When Savannah Salazar was 2 years old, she suffered her first seizure. Then, she had another one. For the next 18 years, she had hundreds of seizures a month, sometimes a week. They could be "tonic-clonic" seizures, meaning her body would go stiff, she might fall, and then she would convulse. Sometimes, she might suffer from "status epilepticus," a non-convulsive seizure state that doesn't stop on its own -- it must be stopped either through a rectal diazepam or, before those existed, by inducing a coma.
Savannah has epilepsy or "seizure disorder," broad clinical diagnostic terms that just mean someone has recurrent seizures. Epilepsy can be caused by brain trauma or disease, like a brain tumor or a severe concussion. But, as in Savannah's case, it can also be the consequence of a genetic mutation. To complicate it all further, epilepsy is a spectrum disorder: Some people may have a brief seizure in the middle of the night once in a while, and others, like Savannah, are much worse.
Her specific kind of genetic epilepsy is known as Lennox-Gastaut syndrome. It affects children, typically before their eighth birthday. People with LGS can suffer from all different kinds of seizures: big and small, convulsive and not, and everything in between.
It is one of several kinds of epileptic encephalopathies, meaning that every seizure you have contributes to cognitive and developmental impairment. So, although Savannah is now 20, she is at the developmental level of a 5-year-old, said her mother, Tracy Dixon-Salazar, the associate research director at Citizens United in Research for Epilepsy in Chicago.
When Savannah was first diagnosed, Ms. Dixon-Salazar said she and her husband felt alone and isolated. "I had to claw my way through to get even the smallest bit of information about it."
She began to read scientific studies and articles published in journals, but had a hard time understanding them. So, she decided to go back to school and polish up her English. While studying for her bachelor's, she realized that it wasn't English she needed to study. It was science.
Ms. Dixon-Salazar went on to receive a Ph.D. in neurobiology.
"I was driven by Savannah, who had this terrible thing."
During the time Ms. Dixon-Salazar was becoming a researcher, she and her husband were also desperate to find a way to help their daughter, whose condition was getting worse. She was sleeping 16 hours a day, and had to wear a helmet so that her head was protected when she had convulsive seizures.
For 18 years, the Dixon-Salazars tried every treatment option they could: 26 different drugs, a vagal-nerve stimulator, holistic recipes and several diets. She was not found to be a candidate for surgery, or they probably would have tried that, too.
Lennox-Gastaut syndrome, which affects roughly 1 in 50,000 to 1 in 100,000 births, is typically difficult to treat, said Elliott Sherr, a pediatric neurologist in the University of California San Francisco Benioff Children's Hospital and a UCSF professor of neurology.
Dr. Sherr is on a team of 150 scientists that have uncovered 25 mutations across nine genes that cause LGS and infantile spasms (essentially LGS as it appears in infants). The study, published in the Aug. 11 online issue of the journal Nature, is the first in a series of studies called EPGP (Epilepsy Phenome/Genome Project, which Savannah Dixon-Salazar participated in) and Epi4K, begun by the National Institutes of Health in 2007 and 2012, respectively. Dr. Sherr helped develop the epileptic encephalopathies group of patients within the genome project.
The hope is that with this knowledge, children like Savannah can get tested early on. If they are a genetic match for the disease, they can get the right treatment for the syndrome, and they can get it before the disease has had time to affect their development. It's part of the growing use of genetic information to advance what has become known as "personalized medicine."
Getting the right treatment
Ms. Dixon-Salazar is excited about the study: "It's the first time that anyone has ever identified anything in Lennox-Gastaut syndrome. Doctors used to say, thankfully, we don't need to know what causes epilepsy because we have so many great treatments."
The beauty of genetic studies, like the EPGP and EpiK4, said Ms. Dixon-Salazar, "is that it allows a personalized treatment option" instead of throwing "drugs at [patients] in a haphazard manner."
It was thanks to a genetic study that the Dixon-Salazars were finally able to put her on the first medication that has worked for more than a few months.
Ms. Dixon-Salazar was doing post-doctoral work for Joseph Gleeson, a professor of neuroscience at the University of California, San Diego's Institute for Genomic Medicine, who ran studies spanning all kinds of neurological diseases.
"Dr. Gleeson saw how much I was struggling with Savannah, and he said, 'Why don't we enroll her and sequence her exome?' "
Sequencing her exome, Ms. Dixon-Salazar explained, basically just means looking at the part of a person's DNA that is in charge of the body's functioning (that's called the exome). Every person has a unique DNA sequence, but humans are similar enough to each other that by comparing a healthy person's DNA to a diseased person's DNA, scientists can pinpoint which part of the DNA is responsible for the disease.
When Ms. Dixon-Salazar looked at her daughter's DNA, she saw that the group of genes regulating calcium going into her brain cells had a lot of mutations, or deleterious changes in DNA. She pursued the matter further, remembering that Savannah's seizures were aggravated when she had taken extra calcium. It turned out that in fact her cells were being told to receive too much calcium too quickly.
So Ms. Dixon-Salazar made a case to the FDA to put her daughter on verapamil, a kind of calcium blocker used for high blood pressure and irregular heartbeats, which is not currently approved for use in people with epilepsy.
Since she began taking verapamil a year and nine months ago, Savannah has been 95 percent seizure-free, and 100 percent free of "status epilepticus." She used to take seven different medications, including the verapamil, but has been successfully weaned off three of them.
Savannah still wears her helmet for safety reasons, but, said her mother, she is opening up. "She is talking like she never talked before. The epilepsy just clouded what she was." They're discovering Savannah has quite a sense of humor, too.
