Developmental Neuro Lecture

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DEVELOPMENTAL DEVELOPMENTAL NEUROLOGYNEUROLOGY

Radha Giridharan, M.D.Radha Giridharan, M.D.

Pediatric NeurologyPediatric Neurology

SUNY Downstate Medical SUNY Downstate Medical CenterCenter

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Developmental NeurologyDevelopmental Neurology

• An understanding of the An understanding of the development of the Nervous System development of the Nervous System is essential to the understanding of is essential to the understanding of Pediatric NeurologyPediatric Neurology

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• The Nervous System begins on the The Nervous System begins on the dorsal aspect of the embryo as a plate dorsal aspect of the embryo as a plate of tissue differentiating in the middle of tissue differentiating in the middle of the ectoderm called the of the ectoderm called the Neural PlateNeural Plate at approximately at approximately 18 days of gestation18 days of gestation. . The lateral margins of the neural plate The lateral margins of the neural plate invaginate and close dorsally to form invaginate and close dorsally to form the the Neural TubeNeural Tube..

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Developmental NeurologyDevelopmental Neurology• MAJOR EVENTS IN HUMAN BRAIN DEVELOPMENT AND PEAK MAJOR EVENTS IN HUMAN BRAIN DEVELOPMENT AND PEAK

TIMES OF OCCURRENCETIMES OF OCCURRENCE

MAJOR DEVELOPMENTAL MAJOR DEVELOPMENTAL EVENTEVENT

PEAK TIME OF OCCURRENCEPEAK TIME OF OCCURRENCE

Primary neurulationPrimary neurulation 3-4 weeks of gestation3-4 weeks of gestation

Prosencephalic developmentProsencephalic development 2-3 months of gestation2-3 months of gestation

Neuronal proliferationNeuronal proliferation 3-4 months of gestation3-4 months of gestation

Neuronal migrationNeuronal migration 3-5 months of gestation3-5 months of gestation

OrganizationOrganization 5 months of gestation – 5 months of gestation – years postnatalyears postnatal

MyelinationMyelination Birth – years postnatalBirth – years postnatal

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• Primary NeurulationPrimary Neurulation refers to the refers to the formation of the formation of the Neural TubeNeural Tube which which results in the formation of the results in the formation of the BrainBrain and and Spinal CordSpinal Cord. Interaction of the . Interaction of the neural tube with the surrounding neural tube with the surrounding mesodermmesoderm gives rise to the dura, the gives rise to the dura, the skull and vertebrae.skull and vertebrae.

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• Disorders of Primary NeurulationDisorders of Primary NeurulationNeural Tube Defects (NTD)Neural Tube Defects (NTD)Order of decreasing severityOrder of decreasing severity

1.1. Craniorachischisis totalisCraniorachischisis totalis

2.2. AnencephalyAnencephaly

3.3. MyeloschisisMyeloschisis

4.4. EncephaloceleEncephalocele

5.5. Myelomeningocele – Spina BifidaMyelomeningocele – Spina Bifida

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• AnencephalyAnencephaly– This results from failure of Anterior This results from failure of Anterior

Neural tube closure. It is associated Neural tube closure. It is associated with defect in the skull. The exposed with defect in the skull. The exposed neural tissue is represented by a neural tissue is represented by a hemorrhagic, fibrotic, degenerated mass hemorrhagic, fibrotic, degenerated mass of neurons and glia with little definable of neurons and glia with little definable structure.structure.

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• AnencephalyAnencephaly– OnsetOnset – Around 24 days of gestation. – Around 24 days of gestation.

75% are still born. Remainder die in 75% are still born. Remainder die in newborn period.newborn period.

– IncidenceIncidence – 0.2/1000 live births. Is – 0.2/1000 live births. Is readily identified prenatally by cranial readily identified prenatally by cranial ultrasound in second trimester of ultrasound in second trimester of pregnancy.pregnancy.

