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KEY FACTS

Terminology
- Hamartomas of multiple organs → CNS, skin, kidney, bone
Imaging
- Cerebral tubers - Cortical/subcortical lesion expanding overlying gyri - T2/FLAIR hyperintense, T1 hypointense after myelination - T1 hyperintense prior to myelination
- Cerebellar tubers - Wedge-shaped foci of volume loss - Often enhance & calcify
- Subependymal nodules (SENs) - Elongated nodules in locations of fetal germinal matrix - Increasing Ca⁺⁺ over time - 30-80% enhance
- Subependymal giant cell astrocytoma (SEGA) - Growing nodule at caudothalamic groove - WHO grade 1 neoplasm
Top Differential Diagnoses
- Focal cortical dysplasia
- Dysembryoplastic neuroepithelial tumor
- Ganglioglioma
- TORCH infections that cause periventricular Ca⁺⁺
- X-linked subependymal heterotopia
Pathology
- 2 distinct gene loci - TSC1 (9q34) encodes hamartin - TSC2 (16p13) encodes tuberin → more severe
Clinical Issues
- Medical antiseizure therapy, resection of seizure focus
- mTOR inhibitors now 1st-line therapy for SEGA
Diagnostic Checklist
- Tubers + SEN pathognomonic for TSC
- Surveillance imaging is performed to detect SEGA

TERMINOLOGY

Abbreviations
- Tuberous sclerosis complex (TSC)
Synonyms
- Bourneville syndrome, Pringle disease, epiloia
Definitions
- Neurocutaneous syndrome: Hamartomatosis - Hamartomas of multiple organs → CNS, skin, kidney, bone
- "Original" phakomatosis - "Phakoma" 1st used by Dutch ophthalmologist to describe retinal hamartoma

IMAGING

General Features

Best diagnostic clue

- Cerebral & cerebellar "tubers"
        - Tubers = potato-like texture observed at surgery
        - Dysplastic lesions present from birth
- Subependymal nodules (SENs)
- Subependymal giant cell astrocytoma (SEGA)

Location

- Tubers → cerebrum (90%) > cerebellum (24-36%)
- SEN → anatomic distribution is same as fetal germinal matrix with preponderance in caudothalamic grooves
        - Caudothalamic groove > body/atrium > temp horn
- SEGA → enlarging mass at foramen of Monro

Morphology

- Tubers
        - Cerebral
                  - Cortical/subcortical tubers expand overlying gyri
                  - Cystic tuber degeneration → "empty gyri"
                  - Often associated with radial migration lines extending toward lateral ventricles
        - Cerebellar
                  - Typically wedge-shaped foci with volume loss & folia distortion
- SENs
        - Usually small, nodular foci along ventricle margin
        - Majority calcify (↑ Ca⁺⁺ with ↑ age)
- SEGAs become more spherical with ↑ size

Radiographic Findings

Radiography

- Sclerotic bone islands (axial skeleton)
- Lucent bone "cysts" with undulating periosteal new bone (hands, feet)

CT Findings

NECT

- SENs → Ca⁺⁺ ↑ with time
- Tubers → low-attenuation subcortical lesion expanding overlying gyri
        - Cerebral tubers usually noncalcified (↑ Ca⁺⁺ with ↑ age)
        - Cerebellar tubers often calcified (~ 30%)
- Hamartomatous lobe → Ca⁺⁺ in dysplasia/hamartoma of entire lobe (frontal) or hemisphere
- Giant optic drusen → Ca⁺⁺ in retinal hamartoma

CECT

- Most SENs enhance → may be masked by Ca⁺⁺
- Some tubers faintly enhance

CTA
```
- Aneurysms occur infrequently (0.74%)
```

MR Findings

T1WI

- SENs → typically slightly hyperintense
        - Best shown on sagittal & coronal images
- Tubers & radial migration lines are T1 hyperintense in very young patients prior to myelination
- Tubers & radial migration lines become T1 hypointense after myelination
- Magnetization transfer ↑ detection of cortical tubers & radial migration lines in children

T2WI

- Tubers/radial migration lines typically inconspicuous in very young patients prior to myelination
        - More apparent (hyperintense) with maturation of normal myelin (hypointense)

