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Congenital DISCLOSURES Malformations I have no disclosures. My family and I have no investments in Jennifer Williams McVige, MD nor do I speak for any company or agency.

Board Certified in Pediatric Neurology, Neuroimaging and Headache Medicine Director of the Concussion Clinic

Dent Neurologic Institute Amherst, NY

American Society of Neuroimaging 39th Annual Meeting, Orlando, FL American Society of Neuroimaging January 2016 39th Annual Meeting, Orlando, FL January 2016

Congenital Malformations Congenital Malformations

LEARNING OBJECTIVES  Brain development = complex cascade of genetic material signaling the formation of intricate structures at critical periods of time. ▸ Recognize imaging features of common congenital malformations.  Congenital malformations = disruption of development by environmental factors, or by inherited or de novo genetic mutations. ▸ Review classification system of congenital malformation  Type insult (hemorrhage, infection, etc) is not as important as the ▸ Discuss genetic and physiologic causes. TIMING and the genetic susceptibility of the fetus.

▸ Describe neuropathologic features.  Advances in the field of neuroimaging have dramatically changed the way we ▸ Order the appropriate neuroimaging study for optimal diagnostic and evaluate and assess patients with cognitive clinical outcomes. and developmental delays.

Barkovich, A.J.and Norman, D.Anomalies of the Corpus Callosum: Correlation with Further Anomalies of the Brain,AJNR Am J Neuroradiol, May/June 1988. 9: p. 493-501. Barkovich, A.J., Pediatric Neuroimaging. Fourth Edition, 2005. Lippincott, Williams, and Wilkins; Phildelphia, PA, p. 291- 422.

Congenital Malformations  A 42 yr old male presented with seizures and developmental delays.  MRI to assess for a cause for the seizures –  Classification: challenging - many brain structures develop  patient was found to have → simultaneously and no two malformations are exactly alike. lobar holprosencephaly, partial agenesis of the corpus callosum, and polymicrogyri.  Incidentally found to have a pituitary macroadenoma.  It is rare for one anomaly to occur in isolation. LOOK for more.

 Patterns of multiple anomalies - Genetic syndrome? VS Sporadic →  ID and localize anomalies → affect on brain, motor or cognitive → development → treatment/ outcomes → quality of life.

 Investigative VS Incidental findings

Barkovich, A.J. and Rayaud, C., Pediatric Neuroimaging. Fifth Edition, 2012 Lippincott, Williams, and Wilkins; Phildelphia, PA, p. 367-544. (Axial T1 weighted contrast, Sagittal T1 weighted 2mm contrast).

McVige in press (2016)

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Normal Pediatric Brain Development Normal Pediatric Cephalad → Caudal Brain Development Dorsal →Ventral Previous theories suggest cephalad → caudal Embryology- NOW replaced with simultaneous Stage 1: Dorsal Induction – development. Formation and closure of neural tube (3-4 wks) This may account for discovery → comorbid malformations. Stage 2: Ventral Induction – Formation of the brain and face (5-10 wks) anterior neuropore prosencephalon (forebrain) Stage 3: Migration and histogenesis (2-5 mos) mesencephalon (midbrain) Stage 4: Myelination (5-15 mos, matures by 3 yrs) rhombencephalon (hindbrain) → myelencephalon ( pons and cerebellum) Barkovich, JA, Pediatric Neuroimaging 4th ed– Various chapters, 2005; Lippincott, Williams & Wilkins, Philadelphia, PA

Congenital Malformations Dorsal Prosencephalon (Forebrain) Classification Agenesis of the 1. Dorsal Prosencephalon (Forebrain): Agenesis of the Corpus Callosum Corpus Callosum: Cerebral Cortical Malformations – lissencephaly, polymicrogyria, Commissures = and schizencephaly connect 2 areas of cortex Can be complete or partial. 2. Ventral Prosencephalon (Forebrain): Anencephaly, Holoprosencephaly, Semilobar,  8-20 weeks gestation in fetus. Lobar Holoprosencephaly and Septo-optic Dysplasia  1.8 to 10,000 live births (↑ in prematurity, mom’s > 35 yr, other anomalies) 3. Midbrain-Hindbrain:  Develops anterior to posterior (rostrum, genu, body, isthmus and Dandy-Walker Malformation and Joubert Syndrome splenium). Anterior dysgenesis = insult such as infection or vascular events. 4. Craniocervical Junction: Posterior dysgeneis = arrested development Chiari Malformation Tang, P.H., et al., Agenesis of the corpus callosum: an MR imaging analysis of associated abnormalities in the fetus. AJNR Am J Neuroradiol, 2009. 30(2): p. Barkovich, A.J. and Rayaud, C., Pediatric Neuroimaging. Fifth Edition, 2012 Lippincott, Williams, 257-63. and Wilkins; Phildelphia, PA, p. 367-544. Barkovich, A.J. and Rayaud, C., Pediatric Neuroimaging. Fifth Edition, 2012 Lippincott, Williams, and Wilkins; Phildelphia, PA, p. 367-544.

