Congenital Malformations of the CNS PDF

**OUTLINE** I. **Brain Malformations** a. Primary Neurulation b. Secondary Neurulation II. **Neural Tube Defects** a. Craniorachischisis Totalis b. Anencephaly c. Myeloschisis d. Encephalocele and Myelomeningocele e. Spinal Dysraphism 1. Spina Bifida Cystica 2. Spina Bifida Occu...

**OUTLINE** I. **Brain Malformations** a. Primary Neurulation b. Secondary Neurulation II. **Neural Tube Defects** a. Craniorachischisis Totalis b. Anencephaly c. Myeloschisis d. Encephalocele and Myelomeningocele e. Spinal Dysraphism 1. Spina Bifida Cystica 2. Spina Bifida Occulta a. Occult Spinal dysraphism f. Chiari Malformations III. **Antenatal Diagnosis for Neural Tube Defects** IV. **Prevention of Neural Tube Defect** V. **Hydrocephalus** VI. **Hydranencephaly** VII. **Prosencephalic Development** a. Disorders of Neuronal Proliferation VIII. Holoprosencephaly 1. Aprosenceophaly -- Atelencephaly 2. Agenesis of Corpus Callosum 3. Agenesis of Septum Pellucidum 4. Septo-optic dysplasia 5. Commissural Plate agenesis IX. **Disorders of Neuronal Proliferation** a. Macrocephaly b. Megalencephaly c. Neurofibromatosis d. Tuberous Scelorosis Complex e. Sturge Weber Syndrome X. **Neural Migration** a. Types of Neural Migration b. Disorders of Neural Migration 1. Schizencephaly 2. Polymicrogyria 3. Lissencephaly 4. Cerebral Heterotopias 5. Porencephaly XI. **Summary** +-----------------------+-----------------------+-----------------------+ | **LEGEND** | | | +=======================+=======================+=======================+ | ⭐ | 🖊️ | 📖 | | | | | | Must | Lecture | Book | | | | | | Know | *\[lec\]* | *\[bk\]* | +-----------------------+-----------------------+-----------------------+ OUTLINE {#outline.TransOutline} ======= To discuss the more common congenital malformations of the CNS, with regards to: - Etiology - Pathophysiology - Risk Factors - Clinical presentation - Co-morbid conditions - Diagnosis - Management BRAIN MALFORMATION {#brain-malformation.TransOutline} ================== - Represent defects during the earliest stage of brain development - Reflect underlying problems in embryology and developmental genetics of the nervous system - Provide an important window into the normal brain development and into the genetic regulation of brain development and function. - Frequently they can occur with other diverse developmental brain disorders both with and without recognized structural defects - Are associated with a wide spectrum of functional deficits including intellectual disability (mental retardation), developmental language disorders, epilepsy, social, and behavioral disabilities, - 🖊️numerous other specific learning disability, attention deficits, motor deficits associated with abnormal motor tone and posture or dyskinesia and also problems associated with sleep, feeding, mood, hormonal, and autonomic dysregulation. - 🖊️ In the Philippines, we don't know the exact number of congenital malformation, we are not really sure how rare or common they are but based on the practice, kaliwa't kanan maybe congenital, maybe acquired +-----------------------------------+-----------------------------------+ | **MAJOR EVENTS IN HUMAN BRAIN | | | DEVELOPMENT** | | +===================================+===================================+ | **Table 1. Major Events in Human | | | Brain Development and Peak Times | | | of Occurrence** | | +-----------------------------------+-----------------------------------+ | Major Developmental Event | Peak Occurrence | +-----------------------------------+-----------------------------------+ | **Primary neurulation** | 3- 4 weeks of gestation | | | | | - first step of brain | | | developments | | | | | | - occurs during the first month | | | of gestation | | | | | | - cephalocaudal manner of | | | distribution | | | | | | - most catastrophic | | | | | | - majority of the neural tube | | | defect occur during the 1^st^ | | | month | | +-----------------------------------+-----------------------------------+ | **Prosencephalic development** | 2-3 months of gestation | | | | | brain divides from left and right | | | hemisphere, supratentorial, | | | infratentorial & cerebellum | | +-----------------------------------+-----------------------------------+ | Neuronal proliferation | 3-4 months of gestation | +-----------------------------------+-----------------------------------+ | Neuronal migration | 3-5 month of gestation | +-----------------------------------+-----------------------------------+ | Organization | 5 months -- years of postnatal | +-----------------------------------+-----------------------------------+ | Myelination | Birth -- years postnatal | +-----------------------------------+-----------------------------------+ - Brain malformations are closely related to neuroembryology +-----------------------------------+-----------------------------------+ | **Table 2. Major Development | | | Event** | | +===================================+===================================+ | Primary Neurulation | - Formation of neural tube and | | | neural cone | | | | | | - NTDs occur here | | | | | | - The earlier lesion, the more | | | destructive it is | +-----------------------------------+-----------------------------------+ | Prosencephalic development | - Brain is divided into left | | | and right, superior, and | | | inferior parts | +-----------------------------------+-----------------------------------+ | Neuronal proliferation | - Division into frontal and | | | temporal | +-----------------------------------+-----------------------------------+ | Neuronal migration | - Migration of cell from bottom | | | to top, inside and out; | | | maturation of the brain | +-----------------------------------+-----------------------------------+ | Organization | - Network formation; | | | establishment of the brain | +-----------------------------------+-----------------------------------+ | Myelination | - Occurs after delivery until | | | 21 years old | +-----------------------------------+-----------------------------------+ PRIMARY NEURULATION {#primary-neurulation.TransSubtopic1} ------------------- **Figure 1. Primary Neurulation**  **Figure 2. Primary Neurulation** - Closure of Rostral neuropore à base of the brain - Caudal neuropore à terminal end of the spinal cord SECONDARY NEURULATION {#secondary-neurulation.TransSubtopic1} --------------------- **Figure 3. Caudal Neural Tube Formation**  **Figure 4. Secondary Neurulation** I. Caudal neuropore associated with secondary neurulation phase II. Canalization of your undifferentiated à central canal of your rostral neural tube (tail end) à ventriculus terminalis à filum terminale (at the tip of your spinal cord). This will play an important role in occult spinal dysraphism. III. 🖊️Canalization of undifferentiated cells will form vacuoles and coalesce together meaning they will stick together and form our central canal (mga ventriculus terminale, filum terminale na nakikita sa buntot) **II. NEURAL TUBE DEFECTS** DISORDERS OF PRIMARY NEURULATION {#disorders-of-primary-neurulation.TransSubtopic1} -------------------------------- - **Embryonic Induction Disorders** - 1-4 weeks of gestation (first month of pregnancy, di nya alam na preggy sya, uminom ng gamot, alcohol directly affect the brain development) - Failure in the induction of mesoderm and neuroectoderm - Failure of neural folds to fuse and form neural tube - 🖊️Craniorachischisis Totalis - Failure of closure meaning completely open brain and spinal cord - Most severe form - Not compatible with life - 🖊️Anencephaly - Open brain - 🖊️Encephalocele -- failure of closure of anterior neuropore; brain herniates into a sac - 🖊️Iniencephaly- defect at the back of cervical area; retroflexion dahil hindi nagfuse ang neck - 🖊️Myelomingocele- most severe other form of NTD on second neural form - 🖊️Meningocele - 🖊️Closed spinal dysraphism-lipoma covering the spinal cord - 🖊️Spina Bifida Occulta CRANIORACHISCHISIS TOTALIS {#craniorachischisis-totalis.TransSubtopic1} -------------------------- - Anencephaly (🖊️no brain) with a contiguous (🖊️nakadikit) spinal defect involving at least the cervical spine -- - **Complete failure or induction of CNS** - There may be a neural platelike structure, but no axial skeleton or dermal covering - Onset no later than 20-22 days ( time specific) - Most aborted; some to early fetal stages - Incompatible with life - No brain - Spinal cord is completely exposed **Figure 6. Craniorachischisis** ANECEPHALY {#anecephaly.TransSubtopic1} ---------- - Most common major CNS malformation in the West - 30x females \> males / 35% recurrence rate / 10% have sibing with NTD - More common in younger and older mother and usually increases in poor socioenconomic status - More commonly seen in Caucasians \> African - **Time specific** -- occurs **AFTER** the onset of neural development **(16days**) but **BEFORE** closure of the anterior neuropore **(24-26 days)** - Approximately 8-10 days time period (2^nd^ to 3^rd^ week of pregnancy) - Maybe due to drugs, infections, or chemical disorders (DM and folic acid deficiency) or genetics **BASIC DEFECTS** 1. Failure of the cephalic neural folds to fuse into a neural tube 2. Degeneration of all forebrain structures - Due to exposure of the brain to the amniotic fluid 3. Mesoderm fails to differentiate into somites - Causes failure of development of the calvarium and vertebrae - Do not survive infancy -- most of them would die within the first weeks of life; - Exhibit slow, stereotyped movements and decerebrate posturing. - Head, facial, and limb movements may be spontaneous, or pain induced. - Moro reflex, brainstem functions, and automatisms (e.g. sucking or rooting) may be more readily elicited - Seizures  **Figure 7. Anencephaly** MYELOSCHISIS {#myeloschisis.TransSubtopic1} ------------ - Failure of posterior neural tube closure. - Neural plate-like structure involves large portions of the spinal cord - Manifests as a flat, raw, velvety structure with NO overlying vertebrae or dermal covering. - **No later than 24 days of gestation** (at the onset of secondary neurulation) - 🖊️Anencephaly -- Brain, Myeloschisis -- Spine **Figure 8. Myeloschisis** ENCEPHALOCELE AND MYELOMENINGOCELE {#encephalocele-and-myelomeningocele.TransSubtopic1} ---------------------------------- - Disorder of induction and migration - Primary defect is the neural tube closure - Defects are time specific +-----------------------------------+-----------------------------------+ | **ENCEPHALOCELE** | **MYELOMENINGOCELE** | | | | | **(cranium bifidum)** | **(spina bifida)** | +===================================+===================================+ | Occipital region or Anterior | Lumbosacral region (last region | | cranial fossa | to close during secondary | | | neurulation) | | (🖊️last | | | region to close during primary | | | neurulation) | | +-----------------------------------+-----------------------------------+ | | | +-----------------------------------+-----------------------------------+ ENCEPHALOCELE (CRANIUM BIFIDUM) {#encephalocele-cranium-bifidum.TransSub-subtopic2} ------------------------------- - Around 26 days (time of closure of anterior neural tube) - **Anterior Cranial fossa** -- more common in Southeast Asia - **Convexity** -- more common in western countries **CONVEXITY ENCEPHALOCELE** - Incidence - 1 in 5-10,000 live births 🖊️More common) - 10-20% of craniospinal dysraphism - Most common form in western hemisphere - Female \> Male - Environmental factors (arsenic, clofibrate, vitamin A in high doses) - Pathology - Deformation of skull base - Abnormal falx and tentorium - Sac of variable size and skin covering - Sac contains meninges, cerebrum, or cerebellum - Dura flared out on inner sac membrane - Defects in commissural system - With hydrocephalus - Clinical evaluation - Defect immediately apparent after birth - Cystic or solid mass lesion (🖊️in your cervical or occipital region or even in your parietal or frontal regions) - Head circumference may be small (microcephaly) - Slopping forehead posteriorly - Wide sutures from hydrocephalus (60-70%) - Transillumination (+) - Chiari III Malformation (🖊️wherein the hindbrain is herniated outside into the sac)  **Figure 9. Convexity Encephalocele** **ANTERIOR CRANIAL ENCEPHALOCELE** - Nasoethmoidal Meningocele - 🖊️Commonly seen in PH but difficult to treat - Very common in Southeast Asia - 9x\> convexity encephaloceles - Neuroschisis occurs after neural tube closure, and primary abnormality is one of mesodermal origin (🖊️face and pag form ng skull) - Clinical Problems - Cranial closure defect - CSF leak ® Meningitis - Obstructed nasal breathing - Snared "nasal polyp" - 🖊️ the sac is extruding to the nose - Hypertelorism - Hydrocephalus - 🖊️ increased intraventricular fluid - **Figure 10. Anterior Cranial Encephalocele**  **Figure 11. MRI imaging of Anterior cranial encephalocele** SPINAL DYSRAPHISM {#spinal-dysraphism.TransSubtopic1} ----------------- SPINA BIFIDA CYSTICA {#spina-bifida-cystica.TransSub-subtopic2} -------------------- - Meningocele (much severe) - 🖊️extrusion of the spinal meninges only to the sac -- no skin covering - Myelomeningocele (most severe) - 🖊️extrusion of the spinal cord and spinal meninges to the sac - Most common in **lumbar or lumbosacral area** - Cervical area à least favorable; can affect breathing - Cervical & thoracic Meningoceles à not associated with hydrocephalus - Normal spine - spinal cord at the tip of the spinal canal **Figure 12. Spinal Dysraphism** **MENINGOCELE** **MYELOMENINGOCELE** -------------------------------------------------------------- ------------------------------------------------------------------------------------------------------------------------ Much severe Most severe 5% incidence rate 95% incidence rate Occurs when the insult happens after the SC has been formed. Arises from an earlier insult, which must occur before closure of the posterior neuropore (26 to 28 days of gestation)  **Figure 13. Spina bifida cystica Myelomeningocele** +-----------------------------------+-----------------------------------+ | **MYELOMENINGOCELE** | | +===================================+===================================+ | **Lesion level** | **Disability** | +-----------------------------------+-----------------------------------+ | Above L3 | - Complete paraplegia and | | | dermatomal para-analgesia | | | | | | - Bladder and rectal | | | incontinence; non ambulatory | | | (even after surgical | | | correction) | +-----------------------------------+-----------------------------------+ | L4 and below | - Same as above L3 except | | | preserved hip flexion, hip | | | adductors & knee extensors | | | | | | - Ambulatory with aid, bracing | | | or orthopedic surgery | +-----------------------------------+-----------------------------------+ | S1 and below | - Same as above L4 and below | | | with preservation of feet | | | dorsiflexors, partial | | | preservation of hip extensor | | | & knee extensor | | | | | | - Ambulatory with minimal aid | +-----------------------------------+-----------------------------------+ | S3 and below | - NORMAL lower extremity motor | | | function | | | | | | - Saddle anesthesia | | | | | | - Variable bladder-rectal | | | incontinence | +-----------------------------------+-----------------------------------+ - 🖊️ Depending on the location of your myeomeningocele will dictate the severity of disability. The higher it is, the much more severe the paraplegia is, lower it is much better yung outcome nila. Mas gusto yung S1 and below because they are able to have normal extremity function, mild saddle anesthesia, and variable bladder and rectal incontinence. SPINA BIFIDA OCCULTA {#spina-bifida-occulta.TransSub-subtopic2} -------------------- - Occult spinal dysraphism - 🖊️ there is closed, no apparent defect to the back but there is apparent dysmorphology in the lumbosacral region, seen in attachment to the spinal cord only - No herniation of the meninges - Skin of the back is completely epithelialized with the following abnormalities: - 35% - dermal sinus or dimple - 29% - lipoma - Hirsute area -- increased hair - Generally involves the POSTERIOR arches of L5 to