Washington University School of Medicine

Tuberous Sclerosis Complex

Tuberous Sclerosis Complex: Mysteries, Manifestations, Mechanisms, and Management

Michael Wong, MD, PhD; Director, Washington University Tuberous Sclerosis Clinic

Overview: The Mystery of TSC
Tuberous Sclerosis (more completely known as Tuberous Sclerosis Complex or TSC) is often viewed as a mysterious disease. First, although this disease is largely obscure and unknown to the general public, TSC is actually relatively common, at least for a genetic disease (~1 in 6000 people). In addition, while many people with TSC exhibit obvious, severe symptoms and classic outward manifestations, others with this disease may appear to be completely asymptomatic. Furthermore, unlike many diseases that afflict only one organ, TSC can affect virtually any organ in the body. Fortunately, with recent significant advances in research, many of the mysteries of TSC are beginning to be unraveled and understood. In this article, I will attempt to briefly summarize 1) the main symptoms and manifestations of TSC, 2) the genetic and biological mechanisms causing the symptoms of TSC, and 3) the available approaches for management of TSC patients. This is intended to represent just a brief overview of TSC - more comprehensive sources of information can be found in the "Further Reading" section below.

Manifestations of TSC
One of the biggest mysteries about TSC is that this disease can present with so many different symptoms or manifestations. The wide variety of symptoms of TSC can be attributed to the equally wide variety of organs in the body that can be affected by this disease. In many cases, neurological symptoms due to involvement of the brain account for the most obvious and often most severe manifestations of the disease. Epilepsy is very common in TSC - some studies have estimated that ~80-90% of patients with TSC will develop seizures at some point. The seizures themselves can vary in their features, ranging from the dramatic convulsion (generalized tonic-clonic seizure) to the more subtle staring spell (absence or complex partial seizure). Infants with TSC often develop a special type of seizure, called infantile spasms, usually involving repetitive clusters of spasm-like or startle-like movements. While the epilepsy in some patients with TSC can be controlled with medication, unfortunately many TSC patients have poorly-controlled seizures. In addition to epilepsy, while many TSC patients have normal intelligence, TSC patients are also at risk for cognitive or learning problems, perhaps occurring in about 50% of TSC patients and ranging from mild learning disabilities and attention problems to severe mental retardation, as well as delays in motor skills. Finally, behavioral problems and autism represent another disabling neurological manifestation that can occur in a significant proportion of TSC patients.

The neurological manifestations of TSC are related to underlying abnormal lesions or growths in the brain, especially the tubers. Tubers are small, discrete areas in the brain, especially the outer region called the cortex, where the brain did not develop normally. Although the terminology can be confusing, tubers tend not to grow like tumors typically do; however, it is believed that the disruption of the normal brain by tubers most likely causes the seizures, and possibly contributes to the cognitive problems and autism in TSC patients. In addition to tubers, TSC brains can also have other abnormalities, in particular subependymal nodules (SENs), which are small bumps lining the spinal fluid-filled spaces (ventricles) towards the middle of the brain. SENs are not thought to directly cause any neurological symptoms. However, some patients with TSC develop subependymal giant cell astrocytomas (SEGAs), which can grow like a typical tumor. When growth of SEGAs obstructs the flow of spinal fluid through the ventricles, this can sometimes lead to a more emergent situation due to pressure build-up in the brain, often presenting with progressive lethargy, behavioral changes, headache, or vomiting.

Besides the neurological symptoms, skin involvement commonly constitutes the other obvious manifestations of TSC that are outwardly apparent. Hypopigmented macules are light-colored (lighter than the patient's normal skin color), flat spots on the skin, that sometimes have a classic "ash-leaf" shape. In some TSC patients, these light spots are so subtle that it takes a special ultraviolet light (Wood's lamp) to detect them. More obvious in appearance, Shagreen patches are raised, rough lesions, resembling an orange peel, often found on the lower back. Facial angiofibromas are small, often red-colored, bumps that typically occur over the bridge of the nose and cheeks on the face - these often do not develop until later in childhood, but can eventually become quite extensive and bothersome. Finally, periungual fibromas refer to small growths along the finger and toe nails.