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• EncephaloceleEncephalocele– This is a restricted disorder of Neurulation involving This is a restricted disorder of Neurulation involving

anterioranterior neural tube closure. 70-80% of neural tube closure. 70-80% of encephaloceles are located in the occipital region, encephaloceles are located in the occipital region, less common site is the frontal region, where it may less common site is the frontal region, where it may protrude into the nasal cavity. Frontal protrude into the nasal cavity. Frontal encephalocele is more common in Southeast Asia. encephalocele is more common in Southeast Asia. In the typical occipital encephalocele, the In the typical occipital encephalocele, the protruding brain tissue is derived from the occipital protruding brain tissue is derived from the occipital lobe and cerebellum. As many as 50% of cases are lobe and cerebellum. As many as 50% of cases are associated with hydrocephalus.associated with hydrocephalus.

– TimingTiming – Estimated to be around 26 days of – Estimated to be around 26 days of gestation.gestation.

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ENCEPHALOCELEENCEPHALOCELE

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• Meckel’s SyndromeMeckel’s Syndrome– Occipital encephalocele, Microcephaly, Occipital encephalocele, Microcephaly,

Microphthalmia, Cleft lip and palate, Microphthalmia, Cleft lip and palate, Polydactyly, Polycystic kidneys, Ambiguous Polydactyly, Polycystic kidneys, Ambiguous genitalia and other deformities.genitalia and other deformities.

– ManagementManagement – Neurosurgical intervention – Neurosurgical intervention is indicated in most patients.is indicated in most patients.

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Developmental NeurologyDevelopmental NeurologyMeningomyelocele (Spina Bifida)Meningomyelocele (Spina Bifida)

– It is the most common major birth defect It is the most common major birth defect among live born infants in the U.S. Incidence among live born infants in the U.S. Incidence is decreasing.is decreasing.0.2-0.4/1000 live births.0.2-0.4/1000 live births.

• Anatomic AbnormalityAnatomic Abnormality– It is due to defect in the closure of the It is due to defect in the closure of the

posterior neural tube. 80% of lesions occur in posterior neural tube. 80% of lesions occur in the Lumbar regionthe Lumbar region

• TimingTiming – around 26 days of gestation – around 26 days of gestation

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MeningomyeloceleMeningomyelocele

• Clinical AspectsClinical Aspects – Motor dysfunction – Motor dysfunction and Hydrocephalusand Hydrocephalus– Motor weakness of the lower extremities Motor weakness of the lower extremities

depends on the level of the lesion. Motor depends on the level of the lesion. Motor level will determine their ability to walk. level will determine their ability to walk. Scoliosis is frequently associated with Scoliosis is frequently associated with high lesions. They also frequently have high lesions. They also frequently have sensory and sphincter involvement.sensory and sphincter involvement.

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LUMBAR MYELOMENINGOCELELUMBAR MYELOMENINGOCELE

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• HydrocephalusHydrocephalus – Site of lesion is – Site of lesion is helpful in predicting the presence and helpful in predicting the presence and development of hydrocephalus. With development of hydrocephalus. With thoraco-lumbar, lumbar and thoraco-lumbar, lumbar and lumbosacral lesions, the incidence is lumbosacral lesions, the incidence is 90%. With occipital, cervical, thoracic 90%. With occipital, cervical, thoracic or sacral lesions, the incidence is 60%.or sacral lesions, the incidence is 60%.

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• Arnold Chiari MalformationArnold Chiari Malformation– Is central to the causation of clinical Is central to the causation of clinical

deficits related to deficits related to brainstem dysfunctionbrainstem dysfunction, , a serious complication in a minority of a serious complication in a minority of patients and patients and HydrocephalusHydrocephalus, a serious , a serious complication in a majority of patients with complication in a majority of patients with MENINGOMYELOCELEMENINGOMYELOCELE..

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• Major featuresMajor features – include – include1.1. Inferior displacement of the medulla and the Inferior displacement of the medulla and the

44thth ventricle into the upper cervical canal. ventricle into the upper cervical canal.

2.2. Elongation and thinning of the upper medulla Elongation and thinning of the upper medulla and lower pons and persistence of embryonic and lower pons and persistence of embryonic flexure.flexure.

