Transcript Tuberous Sclerosis Complex (TSC)

Sergei Kashirny, MD
LSU Neurology
February, 3, 2011
Case.
27 yo Asian female well-known in the clinic has been
followed by neurology since infancy when she
experienced infantile spasms. That condition was
successfully treated with steriods and the patient
remained seizure-free until age 10. At that age she had
her first witnessed generalized tonic-clonic seizure.
Her seizure became more frequent in the next 3 years
and consist with CPS (complex partial seizure) and
CPS with secondary generalization.
 Except the presence of seizures she was the well developed
child and had the average grades at school.
 The patient had extensive work-up for her seizure
including genetic analysis which led to the diagnosis of
Tuberous sclerosis.
 Valproate use led to control of the patient seizures up to
the age 20 when she started to experienced them again.
Currently she has about 1-2 seizures per year.
 Family history:
 maternal uncle has seizure since young age (unclear
etiology)
 29 yo brother with cerebral palsy
 Social : education – high school graduate, occassional
use of ETOH, denies smoking or drugs.
 Physical exam:
 3 hypopegmented maculae on the back (about 3 x 5 cm)
 No cardiac, pulmonary or renal abnormalities
 Neurological exam is benign
RADIOLOGY
CT
MRI
MRI
TUBEROUS SCLEROSIS COMPLEX
Pathophysiology
Clinically, TSC exhibits an autosomal dominant inheritance
pattern, with a high spontaneous mutation rate. Two distinct
genetic loci responsible for TSC have been identified: one on
chromosome band 9q34 (also referred to as TSC1) and another
on chromosome band 16p13 (TSC2).
The TSC2 gene was identified in 1993, and its protein product has
been named tuberin. Tuberin has GTPase-activating properties
and seems to function as a tumor suppressor. The highest levels
of tuberin are found in adult human brain, heart, and kidney.
Individual tubers are thought to arise developmentally when
mutated neural progenitor cells in the subependymal germinal
matrix give rise to abnormally migrating daughter cells that in
turn produce tubers. The tubers may undergo cystic
degeneration or calcification, or exhibit contrast enhancement
on neuroimaging, but these features do not necessarily imply
malignant transformation.
Hamartin, the TSC1 product, was identified in 1997 and may also
function as a tumor suppressor. Hamartin and tuberin together
form a tumor suppressor complex, which, through the GTPase
activating function of tuberin.
Subsequent mutational analysis has shown TSC2 mutations to be
present in 80-90% of affected individuals, while TSC1 mutations
are present in 10-20%.
It is found a higher incidence of "mental handicap" in persons with
TSC2 mutations than in those with TSC1 mutations.
A TSC2 genetic abnormality was found to be associated
consistently with more severe clinical disease regardless of organ
system. Although prominent phenotypic variability was still the
rule, patients with TSC2 abnormalities were more apt to have
higher tuber counts, refractory seizures, autism, larger cardiac
rhabdomyomata, and more severe cutaneous lesions. This
suggests that, while tuberin and hamartin have similar functions,
tuberin plays a more critical role in regulation of cellular
differentiation.
The high incidence of sporadic TSC, coupled with a probable
"second hit" phenomenon, seems a likely explanation for the
marked phenotypic variability observed. The second hit
hypothesis suggests that in addition to an inherited or sporadic
autosomal mutation in one allele of either TSC 1 or TSC 2,
clinical signs and/or symptoms manifest only after a further
mutation or inactivating event in the second, unaffected allele
(“second hit”). This allows considerable potential for diversity,
not only among various deletions and mutations between 2
genetic loci, but also with regard to possible interactions
between protein products of varying functionality arising from
different mutations on each allele.
Further complicating the high spontaneous mutation rate is the
observation that parents of an affected child, who themselves
show no sign of TSC, nonetheless have an increased risk
(approximately 2% overall) of having additional affected
children.
Frequency
Prevalence - 1 case per 10,000 population.
Race
TSC affects all races without a clear-cut predominance.
Sex
TSC affects both sexes equally.
Age
TSC can present at any age.
CLINICAL PRESENTATION
 In 1908 Vogt set the triad of intractable epilepsy,
mental retardation, and adenoma sebaceum; this
description (until relatively recently) represented the
hallmark of tuberous sclerosis complex (TSC) to most
clinicians.