As already mentioned, virtually any organ system can be affected with abnormal growths or tumors in TSC patients, especially the eyes, kidneys, heart, and lungs. Fortunately, in many cases, these tumors do not cause any symptoms and are simply something that may need to be followed with serial radiographic tests. However, while most tumors in TSC usually do not spread (metastasize), behave aggressively, or become cancerous, tumor growth can still sometimes cause serious symptoms. Heart involvement, when significant, usually affects infants and can cause abnormal heart rhythms (arrhythmias) or symptoms of heart failure. Again in many cases, the heart involvement does not cause significant symptoms and, interestingly, the heart tumors (cardiac rhabdomyomas) tend to resolve with age. In contrast, kidney involvement is usually minimal and asymptomatic in infants and children, but as TSC patients get older, growth of kidney tumors (renal angiomyolipomas) can start to cause problems with hypertension and bleeding, and rarely can become cancerous. Similarly, lung involvement is almost never significant until adulthood, and strangely, primarily affects women with TSC (lymphangioleiomyomatosis). If lung involvement progresses, there can be significant compromise of respiratory function, sometimes even requiring lung transplantation. Finally, tiny tumors can occur in the back of the eye, or retina (retinal hamartomas), but fortunately these do not cause significant visual impairment in most cases.

In summary, the symptoms and manifestations of TSC can be extremely variable, with some patients experiencing no significant problems at all, whereas others having serious, life-threatening complications. In general, the neurological symptoms, including epilepsy, learning disabilities/developmental delay, and autism/behavioral problems, tend to be the most obvious and problematic. Other manifestations of TSC may only be detectable on radiographic tests, although occasionally tumor growth can cause symptoms due to organ dysfunction. The diagnosis of TSC generally requires evidence of at least two of the major types of typical tumors or lesions characteristic of this disease.

Mechanisms of TSC
With recent advances in clinical and basic research, much is now understood about the biological mechanisms causing many of the symptoms and manifestations of TSC. In particular, the genetic basis of TSC is now quite well-established. TSC is clearly a genetic disease due to a defect or mutation in one of two genes, known as the TSC1 and TSC2 genes. TSC is considered an "autosomal dominant" disease, which basically means that a person with TSC has a 50% chance of transmitting the gene to any offspring. Although TSC is a genetic disease, there does not necessarily have to be other family members affected with the disease, as the family history can be completely negative. This is because about two-thirds of cases of TSC represent a sporadic, new mutation - meaning that the affected person is the first one in his/her family to have the gene mutation. Patients with sporadic TSC have a 50% chance of passing the gene to their children, but other relatives (the patient's parents, siblings, etc.) are unaffected. In the other one-third of cases, there is a positive family history of TSC, although sometimes mildly affected family members are only realized to have the disease after a relative is diagnosed.

Much information has recently been discovered about the biological function of the TSC genes. The TSC genes directly regulate a number of biochemical pathways, such as the "mTOR" pathway, that control cell growth and proliferation. Mutation of the TSC genes causes some of these pathways to become abnormally active, resulting in increased cellular growth and proliferation and promoting the tendency to form tumors in different organs. Although these biochemical mechanisms do not necessarily explain all the symptoms of TSC, these findings have generated excitement in suggesting the potential development of new drug therapies for tumor growth in TSC.

Management of TSC
Given the variable manifestations of TSC in different patients, the management and treatment approach to each TSC patient must be individualized. Again, the neurological symptoms tend to be the most severe and problematic, potentially requiring a number of therapeutic strategies. For the most part, the neurological symptoms in TSC are treated in a very similar fashion as in other patients with similar neurological symptoms that do not have TSC. Seizures can be treated with a number of available seizure medications ("antiepileptic drugs" or AEDs), although many TSC patients have poorly-controlled seizures despite multiple trials of medications. Of special note, vigabatrin is a seizure medication that seems to have extremely good efficacy for infantile spasms in TSC patients. Unfortunately, there can be significant problems with loss of peripheral vision with vigabatrin - for this reason, it is not yet FDA-approved in the United States, although it is widely used in other countries and FDA approval may occur in the US in the near future. For patients with poorly-controlled seizures on medication, there are a couple of potential non-medical options that can be considered. Previously, TSC patients with epilepsy were often not thought to be good candidates for brain surgery due to the extensive involvement of the brain with multiple tubers. However, more recently it has become clear that epilepsy in at least a subset of TSC patients may benefit significantly from brain surgery to remove active tubers, especially if one or a limited number of tubers can be identified that are causing the seizures. To consider epilepsy surgery, a comprehensive evaluation should occur at a specialized center experienced in epilepsy surgery. A special diet (ketogenic diet) and a vagal nerve stimulator are two other non-medical options that could be of benefit to epilepsy patients, and should be considered in consultation with a specialized center.

