When Charlotte D’Amario was about 4½ months old, she began making odd, forward-lurching movements. At first, her pediatrician thought it was reflux—that she was trying to spit up. “It was getting worse and worse, and no one had a clue as to what it was,” says Allyson, her mother.
Her parents started to videotape her while she made these odd motions. They occurred in clusters of as many as 50 at a time, several times a day. Seeing videos of Charlotte at 8½ months, her pediatrician sent her to a neurologist. An electroencephalogram (EEG) revealed seizure activity, and an MRI scan showed tuber-shaped growths in Charlotte’s brain.
Charlotte was diagnosed with tuberous sclerosis complex (TSC), a rare genetic condition in which benign tumors grow in the brain and other organs such as the skin, heart, eyes, kidneys and lungs. In about 90 percent of children, it causes epilepsy that can result in developmental delays.
Charlotte’s parents were worried. “She wasn’t crawling or rolling, wasn’t hitting those baby milestones,” says Allyson.
A few weeks later, Charlotte met with Mustafa Sahin, MD, PhD, at the Tuberous Sclerosis Program at Boston Children’s. He diagnosed her seizures as infantile spasms and changed her to the appropriate medication—one that immediately stopped the spasms.
But about six months later, the seizures started trickling back. For the next two years, Sahin and his colleague Jurriaan Peters, MD, together with the D’Amarios, tried increasing drug doses and adding new anti-epileptic drugs, but they could not gain control of Charlotte’s seizures.
By this time, it was clear that Charlotte had global developmental delay. At 2, she was still using single words, and at 3 she was just beginning to string two to three words together and use a fork and spoon effectively.
Sahin told the D’Amarios that Charlotte qualified for an international clinical trial of a new TSC treatment. The trial would require weekly visits for two months, including blood draws, which Charlotte hated, with a 50/50 chance that she would get an inactive placebo rather than the real drug. So the D’Amarios opted to try adding another anti-epileptic drug instead.
But as Charlotte began preschool, the seizures worsened, sometimes occurring six times a day. “She did not breathe during seizures and would often vomit,” says Allyson. She and her husband, Eric, were concerned for Charlotte’s safety while at school.
At this point, five anti-epileptic drugs had been tried without success. “We started to explore other avenues of seizure control,” says Peters. That included brain surgery, but when Charlotte was evaluated, her seizures were too generalized to be operable; no exact origin in the brain could be pinpointed.
“That’s when we decided we should give the clinical trial more consideration,” says Allyson.
Attacking seizures at their source
The trial, sponsored by Novartis, is testing a drug called everolimus (Afinitor®). Everolimus is not an anti-seizure drug: it’s used to prevent rejection of transplanted organs and to treat certain cancers, and works by blocking a pathway called mTOR that’s involved in cell growth. Work by Sahin and others has shown that in people with TSC mutations, the mTOR pathway goes on overdrive, causing various abnormalities in brain cells. This defect appears to be the root cause of TSC.
“Everolimus acts just downstream of this defect and undoes part of the negative effects,” says Peters. “It’s a great example of precision medicine.”
Charlotte’s parents enrolled her in the trial in August 2014, and she began taking her assigned medication in October under Peters’ supervision. (Enrollment in the trial is now complete.)
Neither the D’Amarios nor Peters knew whether Charlotte was receiving everolimus or a placebo. But in January 2015, they noticed that the seizures had stopped. In the 4½ months since then, Charlotte has been virtually seizure-free and was able to stop taking one of her three anti-seizure medications. “The only seizures we’ve seen were after weaning the anti-seizure medication and during a fever,” Allyson says.
Improving cognitive function with a drug?
In March, Charlotte began the next, “open label” phase of the trial, in which all patients receive the active drug—and she’s continued to make strides.
“There’s been a great improvement in her speech,” says Allyson. “She’s been very alert, curious and aware lately, commenting on things around her.”
Although the trial is looking specifically at seizures, separate studies at Boston Children’s and elsewhere are finding similar improvements in cognitive function in children with TSC taking everolimus. Data are still being analyzed, but the improvement could be due, in part, to curbing seizures. “We often see that when seizures are controlled, development accelerates,” explains Peters.
Charlotte, who is about to turn 5, begins kindergarten this fall. Her parents may have her do an extra year to help her catch up. Although she also has tumors in her eyes and skin, they are not causing problems, and so far no other organs are affected.
“She has the furthest to go with fine motor skills such as writing and drawing, but she can recognize all her letters and numbers and has met all the goals that have been set for her,” says Allyson. “Now that the seizures have stopped, she doesn’t have to be watched every second. We’re not on high alert all the time, and she can have some real independence. She’s in a great place.”
Learn more about the multi-disciplinary Tuberous Sclerosis Program at Boston Children’s.