Diagnosis, Surveillance, and Management
In 2012, the International Tuberous Sclerosis Complex Consensus Conference reviewed prevalence and specificity of TSC-associated clinical manifestations and updated the TSC diagnostic criteria from 1998. Clinical features of TSC continue to be a principal means of diagnosis but include additional clarification and simplification. In addition, TSC may now be diagnosed via genetic testing.
An Overview of TSC for Healthcare Professionals
The clinical and genetics diagnostic criteria of 2012 are summarized in the table below.
|MAJOR FEATURES||MINOR FEATURES|
|1. Hypomelanotic macules (≥3. at least 5·mm diameter)||1. “Confetti” skin lesions|
|2. Angiofibromas (≥3) or fibrous cephalic plaque||2. Dental enamel pits (>3)|
|3. Ungual fibromas (≥2)||3. Intraorallibromas (≥2)|
|4. Shagreen patch||4. Retinal achromatic patch|
|5. Multiple retinal hamartomas||5. Multiple renal cysts|
|6. Cortical dysplasias*||6. Nonrenal hamartomas|
|7. Subependymal nodules|
|8. Subependymal giant cell astrocytoma|
|9. Cardiac rhabdomyoma|
|10. Lymphangioleiomyomatosis (LAM)**|
|11. Angiomyolipomas (>2)**|
|Definite diagnosis: Two major features or one major feature with ≥ 2 minor features.
Possible diagnosis: Either one major feature or ≥2 minor features.
* Includes tubers and cerebral white matter radial migration lines.
**A combination of the two major Clinical features (LAM and angiomyolipomas) without other features does not meet criteria for a definite diagnosis.
The identification of either a TSC1 or TSC2 pathogenic mutation in DNA from normal tissue is sufficient to make a Definite Diagnosis of TSC. A pathogenic mutation is defined as a mutation that clearly inactivates the function of the TSC1 or TSC2 proteins (e.g., out of frame insertion or deletion or nonsense mutation), prevents protein synthesis (e.g., large genomic deletion), or is a missense mutation whose effect on protein function has been established by functional assessment. Other TSC1 or TSC2 variants whose effect on function is less certain do not meet these criteria and are not sufficient to make a Definite Diagnosis of TSC.
Note that approximately 15% of individuals with TSC have no mutation identified by conventional genetic testing, and a normal result does not exclude TSC or have any effect on the use of Clinical Diagnostic Criteria to diagnose TSC. Clinical genetic testing identifies gene mutations in 75-90% of DNA samples that are submitted for testing from individuals who have a definite diagnosis of TSC based on accepted diagnostic criteria. For the remaining 10-25% of TSC patients there are several explanations for why we cannot find an underlying mutation. There may be a mutation in the TSC1 or TSC2 gene that we cannot detect because it only occurs in some of the patient’s cells but not all of the cells. This situation is called mosaicism meaning that the genetic complement of different cells is different in different cells of the body. Another reason we may not find a mutation is that the mutation may be in sections of the gene that we do not test because we do not understand how changes in these parts of the genes can cause disease.
Surveillance Recommendations in TSC
|PROCEDURE||FOR NEWLY DIAGNOSED
OR SUSPECTED TSC
|FOR INDIVIDUALS ALREADY
DIAGNOSED WITH TSC
|Brain MRI with and without gadolinium||Yes||Every 1-3 years up to age 25; periodically as adults if SEGAs present in childhood|
|Electroencephalogram (EEG)||Yes; if abnormal, follow-up with 24-hour video EEG||Routine EEG determined by clinical need; video EEG when seizure occurrence is unclear or when unexplained behavioral or neurological changes occur|
|TAND checklist||Yes||At least annually at each clinical visit|
|Comprehensive evaluation for TAND||If warranted by TAND checklist analysis||At key development time points (years): 0-3, 3-6, 6-9, 12-16, 28-35, and as needed thereafter|
|Counsel parents of infants||Educate parents to recognize infantile spasms*||Not applicable|
|SKIN, EYES, TEETH|
|Complete eye exam with dilated fundoscopy||Yes||Annually if lesions or symptoms identified at baseline|
|Detailed skin exam||Yes||Annually|
|Detailed dental exam||Yes||Every 6 months|
|Panoramic radiographs of teeth||If age 7 or older||At age 7 if not done previously|
|Fetal echocardiography||only if rhabdomyomas identified by prenatal ultrasound||Not applicable|
|Echocardiogram||Yes in children, especially if younger than 3 years||Every 1-3 years if rhabdomyoma present in asymptomatic children; more frequently in symptomatic individuals|
|Electrocardiogram (ECG/EKG)||Yes||Every 3-5 years; more frequently if symptomatic|
|Abdominal MRI||Yes||Every 1-3 years|
|Glomerular filtration rate (GFR) test||Yes||Annually|
|Clinical screening for LAM symptoms**||Yes||At each clinic visit|
|Pulmonary function test and 6-minute walk test||In all females age 18 or older; in adult males only if symptomatic||Annually if lung cysts detected by high resolution computed tomography (HCRT)|
|High resolution computed tomography (HCRT) of chest||In females 18 years and older; in adult males only if symptomatic||Every 2-3 years if lung cysts detected on HRCT; otherwise every 5-10 years|
|Counsel on risks of smoking and estrogen use||In adolescent and adult females||At each clinic visit for individuals at risk of LAM|
|Genetics consultation||Obtain 3-generation family history||Offer genetic testing of TSC1/2 and counseling if not done previously in individuals of reproductive age|
|*Treat infantile spasms with vigabatrin as first-line therapy. Adrenocorticotropic hormone (ACTH) can be used as a second-line therapy if vigabatrin treatment is unsuccessful.
