UAB drug study first effort to prevent onset of epilepsy in tuberous sclerosis complex
UAB and partners launch the PREVeNT study, aimed at preventing the onset of seizures in children with tuberous sclerosis.
Researchers at the University of Alabama at Birmingham have launched the first drug study aimed at preventing or delaying the onset of epilepsy in children with a genetic condition known as tuberous sclerosis complex. UAB is the lead institution and data center for the PREVeNT study, a national, multisite study funded by a $7 million grant from the National Institutes of Health.
Tuberous sclerosis complex is a genetic disorder that causes tumors to form in many different organs. TSC particularly affects neurologic functions, often leading to seizures, developmental delay, intellectual disability and autism. About 80 percent of children with TSC develop epilepsy within the first three years of life.
“There is a small window, perhaps two to three months in duration, between the first detectable signs of abnormal brain activity and the onset of seizures in infants with TSC,” said Martina Bebin, M.D., professor in the Department of Neurology in the UAB School of Medicine and the study’s primary investigator. “Those detectable signs can be discovered through electroencephalography, or EEG, before any symptoms are present. This window gives us an opportunity for preventive therapeutic intervention to delay or prevent the onset of seizures.”
Previous studies by Bebin’s research team identified EEG biomarkers of abnormal brain activity in infants with TSC. These biomarkers typically are detectable within the first four to six months of the infant’s life, and predate the onset of seizures by two to three months.
Using EEG, the new study will look for the presence of the biomarkers to determine when abnormal brain activity begins, and then launch a drug intervention during the window between the first signs of abnormal brain activity and before seizure onset. The researchers are hoping to determine whether early intervention will have a positive effect on developmental outcomes and delay or prevent the onset of seizures.
Martina Bebin, M.D., professor in the UAB Department of Neurology
The study will recruit 80 infants with TSC at seven sites nationally. EEG monitoring will begin as early as six weeks of age, followed by serial EEG testing during the first 12 months of life. At the first sign of abnormal brain activity, half the infants will receive vigabatrin, a medication used to control infantile spasms, while the other half receive placebo. At the onset of clinical seizures, all of the children will transition to the standard of care for infants with TSC and seizures. The investigators will follow the children for three years to monitor developmental progress and the onset and severity of seizures. “The aim of the study is to determine the impact of a preventive treatment with vigabatrin on the developmental outcome of children at 2 years of age,” Bebin said. “Traditionally, most children with TSC don’t see a neurologist until seizures begin. We want to examine the effects of early intervention, prior to the onset of seizures. If the intervention is successful, it could have a significant impact on clinical practice.”
Bebin says a better understanding of brain activity prior to the onset of seizures could lead to changes in how infants with TSC are monitored and when medical intervention should commence.
UAB is partnering with the Tuberous Sclerosis Alliance in the study. Other study sites are Stanford University, University of California at Los Angeles, University of Houston, Cincinnati Children’s Hospital Medical Center, Minnesota Epilepsy Group and Boston Children’s Hospital.
The study will begin recruiting subjects in fall 2016. Those interested in participating should contact the PREVeNT study at //email@example.com/">firstname.lastname@example.org, at www.clinicaltrials.gov, or through the Tuberous Sclerosis Alliance website at www.tsalliance.org.
By Bob Shepherd
UAB Media Relations
UAB study finds potential treatment target for Guillain-Barré syndrome
Eroboghene Ubogu, M.D., professor in the Department of Neurology
Investigators at the University of Alabama at Birmingham have identified an intriguing potential treatment target for the most common form of Guillain-Barré syndrome. In a study published online in July in Acta Neuropathologica, the authors offer evidence of a crucial pathogenic role for a molecule that is associated with acute inflammatory demyelinating polyradiculoneuropathy — or AIDP, the most common variant of Guillain-Barré syndrome.
Guillain-Barré syndrome is the most common cause of sudden peripheral nerve disease in the world. It is an autoimmune disease affecting about one to three per 100,000 people a year. This year marks the 100th anniversary of the first recognized description of Guillain-Barré syndrome, a disorder that can lead to long-term disability, paralysis and death. There have been no new therapies for more than 20 years.
Autoimmune diseases are characterized by an inappropriate response by the body’s immune system. Normally, the immune system protects the body by attacking foreign invaders such as viruses, bacteria and other pathogens. But for those who develop an autoimmune disease, the immune system fails to work properly and attacks the body’s own healthy tissue with often devastating results.
White blood cells, also known as leukocytes, are the immune system’s front-line soldiers. When the body recognizes the presence of a foreign substance, leukocytes are activated and migrate to the appropriate area to do battle with the invaders. Leukocytes travel from blood vessels into tissues by means of a process called leukocyte trafficking. This is a coordinated process by which leukocytes are attracted to blood vessels, then attach and migrate across them into the tissues to do their work.
“We have had a very poor understanding of the leukocyte trafficking process in Guillain-Barré syndrome,” said Eroboghene E. Ubogu, M.D., professor and director of the neuromuscular division in the Department of Neurology, UAB School of Medicine and lead author of the study. “We knew that leukocytes crossed into nerves through the blood-nerve barrier with deleterious effects, but we did not understand the mechanism. We undertook this study to examine whether a molecule called alpha M integrin, or CD11b, was involved. This molecule was known to make certain leukocytes attach to blood vessels, and our previous published work using AIDP patient leukocytes in the laboratory provided a clue that it may be crucially important.”
Leukocyte cells travel over the endothelial cells of the blood/nerve barrier. Those that stop and attach have the capacity to enter the nerve and cause demyelination.
