Tuberous Sclerosis Complex: Exploring the Complexities
Where epilepsy is concerned there are so many questions surrounding how and where in the brain a seizure is generated. And when it comes to Tuberous Sclerosis Complex (TSC) the answer to these questions are even more compounded by the complexity of this genetic disease that usually affects multiple parts of the brain at the same time.
Dr. Kevin Ess, M.D., Ph.D., Assistant Professor of Neurology and Pediatrics at Vanderbilt University, amongst other researchers, is one of many on an active quest to understand the mechanisms behind this often devastating disorder. “Tubers represent regions of severe cortical malformation. They are particularly problematic when they generate seizures while the brain is still developing. This is the case with so many patients that we see. About 90% of people with TSC have epilepsy at some point in their life. In particular, up to 30-50% of patients with TSC also have infantile spasms. The challenge clinicians face is to get the seizures under the best control possible as we believe that patients with intractable seizures during early development often do poorly. This is the subgroup that is much more likely to have serious comorbid neurological conditions such as autism and mental retardation” said Dr. Ess.
In a recent review article Dr. Ess stated, “It has been postulated that the number of cortical tubers represents a biomarker for the severity of cerebral dysfunction and epilepsy.” In addition to the number of tubers present in the brain there is also the issue of where they are located and whether or not the tuber is actively epileptogenic. According to Dr. Ess, “There are several lines of thinking on how seizures are generated in a person with TSC. There is the theory that the number of tubers in the brain obstructs the brains ability to function normally and “irritates” the adjacent normal brain to such an extent that seizures result. There is also the idea that the tuber itself initiates and somehow propagates seizures. At this point there are a lot of questions and no clear answers. The current consensus in the research and medical community is that both mechanisms are possible.”
What We Know About TSC
What is TSC?
TSC is a genetic disease caused by the inactivation of either the TSC1 or TSC2 genes. This allows the formation of benign tumors in many different organs, primarily in the brain, eyes, heart, kidney, skin and lungs. As they appear to contain abnormally differentiated, non-malignant cells, they are classified as hamartomas. According to the Tuberous Sclerosis Alliance, “The disease affects some people severely, while others are so mildly affected that it often goes undiagnosed. Some people with tuberous sclerosis experience developmental delay, mental retardation and autism. However, there are also many people with tuberous sclerosis living independent, healthy lives.”
What are the current treatments available to patients with epilepsy and TSC?
TSC is the most common known cause of infantile spasms. Infantile spasms usually start very early in a child’s development (between 3 and 12 months). Intuitively we know that the first few years of a child’s brain development are critical because the brain normally undergoes immense changes coincident with the acquisition of higher cognitive functions including language. As Dr. Ess pointed out, “If a child’s seizures are well-controlled, all the other neurological features of TSC such as autism and developmental delay seem to be less likely and less severe. I tell parents of children with TSC that our first goal to get the seizures under control. This is a practical goal as well as we do not have very good therapies for the rest of the neurological features associated with TSC.”
Vigabatrin (Sabril)
Many neurologists believe vigabatrin is the medication of choice for the treatment of infantile spasms in children with TSC. There also are parental organizations that strongly advocate for this therapy. This is based on their personal experiences with this medication that was usually effective in stopping infantile spasms in their children within the first few weeks, sometimes even within the first few days. This experience is not anecdotal however. Well designed clinical trials have repeatedly shown that vigabatrin is very effective in these patients. This medication however is currently not FDA approved due to the concerning side effect of peripheral visual field loss. “The biggest problem parent’s face is that some neurologists won’t even entertain the idea of prescribing vigabatrin because it is not FDA approved. In addition, there can be an economic barrier as insurance companies will never pay for an unapproved drug,” said Dr. Ess. However, he is hopeful that vigabatrin will soon be approved by the FDA as a new drug application was submitted to the FDA early in 2006.