Dysgenesis of the Dysgenesis of the corpus callosum 9 yr old female with developmental delays and seizures. Patient had corpus callosum complete agenesis of the corpus callosum. (MRI - T2 weighted coronal, FLAIR axial)  Association with Chiari II , Dandy Walker, holoprosencephalies and lipomas.  High third ventricle Radiopedia.com  Lateral ventricles appear parallel  Colpocephaly (splaying of the atria)

Osborn, A (2013) Osborn’s Brain. Amirsys Inc. Canada

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6 yr old with ACAIRDI syndrome Dysgenesis of the With Colpocephaly, partial Agenesis of the corpus callosum Agenesis splenium of CC 30 yr old with headaches, low cognitive function, syncope Corpus Callosum and headaches, complete Imaging: agenesis CC and heterotopia Fetal ultrasound - high false positive rate Prenatal MRI - more sensitive to see additional T1 contrast DTI abnormalities Antenatal MRI - is recommended to evaluate for coexisting anomalies. Diffusion tensor imaging (DTI) or tractography - used to identify continuity.

9 yr old with developmental delays and infrequent seizures, partial agenesis splenium CC

Santo, S., et al., Counseling in fetal medicine: agenesis of the corpus callosum. Ultrasound Obstet Gynecol, 2012. 40(5): p. 513-21. Sotiriadis, A. and G. Makrydimas, Neurodevelopment after prenatal diagnosis of isolated agenesis of the corpus callosum: an integrative review. Am J Obstet Gynecol, 2012. 206(4): p. 337 e1-5. and McVige in press (2016)

Agenesis of the corpus callosum Cerebral Cortical Malformations – lissencephaly, pachy/polymicrogyria, and schizencephaly  Caused by: inhibition of neuronal or glial proliferation, migration or cortical organization. T1 contrast – also had gray matter heterotopia  Ex: gene mutations, insult from infection or bleed, exogenous toxins DTI (alcohol or drugs) and endogenous toxin (metabolic disorders).

 Pre or postnatal ultrasound by 20 weeks gestational age -easily missed.

 CT misses as many as 30% of the abnormalities.

 Fetal and postnatal MRI has a higher sensitivity.

 Kulak and colleagues -congenital brain anomalies on MRI in 10.7% of children assessed with spastic type CP → schizencephaly, agenesis of the corpus callosum, polymicrogyria, holoprosencephaly and lissencephaly, as well as cerebral atrophy. Santo, S., et al., Counseling in fetal medicine: agenesis of the corpus callosum. Ultrasound Obstet Gynecol, 2012. 40(5): p. 513-21. Huisman T.A., A. Tekes, and A. Poretti, Brain malformations and fetal ventriculomegaly: What to look for? Journal of Pediatric Neuroradiology, 2011. 1: p. 185-195. Sotiriadis, A. and G. Makrydimas, Neurodevelopment after prenatal diagnosis of isolated agenesis of the corpus callosum: an integrative review. Ghai, S., et al., Prenatal US and MR Imaging Findings of Lissencephaly: Review of Fetal Cerebral Sulcal Development. Radio Graphics, 2006. 26(2): p. 389-405. Am J Obstet Gynecol, 2012. 206(4): p. 337 e1-5. and McVige in press (2016) Kulak, W., et al., Clinical and neuroimaging profile of congenital brain malformations in children with spastic cerebral palsy. Advances in Medical Sciences, 2008; 53(1):42-8.

