Congenital Anomalies of the Central Nervous System

Major Events in Human Brain Development and Peak Times of Occurrence (Menkes) Gestational Age in Months Postnatal 1 2 3 4 5 6 7 8 9 Neurulation (3 – 4 wks) Neural tube Brain & Spinal cord Neural crest PNS & leptomeninges Prosencephalic (2 – 3 mos) Organization (5 – postnatal years) Neuronal Proliferation (3 – 4 mos) Paired cerebral Hemispheres, LV, BG, Thalami, Optic Nerves/ chiasm CC, SP Synaptogenesis  programmed Cell death Myelination (Birth – Postnatal yrs) Full comple- Ment of neu- rons in cerebral hemispheres Neuronal Migration (3 – 5 mos) Formation of myelin  electrical conduction Formation from 4 layered embryonic cortex  6 layered adult cortex

Transverse sections of embryos at Different ages to show the Dev’t of the spinal cord

Early development of the human nervous system late presomite and early neural plate stage early somite and neural groove stage eight-somite and early neural tube stage

Congenital Anomalies in the different stages (Birth – Postnatal yrs) Of CNS development Gestational Age in Months Postnatal 1 2 3 4 5 6 7 8 9 Neurulation (3 – 4 wks) Encephalocoele Myelomenin- gocoele Prosencephalic (2 – 3 mos) Organization (5 – postnatal years) Neuronal Proliferation (3 – 4 mos) Holoprosence- phaly Dandy walker Myelination (Birth – Postnatal yrs) Perinatal Insults ICH/ HIE Tumors CNS Infections Aqueductal Stenosis Hydroceph Perinatal Insults ICH Tumors CNS Infections Neuronal Migration (3 – 5 mos) Schizencephaly Colpocephaly Lissencephaly Agenesis of corpus callosum

Neural Tube Defects (Posterior Midline Defects/Dysraphism) Results from failure of the neural tube to close spontaneously between the 3rd-4th week of in utero development Possible etiologic factors: Radiation Drugs Malnutrition Chemicals Genetic determinants (mutations in folate- responsive and folate-dependent pathways)

Neural Tube Defects Spina bifida occulta Meningocoele/ Myelomeningocoele Encephalocoele Anencephaly Dermal sinus Tethered cord Syringomyelia Diastematomyelia

Neural Tube Defects Diagnostic tool: Failure of closure of the neural tube allows excretion of fetal substances (AFP, acetylcholinesterase) into the amniotic fluid Prenatal screening of maternal serum for AFP during 16-18 week AOG AF AFP obtained between 15-20 weeks’ gestation is most specific Rostral end of the NT closes on the 23rd day and the caudal neuropore closes by the 27th day of development

Neural Tube Defects and FA Maternal periconceptional use of folic acid supplementation reduces the incidence of NT defects by at least 50% US: recommends all women of childbearing age take 0.4 mg of folic acid daily, and women with previous pregnancy of NT defect should be treated with 4 mg of folic acid beginning one month before pregnancy is planned, until at least the 12th week AOG when neurulation is complete Fortification of flour, pasta, rice and cornmeal with 0.15 mg of folic acid/100 g was mandated in the US and Canada in 1998

Spina Bifida Occulta Midline defect of the vertebral bodies without protrusion of the SC or meninges May be asymptomatic without neuro signs In some, patches of hair, lipoma, discoloration of skin or dermal sinus may be present

Spina Bifida Occulta Spine x-ray: defect in closure of the posterior vertebral arches and laminae, usually in L5 and S1 May be associated with syringomyelia, diastematomyelia, and tethered cord Recurrent meningitis of occult origin should prompt careful exam for dermal sinus tract

Neurulation Period 1 2 3 4 5 6 7 8 9 S. N., 2 mos old, female Marked obstructive Hydrocephalus secondary to ARNOLD CHIARI II Neurulation Period Gestational Age in Months Postnatal 1 2 3 4 5 6 7 8 9

Meningocoele Formed when the meninges herniate through a defect in the posterior vertebral arches SC may be normal, or may present with tethering, syringomyelia, or diastematomyelia A fluctuant mass that may transilluminate along the vertebral column

Meningocoele Dxtic: plain x-ray, utz, MRI for the spine, CT of the head to R/O HCP Txtic: Asymptomatic children with N neuro findings and full-thickness skin may have surgery delayed. Patients with leaking CSF or a thin skin covering should undergo immediate repair to prevent meningitis.