**Evaluate for LAM when symptoms such as unexplained chronic cough, chest pain, or breathing difficulties are present including exertional dyspnea and shortness of breath.
Common TSC Manifestations and Symptoms
|FEATURE||DESCRIPTION||AGE OF ONSET||PREVALENCE|
|Hypomelanotic macules||Areas of skin containing less pigment than surrounding skin. Most easily seen by UV light examination (especially in fair-skinned individuals); possible anywhere on skin’s surface, most commonly on trunk and buttocks, rarely on face; can be any shape.||May be present at birth or may develop during infancy.||90%|
|Facial angiofibromas||Solid red or pink papules, bilaterally symmetrical over nose, cheeks and chin||Generally begin to appear between two and five years of age; become more prominent at puberty.||75%|
|Shagreen patches||Large plaques on the lower back with texture of orange peel, which is nearly always specific for TSC||Rarely seen in infants, more common onset in first decade of life.||50%|
|Fibrous cephalic plaques||Large, flesh-colored, fibrous plaques on forehead and scalp.||May be seen in newborns, but typically present along with facial angiofibromas.||25%|
|Ungual fibromas||Multiple (>2) papules arising from the finger or toenail bed.||Usually appear at or after puberty.||20% overall but as high as 80% in older adults|
|Retinal hamartomas||Rounded, nodular or lobulated areas on the retina||May be present in infancy.||30-50%|
|CENTRAL NERVOUS SYSTEM|
|Subependymal nodules (SEN)||Hamartomas located along ependymal lining of the lateral and third ventricles.||Can be seen in newborns.||80%|
|Subependymal giant cell astrocytoma (SEGA)||Hamartomas (tumors) that typically develop from an enlarging SEN, especially near the foramen of Monro.||Most frequently seen in childhood and adolescence (ages 5-18 years). Atypical to occur after age 20 years.||5-15%|
|Cortical or subcortical tubers||Hypomyelinated hamartias involving the cerebral cortex and underlying white matter.||Can be seen as early as 20 weeks gestation, and in newborns.||~90%|
|Epilepsy||Seizure types most frequently seen are partial motor, complex partial and partial secondarily generalized and infantile spasms.||May occur at any age, most commonly in children. Rarely the presenting symptom in adults.||85%|
|Intellectual disabilities including aggression, autism spectrum disorder, developmental delay, hyperactivity, and hyperactivity||Mild to severe.||Children with TSC are at risk and should receive appropriate screening early in life.||45-60%|
|Angiomyolipoma||Proliferations of blood vessels, smooth muscle and fat tissue; more common in females; isolated solitary angiomyolipoma may occur in general population.||Generally very small early, may grow significantly. Usually develop after the age of three.||80%|
|FEATURE||DESCRIPTION||AGE OF ONSET||PREVALENCE|
|Cardiac rhabdomyomas||Most common cardiac tumor in infants and children; can be seen in any of the four chambers, more commonly in ventricles; majority have no cardiac symptoms; arrhythmias seen in some individuals; often regress with age.||Often diagnosed prenatally via ultrasound or in first year.||50%|
|Lymphangioleiomyomatosis (LAM)||Primarily seen in women; presents with shortness of breath or pneumothorax; there exists a distinct group of women with sporadic LAM with lung and kidney involvement without other TSC symptoms and without constitutional mutations.||Adulthood.||30-40% of females; possibly up to 80% of females affected by age 40 years|
|Pulmonary cysts||Isolated single or multiple cysts; may be bilateral.||Young Adulthood.||30-40%|
|Multifocal micronodular pneumocyte hyperplasia (MMPH)||Nodular densities seen on CT scans.||Adulthood.||May be as high as 40-58%|
|ORAL AND HEPATIC|
|Intraoral fibromas||Fleshy growths in the mouth and on gums.||Early to late childhood.||69%|
|Dental enamel pits||Pit-shaped enamel defects on teeth.||Childhood on milk teeth, more common in permanent teeth.||Nearly 100%|
|Hepatic angiomyolipoma||Proliferations of blood vessels, smooth muscle and fat tissue similar and perhaps identical to renal angiomyolipomas.||Childhood and may increase in incidence in adults.||16-24%|
Clinical Management of TSC
Because TSC affects multiple organs, diagnostic studies are recommended for all individuals with a new diagnosis of TSC regardless of their outward manifestations of the disease. For example, published recommendations for diagnostic and follow-up evaluations suggest baseline imaging using either CT or cranial MRI modalities regardless of the presence of neurological symptoms. This suggestion is largely due to the risk of identifying a subependymal giant cell astrocytoma (SEGA), which has an increased growth potential over subependymal nodules (SEN) and therefore needs more extensive follow-up.