FLAIR

- Tubers → hyperintense
        - "Empty gyri" & periventricular cysts suppress completely
- Best sequence for detection of tubers & radial migration lines

T2* GRE

- Helpful to show Ca⁺⁺ in tubers & SENs

DWI

- ↑ ADC values reported in epileptogenic tubers
- ↑ diffusivity & ↓ fractional anisotropy (FA) values in normal-appearing white matter (WM)

T1WI C+

- Best sequence for showing SEN enhancement
- 3-4% of cortical tubers enhance
- 33-92% of cerebellar tubers enhance

MRA

- Aneurysms (0.74%) & ectasias occasionally encountered

MRS

- ↑ myo-inositol (mI) in central & peripheral lesions
- ↓ NAA with ↑ mI in SEN at foramen of Monro = SEGA

Angiographic Findings
- Conventional - Used for diagnosis (beyond CTA/MRA) & treatment of aneurysms
Nuclear Medicine Findings
- PET
```
- Tubers are hypometabolic
```
Other Lesions
- Cerebral aneurysms (0.78%) & dolichoectasia
- Retinal hamartoma - Giant optic drusen
- Renal angiomyolipoma (RAM) - 40-80% incidence - Amenable to embolization to reduce bleeding risk
- Lymphangioleiomyomatosis (LAM)
- Cardiac rhabdomyoma - Present at birth, usually resolves spontaneously - May be multifocal
- Sclerotic bone islands & cysts

Imaging Recommendations

Best imaging tool
```
- MR ± contrast
```

Protocol advice

- Use DWI to assess epileptogenic foci
- ↑ MR field strength may improve tuber detection

DIFFERENTIAL DIAGNOSIS

Infection
- TORCH infections that cause periventricular Ca⁺⁺ - CMV, toxoplasmosis - May be distinguished by location outside distribution of fetal germinal matrix - Periventricular, not subependymal
- Hematogenous spread of infections that cause subcortical lesions - Fungus - Neurocysticercosis
Neoplasms
- Superficial tumors that can resemble tubers - Dysembryoplastic neuroepithelial tumor (DNET) - Ganglioglioma - Angiocentric glioma
- Intraventricular tumors - Choroid plexus tumors - Subependymoma - Central neurocytoma
Focal Cortical Dysplasia
- Especially type II
X-Linked Subependymal Heterotopia
- Gray matter heterotopia along lateral ventricle margins
- No Ca⁺⁺ or enhancement
Subcortical Ischemia, Infarction
- Regions of hyperintense subcortical signal on T2WI & FLAIR
- Restricted diffusion, gyral swelling

PATHOLOGY

General Features

Etiology

- Tuberin & hamartin combine to form complex in vivo
        - Act together to regulate mTOR pathway
                  - **M**ammalian **t**arget **o**f**r**apamycin
        - Normally inhibit part of mTOR activity
        - Regulate cell growth & proliferation
- Mutations prevent them from downregulating mTOR
- Affects germinal matrix → disordered neuronal migration & growth

Genetics

- 2 distinct gene loci
        - *TSC1* (9q34) encodes **hamartin**
        - *TSC2* (16p13) encodes **tuberin**
        - *TSC2*most common with severe phenotype
                  - More likely to have complex partial seizures, infantile spasms, SEGAs, & intellectual disability
- 1/3 familial
        - Autosomal dominant, high penetrance

Associated abnormalities

- RAM → 40-80% incidence, amenable to embolization
- Cardiac rhabdomyomas → majority involute spontaneously

Staging, Grading, & Classification
- SEGA = WHO grade 1 neoplasm
- Diagnostic criteria: 2 major (definite) or 1 major + 1 minor (probable) - Major: Tubers &/or radial migration lines, SEN, SEGA, cardiac rhabdomyoma, RAM, LAM, adenoma sebaceum, sub-/periungual fibroma, hypomelanotic macules, shagreen patch, retinal hamartoma - Minor: WM lesions, dental pits, gingival fibromas, rectal polyps, bone cysts, nonrenal hamartoma, retinal achromic patch, confetti skin lesions, multiple renal cysts
- Genetic testing detects mutations in 60-80% of affected individuals
Gross Pathologic & Surgical Features
- Firm cortical masses with umbilication
Microscopic Features
- Tubers: Balloon cells, giant cells, ectopic neurons - Tubers share many histopathologic features with focal cortical dysplasia (FCD) type 2B
- Myelin loss, vacuolation, & gliosis

