1. New Perspectives on Malformations of Cortical Development with Imaging and Clinical Correlates Taraneh Hashemi-Zonouz, MD, William B. Zucconi, DO, Gino Mongelluzzo, MD, Anita Huttner, MD, S Kathleen Bandt, MD, Dennis Spencer, MD, Richard Bronen, MD Departments of Radiology and Neurosurgery Yale University School of Medicine Taraneh Hashemi-Zonouz, MD, William B. Zucconi, DO, Gino Mongelluzzo, MD, Anita Huttner, MD, S Kathleen Bandt, MD, Dennis Spencer, MD, Richard Bronen, MD Departments of Radiology and Neurosurgery Yale University School of Medicine eEdE-192

2. Disclosures: The authors have no relevant disclosures

3. Learning Objectives: Review relevant updates and trends in the understanding and classification of Malformations of Cortical Development (MCDs) through case presentations of classic imaging phenotypes: Dysplastic Megalencephaly Focal Cortical Dysplasia Lissencephaly Polymicrogyria Heterotopia This presentation assumes a basic understanding of MCD imaging phenotypes.

4. Malformations of Cortical Development (MCDs): Introduction: Patients with MCDs are a genetically and phenotypically diverse population who may present with a broad range of clinical features. Some have focal lesions and late onset focal epilepsy. Others may be discovered incidentally, or during work up for mild, unexplained neurological impairments. Many, however, are afflicted with early onset, diffuse disease and severe developmental disorders and epilepsy. Appropriate workup and diagnosis requires a coordinated effort among expert genetic, clinical and imaging specialties.

5. Malformations of Cortical Development (MCDs): Classification: Currently, classification is organized into III main groups according to the earliest stage at which cortical development is disrupted, the responsible genetic or biological pathway, and imaging features. There is a final fourth group of disorders that defy classification in this scheme. I:Abnormal neuronal and glial proliferation or apoptosis. II: Abnormal neuronal migration. III: Abnormal migration and postmigrational development / cortical organization (which overlaps with migration).

6. Malformations of Cortical Development (MCDs): Classification: Rapidly evolving understanding of the causative genetic, cellular and metabolic pathway abnormalities in MCDs continue to influence the framework for classification. Over 100 genes have been documented in association with MCDs which may alter interdependent developmental processes, some of which are now known to be associated with specific phenotypes. With regard to the malformations, distinction between disorders of neuronal proliferation, migration and organization are less clear in considering the recent discoveries of specific genetic mutations.

7. Case I 14 year old male with focal epilepsy with secondary generalization. He has had learning disabilities since childhood and first presented with a large head, prominence of the left frontal and parietal areas. (A) COR T2 and (B) COR Flair Α B A

8. Case I MRI demonstrates enlargement of the left hemisphere with abnormally hyperintense white matter and poorly defined gray matter. (A) COR T2 and (B) COR Flair Α B A

9. Case I Dysplastic Megalencephaly BA C (A) COR T2 and (B) COR Flair, (C) AX T2 Dysplastic megalencephaly is the most severe form of the megalencephalies. It may only involve a portion of a lobe, an entire hemisphere or even more than 1 cerebral hemisphere. Partly because of this variable MR phenotype, this term is preferred over “hemimegalencephaly” alone.

10. 8 y/o Male with Dysplastic Megalencephaly has partial involvement of the left hemisphere. (a) Axial 3DGR (b) CoronalT1 weighted (c) T2 weighted imaging shows diffuse signal abnormality within the posterior the left cerebral white matter, enlarged ipsilateral ventricle and poor grey white differentiation. Histologic analyses show changes that are identical those of FCD type 2, characterized by large dysmorphic neurons, cortical dyslamination and tuberous sclerosis. Areas of polymicrogyria are often documented as well. BC A Case 2 - companion

11. 4 wk old male who developed clusters of generalized myoclonic jerks, increasing in frequency. By 7 wks he had mouthing movements, eye deviation and was diagnosed with infantile spasms. By 8 months old was experiencing right sided focal seizures with residual weakness on the right side. Can you identify the abnormality? Ax T1Ax IRAx T1 Case 3

12. Findings: Thickened cortex, slightly hyperintense on T1W, blurred gray-white junction (arrows) in the L frontal lobe. Note the disorganized perirolandic sulcal pattern (compare to normal right central sulcus). The patient is now 18 y/o and seizure-free s/ p left functional hemispherectomy. Ax T1 PreCS Central S PostCS Ax IRAx T1 Case 3 Focal Cortical Dysplasia Type 2b Case 3 Focal Cortical Dysplasia Type 2b

13. PostC S Central S PreCS SF S IP S Left Intracranial electrodes and cortical mapping. Mapping demonstrates motor function widely distributed over the perirolandic region. Case 3 Focal Cortical Dysplasia Type 2b Case 3 Focal Cortical Dysplasia Type 2b Pathology: disordered with large neurons in cortex and white matter. Cells in white matter were noted with large nuclei and homogenous pink cytoplasm consistent with balloon cells (black arrows).

14. Case 4-companion Focal Cortical Dysplasia 2b Case 4-companion Focal Cortical Dysplasia 2b 34 year old female presented with focal seizures with impaired consciousness, and secondary generalization beginning at age 15. There is cortical thickening with increased T2 signal confined to the right posterior parietal cortex. Increased T2 signal is also seen in the right cingulate, which at that time was thought to be postictal. In this case, pathology was also consistent with FCD 2b, which along with FCD 1a (lacking balloon cells) are the most common pathologies in surgical epilepsy series. As indicated earlier, pathologic features are often identical to those seen in dysplastic megalencephaly and tuberous sclerosis, hypothesized to be related to common mutations encoding for proteins in the mTOR pathway.