Lissencephaly Cerebral Cortical Malformations  Decrease in the gryal and sucal formation, brain with “smooth” appearance.  Lissencephaly: decreased sulci and gyri,  Pathology: four as opposed to six layer cortex. smooth cortex.  LIS1or DCX gene mutation 40-75% of the time.  Clinical: hypotonia, developmetal delays and seizures in the  Pachygyria: thickened flat gyri. form of infantile spasms.  Polymicrogyri: several small, convolutions and gyri.  Schizencephaly: gray matter lined cleft.

pachygyria Anterior pachygyria Posterior lissencephaly

Ghai, S., et al., Prenatal US and MR Imaging Findings of Lissencephaly: Review of Fetal Cerebral Sulcal Development. Radio Graphics, 2006. 26(2): p. 389-405. Rollins, N., T. Reyes, and J. Chia, Diffusion Tensor Imaging in Lissencephaly. AJNR Am J Neuroradiol, 2005. 26: p. 1583-6.

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Lissencephaly Cerebral Cortical Malformations  Complete lissencephaly absence of gyral formation = agyria. Polymicrogyria  Incomplete lissencephaly or pachygyria > 8mm thickened cortex  Gene: Homeobox gene PAX6 mutations. with a few broad flat gyri where the gray/white junction is indistinct.  Most in the bilateral perisylvian fissure (61%) but can be seen in a More likely to be asymmetric. number of locations.  Band heterotopia or “double cortex”  7Telsa compared to 3 Telsa MRI = limitations – found that most are mildest form of lissencephaly. bilateral manifestations. Occurs predominantly in females, ↑seizures.  Approximately 78-87%  Cobblestone lissencephalies of patients have epilepsy. (Type 2 lisencephaly) “pebbly appearance” associated with congenital muscular dystrophies.  Cortical draining veins may play a role in pathogenesis.

Polymicrogyria Schizencephaly (“split-brain”)

 DTI measures of high FA are a sensitive index which can be  Disorganized gray matter lined cleft extends utilized in clinical practice to detect microstructural damage. from the ependyma of the ventricle to the pial  MRI – Need high resolution multiplanar images. Thick, nodular, surface of the cortex. irregular stippled gray white matter interfaces, 5-7 mm bumps.  Septum pellucidum is typically absent  One third of all cases will have a non-CNS associated abnormality (such as GI or orthopedic).  MRI is more sensitive than CT, MRA and CTA – see some cases of middle cerebral artery occlusion as a cause. Osborn, A.G. Osborn's Brain: Imaging, pathology and Anatomy. 2013 Amirsys; Friesens,Altona, Manitoba, Canada, p. 1045-1130 Osborn, A.G. Osborn's Brain: Imaging, pathology and Anatomy. 2013 Amirsys; Friesens,Altona, Manitoba, Canada, p. 1045-1130 De Ciantis, A., et al., Ultra-high-field MR imaging in polymicrogyria and epilepsy. AJNR Am J Neuroradiol, 2015. 36(2): p. 309-16. Huisman, T.A., A. Tekes, and A. Poretti, Brain malformations and fetal ventriculomegaly: What to look for? Journal of Pediatric Neuroradiology, 2011. 1: p. 185-195.

Schizencephaly Schizencephaly Imaging- CSF filled defect with dysplastic gray matter FLAIR and T2 coronal 60% unilateral, 40% bilateral, 70% dysplastic corpus  callosum. Can have polymicrogyria. Open lip vs closed lip

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Vs Porencephalic cyst Congenital Malformations not lined with gray matter  Anencephaly – failed dorsal induction Failure of the brain and skull to the develop Failure for anterior neuropore to close Assoc olyhydramnios and high alpha fetoprotein Not compatible with life

Barkovich, JA, Pediatric Neuroimaging 4th ed– Various chapters, 2005; Lippincott, Williams & www.obgyn.netsonoworld.comwww.medicine.eg Wilkins, Philadelphia, PA

Congenital Malformations Congenital Malformations  Holoprosencephaly – Failed Ventral Induction Failure separate into 2 hemispheres Cause- teratogens, diabetes or  Holoprosencephaly genetic. 12 regions on 11 chromosome are potential causes. 2.)Semi lobar – form rudimentary lobes and falx, thalami 1.)Alobar- M/C , most severe, complete failure, no falx, one ventricle, partially separate, “Ace of spades,” BG fused fused thalami and BG. 80% mortality <1 yr old.