In order to ensure comprehensive care, referrals to a variety of specialists familiar with TSC should be coordinated. If possible, a referral to a multidisciplinary clinic specializing in TSC is ideal, as the center will likely house all necessary specialists, including a dermatologist, neurologist, geneticist, nephrologist and/or urologist, ophthalmologist and cardiologist.
The clinician making the diagnosis of TSC may recommend that other, at-risk family members also be evaluated for this condition. TSC is an autosomal dominant genetic disorder, and while all persons with TSC are thought to have symptoms, the presentation of their symptoms can be highly variable even within the same family. A determination of whether or not the parents and siblings of a diagnosed child are affected is important to the provision of later genetic counseling, thereby making an accurate diagnosis necessary. While an estimated sixty percent of individuals diagnosed with TSC are born into families with no prior history of the disease (i.e., sporadic mutation), it is becoming more and more common for adults to learn of their own diagnosis following the diagnosis of their child or because of other medical concerns.
There is some debate as to which evaluations are necessary when testing the parents of a newly diagnosed child. The consensus is that a thorough physical examination conducted by a physician familiar with TSC will detect the majority of affected individuals. The evaluation should include a skin examination with a Woods lamp (ultraviolet light) and a retinal examination through dilated pupils. Further examination via diagnostic imaging techniques of the brain and kidneys should be ordered for the parents of children with TSC and/or for adults with medical issues that suggest a diagnosis of TSC. Diagnostic molecular testing should also be discussed with the parents of a newly diagnosed child and/or adults suspected or diagnosed with TSC.
Imaging and Testing
In addition to the three main imaging procedures usually undertaken for an individual with TSC (CT or MRI scans of the brain, renal CT and/or ultrasounds and echocardiograms), additional imaging procedures or testing may be conducted. Some centers perform these evaluations annually, at least until adulthood. This is a topic of some controversy, and the natural history of TSC is currently being studied through the TS Alliance Natural History Database Project. Additional imaging should be performed as necessary to follow growing lesions or to monitor organ involvement.
- POSITION EMISSION TOMOGRAPHY (PET) There is no current indication for routine PET scanning in individuals with TSC. However, PET scans may be useful when individuals are undergoing evaluation as candidates for epilepsy surgery. PET scanning with the tracer alpha-methyltryptophan may have particular utility in identifying epileptogenic tubers as part of the evaluation for epilepsy surgery.
- SINGLE-PHOTON EMISSION COMPUTED TOMOGRAPHY (SPECT) There is no current indication for routine SPECT scanning in individuals with TSC. However, SPECT scans may be useful when individuals are being evaluated as candidates for epilepsy surgery.
- MAGNETOENCEPHALOGRAPHY (MEG) There is no current indication for routine MEG scanning in individuals with TSC. However, MEG scans may be useful when individuals are being evaluated as candidates for epilepsy surgery.