 As many as 50% of people with TSC have normal
intelligence, and increasingly the diagnosis is being
newly made in adults with renal, cutaneous, or
pulmonary manifestations.
Clinical Manifestations of TSC
 Brain: cortical tubers, subependymal nodules,
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subependymal giant cell astrocytomas
Eye: retinal hamartomas
Heart: cardiac rhabdomyomas
Kidney: benign angiomyolipomas, cysts, malignant
angiomyolipomas, renal cell carcinoma
Lung: lymphangioleiomyomatosis, mutifocal
micronodular pneumocyte hyperplasia
Skin: hypomelanotic macules, shagreen patches,
periungual or subungual fibromas, facial
angiofibromas
Behavior: mental retardation, autism, bipolar disorder
Diagnostic criteria
 Definite TSC - Either two major features or one major
feature plus two minor features
 Probable TSC - One major plus one minor feature
 Possible TSC - Either one major feature or two or more
minor features
PHYSICAL:
Neurological findings
 Seizures (90%)
 Mental retardation and learning difficulties (50-60%)
 Sleep disorders (60%)
 Autism and behavioral difficulties (30-50%)
 Subependymal giant cell astrocytoma (15-20%)
 TSC frequently presents with infantile spasm
(generalized epilepsy occurring in infants).
 Infantile spasms are significantly associated with longterm developmental delays and mental retardation.
 Poor seizure control or ineffective control of the
infantile spasms was associated with the highest risk
for poor developmental outcome.
Epilepsy in TSC
 about 90% of patients will experience seizures
 About 20%-30% of those patients have medically
intractable epilepsy
 Aggressive treatment is necessary to reduce risk for
negative neurological outcome (development,
cognition, behavior)
Subependymal nodules
SEGA
Skin findings
 TSC is considered a neurocutaneous disorder, and
another hallmark of this disease is facial angiofibroma.
This used to be called adenoma sebaceum, but it has
nothing to do with an adenoma or with excessive
sebum or acne. These are angiofibromas -- cutaneous
fibromas -- that typically occur in both cheeks in a
butterfly distribution. These lesions can become quite
large. In some patients, they can result in bleeding and
significant cosmetic impairment.
Typical ash leaf macules
Dysplastic periungual fibroma
Cardiac findings:
 Cardiac involvement is usually maximal at birth or early in
life; it may be the presenting sign of TSC, particularly in
early infancy. 50-60% of individuals with TSC have
evidence of cardiac disease, mostly rhabdomyomas.
 Rhabdomyomas are benign tumors that may be focal or
diffuse and infiltrating in character. They produce
symptoms primarily through outflow tract obstruction or
by interfering with valvular function
 Rhabdomyomas develop during intrauterine life (usually
between weeks 22 and 26 of gestation) and can result in
nonimmune hydrops fetalis and fetal death. The majority
of cases, however, are clinically asymptomatic.
 The lesions typically undergo spontaneous regression in
the first few years of life, although residual areas of
histologically abnormal myocardium may persist.
Nonobstructive venticular
rhabdomyomas
Ocular findings:
 Up to 50% of patients have ocular abnormalities. These lesions are retinal
astrocytomas that tend to become calcified over time. They appear as rounded,
nodular, or lobulated areas on funduscopic examination, becoming whitish in
color as they calcify.
Pulmonary findings:
 Symptomatic pulmonary involvement occurs almost exclusively in
adult women, generally aged 30 or older. Recent studies have found
cystic pulmonary abnormalities in 40% of women with TSC. Three
forms have been described: multifocal micronodular pneumocyte
hyperplasia, pulmonary cysts, and lymphangiomyomatosis.
Renal findings:
Renal manifestations are the 2nd most common clinical feature.
1. Polycystic kidney disease
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2.
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in 2-3% of persons with TSC
presents early in life with hypertension, hematuria, or renal
failure
occurs as the result of a genetic abnormality affecting both the
TSC2 gene and the PKD1 gene adjacent to it
have relatively little functional renal tissue, and ultimately require
renal transplantation
highly susceptible to complications of UTI or nephrolithiasis.
Renal cysts (as opposed to polycystic kidney disease) are found
in 20% of males and 10% of females with TSC. They are rarely
if ever symptomatic.
AMLs in 80% of persons with TSC. They also can occur as
isolated lesions in persons without TSC.
