15 - tuberous sclerosis ( epiloia )

DEFINITION:

A neurocutaneous syndrome characterized by cutaneous and neurologic manifestations (mental retardation and seizures), and tumors.

EPIDEMIOLOGY:

• incidence: 1/30,000
• age of onset:
• 1st decade
• risk factors:
• familial - autosomal dominant with variable penetrance
• chrom.#: 9q33-34 (Type 1)
• ?11q23 (Type 2)
• ?12q23.3 (Type 3)
• 16p13 (Type 4)
• if 2 or more siblings with Tuberous Sclerosis (TS) then one parent always has at least one skin manifestation of TS
• sporadic rate varies from 58-77%
• if both parents are normal the TS in a child is probably a new mutation

HISTORY:

1880-1900 - Bourneville and Brissaud

• first pathologic description of TS
• first to call the disease tuberous sclerosis
• first to relate cerebral sclerosis to the renal tumors

1908 - Vogt

• emphasized association of adenoma sebaceum & cerebral sclerosis
• emphasized cardiac and renal tumors are constituents of TS
• triad: mental retardation (MR), seizures, adenoma sebaceum

PATHOLOGY:

1. Tubers

• basic cause is unknown but considered a disorder of early embryogenesis
• greater the # of tubers the greater the neurologic impairment
• found anywhere within the cerebral hemispheres:
• typically present in the subependymal region (located in the walls of the lateral ventricles and on the surface of the basal ganglia) and may extend into the ventricles
• in the region of the foramen of Monro where they may cause obstruction -> hydrocephalus
• also cortical gyri, sulcus terminalis

2. Sclerosis

• areas of:
• decreased numbers of neurons
• areas of increased numbers of oddly-shaped, multinucleated "monster" giant neurons
• proliferation (overgrowth) of fibrillary astrocytes which occasionally differentiate into malignant astrocytomas
• demyelination
• calcium deposition in gliotic areas
• blood vessels with hyaline degeneration of their walls

CLINICAL FEATURES:

• clinical presentation is extremely variable depending on the age of the patient, which organs are involved, and the severity of involvement
• clinical variability even within the same family

1. Cutaneous Manifestations

1. Adenoma Sebaceum (80%)

• rarely present at birth
• usually presents between 4-6 years of age:
• are present in 12% at 1 year
• are present in 33% at 2 years
• are present in 40% at 3 years
• are angiofibromas:
• usually pink or red papules appearing in patches or in a butterfly-shaped distribution on or about the nose, cheeks, and chin
• with time may enlarge, coalesce, and assume a fleshy appearance

2. Ash-leaf Spots (90%)

• hypopigmented oval or leaf-shaped spots
• vary in size from mm -> cm
• vary in number from several to 75 or more
• found on the trunk and limbs in a linear orientation
• apparent at birth and seen prior to 2 years in 50% of patients
• visualized using a Wood's light (melanin absorbs wavelengths at 360 nm)
• represent depigmented macules inwhich the melanocytes are normal but the melanosomes are reduced in number and contain less melanin

3. Shagreen Patches (35%)

• isolated "leathery" raised and thickened plaques
• have an orange-peel consistency
• may be grayish-green or light brown in colour
• found over the lumbosacral or gluteal region
• develop in late infancy or early childhood but may also be present at birth
• may be preceded by patches of grey or white hair (these hairy patches may be the first manifestation of TS)

4. Others

• cafe-au-lait spots (7-16%)
• fibromas:
• flattened and can appear on the trunk, gingivae, periungual region, and along the hairline or eyebrows
• angiomas

2. Neurologic Manifestations

1. Seizures (90%)

• most common symptom of TS
• initally present as infantile spasms:
• 25-50% of patients with infantile spasms later develop signs of TS
• can appear as early as 1 week of age
• later develop other types of generalized seizures:
• tonic, clonic, myoclonic, akinetic, Lennox-Gastaut Syndrome
• epileptogenic focus may occur independently of tubers

2. Mental Retardation (60-70%)

• highly variable but when present is irreversible
• may be initally normal but then deteriorate intellectually during the latter part of the 1st decade (secondary to seizure or increased intracranial pressure)
• earlier the onset of seizures the greater the likelihood of mental retardation (if seizures begin <1>
• all who have mental retardation (MR) have had seizures
• 33% of TS have normal intelligence

3. Others

• hydrocephalus:
• if tubers obstruct the foramina of Monro or the
• Sylvian aqueduct
• developmental delay
• may develop autistic features

