About TSC

Brain Abnormalities

Several types of brain abnormalities may be seen in individuals with TSC, including cortical tubers, subependymal nodules, and subependymal giant cell astrocytoma (SEGA). Some individuals will have all of these changes, whereas others will have none. The vast majority of individuals with TSC, however, will have one of these abnormalities.

  • Cortical tubers are best visualized using MRI of the brain.  The cortical tuber (from which TSC was originally named) is a disorganized area of the brain that contains abnormal cells.  Some individuals with TSC have numerous tubers, whereas others will not have any.  The tubers are more difficult to see in an infant’s brain than in a more mature brain, but it is still possible to image the tubers in a newborn.  Tubers and/or the brain area surrounding a tuber play a role in the development of seizures in individuals with TSC.  However, recent studies have shown that there may also be numerous scattered abnormal cells throughout the brain of an individual with TSC, and the role of these cells in seizure development is not clear.                        
  • Subependymal nodules (SEN) are small accumulations of cells that are located on the walls of the cerebral ventricles (the spaces in the brain that contain cerebrospinal fluid (CSF).  The nodules often accumulate calcium, and are then easily identified on MRI imaging of the brain.
  • Subependymal giant cell astrocytoma (SEGA) occurs in up to 20% of individuals with tuberous sclerosis complex (TSC) and is more likely to develop during childhood and adolescence. SEGA is a type of brain tumor that occurs in individuals with TSC that is noncancerous and is not malignant but can still be very problematic. It is important to monitor for the occurrence of this brain tumor during childhood and until approximately the age of 25 years in individuals with TSC.

What is a SEGA or SGCT?

First, the word subependymal refers to the area below the ependymal lining, a membrane that surrounds the cerebrospinal fluid-filled spaces within the brain. Giant cell refers to the very large, abnormal cells that are found with microscopic examination of the tumor.

Astrocytoma refers to the type of tumor based on the most prevalent cell type. Historically, this tumor type has been classified as a slow-growing astrocytoma. However, since the cells in the tumor are not just astrocytic but also neuronal in origin, the term subependymal giant cell tumor or SGCT has been suggested. At the International TSC Consensus Conference in June 2012 experts recommended to continue using the term SEGA nonetheless for consistency.

SEGAs are usually found in the ventricles in the brain. Ventricles are natural spaces deep inside the brain filled with a clear fluid called cerebrospinal fluid (CSF). SEGAs are noncancerous tumors, meaning they do not metastasize (spread to other parts of the brain or the body). However, the tumor can be problematic because it may grow sufficiently large to block the flow of CSF within the brain, causing an increase in the pressure within the head and enlargement of the fluid-filled spaces (a process known as hydrocephalus).

Typically, SEGAs are very slow growing, but occasionally they may begin to grow more rapidly. It is not known what triggers the growth of a SEGA or why some individuals with TSC have a SEGA, whereas others do not. It is also not known why only some of the small nodules found on the surface of the ventricles, referred to as subependymal nodules (SENs), may eventually grow and become SEGAs.

How do you diagnosis a SEGA?

Individuals with TSC should receive regular brain imaging, at least until adulthood. If regular scanning is performed, a SEGA can usually be noted at an early stage so that appropriate follow-up and/or treatment can be initiated.

New SEGAs seem to very rarely arise after 20-25 years of age. Brain imaging, preferably MRI with and without contrast, should be performed every 1 to 3 years until the age of 25 years. Beyond 25 years of age, screening brain MRI may not be needed and follow-up intervals may be prolonged thereafter if a SEGA has remained stable. Some individuals with TSC have been diagnosed with the disease only after they were diagnosed with asymptomatic SEGA.

What are the symptoms of a SEGA?

An individual with TSC who has a SEGA may initially have no signs or symptoms of having a brain tumor, only to develop symptoms when the tumor has grown large enough to block the flow of CSF. CSF now accumulates and causes increased pressure in the brain. At this stage, some common signs are headaches, nausea, vomiting, clumsiness or inability to walk, increased frequency and/or severity of seizures, behavioral changes, and/or visual problems (blurred or double vision).

The changes may be subtle, so it is important to be vigilant if an individual with TSC is known to have a SEGA. Signs of increased pressure may also be noted by a physician performing a detailed neurological assessment, which includes examining the appearance of the nerves in the back of the eyes.

How do you treat SEGA?

In the past surgery has been the sole treatment strategy for growing and/or symptomatic SEGAs. In 2010, the mTOR inhibitor everolimus (marketed in the United States as Afinitor® and referred to in medical literature as RAD001) was approved by the Federal Drug Administration (FDA) to treat SEGA associated with TSC. Approval was based on the very positive results of an important clinical trial in 2010 and subsequently confirmed by a larger, more detailed phase 3 clinical trial in 2013 documenting successful shrinkage in TSC associated SEGAs.

There are advantages and disadvantages of surgical and medical treatment which should be reviewed with physicians familiar with TSC and SEGA. Aspects that help in decision making are summarized by the expert recommendations from the International Tuberous Sclerosis Complex Consensus Conference in 2012.

Will a SEGA regrow once it has been surgically removed or treatment with mTOR inhibitor has been stopped?

If a SEGA is completely surgically removed, that SEGA will not regrow. However, there have been numerous cases in which neurosurgeons are unsuccessful in the complete removal of a SEGA or in which another SEGA began to grow at a different location after the initial SEGA was removed. In such instances, the remaining or new SEGA will require repeat surgery or medical treatment at some point in the future.