3.3. Inferior displacement of the lower cerebellum Inferior displacement of the lower cerebellum through the foramen magnum.through the foramen magnum.

4.4. A variety of bony defects of the foramen A variety of bony defects of the foramen magnum, occiput and upper cervical region.magnum, occiput and upper cervical region.

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ARNOLD-CHIARI MALFORMATION – ARNOLD-CHIARI MALFORMATION – TYPE 2TYPE 2

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• ManagementManagement– Delivery whenever possible should be by Cesarean Delivery whenever possible should be by Cesarean

section to minimize motor deficit.section to minimize motor deficit.Neurosurgical closure of the back within 24-48 hours.Neurosurgical closure of the back within 24-48 hours.Prevent infection.Prevent infection.

– HydrocephalusHydrocephalus – V-P shunt. Prevent shunt infection. – V-P shunt. Prevent shunt infection.– OrthopedicOrthopedic management. management. Urologic managementUrologic management..– EducationEducation – Most children are of – Most children are of Normal IntelligenceNormal Intelligence. .

They have specific learning disabilities and need They have specific learning disabilities and need special education.special education.

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MeningomyeloceleMeningomyelocele• PreventionPrevention

1.1. Genetic factorsGenetic factors2.2. Environmental factorsEnvironmental factors

• Genetic factorsGenetic factors1)1) Multifactorial inheritanceMultifactorial inheritance2)2) Chromosomal abnormalities (Trisomy 13 & 18)Chromosomal abnormalities (Trisomy 13 & 18)3)3) Meckel SyndromeMeckel Syndrome4)4) Preponderance in FemalesPreponderance in Females5)5) Increased incidence in siblingsIncreased incidence in siblings

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• Environmental InfluencesEnvironmental Influences1.1. Vitamin deficiency – Folic AcidVitamin deficiency – Folic Acid

2.2. Medications – Antiepileptic medications Medications – Antiepileptic medications

i.e. Valproic acid and Carbamazepinei.e. Valproic acid and Carbamazepine

3.3. Maternal HyperthermiaMaternal Hyperthermia

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• Prenatal DiagnosisPrenatal Diagnosis1.1. Maternal serum Alpha Feto Protein.Maternal serum Alpha Feto Protein.

2.2. Amniotic Fluid Alpha Feto Protein and Amniotic Fluid Alpha Feto Protein and Acetylcholinesterase.Acetylcholinesterase.

3.3. Antenatal Fetal Ultrasonography.Antenatal Fetal Ultrasonography.

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• Major Developmental EventsMajor Developmental Events1.1. Primary NeurulationPrimary Neurulation

2.2. Prosencephalic DevelopmentProsencephalic Development

3.3. Neuronal ProliferationNeuronal Proliferation

4.4. Neuronal MigrationNeuronal Migration

5.5. OrganizationOrganization

6.6. MyelinationMyelination

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• Prosencephalic DevelopmentProsencephalic Development1.1. Prosencephalic FormationProsencephalic Formation

2.2. Prosencephalic CleavageProsencephalic Cleavage– HoloprosencephalyHoloprosencephaly

3.3. Midline Prosencephalic DevelopmentMidline Prosencephalic Development– Septo Optic DysplasiaSepto Optic Dysplasia

– Septo Optic Hypothalamic DysplasiaSepto Optic Hypothalamic Dysplasia

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• HoloprosencephalyHoloprosencephaly– TimingTiming – Occurs between 5 – Occurs between 5thth and 6 and 6thth week of week of

gestationgestation

– Anatomic AbnormalityAnatomic Abnormality – Single sphered – Single sphered cerebral structure with a single ventricle. cerebral structure with a single ventricle. Absent olfactory bulbs and hypoplastic optic Absent olfactory bulbs and hypoplastic optic nerves with marked abnormality of the nerves with marked abnormality of the cortical cytoarchitecture with heterotopias. cortical cytoarchitecture with heterotopias.

