CASE REVEAL

TUBEROUS SCLEROSIS COMPLEX

Vince Edward C. Araneta, MD, FPAFP, CSPSH

 LEARNING OBJECTIVES

At the end of the unit topic, the students will be able to:

1. Know the distinguishing features of Tuberous Sclerosis and correlate with

the given CPC case in terms of its pathophysiology

2. Approach and diagnose a patient with seizures and skin lesion caused by
Tuberous Sclerosis

3. Demonstrate knowledge of the general management of patients with

Tuberous Sclerosis.
 Neurocutaneous Syndromes
/ Phakomatoses
Group of CNS disorders characterized by
• brain malformations or
• neoplasms
• skin
• eye lesions.
The term is derived from the Greek root phako, which refers to
the lens
phakomatosis means -tumor-like condition of the eye (lens)
 Neurocutaneous Syndromes

• Neurofibromatosis( types 1 and type 2)

• Tuberous sclerosis
• Sturge-weber syndrome
• Ataxia-telangiectasia
• Von hippel-lindau disease
 Tuberous sclerosis complex (TSC)
Bourneville or Bourneville-Pringle disease.

Characterised by classic clinical triad (vogt

triad)
• Facial lesions ("adenoma sebaceum“)
• Seizure
• Mental retardation.
 Clinically:
➢ Epilepsy affecting 80 – 90%
➢ infantile spasms
➢ simple or complex partial seizures
➢ EEG +ve in 75 % of patients
➢ Cognitive deficits 44 – 65%
➢ Autism and behavioral problems
Tuberous Sclerosis Complex (TSC)
multiple benign hamartomas:

➢Skin ➢Lung
➢Eyes ➢Kidney
➢Brain
➢Heart
 GENETICS
➢ Autosomal dominant
➢ Incidence 1 : 6000 livebirths
➢ Mutation in
➢ TSC-1 (Hamartin) or
➢ TSC-2 (Tuberin)
➢ +ve family history in 7 – 40%
 Hamartin-Tuberin complex
Central regulator of cell cycle
hamartin tuberin
TSC1 TSC2
complex

TSC: loss of
inhibition
to cell cycle

Cell Proliferation
 Diagnostic criteria
Major Features
Identified clinically
➢ Facial angiofibromas • Identified on imaging
or forehead plaque ➢ Cortical tuber

➢ Non-traumatic ungual or ➢ Subependymal nodule

periungual fibroma ➢ Subependymal giant cell
➢ Hypomelanotic astrocytoma
macules ➢ Cardiac rhabdomyoma

➢ Shagreen patch ➢ Lymphangio- myomatosis

➢ Multiple retinal ➢ Renal angiomyolipoma

nodular hamartomas
 Minor Features

➢ Multiple pits in dental enamel ➢ Gingival fibromas

➢ Hamartomatous rectal polyps ➢ Non-renal hamartoma
➢ Bone cysts, ➢ Retinal achromic patch
➢ Cerebral white matter ➢ Multiple renal cysts
migration lines
DERMATOLOGICAL
LESIONS
Fibrous plaque
Gingival
fibromatosis
 Diagnosis
Definite TSC

2 major 1 major + 2 minor

Probable TSC

1 major plus 1 minor

Possible TSC

1 major 2 or more minor

 OPHTHALMIC
MANIFESTATIONS
Retinal hamartoma

Calcified
hamartoma
CNS RADIOLOGY
MANIFESTATIONS
Radiological major criteria
 Cortical Tubers
• Cortical tubers are firm, whitish, pyramid-shaped,
elevated areas of smooth gyral thickening, with or
without central depressions, that grossly resemble
potatoes ("tubers")
• On CT scan,
Seen as hypodense cortical/subcortical masses within
broadened and expanded gyri
Calcifications in cortical tubers increase with age
• Tubers in older children and adults demonstrate
mixed signal intensity on T2/FLAIR
Cortical tuber
 Subependymal Nodules
• appear as elevated, rounded, hamartomatous lesions
• located beneath the ependymal lining of the lateral ventricles,
along the course of the caudate nucleus
• Are small(generally < 1.3cm) nodular "bumps" that protrude from the
walls of the lateral ventricles.
 Subependymal Nodules
• In the unmyelinated brain, SENs appear hyperintense on T1WI and
hypointense on T2WI. With progressive myelination, the SENs gradually
become isointense with WM
• They often calcify with increasing age
• An enhancing or enlarging SEN—especially if located near the
foramen of Monro—is suspicious for SEGA.
• Calcified SENs appear variably hypointense on T2WI and are
especially easy to detect on T2* sequences
Subependymal nodules
Subependymal Giant Cell Astrocytoma
• seen almost exclusively in the setting of TSC.
• well-circumscribed
• solid intraventricular masses
• located near the foramen of Monro.
• SEGAs are WHO grade I tumors that often cause
obstructive hydrocephalus.
most SEGAs are unilateral,
bilateral tumors occur in 10-15% of cases
 Genetic Criteria

TSC1 or
• The identification of either a

TSC2 pathogenicmutation
in DNA from normal tissue is sufficient to
make a Definite Diagnosis of TSC
 Hydrocephalus
New Diagnostic
symptoms or features
papilledema
associated
with increase Serial
morbidity imaging
showing
growth of
lesions
• Cortical Tubers
– Broad, expanded gyrus
– CT: Initially hypodense; Ca++ ↑ with age
• 50% of patients eventually develop ≥ 1 calcified tuber(s)
– MR: Periphery isointense, subcortical portion T2/FLAIR hyperintense

• Subependymal Nodules
– CT: Ca++ rare in first year; ↑ with age
• 50% eventually calcify
• Don't enhance
– MR: T1 hyper-, T2 hypointense; 50% enhance
• White Matter Lesions
– T2/FLAIR hyperintense radial lines/wedges
• Subependymal Giant Cell Astrocytoma
– CT: Mixed-density mass at foramen of Monro, moderate enhancement
– MR: Heterogeneous signal, strong enhancement
Regression of a SEGA after ~15 months
oral rapamycin therapy in a 4-year-old
patient with TSC
Management
• Antiepileptic medications (AEDs) are the mainstay of therapy for patients with TSC.

• 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,
and age, along with AED side-effect profiles and available formulations
Management
Medical Care
mTOr kinase inhibitors:
• Sirolimus (Rapamycin [Rapamune]) is a commercially available
immunosuppressant, which forms an inhibitory complex with the immunophilin
FKBP12, which binds to and inhibits the ability of mTOR to phosphorylate
downstream substrates, such as the S6Ks and 4EBPs.

• It is marketed as an immunosuppressant, owing to its propensity to inhibit T-cell

proliferation, and has been approved for use in this therapeutic setting in the
United States since 2001
Management
Surgery

Surgical treatment of patients with TSC can include the following:

•Focal cortical resection/thermal ablation
•Corpus callosotomy
•Vagus nerve stimulation

•In addition, SEGAs require resection if they produce hydrocephalus or

significant mass effect. If a gross total resection can be achieved, recurrence
is unlikely.
Thank you