Imaging in holoprosencephaly and related disorders

Neuroradiology,holoprosencephaly

1. IMAGING IN HOLOPROSENCEPHALY AND RELATED DISORDERS Presented by: MD KHALAF SABA JR1,RD

2. OVERVIEW Introduction Embryology Epidemiology & Etiology Severity Scale Types and its imaging features CLASSIC VARIANT MIMICS When can the diagnosis be established

3. INTRODUCTION Holoprosencephaly literally means a single (“ holo ”) ventricle involving the embryonic prosencephalon (“pros”) of the brain (“ encephaly ”). They are classified as abnormalities of ventral prosencephalon development. Fetal brain fails to bifurcate into two cerebral hemispheres. DE MYER classified HPE in 2 types Classic – Alobar Semilobar lobar Variant Middle interhemispheric variant Septopreoptic hpe

4. EMBRYOLOGY Normally the development of brain starts in 3 rd week in utero. After the completion of primary neurulation ,the cephalic end of neural tube forms three primary vesicles Prosencephalon Mesencephalon Rhombencephalon At around 5 weeks gestation ,prosencephalon cleaves into 2 secondary vesicles Telencephalon anteriorly-cerebral hemispheres, putamen and caudate nucleus Diencephalon posteriorly-thalamus, GP and optic vesicles.

5. The prosencephalon develops by the process of ventral induction which consists of 3 closely interconnected events. Formation - Aprosencephaly / Atelencephaly Cleavage - Holoprosencephaly Midline development - Corpus Callosum agenesis, septo -optic dysplasia, absence of septum Pellucidum

6. EPIDEMIOLOGY & ETIOLOGY Considered the most common malformation of the brain and face in humans. Prevalence-1 in 10,000 in live and still births 50 per 10,000 in aborted fetuses. Syndromic HPE :-associated with syndromes like Pallister Hall. Non syndromic HPE :-Environmental teratogens( e.g -retinoic acid, alcohol) Maternal factors –pre pregnancy diabetes, smoking and substance abuse.

7. Trisomy 13 Trisomy 18 Chromosome 7q deletion Chromosome 2q deletion Congenital renal anomalies Congenital cardiac anomalies Diabetic embryopathy Facial anomalies At least 12 regions on 11 separate chromosomes have been identified as playing a role in familial HPE. Mutations in 4 main HPE genes (SHH,ZIC2,SIX3,TGIF) are identified in 25% of cases. The most severe forms of HPE are associated with SIX3 and ZIC2 mutations. Recognised associations include:-

8. SPECTRUM OF SEVERITY ANENCEPHALY AP/AT HOLOPROSENCEPHALY ALOBAR SEMILOBAR LOBAR

9. ANENCEPHALY Most severe form of cranial neural tube defects . Characterized by absence of cortical tissue(brain stem and cerebellum may be variably present) as well as the cranial vault. Results from failure of closure of the antral end of the neural tube which normally occurs around 24 th day of embryonal life. Morphological appearance vary from holocrania (most severe) to merocrania (mildest form). No parenchymal tissue is seen above the orbits and calvarium is absent. “Frog eye” or “mickey mouse” appearance may be seen when seen in coronal plane due to absent cranial bone,brain and bulging orbits. Can be diagnosed on usg as early as 11 weeks. By 14 weeks accuracy approaches to upto 100%. IMAGING

10. ALOBAR HOLOPROSENCEPHALY Most severe form of HPE. Absent interhemispheric fissure with fused cerebral hemispheres (poorly developed) Falx is absent and so are the olfactory bulbs and tracts. Optic nerves –normal ,fused or absent. Basal ganglia ,hypothalamic and thalamic nuclei are typically fused. Has a high intrauterine lethality and still birth rate. With severe facial deformities such as cyclopia and proboscis , survival is often less than a week, prognosis of surviving infants is poor.

11. A CSF filled horse shoe shaped single mono ventricle continuing posteriorly with a dorsal cyst. The septum pellucidum,falx cerebri ,interhemispheric fissure and third ventricle are absent. Thalami are fused. Brain stem and cerebellum appears relatively normal. Single primitive ventricle and fused thalami are perhaps the most valuable US clues for Alobar HPE. IMAGING FEATURES

12. Snake under the skull Vascular anomaly seen in holoprosencephaly. Occurs due to forward displacement of anterior cerebral artery by the abnormally fused cortical tissue of 2 frontal lobes.

13. Can have various configurations PAN CAKE CUP BALL

14. DIFFERENTIAL DIAGNOSIS Major differential of alobar type of HPE is Hydranencephaly. In hydranencephaly most of the cerebral tissue has been destroyed in intrauterine life due to some insult /infection. Face is normal. Falx is present.

15. SEMI-LOBAR HOLOPROSENCEPHALY Intermediate in severity between alobar HPE and Lobar HPE. Most severe SHPE shows a rudimentary interhemispheric fissure and incomplete falx. Temporal and occipital horns of the lateral ventricle are partially formed. Septum pellucidum is absent. Dorsal cyst is often present.

