Getting real with Phakomatoses eede-216

Transcription

1 Getting real with Phakomatoses eede-216 Tyler Richards MD John Anderson MD Michael Wien MD University Hospitals Cleveland Medical Center, Department of Radiology

2 Disclosures None of the authors have any conflicts of interest to disclose.

3 Purpose and Outline Demonstrate the role of the neuroradiologist in providing aid in diagnosis, medical and surgical management, and surveillance for complications and neoplasms in patients with phakomatoses. The phakomatosis syndromes affect many organ systems within the body, however, the focus of this exhibit will be on the NEUROIMAGING ONLY. The majority of the exhibit will be focused on five of the most common syndromes (not necessarily in the exact order!) Neurofibromatosis 1 and 2 Tuberous Sclerosis Von Hippel-Lindau Sturge Weber The information will be presented in a quiz format. A summary table will be provided at the end of the exhibit as a reference of the major findings of the more rare phakomatoses.

4 Introduction Phakomatosis is derived from the Greek phakos which means birthmark AKA neurocutaneous syndromes, neuroectodermal dysplasias, among others Group of disorders characterized by involvement of organs that arises from embryonic ectoderm CNS Skin Eyes Other organs are frequently involved as well Phakomatoses were first described by Jan van der Hoeve, a Dutch ophthalmologist, who also first described NF1, Tuberous sclerosis, and von Hippel-Lindau

5 What is the abnormality? Low grade optic glioma Which phakomatosis is this abnormality commonly seen? Neurofibromatosis type 1 Top right: Coronal T1 fat sat post Gd Bottom left: T1 axial Bottom right: T2 axial All images demonstrate expansion of the right optic nerve with mild post contrast enhancement consistent with a low grade optic glioma.

6 Neurofibromatosis type 1 (NF1) 1-4 Most common of the phakomatoses Approx. 1 in 2,600 to 1 in 3,500 live births NF1 gene (chromosome 17q12) mutation results in decreased production of neurofibromin (tumor suppressor) Autosomal dominant Approx. 50% are from spontaneous mutations Clinical presentation Usually suspected based on prominent skin lesions (see diagnostic criteria next slide) Visual symptoms from optic pathway gliomas usually present by 3 years old CNS findings are present in approximately 15-20% Neuroradiologist role Detecting tumors Assessing for interval growth and complications Confirming NF1 diagnosis Myelin Vacuolization Key imaging features include No mass effect and no enhancement (as demonstrated on the T1 post Gd image to the right) T2/FLAIR hyperintense (see FLAIR ax on left) Increase from age 3 12 y/o then regress No clinical implications Present in up to 93% of pediatric NF1 patients

7 Neurofibromatosis type 1 (NF1) 1-3 Diagnostic criteria TWO or MORE of the following: Bony Dysplasia Two or more neurofibromas Plexiform neurofibroma Optic pathway glioma Six or more café-au-lait spots Axillary or inguinal freckling Two or more Lisch nodules Findings that can be seen on neuroimaging in Bold Additional neuroimaging findings (not mentioned in subsequent slides): Aqueductal stenosis Orbital involvement Buphthalmos Spine Malignant peripheral nerve sheath tumors Dural ectasia Lateral thoracic meningoceles Neurovascular (rare) Stenosis/Occlusion Moya moya AV malformations Dolichoectasia Aneurysms American Academy of Pediatrics does not recommend routine CNS imaging for surveillance in NF1 patients without symptoms

8 Low grade Optic Pathway Glioma 2,4 Incidence of 1.5 to 15% of NF1 Mean age of 4.9 years Any portion of optic pathway from optic nerves optic radiations (including hypothalamus) Imaging findings Morphology Optic nerve glioma Elongation, bucking, and enlargement Expansion of the optic nerve sheath CSF Enlargement/mass effect of chiasm or whichever structure it involves MRI Orbits w/ Gd = study of choice T1 hypointense T2 hyperintense +/- enhancement (usually homogeneous unless tumor is large) Treatment Based on interval change in size and vision Surgery, chemotherapy, and/or radiation Above images demonstrate an enlarged optic nerve traction back to an enlarged optic chiasm consistent with an optic pathway glioma.