CLINICAL ISSUES

Presentation
- Classic clinical triad: Adenoma sebaceum, seizures, intellectual disability - Seen in only 30-40%
- Infantile spasms → poorer outcome
- Autism

Demographics

Age

- Rhabdomyomas present prenatally & in infancy
- CNS lesions present in infancy & childhood
- Skin lesions present in childhood
- Renal, lung, & bone lesions present in adolescence & adulthood

Epidemiology
```
- 1:10,000 incidence
```

Natural History & Prognosis
- Prognosis dependent upon severity of symptoms (seizures, arrhythmias, renal insufficiency) & success of treatment
Treatment
- Medical antiseizure therapy, resection of seizure focus
- mTOR inhibitors now 1st-line therapy for SEGA - Have been shown to be highly effective at reducing seizure frequency

DIAGNOSTIC CHECKLIST

Consider
- ↑ incidence of non-CNS lesions as patients age
Image Interpretation Pearls
- Do not forget to look for vascular lesions

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References

Selected References

Images

Selected Images

Axial FLAIR MR in a 6-year-old boy with tuberous sclerosis complex (TSC) shows a moderate to severe burden of cerebral tubers and right subependymal giant cell astrocytoma (SEGA) . Cystic change is seen in a left parietal lobe tuber . Tubers are dysplastic lesions that are present in nearly all patients with TSC.

Axial T1 C+ MR in a 9-year-old girl with TSC shows a lobular, homogeneously enhancing mass in the left caudothalamic groove, consistent with a SEGA. Note the subependymal nodule .

Axial T1 C+ MR in a 4-year-old boy shows a wedge-shaped, enhancing left cerebellar tuber . The majority of cerebellar tubers enhance, in contrast to the supratentorial cerebral hemisphere tubers, which rarely enhance.

Axial NECT in a 23-month-old girl with TSC shows multiple calcified subependymal nodules . Note that the location of the nodules adheres to the distribution of fetal germinal matrix with a preponderance in the caudothalamic grooves.

Axial T1 MR in a female infant with TSC at 3 months (left) & 10 months (right) of age shows how the cerebral tubers & radial migration lines are relatively hyperintense before myelination (left) & relatively hypointense after myelination (right).

Axial T2 MR in the same patient at 3 months (left) & 10 months (right) of age shows how the cerebral tubers are inconspicuous prior to myelination (left) but become conspicuous after myelination (right).

Axial T2 MR SSFSE of a 36-weeks gestation fetus shows a hypointense subependymal nodule . Other non-CNS features confirmed a diagnosis of TSC.

Axial T1 C+ MR in a 4-year-old girl shows a large SEGA in the left caudothalamic groove (left). Three months after initiation of an mTOR inhibitor (right), the SEGA has substantially decreased in size. mTOR inhibitors are often used as 1st-line therapy for symptomatic SEGAs & have secondary benefits of decreased seizure frequency.

Axial SWI MR in a 4-year-old boy with TSC shows signal loss within a calcified, wedge-shaped cerebellar tuber . Approximately 1/3 of all cerebellar tubers are calcified. In contrast to cerebral tubers, which show gyral expansion, cerebellar tubers typically show volume loss.

High-resolution axial T2 TSE MR in a 10-month-old girl with TSC shows small, bilateral retinal contour abnormalities , consistent with retinal hamartomas.

Additional Images

Axial FLAIR MR in a 3-year-old boy with TSC shows a moderate to severe burden of cerebral tubers. Cystic change is seen in a left parietal lobe tuber . FLAIR is the most sensitive sequence for tuber detection. Tubers are dysplastic lesions that are present in nearly all patients with TSC.

Axial T1 C+ MR in the same patient shows a wedge-shaped, enhancing right cerebellar tuber . The majority of cerebellar tubers enhance, in contrast to the cerebral tubers, which rarely enhance.