"Epilepsy is really common. It affects about 2 to 3 percent of the population, and of those, one in three don't respond to drug treatment," said Ms. Dixon-Salazar, adding this means that "1 percent [of the population] are still living with uncontrolled seizures."
When patients don't respond to one drug treatment, generally doctors try another, and another, hoping that eventually one will work. That's why Savannah tried 26 different medications.
Often, after two medications, said James Valeriano, the director of the Comprehensive Epilepsy Center at Allegheny General Hospital, doctors will suggest another treatment plan, such as a combination of medicines, a vagal-nerve stimulator (an implanted device like a pacemaker with a wire that sends electrical stimuli up through the brain), or even brain surgery.
Some also try diets, like the ketogenic diet, in which 80 percent of your calories must come from fats.
According to Dr. Valeriano, some patients respond well to these treatments. Fifty percent of those who use the vagus stimulator see a 50 percent decrease in their seizure activity. And surgery has a 65 percent success rate for those who qualify.
And sometimes, a new drug does help, at least for a few months, a time called the "honeymoon period." Or, it is just about trying to find a combination of drugs that works for the patient. But drugs can also be harmful and aggravate the seizure disorders, as they did in Savannah's case, and as they did in the case of Neva Hirschkorn's son, Sean.
Sean has a another rare form of intractable childhood epilepsy known as Dravet syndrome. Like Savannah, it is accompanied by cognitive impairment.
Although doctors knew he had some kind of epilepsy when he began experiencing seizures at age 8, Sean was not diagnosed with Dravet until it was too late to inhibit cognitive damage.
Ms. Hirschkorn, of Stockton, Calif., left her job at the Epilepsy Foundation of Northern California to be home with her son when he turned 22 and aged out of the school system. She continues to volunteer with Epilepsy California and pursues work with other Dravet syndrome advocacy groups.
She said that he was prescribed drugs that are known to actually increase epilepsy in children with Dravet, including Tegretol, Lamictal, Dilantin, Mysoline and Sabril.
"These drugs cause more seizures," she said, which in turn cause more brain damage.
Like Savannah, Sean is now on a drug treatment (Onfi and Depakote ER) that has almost eliminated his seizures, but he cannot escape the cognitive damage.
"My hope and dream is that someday, it will be a requirement to prescribe these drugs that have been contraindicated for Dravet, until after genetic tests are done."
Genetic testing for LGS
Unlike other genetic diseases, like cystic fibrosis, it is rare to find two children in the same family who suffer from Lennox-Gastaut syndrome, said Dr. Sherr in a press release.
This makes it likely that the mutations causing LGS are "de novo," or brand new in the child's DNA. The scientists found 264 children whose severe epilepsy did not have an environmental source. They then compared their genetic information and that of their parents to the DNA of thousands of people with similar heritage but who did not show evidence of the disease.
That is how they pinpointed the mutations and the genes behind the syndrome.
One of these genes is thought to be the same gene involved in Angelman's syndrome, a complex genetic disorder that mostly affects the nervous system. There is a treatment for Angelman's that could potentially benefit LGS patients.
The hope is that through genetic testing, children with LGS can be identified early on.
Genetic testing for individuals is not cheap -- roughly $7,000-$8,000, according to Ms. Dixon-Salazar. And most insurance companies don't cover it yet, although Ms. Hirschkorn said she only had to pay $100 out of pocket. Regardless, she added, it's cheaper than the millions in hospital and ambulance and drug fees your insurance company pays when you don't get the right treatment from the start.
Plus, she said, to be able to help her son, "I would have moved heaven and Earth."
Getting treatment early
"I do a lot of 'what if,' " Ms. Dixon-Salazar said. "What if we had put her on these meds when she was 2? Wouldn't it be amazing if we could intervene when the kids were young?"
Despite Savannah's recent improvement, the cognitive damage caused by the 30,000-plus seizures she has had over the course of her life cannot be erased.
Jennifer Shuckrow, of McCandless, has a daughter, Abby, who began experiencing infantile spasms when she was 2 months old. The infantile spasms have now developed into LGS. She is 9, but "she doesn't look 9. The seizures started when she was 2 months old, and her development almost ended."
Ms. Shuckrow describes her daughter's seizures as "really bizarre startle reflexes. The first few, you just don't think they are seizures."
When she was very young, Abby would have chains of them, totaling up to 50, 60, 70, or even a couple of hundred a day.
Dr. Sherr said that sometimes infantile spasms can be even more subtle -- as subtle as a head nod, so it can take some time for parents and doctors to diagnose the epilepsy.
"Down the road, one could envision identifying kids at risk for these kinds of epilepsies, be vigilant, notice that they have them right away. The faster you get into treatment, the better you are," said Dr. Sherr.
When Abby was quite young, her parents thought a lot about genetic testing.
"We submitted her to a battery of genetic tests -- so many over such a different period. We'd be at the doctor's office and they would say, 'Oh, by the way, this test came back, and she doesn't have this," said Ms. Shuckrow.
But when it became clear that it was getting impossible to stop the developmental delay, the Shuckrows stopped thinking so much about genetic testing.
"We've shifted focus from what caused it to making her life the best that it can be," her mother said.
"You don't want to oversell what we can do tomorrow morning," said Dr. Sherr, though he added, "This is the beginning of the opening up of the book ... [So that someday] we can definitively say to families, 'We know what the cause is.' " And then, for some of them, a personalized, targeted treatment can be prescribed, early on.
Maggie Neil: email@example.com.