16. Most of the interhemispheric fissure appears formed. Deep nuclei exihibit various degree of separation. Basal ganglia and hypothalami are still largely fused. Caudate nuclei appear continuous across the midline. A rudimentary third ventricle ,partially separated thalami. Splenium of corpus callosum is present but body and genu are absent. IMAGING FEATURES

17. CT

18. MRI

19. LOBAR HOLOPROSENCEPHALY Most well differentiated type of HPE. Interhemispheric fissure and falx are clearly developed,although their most anterior aspects are shallow and dysplastic. Third ventricle and lateral ventricle are well formed Septum pellucidum is absent Frontal horns are almost always dysmorphic

20. Cerebral hemispheres including thalami and most of the basal ganglia-mostly separated. Some of the most rostral and ventral portions of frontal lobes appear continuous across midline. Caudate head may remain fused. Frontal horns of lateral ventricle are present but dysplastic. Temporal and occipital horns are better defined. Third ventricle appears normal. There is no septum pellucidum. Corpus callosum-normal/incomplete/hypoplastic. Walls of hypothalamus remains fused and optic chiasm is often smaller . IMAGING

21. DIFFERENTIAL DIAGNOSIS Syntelencephaly {middle interhemispheric variant} Body of corpus callosum is missing and posterior frontal lobes are continuous across midline. Septo optic dysplasia Frontal horns are well formed in SOD. Arrhinencephaly Optic bulbs are usually present in lobar HPE.

22. HOLOPROSENCEPHALY VARIANTS

23. SYNTELENCEPHALY Also known as Middle interhemispheric variant. Anterior and posterior hemispheres are separated by falx and interhemispheric fissure,mid sections appear fused across midline. In contrast to classic HPE,ventral aspects of basal forebrain largely spared ,so basal ganglia and olfactory sulci appears normal. Imaging findings are diagnostic in MIV. Corpus callosum splenium and genu present but body is absent. Posterior frontal lobes continuous across midline. Lateral ventricle bodies appears narrow and fused.

24. SEPTO-PREOPTIC HOLOPROSENCEPHALY Mild form of HPE. Failure of hemispheric separation is restricted to subcallosal and/or preoptic regions. Patient presents with mild midline cranio facial abnormalities. Variants include:- 1.Solitary median maxillary central incisor(SMMCI) 2.Congenital nasal pyriform aperture stenosis(CNPAS)

25. Solitary median maxillary central incisor Syndrome (SMMCI ) Rare, can have multiple midline abnormalities Patient generally present with breathing difficulties. Neurodevelopmental delay with hormonal disturbances . Isolated dental abnormalities with a single maxillary incisor and v shaped palate with complex abnormalities involving the brain. Anomalies of fornix,septum pellucidum and anterior corpus callosum are often present. Azygous anterior cerebral artery and pituitary stalk hypoplasia often present. IMAGING

26. CONGENITAL NASAL PYRIFORM APERTURE STENOSIS Can exist as an isolated abnormality. Choanal atresia, mid nasal stenosis or aperture stenosis. CNPAS can co exist with SMMCI. It is associated with hypothalamic pituitary adrenal axis dysfunction.

27. SEPTO OPTIC DYSPLASIA Well differentiated form of lobar HPE. Also known as de’morsier syndrome. Two cardinal pathologic features Absence of septum pellucidum Optic nerve hypoplasia. SOD with other anomalies like schizencephaly or callosal dysgenesis syndrome called as SOD plus. Mostly sporadic,in some cases mutation of homeobox HESX1 gene is noted. Most common clinical feature –visual impairment, Endocrine abnormalities( hypoglycemia,DI ),Growth retardation.

28. The optic chiasm and one or both optic nerves appear small in about half of the cases. Coronal images show absent or hypoplastic septum pellucidum. Frontal horns appear squared off or box like with inferior pointing IMAGING

29. Saggital images shows absent septum pellucidum, low lying fornix giving the lateral ventricles an empty appearance.

30. ARRHINENCEPHALY Olfactory bulb and tracts are absent. Most cases occur with other midline facial anomalies like cleft lip ,cleft palate, nasal and other o cular abnormalities. Olfacory aplasia /hypoplasia associated with hypogonadotrophic hypogonadism- kallman syndrome. Olfactory agenesis occurs in 25% cases of CHARGE syndrome.

31. HOLOPROSENCEPHALY MIMICS

32. HYDRANENCEPHALY Severe brain destruction in utero. Water without the brain. In rare instances,only one hemisphere is involved referred as hemi hydranencephaly. As a result of vascular accident,internal carotid artery circulation gets compromised before 16 th week of gestation followed by liquefactive necrosis of the cerebrum. Most of the cerebral hemisphere is replaced by thin csf filled sac filling most of the supratentorial space.

33. General features- normal or large head with fluid filled cranial vault (“water bag brain”) with small remnants of brain parenchyma with normal falx and posterior fossa. IMAGING

34. DIFFERENTIAL DIAGNOSIS ALOBAR HPE Falx and interhemispheric fissure is absent and basal ganglia remains fused. SEVERE OBSTRUCTIVE HYDROCEPHALUS A thin cortex can be seen compressed against the dura. SEVERE CYSTIC ENCEPHALOMALACIA Large ventricles with multiple csf filled cavities within the brain.

35. WHEN CAN THE DIAGNOSIS BE ESTABLISHED Diagnosis of HPE spectrum can be made prenatally even before 10 weeks of gestation. Commonly it is made between 10-14 weeks on the basis of abnormal facial morphology and the absence of BUTTERFLY SIGN. By the second trimester the diagnosis is made on the basis of features of HPE as described earlier. (most important-absence of cavum septum pellucidum.)

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