S1 - Symptoms: - Neurogenic bladder or incontinence; the most common manifestation - Foot deformities - Lower extremity weakness or spasticity - They usually present during late childhood or early adolescence because you will only find the problem during rapid growth - 🖊️kasi na-strech yung spinal cord because it is anchored to the terminal end of the spinal canal **Figure 14. Spina Bifida Occulta** #### Order of time of origin during development (OSD) {#order-of-time-of-origin-during-development-osd.TransSub-subtopic3} - Myelocystocele - Diastematomyelia-diplomyelia (Split cord syndrome) - **TYPE 1 (Diastematomyelia/Diastomyelia)** - Two hemicords are contained within their own dural tubes. - Diastematomyelia, this is what we call split cord syndrome meaning there's a bony protrusion splitting the spinal cord into two. - **TYPE 2 (Diplomyelia)** - Two hemicords are housed in a single dural tube and are separated by a nonrigid fibrous median septum. - In contrast with Diplomyelia, meaning to say "diplo" --- "two" and there are two cords. There are two complete spinal cords separated into two. - Meningocele-lipomeningocele - Lipoma, teratoma, other tumors - Dermal sinus with or without ''dermoid'' or ''epidermoid'' cyst - ''Tethered cord'' (without any of the above) -- less severe - 🖊️ When you say tethered cord, nakatali siya or naka- anchor siya at the base of the spinal canal  **Figure 15. Diastematomyelia -- diplomyelia** #### Other manifestations of OSD {#other-manifestations-of-osd.TransSub-subtopic3} **Figure 16. (a) presence of lipoma; (b) deviation of gluteal fold; (c) birthmark**  **Figure 17. (a) hemangioma (c) tail (d) hirsute area** - 🖊️ When you see this, you need to do neuroimaging - MRI \>\>\> CT scan - Important to diagnose OSD EARLY - If left untreated, it may cause progressive loss of neural function during childhood growth spurt - Tx: Operative detethering - 🖊️ puputulin yung anchor para hindi na siya nas-stretch **Figure 18. indication for imaging studies** CHIARI MALFORMATION {#chiari-malformation.TransSubtopic1} ------------------- - Malformations associated with myelomeningocele **CHIARI MAFORMATION 1** - Sudden downward displacement of medulla and cerebellar tonsils into the canal - This is usually secondary to small posterior infratentorial region of the posterior brain. - Syringomyelia - Once there is herniation down the foramen magnum, it can cause Syringomyelia meaning there is entrapment of fluid into the spinal canal causing paresis and pain - Most common and usually encountered in adult, not often seen in children  **Figure 19. Chiari 1 malformation** CHIARI 2 MALFORMATION {#chiari-2-malformation.TransSub-subtopic2} --------------------- - Aka Arnold-chiari - Herniation of the cerebellar tonsils - Leads to Hydrocephalus - Enlarged ventricles - Kink in the medulla - Combination of Myelomeningocele (most commonly associated) and hydrocephalus - May also cause Syringomyelia (also found in Chiari 1) - Common in children (vs Chiari 1 mostly seen in adult) **Figure 20. Chiari 2 (Arnold-chiari)** CHIARI 3 MALFORMATION {#chiari-3-malformation.TransSub-subtopic2} --------------------- - Most rare type - Associated with Occipital encephalocele - Further herniation of the cerebellum below (out) the foramen magnum forming an encephalocele in addition to spina bifida - They can also have another myelomeningocele in the lumbosacral region - Easier to remove  **Figure 21: Chiari 3 Malformation** CHIARI 4 MALFORMATION {#chiari-4-malformation.TransSub-subtopic2} --------------------- - aka cerebellar hypoplasia - Most severe (compare to Chiari 3-most rare) - Hypoplasia / aplasia of the cerebellum with spina bifida - Significant risk of sudden death in infant because of cerebellum is undeveloped - NOT compatible with life **Figure 22. Chiari 4 Malformation** ANTENATAL DIAGNOSIS {#antenatal-diagnosis.TransOutline} =================== - 🖊️ antenatally diagnose NTD by determining your AFP in the maternal serum or amniotic fluid - Elevated α-fetoprotein is associated with: - Anencephaly - Open spina bifida - Cranium bifidum - Normal adult: \ 1000 ng/ml -- suggests open neural tube defect - Obtained between **15 to 20wks** -- most specific timing - Maternal serum & amniotic fluid -- 15--500 ng/ml (Normal) - ️ beyond that you might be dealing with neural tube defects - Sonography can differentiate between ventral wall defects and NTDs and can identify additional structural malformations that are characteristic of fetuses with chromosomal abnormalities. - Who should be screened? - Mothers WITH 1 or more children with neural tube defects, spinal dysraphism or multiple vertebral anomalies. - Family history - Surviving patient with spina bifida. PREVENTION OF NEURAL TUBE DEFECTS {#prevention-of-neural-tube-defects.TransOutline} ================================= FOLIC ACID SUPPLEMENTATION {#folic-acid-supplementation.TransSubtopic1} -------------------------- - FOLIC ACID + Vit C + RIBOFLAVIN → 28 days before conception TO 2nd missed menstrual period - REDUCES risk for NTD from 4.2% to 0.5% - FOLIC ACID 0.4mg(400mcg) DAILY - ALL women of childbearing age, even when not pregnant - HIGH RISK WOMEN for NTD - 4mg of folic acid daily, OR - 0.8 mg beginning 1 month before the time of the planned conception HYDROCEPHALUS {#hydrocephalus.TransOutline} ============= - 🖊️ Have been associated with numerous neural tube defects and it is not a singular disease entity - A state of progressive ventricular enlargement - Can be congenital or acquired - Most cases appear to be disorders in development of the brain and its CSF circulatory system - **ETIOLOGY:** - **impaired circulation and absorption of CSF** - **increased production of CSF** - such as in choroid papilloma - **Must be differentiated from ventriculomegaly** - Ventriculomegaly is defined as axial diameter greater than 10 mm across the atrium of the posterior or anterior of the lateral ventricles **without signs of increased pressure** - 🖊️ dapat normal pressure yung loob ng ventricle*.