- ELECTROENCEPHALOGRAM Electroencephalogram (EEG) should be performed on individuals with TSC when seizures are suspected. Follow-up EEGs are performed as clinically indicated. Some individuals with TSC have coexisting recognizable epilepsy syndromes such as West syndrome (i.e., infantile spasms) or Lennox-Gastaut syndrome. If so, prolonged video/EEG telemetry may be useful to help:
- Detect syndrome-specific EEG findings
- Capture and classify each of the multiple seizure types
- Educate parents on which of the events are seizures and which are non-epileptic behavioral events
- ELECTROCARDIOGRAM AND ECHOCARDIOGRAPHY A baseline electrocardiogram (ECG) is recommended for all individuals newly diagnosed with TSC since cardiac arrhythmias, although rare, may have sudden death as their presenting symptom. Follow-up ECGs should be performed every two to three years thereafter until puberty or as needed. A baseline echocardiogram should be performed on all children diagnosed with TSC and later as clinically indicated. Adults with a new diagnosis of TSC should undergo echocardiography only if symptomatic.
- DIFFUSION TENSOR IMAGING (DTI) There is no current indication for routine DTI in individuals with TSC. However, DTI may be useful when individuals are being evaluated as candidates for epilepsy surgery. DTI is being utilized as a research tool to study the correlation in white matter integrity and neurologic impairment in individuals with TSC. DTI may have particular utility in identifying individuals at risk for developing autism.
- FUNCTION MRI (MRI) There is no current indication for routine MRI in individuals with TSC. However, fMRI of the brain may be useful when individuals are being evaluated as candidates for epilepsy surgery.
The goals of treatment for individuals with TSC are the same as for all individuals with a multi-system chronic condition: providing the best possible quality of life with the fewest complications from the underlying disease process, fewest adverse treatment effects and fewest medications.
TSC often has been under-treated, particularly from a neurological standpoint, often based on the unfounded view that these individuals will have a poor outcome regardless of any therapy undertaken. This is clearly not the case. Even in individuals with TSC and infantile spasms, long- term outcome is not universally poor, as has been classically thought. At least 9 percent of individuals with TSC and infantile spasms have normal intelligence as adults or at long-term follow-up.
A recent study indicates that infants diagnosed with TSC prior to the onset of seizures who are treated with vigabatrin in response to the development of an abnormal EEG have fewer seizures, a lower incidence of drug-resistant epilepsy, and fewer children require polytherapy to treat their epilepsy. In addition, fewer treated children had significant developmental delay and intellectual disabilities at 24 months of age compared to children with TSC who were treated only after the onset of clinical seizures.
Appropriate and effective therapy is not only aggressive but also relies upon recognition of the natural history of the various lesions of TSC. For example, large angiomyolipomas may be mistaken as renal cell carcinomas, solely on the basis of their size. Embolization or kidney-sparing surgery should always be done so as to avoid the unnecessary removal of the affected kidney.
Antiepileptic Drug Therapies
The main complication of TSC requiring long- term medical therapy is epilepsy. Antiepileptic medications (AEDs) are the mainstay of therapy for individuals with TSC. Unfortunately, no one medical treatment usually results in satisfactory relief for all or even most individuals with TSC. A combination of medical treatment modalities is then frequently required.
The choice of specific AEDs for treating seizures in individuals with TSC is based on the seizure type(s), epilepsy syndrome(s), other involved organ systems, age of the individual, and AED side effect profiles and formulations available.
The consensus developed at the NIH Tuberous Sclerosis Complex Consensus Conference in 1998 and confirmed in 2012 was that vigabatrin was the drug of choice to treat infantile spasms in children with TSC. vigabatrin (Sabril®) was approved by the FDA in the United States in 2009. The FDA requires that physicians who wish to prescribe vigabatrin register prior to prescribing the medication. For more information, go to sabril.net.
Adrenocorticotropic hormone (ACTH) may be used for the treatment of infantile spasms in TSC if vigabatrin is not effective.
H.P. Acthar Gel® (ACTH) was approved by the FDA for the treatment of infantile spasms in 2010. The advantage of vigabatrin use is the ability to rapidly escalate the dosage at the initiation of treatment, rapid efficacy, suitability for outpatient treatment and particularly good tolerability with generally only minor adverse effects with the exception of visual field loss (see below). There is only preliminary evidence that other broad spectrum AEDs may prove useful to treat infantile spasms.
The safety of vigabatrin has caused concern since a specific visual field loss has been documented in treated adults and some children. There have been only isolated reports of visual field loss in children on short-term treatment with vigabatrin having infantile spasms, but the parents must weigh the benefits and risks of vigabatrin treatment with their child’s health care providers. The current problem is determining the risk-benefit ratio of vigabatrin in children with infantile spasms, and specifying the groups where its use could be optimal. Visual field loss is usually asymptomatic and can be detected only by perimetric visual field studies. In children, especially in very young children or those with intellectual disabilities, it is difficult if not impossible to detect the visual field loss, and it is not yet known if children are at higher or lower risk of this adverse effect. Until a clear answer about the occurrence of this adverse effect in children has been established through randomized study, vigabatrin may still be considered first-line therapy in infantile spasms. Children who do not achieve a good response to vigabatrin should be switched to ACTH or to a corticosteroid such as prednisone.