9 Other Gliomas 2,4 Brainstem Gliomas Medulla > midbrain > pons Usually benign course and may regress Usual MRI characteristics T1 isointense T2 hyperintense +/- enhancement Intraparenchymal astrocytomas Rare in NF1 but increased risk Usually low grade Mean age around 20 years Cerebellar gliomas Rare in NF1 but usually malignant Occur at later age and better prognosis than sporadic cases Atypical pilocytic most common type What is the abnormal finding and what is it concerning for given diagnosis of NF1? FLAIR axial (above) and T1 post Gd axial (below) demonstrate a T1 hypointense round mass with no significant enhancement in the posterior medulla which appears hyperintense on FLAIR. However, it demonstrated significant interval growth compared to the prior examination concerning for a low grade brainstem glioma.

10 Paraspinal Neurofibromas 2,4 Frequently cause problems Vertebral dysplasia dystrophic scoliosis Nerve root and spinal cord compression Vertebral body collapse What is the abnormal finding and what does it likely represent? MRI findings T1 iso to hypo T2 hyper with hypo center Avid enhancement May require surgical treatment T1 axial ABOVE and T1 Fat Sat post Gd LOWER Small T1 isointense nodule at the left L5/S1 neural foramen which demonstrates avid enhancement. This likely represents a paraspinal neurofibroma.

11 What is the abnormality? Bilateral vestibular schwannomas Which phakomatosis is this abnormality commonly seen? Is it diagnostic of the disorder? Neurofibromatosis type 2 and Yes! Coronal (top right) and axial (bottom middle) T1 post Gd images demonstrate bilateral cerebellar pontine angle enhancing masses which expand the bilateral internal auditory canals most consistent with bilateral vestibular schwannomas.

12 Neurofibromatosis type 2 (NF2) 1,2,5 Somewhat of a misnomer, no skin neurofibromas in NF2 MISME is good mnemonic which is acronym for multiple inherited schwannomas, meningiomas, and ependymomas Incidence ~ 1:60,000 Genetics Mutations in NF2 gene, chromosome 22 Dominant inheritance 50% represent new mutations Up to 1/3 are mosaic for the disease mutation Different types of mutations cause variable severity of disease Clinical presentation Hearing loss, tinnitus and/or imbalance Skin lesions are much less prominent than NF1 and only 10% of patients have >10 lesions Frequently imaging diagnosis after symptoms Significantly reduced life expectancy and quality

13 Diagnostic criteria Main NIH criteria 5 Bilateral vestibular schwannomas (VS) or family history of NF2 plus 1) Unilateral VS or- 2) Any 2 of the following Meningioma Glioma Neurofibroma Schwannoma Posterior subcapsular lenticular opacities Can also be diagnosed with genetic testing Note ependymomas, although common, are not part of diagnostic criteria. Suggested imaging screening protocol 5 Screening for VS should start at 10 years old (y/o) Brain MRI Every 2 years for unaffected patients <20 y/o Every 3-5 years for unaffected patient >20 y/o At least every year in patient s with known tumor Spine MRI Every 3 years or more often if new symptoms If initial scan is negative, further scan in 5-10 years General suggestions only, each patient should have surveillance customized to their disease

14 Intracranial Schwannomas 2,5-6 Incidence 95% of NF2 patients Mean 26 y/o Bilateral vestibular schwannomas (VS) are essentially pathognomonic Caution if patient presents < 50 y/o with bilateral vestibular schwannoma 25% change they are sporadic, >70 y/o approx. 50% chance of sporadic and not due to NF2 (NF2 or chance) 50% NF2 patients have schwannomas of other cranial nerves (CN) CN 5 > CN3 > CN12 MRI w/ Gd T1 hypo to iso T2 hyper Homogeneous enhancement If large may have areas of necrosis +/- hemorrhage with hetero enhancement Axial (left) and coronal (below) T1 post Gd demonstrate bilateral enhancing masses extending from the internal auditory canals. Note is also made of a T1 hypointense nonenhancing cystic lesion in the posterior fossa likely represent an arachnoid cyst. CT Hypodense to isodense, +/- calcifications Treatment Observation for asymptomatic tumors <1.5cm Radiosurgery for tumors <2.5cm Surgical resection if too big or hearing loss