15. 29 year old male with intractable focal motor seizures. Thickened cortex with blurring of the grey white junction (arrow) is noted adjacent to Primary Sensory cortex explaining the bilateral leg sensory seizures. Pathology revealed Focal Cortical Dysplasia Type 2a (no balloon cells). Case 5 - companion Beyond FCD II : Recent Updates in classification: FCD Type I: Microscopically identified dyslamination of neocortex. FCD III is associated with additional pathology: IIIa = FCD + hippocampal sclerosis IIIb = FCD + epilepsy associated tumors IIIc = FCD + epileptogenic lesion acquired early in life

16. “Smooth brain” and the associated subcortical band heterotopia is characterized by an abnormally thick cortex and pachygyria or agyria. It is the prototypical malformation associated with abnormal neuronal migration. Several phenotypes are known which vary in severity. Recent developments in the genetic abnormalities associated with the Lissencephaly spectrum reveal mutations that are common to Polymicrogyria- like malformations in genes encoding for tubulin, known as the tubulinopathies. These genes are active earlier than those associated with PMG/Schizencephaly, during early stages of proliferation, differentiation and axonal guidance. Case 6 11 month old male who presented with history of global developmental delay and infantile spasms who developed seizures at 9 months characterized by extensor posturing, and head nodding. Cor T2 Ax T1 Note the 3 layered appearance Yw arrow: thin cortical ribbon Orange arrow: cell sparse zone Green: thick band of disorganized neurons Classic Lissencephaly

17. Case 6 Cor T2 Ax T1 Classic Lissencephaly Many mutations correlate well with the MR phenotype: An anterior to posterior gradient of the malformation (posterior more severe) as seen in the, is more compatible with LIS1, TUBA1A, TUBBG1 mutations. If the anterior brain is more affected, DCX, ACTB mutations are more likely.

18. MPR Bilateral Perisylvian PMG Case 7 Can you identify the cortical malformation? Polymicrogyric cortex has many small convolutions, which may or may not be resolved on visual inspection of the brain surface or on routine MRI studies, especially in young patients with immature myelination. The cortex can therefore appear artificially thick. High field, optimized imaging is necessary to make the diagnosis. PMG can result from genetic and acquired causes. Regulatory G protein mutations can selectively result in bilateral perisylvian PMG.

19. Case 8 Gray matter Heterotopias are the most common MCDs seen in clinical practice PVNH is the most common form. Subcortical and multifocal forms are also seen. Periventricular nodular heterotopia (PVNH) Diagnosis? The most common cause of diffuse PVNH are X-linked FLNA gene mutations, which have a homogeneous imaging phenotype including contiguous periventricular nodular aggregates of heterotopic gray matter, mild hypoplasia of the cerebellar vermis and mega cisterna magna. Sag T1 of the same patient is shown to the right.

20. Conclusions: Rapidly evolving understanding of the causative genetic, cellular and metabolic pathway abnormalities in MCDs continue to influence the framework for classification, and will lead to a better understanding of epilepsy, developmental disorders and their treatments. At this time, imaging maintains an important role in patient workup.

21. References: Aronica, E. and P. B. Crino (2014). "Epilepsy Related to Developmental Tumors and Malformations of Cortical Development." Neurotherapeutics 11(2): 251-268. Barkovich, A. J., W. B. Dobyns and R. Guerrini (2015). "Malformations of cortical development and epilepsy." Cold Spring Harb Perspect Med 5(5): a022392. Blumcke, I., M. Thom, E. Aronica, D. D. Armstrong, H. V. Vinters, A. Palmini, T. S. Jacques, G. Avanzini, A. J. Barkovich, G. Battaglia, A. Becker, C. Cepeda, F. Cendes, N. Colombo, P. Crino, J. H. Cross, O. Delalande, F. Dubeau, J. Duncan, R. Guerrini, P. Kahane, G. Mathern, I. Najm, C. Ozkara, C. Raybaud, A. Represa, S. N. Roper, N. Salamon, A. Schulze-Bonhage, L. Tassi, A. Vezzani and R. Spreafico (2011). "The clinicopathologic spectrum of focal cortical dysplasias: a consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission." Epilepsia 52(1): 158-174. Crino, P. B. (2015). "mTOR Signaling in Epilepsy: Insights from Malformations of Cortical Development." Cold Spring Harbor Perspectives in Medicine 5(4).

22. Guerrini, R. and W. B. Dobyns (2014). "Malformations of cortical development: clinical features and genetic causes." The Lancet Neurology 13(7): 710-726. Kuzniecky, R. (2015). "Epilepsy and malformations of cortical development: new developments." Current Opinion in Neurology 28(2): 151-157. Lhatoo, S. D., N. Moghimi and S. Schuele (2013). "Tumor-related epilepsy and epilepsy surgery." Epilepsia 54: 1-4. Martins, W. A., E. Paglioli, M. Hemb and A. Palmini (2015). Dysplastic Cerebellar Epilepsy: Complete Seizure Control Following Resection of a Ganglioglioma. Micol Babini, Marco Giulioni, Ercole Galassi, Gianluca Marucci, Matteo Martinoni, Guido Rubboli, Lilia Volpi, Mino Zucchelli, Francesca Nicolini, Anna Federica Marliani, Roberto Michelucci and Fabio Calbucci (2013). "Seizure outcome of surgical treatment of focal epilepsy associated with low-grade tumors in children." Journal of Neurosurgery: Pediatrics 11(2): 214-223. Palmini, A., E. Paglioli and V. D. Silva (2013). "Developmental tumors and adjacent cortical dysplasia: Single or dual pathology?" Epilepsia 54: 18-24. Rossi, M. A. (2014). "Focal Cortical Dysplasia-Associated Tumors: Resecting Beyond the Lesion." Epilepsy Currents 14(5): 264-265.