Other neurological symptoms of TSC, such as learning problems, developmental delay, behavioral issues, and autism, are approached primarily with educational strategies, therapy services, and behavioral management techniques, with similar approaches used for these relatively common problems in many patients, with or without TSC. From the standpoint of childhood learning and development, it is generally wise to be "pro-active" in the educational process of TSC patients. Even children with TSC who appeared to have normal developmental milestones can sometimes be found to have mild learning disabilities or attentional problems that cause significant impediments to success in school. Behavioral problems and autistic behavior can be especially difficult to deal with from the family and school's perspective. However, a variety of behavioral therapies, as well as occasional, judicious use of medication, can help make these problems manageable.

The variety of skin lesions in TSC can sometimes require more specific medical management. The hypopigmented macules are often not very noticeable and usually do not require any specific treatment, although use of cosmetic creams can make them less conspicuous. However, facial angiofibromas can become quite extensive and bothersome. In many cases, laser therapy can be considered for removal of these angiofibromas. Unfortunately, the angiofibromas may often recur, requiring repeated rounds of laser therapy. Periungual fibromas can also be surgically removed, if they bleed or become painful. Medical treatment for dermatological symptoms of TSC should ideally be performed in conjunction with a specialist, such as an experienced dermatologist or plastic surgeon.

In terms of most of the remaining organs affected by tumor growth by TSC, significant problems that require treatment may develop when tumors grow very large or cause functional obstruction within organs. For example, in rare cases, cardiac rhabdomyomas may obstruct effective blood flow from the heart, potentially requiring surgical intervention, or may induce abnormal rhythms of the heart, requiring pacemaker placement or medications for arrhythmias. If SEGAs within the brain start to obstruct spinal fluid flow, surgical removal of these tumors may be indicated. If excessive kidney tumor growth starts to cause functional problems, such as hypertension, surgical removal, or a less invasive procedure, called embolization, may be considered. In the future, specific medication treatments, which are currently in development, might serve as an alternative to surgery for treating tumors in TSC. Again, educated decisions about potential treatment of TSC-related tumors are ideally made in conjunction with experienced specialists knowledgeable about the involved organs.

For TSC patients who are essentially asymptomatic, of course little is required in terms of active management and treatment. However, even asymptomatic patients with TSC should receive periodic monitoring with radiographic tests to ensure that there is not excessive tumor growth in at-risk organs. In infants with documented cardiac rhabdomyomas, a cardiologist will often want to follow them for some time period, usually with serial echocardiograms. A panel of TSC experts has also made general recommendations to perform a routine screening brain MRI and renal ultrasound about once every one to three years, essentially for life, and more often if there are specific concerns. Women with TSC should have an initial screening chest CT at age 18 years to look for lung involvement. Judicious radiographic screening may help prevent emergent situations from arising unexpectedly.

Conclusions: Solving the Mysteries of TSC?
Overall, TSC can be a very challenging, perplexing, and mysterious disease for the patient, family, and doctors alike. Maintaining flexibility and utilizing a multidisciplinary, open-minded approach help deal with the various challenges that may arise with TSC. Fortunately, there have truly been significant advances in research in our understanding the biological mechanisms causing TSC. These recent scientific discoveries have led directly to real possibilities for improving the management of TSC patients. For example, the discovery that the TSC genes regulate cell growth and proliferation through the mTOR pathway has already resulted in very promising clinical trials that suggest that the drug, rapamycin, may prevent progression of kidney and lung tumor growth in TSC patients. Similar clinical trials are ongoing for neurological involvement, such as SEGA growth, in TSC. Thus, there is now more hope than ever that research can start providing some answers to the many mysteries of TSC, which should ultimately help improve the lives of TSC patients.

Further Reading

Crino, P, Nathanson KL, and Henske, EP. The tuberous sclerosis complex. New England Journal of Medicine 2006, Vol. 355:1345-1356.

Curatolo, Paolo, ed. Tuberous Sclerosis Complex: From Basic Science to Clinical Phenotypes. London: Mac Keith Press, 2003.

Sheffield, Chris and Patrick Sheffield. Living with Tuberous Sclerosis: Stories of Love and Hope. Landover, MD: National Tuberous Sclerosis Association, 1999.

Tuberous Sclerosis Alliance website: http://www.tsalliance.org/