Cassidy & Allenson [2005] Management of http://www.ncbi.nlm.nih.gov/books/NBK1530/ Genetic Syndromes. Copyright John Wiley & http://www.ncbi.nlm.nih.gov/books/NBK1530/Cassidy & Allenson [2005] Sons Limited. Management of Genetic Syndromes. Copyright John Wiley & Sons Limited

Congenital Malformations Congenital Malformations  Holoprosencephaly http://www.ncbi.nlm.nih.gov/books/NBK1530/  Holoprosencephaly Failed Ventral Induction: 3.) Lobar – Best differentiated, fusion of anterior inferior frontal lobes, 4.) Septooptic dysplasia (SOD) – no septum pellucidum and atrophy of frontal horns dysplastic, no septum pellucidum, falx present, visual optic nerves. Can sometimes occur with schizencephaly. Homebox and hypothalamic/pituitary abnormalities. gene mutation. Visual and endocrine issues. www.scielo.br

Cassidy & Allenson [2005] Management of Genetic Syndromes. Copyright John Wiley & Sons

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Osborn, A (2013) Osborn’s Brain. Hindbrain MalformationsAmirsys Inc. Canada Dandy Walker  Dandy Walker – hypoplasia/dysplasia of cerebellum (vermis), poor development roof 4th ventricle, torcula elevated, tentorium and transverse sinus displaced. Brainstem is normal in milder forms small in severe forms.  Joubert Syndrome –“Molar tooth”hindbrain/midbrain formation, enlongated superior cerebellar peduncles, absence of normal vermian folia

Dandy Walker Malformation Radiopedia Joubert Syndrome archneur.jamanetwork.com

Dandy Walker Spectrum Dandy Walker “Variant”

 1.) Cerebellar hypoplasia  Milder form  2.) Mega cisterna magna (≤10 mm diameter on sagittal sequences)  Variable hypoplasia of inferior vermis  3.) Retrocerebellar arachnoid cysts without fastigial  It is believed that they occur on a spectrum due recess. to mesenchymal-neuroepithelial signaling deficits.  Normal sized posterior fossa (No torcular inversion).

Chiari Malformation Molar Tooth Malformations Inferior herniation of a cerebellar tonsil through the foramen magnum with Joubert small 4th ventricle.

Classification of Chiari Malformations Type 0 No tonsilar extension with syringomyelia and/or obstruction/compression structures in posterior fossa Type I Elongation of tonsils and medial inferior lobes of cerebellum into cone-shaped projections, accompany the medulla oblongata into the spinal canal Type II Displacement of inferior vermis, pons, and medulla oblongata with elongation of the 4th ventricle (most with spina bifida) Type III The entire cerebellum herniates into the cervical canal Type IV Cerebellar hypoplasia

McVige J, Leonardo J. “Imaging of Chiari Type I Malformation and Syringohydromyelia.” Neurologic Clinics Neuroimaging Edition; Vol 32. February 2014. 95‐126 McVige J, Leonardo J. “Neuroimaging and the Clinical Manifestations of Chiari Malformation Type I (CMI)”. Current Pain and Headache Reports. Springer. 2015 (In Press)

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Classification CMI CM I measurements Tonsillar Decent Classification of CMI (in reference to basion-opistion line) Imaging: Pointed pegged < 3 mm Normal(“cerebellar tonsillar or ectopia”) cerebellar 3-5 mm Borderline CMI (can be tonsils, abnormal if there are co- occurring pathologies e.g. crowed syringohydromyelia or foramen clinical symptoms) magnum, small 1 Sagittal MR measurements of tonsillar descent in a CMI patient. Foraminal line “A” spans from short > 5 mm CMI in patients older than clival tip to undersurface of subocciput. Tonsillar line “B” is drawn perpendicular from the foraminal 15 years clivus, steeply line to the caudal tip of the tonsils. Note the syrinx. > 6 mm CMI in patients younger angled. 2 Coronal MR measurements of tonsillar descent in a CMI patient. Foraminal line “A” is drawn than 15 years across the foramen magnum, underneath the subocciput. McVige J, Leonardo J. “Imaging of Chiari Type I Malformation and Syringohydromyelia.” Neurologic Clinics Neuroimaging McVige J, Leonardo J. “Imaging of Chiari Type I Malformation and Syringohydromyelia.” Neurologic Clinics Neuroimaging Edition; Vol 32. February 2014. 95‐126 Edition; Vol 32. February 2014. 95‐126, McVige J, Leonardo J. “Neuroimaging and the Clinical Manifestations of Chiari McVige J, Leonardo J. “Neuroimaging and the Clinical Manifestations of Chiari Malformation Type I (CMI)”. Current Pain Malformation Type I (CMI)”. Current Pain and Headache Reports. Springer. 2015 (In Press) and Headache Reports. Springer. 2015 (In Press)

CM Type I with syringohydromyelia Chiari Type I Malformation

 CMI - Often dxed incidentally after head injury, accident, infection, or pregnancy.  Incidence: Retrospectively reviewed 599 MRI of patients with headache. 24 (0.04%) incidentally found to have CMI (Lewis et al).  High frequency of a temporal association between CMI symptoms and minor head injury. (Massimi et al.)  Severity of clinical presentation is not always correlated with degree of cerebellar tonsillar ectopia, however, other studies refute this.