Medical reports and prospective clinical trials showed that SEGAs do regrow if treatment with a mTOR inhibitor is stopped. It is not yet known if and when long-term treatment with an mTOR inhibitor will eventually avert the risk of re-growth.

What is the danger in not treating a growing SEGA?

The danger in not treating a SEGA that is increasing in size is that it will eventually block the flow of CSF and cause a significant increase in pressure in the brain, leading to severe headaches, nausea, and vomiting. Increased frequency and/or severity of seizures, neurological and behavioral changes, clumsiness, visual disturbance and even loss of vision may be associated. Hydrocephalus caused by the SEGA can be life threatening and necessitates treatment.

Who do I contact if I, or my child, have symptoms of a SEGA?

You should contact your physician as soon as possible. If you are not currently under the care of a neurologist, you should contact your primary care physician. Ultimately, you will probably be referred to a neurologist, neuro-oncologist or neurosurgeon who is familiar with the treatment of SEGAs.

How do I select a neurosurgeon?

Most neurosurgeons have specialties within the field of neurosurgery, so you should look for a neurosurgeon who has training in brain tumor surgery in children and, if possible, surgery for SEGA.

When you meet with the neurosurgeon, you might ask the following questions:

  • How many times have you performed surgery to remove a SEGA from other individuals with TSC?
  • What was the age range of the individuals with TSC on whom you have operated?
  • What is the surgical approach you will use to remove the SEGA?
  • What are the possible complications that might occur during and after the surgery?
  • Once the surgery is complete, what will the recovery time be?
  • What is the chance that the same SEGA will regrow?
  • How will this be monitored post-surgery?
  • Is treatment with a mTOR inhibitor an option?
  • What are the side effects of treatment with a mTOR inhibitor?

Where can I go for more information?

Afinitor®
Website: www.afinitor.com

American Brain Tumor Association
8550 W. Bryn Mawr Ave. Ste 550, Chicago, IL 60631
Phone: 1-773-577-8750, CareLine: 1-800-886-2282
Email: info@abta.org
Website: www.abta.org

Child Neurology Foundation
201 Chicago Avenue #200
Minneapolis, MN 55415
Phone: 952-846-7942
Website: www.childneurologyfoundation.org

Children’s Brain Tumor Foundation
274 Madison Avenue, Suite 1004, New York, NY   10016
Phone: 212-448-9494 866-CBT-HOPE (228-4673)
Email: info@cbtf.org
Website: www.cbtf.org

The Childhood Brain Tumor Foundation
20312 Watkins Meadow Drive, Germantown, MD 20876
Phone: 301-515-2900, Toll-Free: 877-217-4166
Email: cbtf@childhoodbraintumor.org
Website: www.childhoodbraintumor.org

National Brain Tumor Society
55 Chapel St. Ste 200, Newton, MA 02458
Phone: 617-924-9997
Website: www.braintumor.org

National Cancer Institute, National Institutes of Health
Cancer Topics / “What you need to know about brain tumors”
Website: www.cancer.gov/cancertopics

National Institute of Neurological Disorders and Stroke, National Institutes of Health
NIH Neurological Institute, PO Box 5801, Bethesda, MD 20824
Phone: 1-800-352-9424 or 1-301-496-5751
Website: www.ninds.nih.gov
For access to free Telecommunications Relay Services (TRS) for people with hearing or speech impairment dial 7-1-1 on your telephone.

Pediatric Brain Tumor Foundation
302 Ridgefield Court, Asheville, NC 28806
Phone: 1-828-665-6891 or 1-800-253-6530 (8:30 am – 5:00 pm Eastern Time)
FAX: 1-828-665-6894
Website: www.pbtfus.org

References

  • Franz DN, Belousova E, Sparagana S, et al. (2013) Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 381: 125-132.
  • Franz DN, Krueger DA, Balko MG (2010) Subependymal giant cell astrocytomas, In, Tuberous Sclerosis Complex: Genes, Clincal Features, and Therapeutics, DJ Kwiatkowski, VHWhittemore, EA Thiele (Editors), Weinheim: Wiley-Blackwell, pp: 211-228.
  • Goh S, Butler W, Thiele EA (2004) Subependymal giant cell tumors in tuberous sclerosis complex. Neurology 63:1457-1461.
  • Krueger DA, Care MM, Holland K, Agricola K, Tudor C, Mangeshkar P, Wilson KA, Byars A,Sahmoud T, Franz DN (2010) Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med 363(19):1801-11.
  • Krueger DA, Northrup H; International Tuberous Sclerosis Complex Consensus Group (2013) Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 49:255-65.
  • Roach ES, DiMario FJ Jr, Kandt RS, Northrup H (1999) Tuberous Sclerosis Complex Consensus Conference: Recommendations for diagnostic evaluation. J Child Neurol 14:401-407.
  • Roth J, Roach SE, MD; Bartels U, Jóźwiak S, Koenig MK, Weiner HL, Franz DN, Wang HZ (2013) Subependymal giant cell astrocytoma: diagnosis, screening, and treatment.
  • Reviewed and updated by Darcy Krueger, MD, and David Franz, MD, February 2011, by TS Alliance and Ute Bartels, MD August 2013 (References updated August 2014).

Reviewed and updated by Darcy Krueger, MD, and David Franz, MD, February 2011, by TS Alliance and Ute Bartels, MD August 2013 (References updated August 2014)