* TYPES {#types.TransSubtopic1} ----- OBSTRUCTIVE HYDROCEPHALUS {#obstructive-hydrocephalus.TransSub-subtopic2} ------------------------- - 🖊️ Occurs when the flow of CSF is blocked along one or more of the narrow passages connecting the ventricles usually secondary to a congenital malformation such as: - Aqueductal Stenosis (most common) - Myelomeningocele, Arnold-Chiari Type 2 Malformation - Dandy-Walker Malformation - Characterized by a dilated 4th ventricle, agenesis of cerebellar vermis, hydrocephalus  **Figure 23.** Dandy-Walker malformation primary criteria "COMMUNICATING" HYDROCEPHALUS {#communicating-hydrocephalus.TransSub-subtopic2} ----------------------------- - Occurs when the flow of CSF is blocked after it exits the ventricle - 🖊️ you usually see an open 3rd and 4th ventricle and you cannot see any obstruction - Secondary to post-infectious process (Meningitis) - Secondary to post-hemorrhagic process or an acquired etiology - More on acquired process - 📖 in communicating hydrocephalus, the flow is not obstructed but CSF is inadequately reabsorbed in the subarachnoid space, whereas in non-communicating or obstructive hydrocephalus, the flow of CSF from the ventricles to the subarachnoid space is obstructed. CLINICAL MANIFESTATIONS {#clinical-manifestations.TransSubtopic1} ----------------------- - **Infants:** - Inc. rate of head enlargement -- **most prominent sign** - 🖊️ kapag hindi naoperahan ang pasyente - Anterior fontanel -- wide open & bulging - Scalp veins are dilated and prominent - **"Sunset eyes"** - 🖊️ Because of the increased pressure there is already an impingement of the suprapineal recess on the tectum of the midbrain, and we know that midbrain is the location of your cranial nerves 3, 4, and 6, kaya titingin sila sa baba because of the increased pressure - **Older children** - **Increased intracranial pressure** - progressive headaches, strabismus, ataxia - 📖 head circumference is usually within normal limits if hydrocephalus develops after closure of the cranial sutures, or may be increased in children with preexisting (infantile) but unrecognized progressive hydrocephalus A baby with large eyes Description automatically generated **Figure 24. Head enlargement secondary to hydrocephalus (severe form)** TREATMENT {#treatment.TransSubtopic1} --------- - **Surgical Management** - Ventriculo-Peritoneal Shunting (VPS) - 🖊️ wherein you bypass the blockade by inserting a shunt diverting it to the peritoneal cavity and this one is a permanent insertion into the child  **Figure 25. VPS procedure** HYDRANENCEPHALY {#hydranencephaly.TransOutline} =============== - Maybe confused with hydrocephalus - CEREBRAL HEMISPHERES -- **ABSENT** - pinanganak na walang utak, yung **cranium is present but there is no brain inside** - Replaced with membranous sacs filled with CSF - MIDBRAIN and BRAINSTEM -- **PRESENT** - 🖊️ Cause for hydranencephaly is usually unknown, but it is postulated that there is a bilateral occlusion of the internal carotid creating an **antenatal massive stroke during fetal development** causing severe neuronal destruction - 🖊️ The affected infants can have normal or enlarged head at birth and usually the child will be presenting with irritability, poor feeding, seizures, and spastic quadriparesis and have little or no cognitive development because wala siyang cerebral hemisphere - **TREATMENT: VP shunting** -- nursing care - para lang hindi lumaki nang lumaki ulo niya. A baby with a brain and an x-ray Description automatically generated **Figure 26. Hydranencephaly** - PROSENCEPHALIC DEVELOPMENT {#prosencephalic-development.TransOutline} ========================== **Figure 27. Prosencephalic Development** - Peak Time Period -- 2--3 months - Major events - Prechordal mesoderm = forms the face and forebrain - Prosencephalic development - Prosencephalic formation - Prosencephalic cleavage = division to left and right - Paired optic and olfactory structures - Telencephalon → cerebral hemispheres - Diencephalon → thalamus, hypothalamus - Midline Prosencephalic development - Major portion of face, Corpus callosum, septum pellucidum, optic nerves (chiasm), hypothalamus - Rhombencephalon → brainstem DISORDERS OF PROSENCEPHALIC {#disorders-of-prosencephalic.TransSubtopic1} --------------------------- DEVELOPMENT {#development.TransSubtopic1} ----------- +-----------------------------------------------------------------------+ | **Table 3. Disorders of Prosencephalic Development** | +=======================================================================+ | A. **Prosencephalic Formation** | | | | Aprosencephaly/Atelencephaly | +-----------------------------------------------------------------------+ | B. **Prosencephalic Cleavage** | | | | Holoprosencephaly/holotelencephaly | +-----------------------------------------------------------------------+ | C. **Midline Prosencephalic Development** | | | | Agenesis of corpus callosum | | | | Agenesis of septum pellucidum (with or without cerebral clefts) | | | | Septo-optic dysplasia | | | | Septo-optic-hypothalamic dysplasia | +-----------------------------------------------------------------------+ A diagram of the brain Description automatically generated **Figure 28. Disorders of Prosencephalic Development** - 🖊️**Aprosencephaly** -- complete absence of formation of telencephalon, so nawala yung brain nya and what you retain is a rudimentary structure which is incompatible with life - 🖊️**Holoprosencephaly** -- complete absence of division, parang isang brain lang na walang left and right - 🖊️**Agenesis of corpus callosum** -- loss of communication between left and right brain - 🖊️**Agenesis of septum pellucidum** -- presence of corpus callosum but absent division between left and right - 🖊️**Septo-optic dysplasia** -- optic nerves are hypoplastic + absent septum pellucidum (less severe) A close-up of a baby\'s head Description automatically generated **Figure 29.** (Left) **Aprosencephaly** 🖊️*failure to divide left and right*; **(**Right**) Atelencephaly** 🖊️*absence of formation* *of mesoderm so walang mata at ilong* HOLOPROSENCEPHALY {#holoprosencephaly.TransSub-subtopic2} ----------------- - Failure of the horizontal, transverse, and sagittal cleavages of the prosencephalon - 🖊️ Meaning nawala yung division from forebrain, temporal region, and posterior region. - Damage occurs on the **5th-6th week of gestation** - 4 Types of Holoprosencephaly - **Alobar** -- single sphered cerebral structure with a common ventricle, fusion of basal ganglia, and thalamus. Absence of corpus callosum, olfactory bulbs and tracts, and hypoplasia of optic nerves. - **Semilobar** -- failure of separation of the anterior hemispheres with presence of a posterior portion of the interhemispheric fissure. Absence of the anterior portion of corpus callosum. - **Lobar** -- cerebral hemispheres are nearly fully separated. Posterior callosum is well developed, although the anterior callosum may be somewhat underdeveloped. - **Syntelencephaly** -- least severe; posterior frontal and parietal region fail to separate; absent corpus callosum.  **Figure 30. Holoprosencephaly** 🖊️you can see that there is absent division in the middle A collage of images of a child\'s brain Description automatically generated **Figure 31. Holoprosencephaly** 🖊️can be associated with facial abnormality - 🖊️ The range of prosencephalic disorders is from abnormal to normal. All of these, especially aprosencephaly, are lethal and they rarely survive beyond neonatal period. DISORDERS OF PROLIFERATION {#disorders-of-proliferation.TransOutline} ========================== - Occurs: 3^rd^ -- 4^th^ month AOG - Ventricular zone & subventricular zone = sites of proliferation - Embryonic stem cell -\> Progenitor cells - Neuronal stem cell -\> Proliferative units (multiplies, eventually differentiates into astrocytes)  **Figure 43. Neuronal Proliferation** MICROCEPHALY {#microcephaly.TransSubtopic1} ------------ - Small head circumference for age \[\ - 🖊️(A-D) Microcephaly with simplified gyral pattern only - (E-F) Microcephaly with simpilified gyri and pontocerebellar hypoplasia - (G-H) Microcephaly with simplified gyri and enlarged extraaxial space - (I-J) Microcephaly + enlarged extraaxial + pontocerbellar - hypoplasia - (K-L) Normal brain MACROCEPHALY {#macrocephaly.TransSubtopic1} ------------ - Head circumference: 2 SD / \ the mean for age, gender, & ethnicity MEGALENCEPHALY {#megalencephaly.TransSubtopic1} -------------- - Oversized and overweight brain (increased brain mass) that exceeds the mean by 2 SD or more for age, gender, & ethnicity **Figure 33. Megalencephaly** (Doc read the Types) MACRENCEPHALY {#macrencephaly.TransSubtopic1} ------------- - **Associated Disturbance of Growth** - **Achondroplasia (Dwarfism) ★** - **Head \> torso (normal in infants)** - **Beckwith Syndrome** - **Cerebral Gigantism** - **Fragile X Syndrome** - **Marshall-Smith Syndrome** - **Thanatophoric Dysplasia** - **Weaver Syndrome** NEUROFIBROMATOSIS {#neurofibromatosis.TransSubtopic1} ----------------- NF Type 1 {#nf-type-1.TransSub-subtopic2} --------- - Von Recklinghausen Disease - Autosomal dominant - 1/4000 - **[DIAGNOSTIC CRITERIA: 2 out of 7]** - **6 \> cafe-au-lait macules over 5mm** in greatest diameter in [prepubertal] and over **15mm** in greatest diameter in [postpubertal] individuals - **Axillary / inquinal freckling** consisting of multiple hyperpigmented areas 2-3mm in diamter - **2 \> Iris Lisch nodules** - A distinctive osseous lesion such as sphenoid dysplasia - Optic gliomas - 1^st^ degree relative with NF-1  **Figure 34. Diagnostic Criteria of NF-1** **Figure 35. Components of NF-1** NF Type 2 {#nf-type-2.TransSub-subtopic2} --------- - Less common (10% of NF Px) - Main Feature: ACOUSTIC NEUROMA ★ or Bilateral vestibular schwannomas TUBEROUS SCLEROSIS COMPLEX {#tuberous-sclerosis-complex.TransSubtopic1} -------------------------- - 2 genetic foci mutation - Harmartin (TSC1) & Tuberin (TSC2) - Role in neuronal proliferation  **Figure 36. Manifestations of Tuberous Sclerosis** TSC CRITERIA {#tsc-criteria.TransSub-subtopic2} ------------ - Atleast 2 major or 1 major + 2 minor features are present - Major criteria: Skin, brain, eye