Long-term use of agents with prominent sedating properties, such as benzodiazepines or barbiturates, generally should be avoided. These drugs often aggravate underlying behavioral or cognitive problems, and there are less toxic and often more effective alternatives.
WARNING: Carbamazepine, oxcarbazepine and phenytoin may cause exacerbation of seizures, particularly in younger children and infants with TSC, and some clinicians believe that these AEDs can precipitate or aggravate infantile spasms. While often valuable in older children and adults in whom partial seizures predominate, caution is warranted in their use in infants and young children. It is recommended that these drugs not be used in children with TSC who are experiencing infantile spasms.
An additional therapy for intractable epilepsy is the ketogenic diet. The classical ketogenic diet and variations of the diet such as the low glycemic index treatment or modified Atkins diet have been increasingly used in recent years due to their efficacy and a perception by families that it is more “natural” treatment. While it is often effective for some children, the ketogenic diet should be considered like any other medical intervention to have significant side effects and possible complications. These include kidney stones, hypoglycemia, metabolic distur- bances and suppression of growth. In addition, the diet requires a very motivated and compliant family to adhere to the diet to ensure a state of ketosis in the individual. Despite these caveats and concerns, the ketogenic diet is clearly efficacious in some individuals who have medically refractory seizures and should be considered for children with intractable epilepsy.
Neurosurgical care for seizures in an individual with TSC may involve focal cortical resection, corpus callosotomy, vagus nerve stimulation and/or MRI-guided laser ablation.
- FOCAL CORTICAL RESECTION: In selected individuals with TSC, the resection of one or more seizure foci can be beneficial. Neurosurgeons with experience performing epilepsy surgery will do a complete evaluation to determine if an individual with TSC is likely to benefit from surgery. Even if seizure freedom is not achieved, surgery may reduce the severity and frequency of seizures for individuals with TSC. Epilepsy surgery should be considered for any individual with TSC who has seizures that are not controlled by AEDs.
- CORPUS CALLOSOTOMY: Corpus callosotomy can be effective in reducing atonic and tonic seizures (i.e., drop attacks), but usually is not helpful for other seizure types and is considered palliative rather than curative. Seizure freedom following corpus callosotomy is rare, but can occur.
- VAGUS NERVE STIMULATION: In the overall epilepsy population, 30 percent of individuals treated with vagus nerve stimulation (VNS) experienced at least a 50 percent reduction in seizure frequency, while 30 percent had a 90 percent or greater reduction and 40 percent had no improvement at all. In a small study of 20 individuals with TSC, nine individuals experienced (without adverse effects) at least a 50 percent reduction in seizure frequency, while 30 percent had no improvement at all. In a small study of 10 individuals with TSC, nine of these individuals experienced (without adverse effects) at least a 50 percent reduction in seizure frequency; half had a 90 percent or greater reduction in seizure frequency following treatment with VNS. Although the results of this one study are promising, the small number of study participants with TSC makes it difficult to generalize to the entire TSC population.
Precautionary Information about MRIs and VNS
The VNS device has been shown to pose no known hazards in magnetic resonance (MR) environments when specified conditions for use are followed. Potential risk to patient safety for anyone with an implanted device during an MRI procedure is the heating effects of the implanted lead wire due to radio frequency (RF) heating caused by exposure to the MRI system. A broken lead should be removed prior to doing an MRI procedure, as this may present risk of tissue damage due to potential increased temperature of the lead.
MRI-GUIDED LASER INTERSTITIAL THERMAL THERAPY This is a minimally invasive alternative surgical technique which utilizes light energy to destroy soft tissue including tumor or damaged tissue. Laser energy is delivered to the focal epileptic lesion using a laser probe inserted into the epileptogenic focus while guided by MRI imaging. This technique has been reported in medical journals to be pain-free and require a short recovery time.
If you have any questions or need more information about diagnosis, surveillance, and management of TSC, contact:
Steve Roberds, PhD
Chief Scientific Officer
Tuberous Sclerosis Alliance
801 Roeder Road, Suite 750
Silver Spring, MD 20910
Telephone: 1-800-225-6872 or 301-562-9890 ext. 225