Renal cell carcinoma
Other organ systems
 Gingival fibromas 
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70% of adults
50% of children with mixed dentition
 Hepatic cysts and AMLs
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asymptomatic and nonprogressive,
24% of patients
marked female predominance
 Arterial aneurysms
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small number of patients
Intracranially, in the aorta and axillary arteries
Work-up
 CT/MRI brain
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every 2 years in asymptomatic patients, at least until puberty
 Renal ultrasound
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To assess AMLs or cysts
Due to under-recognition and underestimation of AML
occurrence and size, renal ultrasound is losing favor and is
being replaced by abdominal MRI.
abdominal MRI - every 2-3 years
 Echocardiogram
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Baseline evaluation
Usually not repeated if no lesions
 EKG
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Baseline evaluation and then every 2-3 years
 EEG
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Evaluate for seizure
Repeat as clinically indicated
 PET scan
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Evaluation for epilepsy surgery
Scanning with alpha-methyltryptophan to identify epileptogenic
tubers
 Molecular genetic testing
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Commercially available
Under optimal circumstances, identifies mutations in 75-80%
Negative genetic test result does not exclude a diagnosis
Diagnosis should be made in most cases using established criteria
Genetic testing is useful in uncertain or questionable cases:
 for prenatal diagnosis
 for screening family members of an affected individual
The utility of molecular diagnostic testing is limited by the cost
MEDICAL TREATMENT
 Serolimus (rapamycin)
 Everolimus – FDA has granted accelerated approval
(11/2010) for SEGA that cannot be treated with surgery
 Serolimus (Rapamycin):
 almost 50% decrease in renal angiomyolipomas (AML) volumes by
the end of the 12-month rapamycin administration period
 improvements in forced expiratory volume (FEV1), forced vital
capacity (FVC) and residual volume (RV) in patients with pulmonary
lymphangioleiomyomatosis (LAM).
 Described regression of subependymal giant cell astrocytomas
(SEGA) in association with rapamycin.
 Everolimus:
 reduced SEGA volume by 30% in 78% patients; and by at least 50% in
32% patients in the first 6 months of treatment
 reduced SEGA volume by about 50% by 18 months
 improvements in seizure control: nearly 20% of patients experiencing
seizure freedom and more than 50% experiencing a more than 50%
reduction in seizure frequency
 improvement in quality of life measures and no change in
neuropsychiatric parameters.
Infantile spasns in TSC
 Vigabatrin is the treatment of choice in TSC
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Irreversible inhibitor of GABA transaminase
Risk for adverse effect on peripheral vision
As high as 95% response rate in TSC
 Steroids (ACTH or oral prednisone)
 Valproate, topiramate, clonazepam minimally effective
as single agents but may have beneficial adjunctive use
Epilepsy treatment
 The main complication of TSC requiring long-term therapy is
epilepsy.
 Antiepileptic medications (AEDs) are the mainstay of therapy for
patients with TSC.
 No one medical treatment gives satisfactory relief for all patients.
 A combination of medical treatment modalities frequently is
required.
 The choice of specific AED(s) for treating seizures in patients with
TSC is based on the patient's seizure type(s), epilepsy syndrome(s),
other involved organ systems, age of the patient, and side effect
profiles and formulations available.
 Vigabatrin is the drug of choice for children with TSC and infantile
spasms.
 Long-term use of benzodiazepines or barbiturates should be avoided.
These drugs often aggravate underlying behavioral or cognitive
problems and have many less toxic and often more effective alternatives.
 Carbamazepine, oxcarbazepine, and phenytoin may cause exacerbation
of seizures, particularly in younger children and infants, and can
precipitate or aggravate infantile spasms. They should not be used in
children with TSC who are experiencing infantile spasms.
Epilepsy surgery
 Aggressive treatment should include the epilepsy
surgery:
60% of patients can expect to be seizure-free
 10% would have rare seizures
 10% would have a greater than 90% reduction
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SURGICAL TREATMENT
A. Focal cortical resection
B. Corpus callosotomy
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Can be effective in reducing atonic and tonic seizures (ie, drop
attacks)
typically is not helpful for other seizure types
Seizure freedom following corpus callosotomy is rare but can occur.
C. Vagus nerve stimulation
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Simple and complex partial seizures appear to respond better than
partial seizures with secondary generalization.
D. SEGA resection
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When produce hydrocephalus or significant mass effect
If a gross total resection can be achieved, recurrence is unlikely
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