specific syndrome through genetic testing can help guide therapy. “We have some very good information about specific genes and their interactions, which can impact therapeutic decision-making,” notes Dr. Paolicchi. “For example, sodium channel blockers must be avoided for patients with a sodium channel (SCN) aberrant disorder, as they will usually worsen the patient's situation. If we suspect that disorder, or certainly if the genetic tests reveal those disorders, we have to take patients off thosemedications. Secondly, patients with the SCN mutations tend to respond extraordinarily well to dietary therapy.  If that has not yet been recommended, we have a very frank and detailed discussion with families and caregivers about which of the dietary therapies may best fit the patient's care. Thirdly, long-acting benzodiazepines tend to be extremely effective for that category of disorder. There is also a specific medication, stiripentol, that's now available from Europe but not yet readily available in the United States. In this example there is a progression of treatment choices based on the identification of a particular syndrome.”

A more precise diagnosis also helps clinicians avoid inappropriate therapy. “This is a very important message for clinicians to note,” stresses Dr. Paolicchi. “It used to be that once a patient had what we now term medically refractory epilepsy, or treatment refractory epilepsy, we would either consider surgery or possibly some other therapy. Now we're telling clinicians to proceed more quickly to genetic testing, because if the cause is a genetic epilepsy, it will allow more focused therapy and avoid a likely unnecessary surgery.”

Rationale for Timely Testing

“It’s been shown that the best indicator of treatment-resistant epilepsy long-term is the response to medications in the first year.1 So, it becomes clear early on whether someone is going to be a treatment refractory patient or not, especially in pediatrics. By moving rapidly to genetic testing for these patients, clinicians can direct more effective therapy. While patients may continue to have seizures, the goal is to minimize the seizures while maximizing the quality of life.  In other words, to put them on more effective therapies that have less side effects and allow them to function and develop, while minimizing the overall amount of therapy. Sometimes patients in this category can end up on multiple medications, several of which may not be of benefit, so this is another way to manage them more effectively.”

‘In general, we do not advocate surgery for patients with genetic epilepsy, unless they have some form of focal anatomical problem. Therefore, identifying a genetic etiology early may also help a patient avoid an unsuccessful procedure. If a patient has genetic epilepsy, that abnormal gene is present in all their genes, so removing an active area isn't necessarily going to help over time.  Now, there are exceptions to that rule, especially in the case of tuberous sclerosis, but it is in general, a contraindication for resective surgery in these patients.”

Gene-specific Therapies

A promising area in the field is the development of gene-specific therapies.  “Some of these are now becoming available,” says Dr. Paolicchi. “For example, there is a newer medication that works on the potassium channel, and there is a known genetic abnormality at the potassium channel called KCNQ2, that causes seizures in young children. There are concerns regarding the use of this medication, and direct trials are not available, but it offers a suggestion towards a future of directed therapies. New medications are becoming available that may be more specific to the genetic epilepsies and hopefully in the future we will have more gene-directed therapies. In the meantime, we continue to develop information about how best to treat these genetic epilepsies, which is crucial to patient care.”


  1. Patrick Kwan P, and Brodie, MJ. Early identification of refractory epilepsy. N Engl J Med 2000; 342:314-319 http://www.nejm.org/doi/full/10.1056/NEJM200002033420503 Accessed October 8, 2014.
  2. The Epilepsy Phenome/Genome Project Clin Trials August 2013 10: 568-586 http://www.epgp.org/Documents/EPGP_PUB_Overview.pdf Accessed October 8, 2014.
  3. The Human Epilepsy Project. http://humanepilepsyproject.org/ Accessed October 8, 2014.

Released on Tuesday, October 28, 2014