Steroid therapy
Steroid Therapy (adrenocorticotropic hormone [ACTH] or prednisone) is the primary treatment for infantile spasms in the United States. “And while steroid therapy has proven to be effective in treating infantile spasms, it is probably not as effective as vigabatrin”, asserted Dr. Ess. “While the data is compelling, many patients with TSC and infantile spasms are placed on ACTH or other medications, largely due to the barriers to vigabatrin access that exists in the United States”.
Can genetic testing be conducted to find out if a particular family member has TSC?
The Human Genome Project (HGP) started in 1990 and completed in 2003 is the foundation for so much of what we currently know about the approximately 20,000-25,000 genes in human DNA. Because of the HGP, companies such as Athena Diagnostics are able to sequence both the TSC1 and TSC2 genes in their entirety to confirm if a particular person has TSC and to pinpoint the exact genetic abnormality. Currently, if a person with known TSC undergoes genetic testing the sensitivity for detecting the precise genetic abnormalities of the TSC1 or TSC2 genes is approximately 80%. The power of genetic testing is to then allow testing of other first degree family members who are suspected of having the disease as well. According to Dr. Ess, “approximately 1/3 of cases of TSC are familial, the majority then represent sporadic cases that will not have family involvement. It should be emphasized however, that genetic testing is not perfect. Often patients without a positive genetic test clearly have TSC based on clinical examination and imaging criteria”.
“In addition to genetic testing, there are also a growing number of patients that come to our attention even before they are born. This is due to the widespread use and increased resolution of fetal ultrasound technology that can detect cardiac rhabdomyomas. These benign cardiac tumors are often associated with TSC. While up to 50% of children with TSC may have rhabdomyomas, they lead to cardiac problems only rarely and as a rule will spontaneously regress during childhood”.
Hope, Help and Resources
Dr. Ess admits that informing parents at any point in their young child’s life that their child has TSC is challenging and sometimes heart breaking. His goal for parents and those facing TSC is to stay hopeful and optimistic as many who live with TSC are able to lead fulfilling and healthy lives. “I want patients and the public to know that TSC is not as devastating a diagnosis as it used to be. There are rapid advancements being made that will lead to new therapies.” He encourages everyone to visit the Tuberous Sclerosis Alliance website to learn more about TSC as well as get local community support.There are also various TSC clinics specializing in the treatment of TSC located throughout the United States.
About Dr. Kevin Ess
Dr. Kevin C. Ess graduated from the College-Conservatory of Music in Cincinnati with a B.M. in Music Performance in 1989. He then earned a PhD in Developmental Biology (1996) and a M.D. degree (1998) from the University of Cincinnati. After an internship in Pediatrics at Denver Children’s Hospital, he became a Resident in Neurology and Pediatric Neurology at Washington University in St. Louis. Dr. Ess next completed fellowship training in Pediatric Neurophysiology at Washington University as well as post-doctoral research in the laboratory of Dr. David Gutmann, a noted scientist who introduced him to TSC research. He was appointed Instructor of Neurology and Pediatrics at Washington University in St. Louis from 2004-2006.
Dr. Ess joined the faculty at Vanderbilt University Medical Center in 2006 as an Assistant Professor in the Departments of Neurology and Pediatrics. He is also a member of the John F. Kennedy Center for Research on Human Development. His research interests focus on mechanisms of normal cortical development and how genetic aberrations result in brain malformations, epilepsy, and autism. His clinical activities focus on the management of intractable epilepsy in children. This includes various medical therapies as well as the ketogenic diet and epilepsy surgery. He has a special interest in the diagnosis and treatment of the genetic disorder Tuberous Sclerosis Complex. He established a Tuberous Sclerosis Clinic at St. Louis Children’s Hospital in 2002. A comprehensive Tuberous Sclerosis Clinic was started at Vanderbilt Children’s Hospital in the Spring of 2006.
References
Ess KC: The Neurobiology of Tuberous Sclerosis Complex. Semin Pediatr Neurol 13: 37-42, 2006