McVige J, Leonardo J. “Imaging of Chiari Type I Malformation and Syringohydromyelia.” Neurologic Clinics Neuroimaging Edition; Vol 32. February 2014. 95‐126 McVige J, Leonardo J. “Neuroimaging and the Clinical Manifestations of Chiari Malformation Type I (CMI)”. Current Pain and Headache Reports. Springer. 2015 (In Press)

Chiari Type I Malformation Chiari Type I Malformation MRI CINE

MRI CINE A. Pre op CINE flow study B. Post op CINE

www.neurology.org

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Chiari Malformation Type I - Chiari Malformation Type I Syrinx - Syrinx  Associations with CM I- Cervical cord syrinx 20 - 70%, Hydrocephalus 30% , Skeletal anomalies in 23 - 45% (scoliosis, fused vertebrae)  Dilation of the central cord > 3 mm in diameter c/w syrinx,  Syringohydromyelia 10-20% asymptomatic, 40-80% symptomatic.

 Hydromyelia - dilated central canal.  Syringomyelia - cavitation of the cord extending laterally.  Syringohydromyelia - combination of both hydromyelia and syringomyelia.  www.clinicalimagingscience.org  MRI of cervico-dorsal spine.  Syringobulbia - cavitation extends to the medulla  (a) Sagittal T2 weighted image showing herniation of cerebellar tonsils with syrinx in visualized spinal cord Osborn, A (2013) Osborn’s Brain. Amirsys Inc. Canada (b) axial T2 syringohydromyelia

Chiari Malformation Type II Neuroimaging Chiari Osborn, A (2013) Osborn’s Brain. Amirsys Inc. Canada  New research has shown that DTI measures of teddybrain.wordpress.com low FA in CMI correlate with the degree of microstructural abnormalities.  SPECT scans- assess for the presence of chemical alterations in the brain parenchyma,  Disorder of neural tube and could be used to assess for aberrant paraxial mesodermal closure.  ½ are due to MTHFR and folic acid deficiency, also neuroectodermal development. teratogens and seizure meds. Elevated AFP.  Imaging: 90% myelomenigocele and hydrocephalus, Eshetu, T., et al., Diffusion tensor imaging in pediatric Chiari type I malformation. Dev Med Child Neurol, 2014. 56(8): p. corpus callosum dysgenesis, polymicrogyria, 742-8. heterotopia, low lying transverse sinus, Short concave clivus.

Primary cerebellar agenesis Chiari II Malformation (formerly Chiari Malformation Type III)

 Small posterior fossa with caudally displaced brainstem. Microcephaly is common.  Cephalocele that can exceed the size of the cranium.  Imaging- dysplastic cerebellum and brainstem, encephalocele, distorted 3rd and  100% assoc with neural tube closure defect, usually lumbar myelomenigiocele. 4th ventricle.  Cervicomedullary kinking Osborn, A (2013) Osborn’s Brain. Amirsys Inc. Canada radiopaedia.org

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Chiari III Malformation Chiari IV

 Severe cerebellar hypoplasia  Small brain stem.  Large posterior fossa CSF spaces.

 Cervical occipital encephalocele + Chiari II  +/- hydrocephalus

 Neuroimaging abnormalities can be found incidentally References on routine images or in a patient with developmental delays or neurologic impairment.  Barkovich, Moore, Joneset al. Pediatric Neuroimaging, 2010, Amirsys publishing  The degree of clinical impairment may not correlate  Osburn, Blaser, Salzman et al. Diagnostic Imaging with level of disability and in other disorders there is a Brain, 2004, Amirsys publishing strong correlation.

 Images were courtesy of DENT Neurologic Institute,  Knowledge of the common congenital malformations Dr Laszlo Mechtler, Dr Ronald Alberico, Women’s and is essential for the pediatric and adult neurologist, as Children’s Hospital of Buffalo, Barkovich and Osburn well as a neuroimager to provide appropriate diagnostic texts and on line images from google images various and prognostic information. sources.

Thank you

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