15 Intracranial and Spinal meningiomas 1,2,5 What might the abnormal enhancement that the blue arrows are pointing to represent? Given that they are at the location of the right CN 3, the lesion is likely a schwannoma Features Tend to occur at younger age compared to sporadic cases If meningioma in a child if found, NF2 should be considered 60-80% of NF2 patients develop some type of spinal tumor visible on MRI What might the abnormal enhancement that the green arrows are pointing to represent? Meningiomas from the cerebral falx CT Hyperdense w/ avid enhancement MR Isointense to gray matter on T1 and T2 Enhance homogeneously Hyperostosis of skull

16 Ependymomas 2,7 Generally asymptomatic even when expanding cord Incidence 33-53% What does the lesion that the blue arrows are pointing to represent? Classic ependymoma with hypointense hemosiderin cap and associated hyperintense cyst on T2 (left) with enhancement of the solid portion (right) What is the sign within the circle called and what does it represent? String of pearls representing additional small ependymomas Location Cervical cord > cervicomedullary junction > thoracic > lumbar Uncommon in brain in NF2 MRI Heterogeneous mass T1 slightly hypo to iso May have hyperintense hemorrhage T2 hyperintense +/- hypointense hemosiderin cap +/- hyperintense associated cyst Surrounding cord edema Homogeneous or heterogeneous enhancement String of pearls sign (see image) Treatment Asymptomatic surveillance If symptomatic surgery considered

17 Which of the phakomatoses has these findings? Tuberous Sclerosis What are the calcifications? Calcified subependymal nodules

18 Tuberous Sclerosis Complex (TSC) 8 Second most common of the phakomatoses 1/6,000 to 1/10,000 live births with population prevalence ~ 1 in 20,000 Clinical presentation Benign tumors in many organs including brain Most patients have epilepsy Approx ½ have some type of cognitive deficit, learning disorder, or behavioral problems which are given the umbrella term TSC-associated neuropsychiatric disorders (TAND) Brain pathology results in the greatest morbidity and mortality of TSC patients Genetics Autosomal dominant inheritance, however, de novo mutations account for ~ 80% of cases Pathogenic mutation in causative genes TSC1 (9q34) codes for hamartin TSC2 (16p13.3) codes for tuberin Role of radiologist Assist in diagnosis Monitor subependymal nodules/giant cell astrocytoma lesion size

19 Diagnostic criteria Major Features 8 Hypomelanotic macules ( 3) Minor features Confetti skin lesions Angiofibromas ( 3) or fibrous cephalic plaque Dental enamel pits (>3) Ungual fibromas ( 2) Shagreen patch Multiple retinal hamartomas Cardiac rhabdomyoma Lymphangioleiomyomatosis Angiomyolipomas ( 2) Cortical dysplasias (including tubers and white matter migration lines) Subependymal nodules Subependymal giant cell astrocytoma (Pathology seen on neuroimaging in bold) Intraoral fibromas ( 2) Retinal achromic patch Multiple renal cysts Nonrenal hamartomas Definite diagnosis if 2 major features or one major and 2 minor features Possible diagnosis if 1 major or 2 minor features

20 Subependymal nodules % of TSC patients Hamartomatous lesion line the 3 rd and lateral ventricles Tend to calcify with age 90% calcified by adulthood Imaging findings Variable enhancement T1 hyperintense Iso to hyperintense on T2 and FLAIR when not yet calcified Often seen prenatally T1 axial (above) and T1 axial post Gd (below) demonstrate enhancement of the nodular lesions in the frontal horns of the bilateral ventricles. Given their size and stability over several years, these are consistent with subependymal nodules in this TSC patient.