lesions; tumors in the heart, kidneys, or lungs. - **SKIN:** - Hypomelanotic ash leaf macules (at least 3) - Sebaceous adenomas (cheek and nose) - Shagreen patch (lumbosacral region) - Subungal/periungal fibromas \*All are problems in protein production - **RETINA:** - Mulberry tumors -- round, flat, grey lesions (disc region) - Hamartoma - **BRAIN:** - Cortical tubers: - Loc. In convolusions of the cerebral hemisphere & subependymal region - Calcification & project into the ventricular cavity -\> candle-dripping appearance - 🖊️TSC: - Very careful look at the skin bc any skin defect can also have CNS manifestation - Hypomelanotic lesion, 1st one you consider is TS in infants, primary manifestation na magkakaroon ng defect - Commonly unrecognized condition (rare) - One of the most common causes of drug-resistant epilepsy in the PH  **Figure 37. Features on Tuberous Sclerosis Complex** STURGE WEBER SYNDROME {#sturge-weber-syndrome.TransSubtopic1} --------------------- ENCEPHALOTRIGEMINAL ANGIOMATOSIS {#encephalotrigeminal-angiomatosis.TransSub-subtopic2} -------------------------------- - Angiomas involving the leptomeninges, facial skin (port wine stain) - Opthalmic & maxiallary distribution of the trigeminal nerve - Morbidities: Glaucoma, bupthalmos, lack of growth hormone, epilepsy, hemiparesis, transient stroke-like episodes, developmental delay **Figure 38. (Top) Angiomas (Down) CT Findings on SWS** NEURONAL MIGRATION {#neuronal-migration.TransOutline} ================== - 🖊️When the cells are produced, they migrate to the areas where they are supposed to be located - ⭐Peak Time Period: 3 - 5 months (️ of pregnancy) - Major Events - Cerebrum - Radial migration: cerebral cortex (projection neurons), deep nuclei - Tangential migration: cerebral cortex (interneurons) - Cerebellum - Radial migration: Purkinje cells, dentate nuclei - Tangential migration: external → internal granule cells TYPES OF NEURONAL MIGRATION {#types-of-neuronal-migration.TransSubtopic1} --------------------------- TANGENTIAL MIGRATION {#tangential-migration.TransSub-subtopic2} --------------------  **Figure 39. Tangential Migration** - 🖊️ this is usually the production of your supportive cells into your neurons RADIAL MIGRATION {#radial-migration.TransSub-subtopic2} ---------------- **Figure 40. Radial Migration** - 🖊️ the formation of fibers that protrude into the different layers of your cerebrum. So pag nagka-problema sa migration ng cells na yan, they can have different disorders. TYPES OF NEURONAL MIGRATION {#types-of-neuronal-migration-1.TransSubtopic1} --------------------------- **Order of Decreasing Severity** 🖊️ *important because can present as early onset seizures in* *Infants* - Schizencephaly - most common and most severe - Lissencephaly - pachygyria - Polymicrogyria 🖊️ small sulci, small gyri in the brain - Heterotopia 🖊️ abnormal brain in different locations - Focal cerebrocortical dysgenesis - Often **Concomitant Abnormalities of Corpus Callosum and Neuronal Cell Proliferation** - Another term -- **DISORDERS OF CORTICAL MALFORMATIONS** SCHIZENCEPHALY {#schizencephaly.TransSub-subtopic2} -------------- - Full thickness clefts in the brain that are lined by polymicrogyria. 🖊️ May big cleft, parang nabiyak, di na siya nag-migrate, nasira yung one part. There is full thickness cleft in the brain and are lined by abnormal gyrus, maliliit na gyri*.* - The most recognized pattern and specific pattern of PMG occurs in Schizencephaly (SCH) - Highly associated with neurologic deficits - Epilepsy - Focal motor weakness - Cognitive impairment 🖊️ this is one of the more common causes of drug-resistant Epilepsy  **Figure 41. Open Lip Schizencephaly** - 🖊️May cleft, may hati, Nahati yung kanyang brain. Classic disorder of neuronal migration in children. Nagfail to migrate yung areas of brain. Kaya may big cleft at one side of the brain. Ito actually bilateral. - 🖊️Polymicrogyric cortex often appears mildly thickened on imaging (usually 6-10 mm) due to cortical overfolding rather than cortical thickening. LISSENCEPHALY - PACHYGYRIA {#lissencephaly---pachygyria.TransSub-subtopic2} -------------------------- - ️ Lissencephaly (LIS) or "smooth brain" is a classic malformation associated with deficient neuronal migration. There was absence of sulci and gyrus - ️ LIS is recognized based on an abnormal gyral pattern consisting of absent or abnormally wide gyri and thick cortex. - ️ **Agyria** -- absent gyrus, appears smooth - ️ **Pachygyria** -- abnormally thick cerebral cortex. Similar with lissencephaly but less marked; gyri are relatively few, unusual A close-up of several images of a human body Description automatically generated **Figure 42. Lissencephalic Cerebral Cortex** - Smooth brain meaning nawala yung sulci and gyri nya. - ️(A.) This is the **normal** distribution of the cells, 6 layers of the neurons - ️ (B.) On **Type 1**, there is a complete disorganization - nawala yung first level, second level, third, etc. - ️(C.) On **Type 2**, there are patches, too disorganized. - **[LISSEN TYPES]** - **Type I (classic) lissencephaly** - The neocortex is represented by a narrow band of (pyramidal) cells, separated by a cell-sparse zone from vertically arranged columns of neurons arrested during migration. - **Type II (Walker-Warburg) lissencephaly** -- The neocortex is disorganized into ectopic clusters of neurons. Note the radial projection of white matter, with associated fibrovascular tissue, into the cortex between the clusters. This arrangement results in the "cobblestone" appearance on magnetic resonance imaging (H&E, bar = 1 mm). Also note the protrusion of migrating neurons through the glia limitans, leading to the uneven or pebbly cortical surface.  **Figure 43. Pachygyria** - ️ Depending on the gene mutation there are different syndromes. Again, these are highly associated with gross motor or cognitive delays and seizures and other motor and cognitive impairments. Usually, they are special children kapag nagkaroon sila ng ganito. CEREBRAL HETEROTROPIA {#cerebral-heterotropia.TransSub-subtopic2} --------------------- - ️ Heterotopias are disorders of neuronal migration of the grey matter and are not recognizable on ultrasound scan, but are known to be associated with a number of structural abnormalities that can be recognized. - ️ They are collections of grey matter in abnormal locations as a result of failure of normal radial migration and are most commonly found in the sub-ependymal or periventricular region. **Figure 44. Double Band Cerebral Heterotopia** - ️ There is an abnormal layer and formation of cells. Diba dapat lahat ng grey matter nasa taas then white matter sa baba, in this radiograph may abnormal grey matter below the white matter (Double band heterotopia). This is not surgically amenable.  **Figure 45. Focal Heterotopia** - ️ Heterotopias can be diffused or focal. This is usually associated with focal seizures or drug-resistant focal seizures in infants and children. This may also result in global developmental delays. POREBCEPHALY {#porebcephaly.TransSub-subtopic2} ------------ - Cysts or cavities within the brain that result from developmental defects or acquired lesions. - ️ during the 3rd-5th month of pregnancy - Affected infants tend to have many problems, including intellectual disability, spastic hemiparesis or quadriparesis, optic atrophy, and seizures. A close-up of a brain scan Description automatically generated **Figure 46. Prosencephaly** - ️ This can occur anywhere in the brain and depending on the location of the cysts will have different manifestations of conditions. SUMMARY {#summary.TransOutline} ======= - Congenital malformations of the CNS are heterogenous in their clinical presentation. - Congenital Malformation of the CNS is grouped according to which stage of neuronal development was disrupted. - Always remember where and when the defect started REVIEW QUESTIONS {#review-questions.TransOutline} ================ Questions given during the plenary session: 1. What is the condition called? a. Holoprosencephaly b. **Anencephaly** c. Hydrocephalus d. Craniorachischisis Totalis 2. Which of the following is true regarding this condition? a. This is a disorder of neuronal migration b. This is a disorder of secondary neurulation c. **This is a disorder of both neuronal induction and migration** d. This is a disorder of primary neurulation 3. Which of the following is true regarding this condition a. This is more common in Western countries b. This is an autosomal dominant train in families c. **This is preventable by intake of folic acid prior to pregnancy** d. This condition is not compatible with life 4. What is this condition called? a. Chiari I Malformation b. **Chiari II Malformation** c. Chiari III Malformation d. Meningocele  5. What is the diagnosis for these cases? a. Holoprosencephaly b. **Hydrocephalus** c. Hydranencephaly d. Ventriculo-megaly 6. What is the diagnosis for these imaging findings? a. Hydranencephaly b. Obstructive type of hydrocephalus c. **Communicating type of hydrocephalus** d. Ventriculomegaly 7. What is the diagnosis? a. Aicardi Syndrome b. Holoprosencephaly c. Sturge-Weber Syndrome d. **Dandy-Walker Malformation** 8. What is the do you call the neurological finding associated with this condition? e. Micrencephaly f. Hydrocephalus g. **Macrencephaly** h. Hydranencephaly  9. Which of the following statements is true regarding this condition? i. This is the disorder of neuronal organization j. This is the disorder of neuronal proliferation k. This is the disorder of prosencephalic development l. **This is the disorder of neuronal migration** 10. An infant was brought to the ER due to the recurrent seizures. You also noted that she had significant development delays and peculiar skin findings. What is the most likely diagnosis? m. Sturge-Weber Synrome n. Neurofibromatosis Type 1 o. **Tuberous sclerosis** p. Hypomelanosis of Ito REFERENCES {#references.TransOutline} ========== 1. Villaluz, M. M. G. (2023, August). Neurologic Examination in Infants and Children. Lecture. 2. Menkes, J. H., Sarnat, H. B., & Maria, B. L. (2006). Child Neurology (7th ed.). Lippincott Williams & Wilkins. 3. Batch 2024 Trans APPENDIX ======== - To prevent any changes in the format, please **[leave the blank space above the appendix]**. - If there is no appendix, do not delete this portion. - Instead, you may write ***No appendices*** - All appendices in any trans should be in one column - Figures and tables that's large in size should be placed here - Includes figures and tables used to rationalize the answers in the review questions - Table for the abbreviations used must be included in the appendix Note: You may insert meme and any motivation quotes in the trans. Please place them accordingly, suggested area is at the end of the trans.