3. Tumors

1. Retinal (50-80%)

1. Mulberry Tumor

• a nodular astrocytoma of the retina on or about the optic nerve head
• refractile, yellowish, multinodular cystic lesions

2. Hamartomas

• round or oval grey-yellow glial flat patches found centrally or peripherally
• complications do not include papilledema or impaired vision

2. Renal (50-80%)

1. Angiomyolipomas

• multiple yellow-white nodules or cystic tumors embedded within the parenchyma
• usually benign but may cause hematuria, pain, and renal failure

3. Heart (50%)

1. Cardiac Rhabdomyomas

• solitary or multiple; infiltrative and/or diffuse
• solitary lesions usually found at the apex of the left ventricle
• may cause congestive heart failure or arrhythmias but tend to slowly resolve spontaneously
• may cause death before skin manifestations evident

4. Cutaneous (20%)

1. Koenen's Tumors

• subungual or periungual fibromas
• usually first appear in adolescence
• toes > fingers

5. Intracranial (15%)

1. Astrocytomas

• fibrillary astrocytomas may differentiate into giant cell astrocytomas
• occur around the walls of the lateral ventricle or the anterior portion of the 3rd ventricle
• may present as:
• elevated intracranial pressure (papilledema, headache, nausea, vomiting)
• diminished vision
• lateralizing signs (hemiparesis)

6. Oral

• oral fibromas or papillomas
• usually found on the anterior aspect of the gingiva

4. Other Manifestations

1. Respiratory

• lesions in lungs are either cystic or fibrous
• angiomyolipomas may produce these generalized multicystic or fibrous pulmonary changes
• may present with SOBE, and/or spontaneous pneumothorax
• females more affected than males

2. Musculoskeletal

• cystic changes and periosteal thickening of bones in hands and feet

INVESTIGATIONS:

1. Imaging Studies

1. CT

· 1. Intracranial Calcifications (60%)

• most reliable finding in TS is calcified subependymal tubers
• also occur in the region of the foramina of Monro and periventricular regions
• multiple scattered calcium deposits may vary in size up to several cm
• occur as early as 5 months and become more prominent with time (typically around 3-4 years of age)

· 2. Others

• only 5% of patients with the clinical features of TS have normal CT's
• may also identify cerebral atrophy, subependymal tumors, ventriculomegaly, and areas of diffuse demyelination

2. MRI

• preferable for the visualization of cortical tubers, areas of heteropias, and hamartomas
• tubers which project into the lateral and 3rd ventricles may appear as "candle drippings"
• important to identify heteropias as these may act as seizure foci

3. Skeletal X-Rays

• cystic rarefaction of phalanges and metacarpals (67%) appear around puberty
• sclerotic areas of long bones
• areas of variable skull bone density with thickened calvaria

4. Chest X-Rays

• fine reticular infiltrates and/or multicystic changes

2. EEG

1. Infantile Spasms

• hypsarrhythmias, can persist up to 8 years of age

2. Generalized Seizures

• generalized slow wave-and-spike activity or independent multifocal spike discharges

3. Cerebral Spinal Fluid

• elevated protein with elevated intracranial pressure (ICP)

MANAGEMENT:

1. Supportive

• a multidisciplinary approach involving:
• Paediatrics, Neurology, Ophthalmology, Nephrology, Cardiology, Dermatology, Neurosurgery, Orthopedics, PT, OT, Respirology
• ensure regular follow-up for tumor surveillence
• supplemental education

2. Cutaneous Manifestations

• surgical resection if lesions are continually irritated or subjected to trauma

3. Neurologic Manifestations

1. Infantile Spasms

• hormonal therapy: ACTH, prednisone
• anticonvulsants: clonazepam, VPA, nitrazepam, clobazam
• ? pertussis immunization -> triggers infantile spasm
• recommend not giving pertussis immunization to infants with TS

2. Generalized Seizures

• anticonvulsant therapy and may be difficult to control

3. Developmental delay

• physiotherapy, early intervention

4. Tumors

1. Surgical Resection

• of intracranial tumors if complications:
• elevated ICP -> hydrocephalus
• malignant transformation
• of other tumors if complications:
• cardiac -> congestive heart failure or arrhythmias
• renal -> renal failure

5. Others

1. Genetic Couselling

• 25% of parents without personal or family history of TS may be shown by careful history, physical (Wood's light, fundoscopic exam), & investigations (CT, renal ultrasound) to be affected
• incompletely affected parents (those with isolated findings such as adenoma sebaceum, retinal hamartomas, viseral tumors) can have children with complete TS