21 Subependymal Giant Cell Astrocytoma (SEGA) 9,12-14 Benign WHO grade I tumors Almost always associated with TSC Seen in 5-20% of TSC patients Frequently located adjacent to the Foramen of Monro Treatment Surgical excision Increase in tumor size, hydrocephalus or intratumoral hemorrhage mtor Inhibitors (ex. everolimus and sirolimus) Stereotactic radiosurgery Surveillance Given that this lesion in an TSC patient measures 1.1 cm in diameter and has grown compared to the prior examination, what is the diagnosis? Given enhancement, interval growth, and location near the left Foramen of Monro, the enhancing mass is consistent with a SEGA Imaging diagnosis for SEGA from the International Tuberous Sclerosis Complex Consensus Conference of 2012 Lesion at the caudothalamic groove with either a size of more than 1 cm in any direction Subependymal lesion at any location that has shown serial growth on consecutive imaging regardless of size Histologically same as subependymal nodules Other typical imaging characteristics Most avidly enhance in heterogeneous pattern +/- calcifications Hyperintense on FLAIR

22 Cerebral White Matter Radial Migration Lines 11,15 >80% of TSC patients What do the linear areas of increased FLAIR signal represent? Cerebral White matter radial migration lines Result of abnormal neuronal migration during development Occasionally extend to cortical or subcortical tubers Imaging Frequently frontal lobes, often bilateral Thin straight lines T1 iso- to hypointense T2/FLAIR hyperintense Rarely enhance Clinical implications Increased number increases risk of cerebral dysfunction and poor seizure control

23 Cortical Tubers 9,16 90% of TSC patients Disorganized neurons and glial cells Frontal > parietal > occipital > temporal lobe Infratentorial = rare Imaging Classically triangular in shape with apex toward the ventricles T1 hypointense T2/FLAIR Hyperintense Opposite signal characteristics in infants due to low myelination 10% enhance Important clinical implications High number of cortical tubers is correlated with severity of cerebral dysfunction and poor seizure control Epileptogenic tubers are often resected Increased FDG uptake on FDG/PET DTI abnormalities Increased ADC values Axial and coronal FLAIR images demonstrate numerous hyperintense triangular shaped lesions in the supratentorial brain which represent cortical tubers.

24 Von Hippel-Lindau Syndrome 17,18 Inheritance Autosomal dominant Mutation of VHL suppressor gene Clinical features Many types of tumors (see next slide) Mostly asymptomatic Shortened life expectancy of 49 y/o

25 Diagnostic Criteria 17,18 If family history of VHL One of the following tumors establishes diagnosis Retinal or CNS hemangioblastoma Clear cell renal cell carcinoma Pheochromocytoma Pancreatic endocrine tumor Endolymphatic sac tumor If no family history Any 2 of the above tumors establishes diagnosis Two of the same tumor type counts (ex. 2 CNS hemangioblastomas = VHL diagnosis) What about the skin lesions? VHL patients can have capillary malformations of the head and neck Occasionally have café au-lait lesions as well

26 Hemangioblastomas 18 CNS hemangioblastoma (HGBL) Younger age and worse prognosis in VHL compared to sporadic cases Cerebellum (44-72% VHL patients) > Spinal cord > brainstem >>> supratentorial Imaging findings Solid, cystic, hemorrhagic or mixed Most commonly cystic w/ enhancing nodule MR T1 nodule isointense +/- flow voids T2 nodule hyperintense FLAIR both nodule & cyst hyperintense Hemorrhage not typical but does occur Treatment Consider surgery or radiotherapy for symptomatic lesions Retinal HGBL Identical histopathologically to CNS HGBL Can progress to cause blindness Imaging findings T1 signal higher than vitreous w/ avid enhancement Usually known by ophthalmology long before seen on imaging d/t symptoms FLAIR axial (top) demonstrates a heterogeneous mass centered near the cerebellar vermis and 4 th ventricle with some cystic components. T1 axial (middle) and post Gd (bottom) demonstrate an enhancing solid component of the tumor. Pathology was consistent with a HGBL.