Axial SWI MR in a 9-year-old boy with TSC shows signal loss within a calcified, wedge-shaped cerebellar tuber . Approximately 1/3 of all cerebellar tubers are calcified. In contrast to cerebral tubers, which show gyral expansion, cerebellar tubers typically show volume loss.

Axial T1 C+ MR in a 4-year-old girl with TSC shows a lobular, homogeneously enhancing mass in the left caudothalamic groove, consistent with a subependymal giant cell astrocytoma.

Axial T1 MR in a 3-month-old girl shows hyperintense radial migration lines & cortical/subcortical tubers .

Axial T2 MR in a 9-year-old boy with TSC shows a wedge-shaped tuber in the right cerebellum. The decreased T2 signal intensity suggests associated mineralization.

Axial T2 MR shows a mass-like tuber in the left cerebellum in this 11-year-old TSC patient. Infratentorial tubers are much less common than supratentorial ones.

AP catheter angiography with injection of the vertebral artery shows a large mid-basilar aneurysm in a 19-month-old with TSC. Aneurysms are a known, but uncommon, manifestation of this disorder.

MRS shows a characteristic short-echo proton spectroscopy profile of a SEGA with depression of NAA , elevation of choline , & elevation of myoinositol .

Axial T1 C+ MR shows multiple enhancing subependymal nodules in a patient with TSC. Enhancement of these nodules is much easier to discern on MR than CT & does not in itself indicate transformation to a SEGA.

Axial FLAIR MR shows bilateral SEGAs at the foramina of Monro that had grown over a 1-year period. These tumors become symptomatic when they cause obstructive hydrocephalus.

Axial FLAIR MR in the same patient 6 months later, after treatment with an mTOR inhibitor, shows a significant decrease in the size of the tumors .

Axial NECT shows a calcified lesion of the left frontal lobe in a child with TSC. These stable hamartomatous lesions can be excised to treat seizures. Note the subependymal nodules in the temporal horns.

Axial FLAIR MR in a 3-year-old shows tubers , radial white matter lesions , & a subependymal nodule . Note the "empty gyri" in the left parietal lobe tuber .

Coronal NECT in a 7-year-old girl shows prominent calcifications in the subcortical & deep white matter in association with cerebral tubers.

Axial NECT of the left globe shows a calcified retinal lesion in a patient with TSC. These hamartomas, sometimes called giant optic drusen, are one of the major criteria for the diagnosis of TSC.

Axial FLAIR MR shows multiple tubers & white matter lesions in a teenager with tuberous sclerosis complex. Note the gyral enlargement & distortion of the tubers as well as the radiating, linear white matter abnormalities that track centrally toward the ventricles.

Axial NECT in this 1-year-old boy with TSC shows a large hamartomatous lesion in the right frontal lobe with overlying cortical malformation, extensive calcification, & volume loss.

Axial T2 FS MR in this 1-year-old boy with TSC shows a large hamartomatous lesion in the right frontal lobe with overlying cortical malformation, extensive calcification, & volume loss.

35 KiB Raw Permalink Blame History

KEY FACTS

Terminology

Imaging

Top Differential Diagnoses

Pathology

Clinical Issues

Diagnostic Checklist

TERMINOLOGY

Abbreviations

Synonyms

Definitions

IMAGING

General Features

Best diagnostic clue

Location

Morphology

Radiographic Findings

Radiography

CT Findings

NECT

CECT

CTA

MR Findings

T1WI

T2WI

FLAIR

T2* GRE

DWI

T1WI C+

MRA

MRS

Angiographic Findings

Nuclear Medicine Findings

PET

Other Lesions

Imaging Recommendations

Best imaging tool

Protocol advice

DIFFERENTIAL DIAGNOSIS

Infection

Neoplasms

PATHOLOGY

General Features

Etiology

Genetics

Associated abnormalities

Staging, Grading, & Classification

Gross Pathologic & Surgical Features

Microscopic Features

CLINICAL ISSUES

Presentation

Demographics

Age

Epidemiology

Natural History & Prognosis

Treatment

DIAGNOSTIC CHECKLIST

Consider

Image Interpretation Pearls

References

Selected References

Images

Selected Images

Additional Images

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