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HoloprosencephalyHoloprosencephaly

• Clinical AspectsClinical Aspects– Facial abnormality – marked hypotelorism with Facial abnormality – marked hypotelorism with

nasal abnormality and median cleft lip and palate.nasal abnormality and median cleft lip and palate.Seizures and severe developmental delay.Seizures and severe developmental delay.

• GeneticsGenetics– Chromosomal abnormalities are frequently seen Chromosomal abnormalities are frequently seen

such as Trisomy 13, Trisomy 18 and in chromosome such as Trisomy 13, Trisomy 18 and in chromosome 2,3,7…., but majority have normal chromosomes2,3,7…., but majority have normal chromosomes

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• Neuronal ProliferationNeuronal Proliferation– Peak time period – 3-4 months.Peak time period – 3-4 months.

Ventricular zone and subventricular Ventricular zone and subventricular zone are the sites of proliferation.zone are the sites of proliferation.

– DisordersDisorders1.1. MicrocephalyMicrocephaly

2.2. MacrocephalyMacrocephaly

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• MicrocephalyMicrocephaly - Causes - Causes

1.1. Primary MicrocephalyPrimary Microcephaly

2.2. Secondary MicrocephalySecondary Microcephaly

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• Primary MicrocephalyPrimary Microcephaly– Microcephaly vera (genetic)Microcephaly vera (genetic)– Chromosomal disordersChromosomal disorders– Defective neurulationDefective neurulation

•AnencephalyAnencephaly

•EncephaloceleEncephalocele

– Defective prosencephalizationDefective prosencephalization•Agenesis of corpus callosumAgenesis of corpus callosum

•Holoprosencephaly (arhinencephaly)Holoprosencephaly (arhinencephaly)

– Defective cellular migrationDefective cellular migration

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• Secondary MicrocephalySecondary Microcephaly– Intrauterine disordersIntrauterine disorders

• InfectionInfection• ToxinsToxins• VascularVascular

– Perinatal brain injuriesPerinatal brain injuries• Hypoxic-ischemic encephalopathyHypoxic-ischemic encephalopathy• Intracranial hemorrhageIntracranial hemorrhage• Meningitis and encephalitisMeningitis and encephalitis• StrokeStroke

– Postnatal systemic diseasesPostnatal systemic diseases• Chronic cardiopulmonary diseaseChronic cardiopulmonary disease• Chronic renal diseaseChronic renal disease• MalnutritionMalnutrition

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MacrocephalyMacrocephaly

• CausesCauses1.1. HydrocephalusHydrocephalus

2.2. MegalencephalyMegalencephaly

3.3. Thickened SkullThickened Skull

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Causes of HydrocephalusCauses of Hydrocephalus1.1. CommunicatingCommunicating

2.2. ObstructiveObstructive

3.3. HydranencephalyHydranencephaly

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HYDROCEPHALUS - SUNSETTINGHYDROCEPHALUS - SUNSETTING

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SUNSETTING SIGNSUNSETTING SIGN

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• HydrocephalusHydrocephalus – Communicating – Communicating1.1. AchondroplasiaAchondroplasia

2.2. Basilar ImpressionBasilar Impression

3.3. Benign enlargement of subarachnoid Benign enlargement of subarachnoid spacesspaces

4.4. Choroid plexus papillomaChoroid plexus papilloma

5.5. Meningeal MalignancyMeningeal Malignancy

6.6. MeningitisMeningitis

7.7. PosthemorrhagicPosthemorrhagic

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• HydrocephalusHydrocephalus – Obstructive – Obstructive1.1. Aqueductal stenosisAqueductal stenosis

– InfectiousInfectious– X-linkedX-linked

2.2. Chiari malformationChiari malformation3.3. Dandy-Walker malformationDandy-Walker malformation4.4. Klippel-Feil syndromeKlippel-Feil syndrome5.5. Mass lesionsMass lesions

– AbscessAbscess– HematomaHematoma– Tumors and Neurocutaneous syndromesTumors and Neurocutaneous syndromes– Vein of Galen malformationVein of Galen malformation– Walker-Warburg syndromeWalker-Warburg syndrome