27 Other Neurologic Tumors 18,19 Endolymphatic sac tumor Bilateral is pathognomonic for VHL Slow growing tumors consisting of hemorrhage, hemosiderin and cholesterol clefts with inflammatory giant cell reaction Posterior petrous temporal bone Local destruction but no mets Imaging findings CT: geographic or moth-eaten osseous destruction w/ peripheral rim of calcification, central spiculated calcifications w/i the solid tumor MR: T1 hyperintense foci = hemorrhage vs. cholesterol, T2 heterogeneous, enhancement heterogeneous Paraganglioma Rare in VHL however at increased risk compared to the rest of the population Imaging findings CECT avidly enhancing mass Carotid body tumor splays the carotid vessels at the bifurcation MR Salt and pepper appearance High signal of tumor = salt and low signal of vascular flow voids = pepper Sagittal and Coronal CECT demonstrate an avidly enhancing mass at the left carotid bifurcation with a necrotic central that splays the internal and external carotid arteries. Pathology was consistent with a carotid body tumor/paraganglioma

28 Which of the phakomatoses can have these calcifications? Sturge Weber Syndrome What do they represent? Dense dystrophic cortical calcifications from venous stasis Superior Inferior

29 Sturge Weber Syndrome 20 Unique phakomatosis Sporadic disorder No definite increased risk of any malignancy 1 in 50,000 live births Clinical features Seizures 80% Infantile spasms 6% Contralateral Hemianopia, Hemiparesis, and/or hemiatrophy Developmental delay and poor intellectual function Especially in bilateral cerebral hemisphere involvement Nevus flammus (port wine stain) almost always involves the ophthalmic branch of CN5 Bilateral in 33% Treatment Control of seizure activity Antiepileptic drugs, 1 st line Refractory Surgery, anything from focal resection to hemispherectomy +/- ASA 81mg

30 Pathophysiology 20 Primary problem is lack of superficial cortical venous drainage of the affected hemisphere (occurs ~5-8 weeks post conception) Blood redirected through developing leptomeninges Abnormal vascular channels/leptomeningeal angiomatosis Blood is also channeled to deep venous system persistence of embryological venous structures & developmental arteriovenous anomalies This alternative circulation is not as effective Venous stasis and hypoxia atrophy and dystrophic calcification

31 Imaging findings 20 Major 3 neuroradiologic features Atrophy Gyral calcification Dense gyriform calcification near meninges most common (68%) Occipital and parietal lobes most often Diffuse microcalcification in 16% Leptomeningeal (LM) enhancement LM enhancement on T1 post Gd is considered gold standard (more sensitive than CE CT) when assessing extent of disease Distribution occipital > parietal > temporal > frontal ROLE OF RADIOLOGIST IS Confirm the diagnosis (clinical diagnosis) Assess the extent of disease Look for clinically relevant associated abnormalities

32 What are the key findings in this Sturge Weber patient? Bilateral cerebral atrophy, greater on the right compared to the left. Patient had bilateral port wine stain lesions as well.

33 Same patient as prior slide, what additional classic finding is shown on these axial images (left is post Gd T1,right is T2)? Leptomeningeal enhancement is seen along the right frontal lobe on the T1 post Gd.

34 What type of vascular compensatory response are these post Gd T1 axial images demonstrating? Alternative drainage system through dilated medullary veins into prominent subependymal veins which will then empty into the deep venous system.

35 Bonus Case What are the key findings? T1 hyperintense signal from melanin in the amygdala, cerebellar hemisphere, and brainstem For which rare phakomatosis are these findings pathognomonic? Neurocutaneous melanosis What finding (which is not present) correlates with a poor prognosis and why? Hydrocephalus, if present, greatly increases the risk that the patient will develop melanoma

36 Rare Phakomatoses Ataxia Telangiectasia Neurocutaneous Melanosis Cowden syndrome (Multiple hamartoma syndrome) Major features Prevalence Pathophysiology Progressive spinocerebellar degeneration - Ataxia - Choreoathetosis - Later, spinal muscular atrophy. Ocular and cutaneous telangiectasia. Variable immunodeficiency - Recurrent sinopulmonary infections Multiple or giant melanocytic cutaneous nevi Abnormal intra-axial or leptomeningeal melanin deposition (melanosis) Hydrocephalus Macrocephaly Multiple mucocutaneous lesion; trichilemmomas, acral keratoses, papillomas, or neuromas GI hamartomas Dysplastic cerebellar gangliocytoma when in association with Lhermitte-Duclos disease. 1:40, ,000 Patients have marked predisposition for malignancy. 1:50, ,000 Symptomatic cases present within first two years of life and are often fatal within 3 years of diagnosis. 1:200, ,000 Increased risk of cancers of the breast, endometrium, and thyroid. Autosomal recessive mutation of ATM tumor suppressor gene, which codes a protein kinase which upregulates p53 following DNA double-strand breaks. Sporadic somatic mutation of NRAS gene causing abnormal proliferation of neural crest derived melanocytes. Fourth ventricle obstruction and hydrocephalus caused by melanocytic infiltration. Leptomeningeal involvement carries increased risk of malignant transformation. Autosomal dominant mutation of PTEN tumor suppressor gene, which codes a protein phosphatase which inhibits the AKT/mTOR cell signaling pathway important for cellular metabolism and proliferation. This leads to multiple hamartomatous growths.