In the AIDP variant of Guillain-Barré syndrome, the focus of the autoimmune attack is the myelin sheath, a layer of insulation that surrounds nerve axons, similar to the insulation around the wires of an electric cable. The myelin sheath’s role is to rapidly move electrical impulses along nerves, and if it is damaged — or demyelinated — then nerve function is compromised.
The first step taken by Ubogu and his team was to examine nerve samples from an archive of patients with AIDP located in the Shin J. Oh Muscle and Nerve Histopathology Laboratory at UAB. Oh, a professor emeritus in the UAB Department of Neurology, is a pioneer in the study of neuromuscular diseases.
“From these archived nerve samples, we studied three adult patients with AIDP compared to three matched controls,” Ubogu said. “We hypothesized that we would find CD11b on the leukocytes in those AIDP patient nerve samples, and we did. It was especially present in areas with significant demyelination.”
Next, Ubogu and his team looked at an animal model of AIDP where they were able to block CD11b early in the disease process. With CD11b inhibited, the affected mice exhibited less overall weakness and reduced inflammation, as well as less demyelination and axon loss.
“These two results strongly indicated that CD11b is essential for these autoimmune leukocytes to migrate into the nerves and cause demyelination in AIDP,” he said. “What we still didn’t know was how the cells physically managed to cross the blood-nerve barrier. Was the barrier leaky with gaps between cells? Did the leukocytes push through or between the blood-nerve barrier endothelial cells?”
Using a technique called phase contrast video microscopy, Ubogu’s team produced videos that show AIDP patient leukocytes as they migrated across the layer of endothelial cells that form the blood-nerve barrier in the laboratory. Normally, the leukocytes keep on moving, but Ubogu’s video evidence indicates that some leukocytes are able to stop and squeeze in between endothelial cells. CD11b played a crucial role in this process.
The team verified the laboratory results in actual patients by looking at the inflammation in the nerves of AIDP patients at very high magnification. This showed leukocytes crossing between the blood-nerve barrier endothelial cells without gaps in the barrier or change in how the barrier is structured.
“In a healthy immune system, one of CD11b’s normal jobs is to make specific leukocytes adhere to the surface of blood vessel cells,” Ubogu said. “Unfortunately, they do the same in the AIDP form of Guillain-Barré syndrome. This allows the autoimmune leukocytes to adhere to the blood vessel walls within the inner parts of the nerve, ultimately migrating with direct access to the axons where demyelination can occur.”
Ubogu says the results of these proof-of-concept studies strongly point to CD11b as a treatment target for peripheral nerve inflammation.
“If we can find ways to block or inhibit CD11b early on, we should be able reduce or limit the amount of abnormal leukocyte trafficking, inflammation, and the resulting demyelination and loss of axons in AIDP,” he said. “This should result in better patient outcomes. Another approach might be to selectively remove CD11b leukocytes from the blood circulation so that they are not available to adhere to the blood-nerve barrier endothelial cells in patient’s nerves. Either way, our findings suggest that CD11b is a key candidate for specific drug development strategies in Guillain-Barré syndrome.”
Ubogu says the findings are very exciting, as they provide knowledge of leukocyte trafficking in human nerves, but more work needs to be done in affected patients to develop an effective drug. The findings may also be applicable to other peripheral nerve inflammatory diseases. The research was funded by the National Institutes of Health and UAB.
Collaborators on the study are Chaoling Dong, Steven P. Palladino and Eric Scott Helton, Ph.D., of theNeuromuscular Immunopathology Research Laboratory, Division of Neuromuscular Disease, Department of Neurology at UAB.
By Bob Shepherd
UAB Media Relations
UAB Neurology and Neurosurgery ranked as “Best Hospital” for Neurology and Neurosurgery
UAB Hospital remains at top in Birmingham and Alabama, and rises in several specialty rankings in 2016-2017 U.S. News & World Report Best Hospitals report.
The UAB Health System is dedicated to providing every patient with the best experience and highest quality care available.
U.S. News & World Report’s 2016-2017 Best Hospitals report ranks UAB Hospital No. 1 in Birmingham and Alabama, and nine UAB specialties are listed among the nation’s top 50, up from six specialties the previous year.
“We are proud to be one of the best hospitals in America, and located in Alabama,” said Health System CEO Will Ferniany. “UAB Medicine is something all people in Alabama should be proud of. We even have a bumper sticker that says ‘Our Nationally Ranked Team Wears Scrubs.’ While we are nationally ranked and internationally known, our faculty and staff never forget they are here to serve the people of Alabama with the best medical care possible.”
Rheumatology (11), Gynecology (16) and Nephrology (20) appeared in the nation’s top 20; Neurology and Neurosurgery (25), Pulmonology (29), Ear, Nose and Throat (29), and Diabetes and Endocrinology (30) appeared in the top 30; and Cardiology and Heart Surgery (37) and Urology (47) rounded out UAB’s highest-ranked programs.
The biggest jumps in rankings came from Ear, Nose and Throat and Diabetes and Endocrinology, which were ranked as high-performing last year and both leapt to top-30 national rankings this year. Cardiology and Heart Surgery went unranked last year and appeared at 37 this year. Rehabilitation, Orthopedics, Cancer and Geriatrics all earned the high-performing designation.
Rankings like U.S. News & World Report’s are just one tool available to patients as they make informed decisions about their health care, Ferniany says. UAB Medicine recently launched another when it became the first care provider in Alabama to empower patients to publicly rate and review its physicians — a reliable source of verified and up-to-date information from actual patients in UAB’s Find a Provider directory. The rating and reviews feature gives patients an alternative to third-party rating sites that often exist with little if any oversight and feature outdated, inaccurate and in some cases libelous information. At its launch, more than 81 percent of eligible UAB physicians had a posted rating of at least four stars on the five-star scale.
UAB Media Relations