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• HydrocephalusHydrocephalus – Hydranencephaly – Hydranencephaly1.1. HoloprosencephalyHoloprosencephaly

2.2. Massive hydrocephalusMassive hydrocephalus

3.3. PorencephalyPorencephaly

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Developmental NeurologyDevelopmental Neurology• Causes of MegalencephalyCauses of Megalencephaly

– AnatomicAnatomic1.1. Genetic megalencephalyGenetic megalencephaly

2.2. Megalencephaly with achondroplasiaMegalencephaly with achondroplasia

3.3. Megalencephaly with gigantismMegalencephaly with gigantism

4.4. Megalencephaly with a neurologic Megalencephaly with a neurologic abnormalityabnormality

5.5. Neurocutaneous disordersNeurocutaneous disorders• Epidermal nevus syndromeEpidermal nevus syndrome• Hypomelanosis of ItoHypomelanosis of Ito• Incontinentia pigmentiIncontinentia pigmenti• NeurofibromatosisNeurofibromatosis• Tuberous sclerosisTuberous sclerosis

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Developmental NeurologyDevelopmental Neurology• Causes of MegalencephalyCauses of Megalencephaly

– MetabolicMetabolic1.1. Alexander diseaseAlexander disease2.2. Canavan diseaseCanavan disease3.3. Galactosemia: Transferase deficiencyGalactosemia: Transferase deficiency4.4. GangliosidosisGangliosidosis5.5. Globoid leucodystrophyGloboid leucodystrophy6.6. Glutaric aciduria type IGlutaric aciduria type I7.7. Leucoencephalopathy with swelling and Leucoencephalopathy with swelling and

cystscysts8.8. Maple syrup urine diseaseMaple syrup urine disease9.9. Metachromatic leucodystrophyMetachromatic leucodystrophy10.10.MucopolysaccharidosesMucopolysaccharidoses

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• Neuronal MigrationNeuronal Migration– Peak time period – 3-5 months. Migration to cerebral Peak time period – 3-5 months. Migration to cerebral

cortex and cerebellumcortex and cerebellum

• Disorders of Neuronal MigrationDisorders of Neuronal Migration– Order of decreasing severityOrder of decreasing severity

• SchizencephalySchizencephaly• Lissencephaly-pachygyriaLissencephaly-pachygyria• PolymicrogyriaPolymicrogyria• HeterotopiasHeterotopias• Focal cerebrocortical dysgenesisFocal cerebrocortical dysgenesis

– Agenesis of Corpus Callosum may accompany these Agenesis of Corpus Callosum may accompany these disorders.disorders.

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LISSENCEPHALYLISSENCEPHALY

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Developmental NeurologyDevelopmental Neurology• OrganizationOrganization

– Peak time periodPeak time period•5 months gestation to years postnatal.5 months gestation to years postnatal.

– Major EventsMajor Events•Subplate neurons – establishment and Subplate neurons – establishment and

differentiationdifferentiation•Lamination – alignment, orientation and Lamination – alignment, orientation and

layering of cortical plate neuronslayering of cortical plate neurons•SynaptogenesisSynaptogenesis•Cell death and selective elimination of Cell death and selective elimination of

neuronal processes and of synapsesneuronal processes and of synapses•Glial proliferation and differentiationGlial proliferation and differentiation

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Developmental NeurologyDevelopmental Neurology• Disorders of OrganizationDisorders of Organization

– Primary DisturbancePrimary Disturbance• Mental retardation, with or without seizuresMental retardation, with or without seizures

• Down syndromeDown syndrome

• Fragile X syndromeFragile X syndrome

• Angelman syndromeAngelman syndrome

• Infantile AutismInfantile Autism

• Duchenne muscular dystrophyDuchenne muscular dystrophy

• Other rare disordersOther rare disorders

– Potential DisturbancePotential Disturbance• Ventilator-dependent premature infantVentilator-dependent premature infant

• Other perinatal and postnatal insultsOther perinatal and postnatal insults

• Experiential effectsExperiential effects

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Developmental Neuro Lecture