37 Extremely Rare Phakomatoses Major Features Incontinentia Pigmenti Swirled streaks of skin lesions which lead to marble cake pattern of hyper- and hypopigmented skin and scarring. Peg or cone shaped teeth Ocular abnormalites. Rarely, neurologic complications; neonatal strokes, seizures, delayed motor development. Wyburn-Mason syndrome Encephalocraniocutaneo us lipomatosis; Haberland Syndrome Multiple, usually, unilateral AVMs affecting the retina, optic chiasm, basal ganglia, and mesencephalon. Intracranial or intraspinal lipomas Cerebral asymmetry Ocular choristomas Subcutaneous lipomas, alopecia, and/or fatty nevi PHACE syndrome Posterior fossa malformations Hemangiomas Head and neck Arterial abnormalities Cardiac anomalies Eye abnormalities (optic nerve hypoplasia, glaucoma, cataracts) Gomez-Lopez- Hernandez syndrome Rhombencephalosynapsis Alopecia Trigeminal anesthesia Corneal opacities Prevalen ce 0.6:1,000,000 F>>M <100 reported cases. 57 reported cases <100 reported cases F>>M 21 reported cases Pathophysiology X-linked dominant mutation of IKBKG gene responsible for regulation of nuclear factor-kappa-b, a group of anti-apoptotic proteins. Nonhereditary. Thought to result from embryonic defects during blood vessel organogenesis. Lesions tend to originate from same embryonic region of origin. Nonhereditary. Dysgenesis of the cephalic neural crest and the anterior neural tube is the most widely accepted theory of pathogenesis. Unknown. Likely X-linked dominant transmission. Unknown. Nonhereditary

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39 Citations 15. Bernauer TA. The Radial Bands Sign. Radiology 1999;212: Goodman M, Lamm SH, Engel A, et al. Cortical Tuber Count: A Biomarker Indicating Neurologic Severity of Tuberous Sclerosis Complex. Journal of Child Neurology 1997;12: Maher ER, Neumann HP, Richard S. von Hippel Lindau disease: A clinical and scientific review. Eur J Hum Genet 2011;19: Leung RS, Biswas SV, Duncan M, et al. Imaging Features of von Hippel Lindau Disease. RadioGraphics 2008;28: Gaal J, Nederveen V, H F, et al. Parasympathetic Paragangliomas Are Part of the Von Hippel-Lindau Syndrome. J Clin Endocrinol Metab 2009;94: Griffiths PD. Sturge-Weber syndrome revisited: the role of neuroradiology. Neuropediatrics 1996;27: Delfino LN, Fariello G, Quattrocchi CC, et al. Encephalocraniocutaneous lipomatosis (ECCL): neuroradiological findings in three patients and a new association with fibrous dysplasia. Am J Med Genet A 2011;155A: Lee AW, Chen CS, Gailloud P, et al. Wyburn-Mason syndrome associated with thyroid arteriovenous malformation: a first case report. AJNR Am J Neuroradiol 2007;28: Livingstone E, Claviez A, Spengler D, et al. Neurocutaneous melanosis: a fatal disease in early childhood. J Clin Oncol 2009;27: Reference GH. incontinentia pigmenti. Genetics Home Reference. 25. OMIM - Online Mendelian Inheritance in Man. 26. RESERVED IU--AR. Orphanet.