At four years old, Zane Smith is a “proper little boy,” as his mother, Kim, describes him, who likes Ghostbusters, Marvel superheroes, roughhousing and playing with cars. But Zane also has a rare form of a brain condition called cerebral cavernous malformation (CCM) that can leave the rambunctious preschooler tired and listless, or worse, suffering from severe headaches, nausea and seizure-like symptoms.
Cerebral cavernous malformations are lesions in the brain that form caverns where tiny blood vessel capillaries can expand like a balloon and leak blood or exert pressure on the brain. There is no known treatment to prevent these lesions from forming, or prevent the blood vessels from leaking, and they can only be removed with surgery.
CCM afflicts anywhere between 1 in 600 to 1 in 200 people, and about a third of those cases are caused by inherited mutations in one of three genes known as CCM1, CCM2 and CCM3. Zane has the CCM3 mutation, which is the least common familial form, and also the most aggressive. Only about 30 to 40 families in the United States are known to carry the CCM3 mutation, which compared to other forms, causes earlier onset of symptoms, higher rates of neurologic complications and more lesions. About half of CCM3 cases require brain surgery because of serious bleeds before the age of 10.
Dr. Issam Awad, director of neurovascular surgery at the University of Chicago Medicine, is one of the world’s leading experts on CCM. He has studied the disease for more than 25 years, and has developed genetically engineered animal models of CCM. He is also conducting research to identify mechanisms of CCM lesion formation that are the basis for developing medications to treat this disease. In a 2011 research study published in Stroke, he and his colleagues showed that a drug called fasudil prevented lesions from forming in a mouse model of CCM. This is the first potential treatment of a cerebrovascular disease based on its genetic mechanisms.
Awad’s clinic sees 20 to 30 new CCM patients per year. He monitors about 100 patients on a regular basis, performing yearly MRI scans to identify new lesions and assess how existing ones are changing. Because the disease is so rare, many physicians only see one or two such cases per year. Awad said the critical mass of CCM patients at University of Chicago Medicine allows him and his colleagues to continually refine their expertise.
“What this has given us is a certain knowledge base about what to expect and what to look for in a typical patient,” he said. “That gives the families and us an ability to compare and contrast cases, and also be able to anticipate what a lesion that may be misbehaving looks like, and recognize that better than doctors who don’t see all of those cases all the time.”
In addition to this knowledge about what to expect from the disease, Awad and his team have developed sophisticated MRI techniques that can count the number of lesions in the brain more accurately, and analyze their composition and the condition of the surrounding brain tissue. They can use this information to assess how the disease is progressing and anticipate potential trouble spots that may require surgical intervention.
Kim Smith and Zane’s father, Lee, traveled with Zane to Chicago recently from their home outside of Cambridge, England, to see Dr. Awad. They found out about UChicago’s CCM clinic through the Angioma Alliance, a patient support group for CCM patients. The group has designated Awad’s clinic as the preferred referral site for patients with the CCM3 mutation, and they help families raise money to travel to Chicago for consultation and imaging.
When the family’s local newspaper in England published an article about Zane’s case online, it went viral. With support from the Cavernoma Alliance UK, a partner of the Angioma Alliance, they raised the $8,000 they needed to travel to Chicago in less than a day, with donations coming in from all over the world. “That was amazing, it was really one of those moments of joy,” said Kim.
Zane’s MRI scans in Chicago showed that he has almost 40 lesions, twice as many as doctors in the United Kingdom suspected. Awad said that he will continue to monitor Zane’s progress with additional imaging scans once a year and, perhaps most importantly for Zane’s family, be just a phone call or email away.
In the meantime, Awad said his team continues to refine its expertise for patients like Zane.
“We probably have more advanced imaging sequences than any other center in the world, and finally, our laboratory is right down the hall at the same institution,” he said. “We are the ones studying the disease therapy in the animals, so having all of that continuum, from the molecular models, to the animals, to the imaging, to the human cases, really brings a critical mass of expertise together for the benefit of our patients.”