Meningocoele Anterior meningocoele may project into the pelvis through a defect in the sacrum causing symptoms of constipation and bladder dysfunction Female patients may have associated anomalies of the genital tract (rectovaginal fistula, vaginal septa) Dxtic: plain x-ray, CT, MRI

Myelomeningocoele Most severe form of dysraphism involving the vertebral column with an incidence of 1/4000 LB Risk of recurrence after one affected child increases to 3-4% and increases to ~10% with 2 previous abnormal pregnancies Certain drugs that antagonize folic acid (TMP, AEDs: CBZ, PHY, Pb, primidone) increase the risk of myelomeningocoele Valproic acid cause NT defects in ~1-2% of pregnancies

Myelomeningocoele May be located anywhere along the neuraxis but the LS region accounts for 75% of the cases Extent and degree of the neuro deficit depend on the location CM: flaccid paralysis, absent DTRs, sensory deficit below the affected level, postural abn of the LE (clubfeet, subluxation of the hips), constant urinary dribbling and a relaxed anal sphincter

Myelomeningocoele HCP in association with a type II Chiari defect develops in at least 80% with myelomeningocoele Infants with HCP and Chiari II develop symptoms of hindbrain dysfunction: difficulty feeding, choking, stridor, apnea, VC paralysis, pooling of secretions, spasticity of UEs Chiari crisis is due to downward herniation of the medulla and cerebellar tonsils

Myelomeningocoele Requires a multidisciplinary approach: surgeon, therapist, pediatrician Surgery: repair and shunting; orthopedic procedure, urologic evaluation GUT: regular catheterization to prevent UTI and reflux leading to PN and hydronephrosis, urine cult, serum elec, creatinine, renal scan, IV pyelogram, Utz Rehab: functional ambulation (sacral or LS lesion)

Myelomeningocoele Prognosis: MR- 10-15% Most deaths occur before age 4 years 70% have normal intelligence, but learning problems and seizure disorders are common History of meningitis or ventriculitis adversely affect the ultimate IQ

11 mos old, male Neurulation Period 1 2 3 4 5 6 7 8 9 Postnatal Gestational Age in Months Postnatal 1 2 3 4 5 6 7 8 9

Encephalocoele Cranium meningocoele: CSF-filled meningeal sac only Cranial encephalocoele: contains the sac plus cerebral cortex, cerebellum or portions of the brainstem usually with abnormalities Usually occurs in the occipital region or below the inion, although in some countries, frontal or nasofrontal encephalocoeles are more prominent

Encephalocoele Dxtic: Prognosis: Plain x-ray of the skull and cervical spine Cranial utz In utero: AFP, biparietal diameter Prognosis: Encephalocoele- at risk for visual problems, microcephaly, MR, seizures Meckel-Gruber syndrome: AR condition, occipital encephalocoele, cleft lip or palate, microcephaly, microphthalmia, abnormal genitalia, polycystic kidneys, and polydactyly

Anencephaly Large defect of the calvarium, meninges, and scalp associated with a rudimentary brain which results from failure of closure of the rostral neuropore Primitive brain consists of portions of connective tissue, vessels and neuroglia The cerebral and cerebellar hemispheres are usually absent, and only a residue of the brainstem can be identified; the pituitary gland is hypoplastic, and the SC pyramidal tracts are absent

Anencephaly Associated anomalies: folding of the ears, cleft palate, congenital heart defects (10- 20%) Die within several days of birth Frequency: 1/1000 LB Recurrence risk: 4% and increases to 10% with 2 previously affected pregnancies Monitoring of succeeding pregnancies: amniocentesis, AFP levels, Utz between 14- 16th week of AOG

P.M, 22 days old CA 36-37 wks, with cleft lip and palate Holoprosencephaly, semilobar Macrogyria Absent Septum Pellucidum Dysgenesis of the Corpus Callosum

Anterior Midline Defects (Holoprosencephaly) Alobar, semilobar, lobar, middle interhemispheric fusion variant Alobar holoprosencephaly: single midline ventricular cavity, absent falx, inferior frontal and temporal regions are absent, only the primary motor and sensory cortex may be present Failure of cleavage of the hemispheres which occur at 33 days AOG Defective expression of the gene Sonic hedgehog (Shh) at 7q Associated with maternal diabetes

Holoprosencephaly Clinically, present with profound MR, Szs, rigidity, apnea and temperature imbalance; HCP can develop with aqueductal obstruction; endocrine disorders can present with hypothalamic or pituitary malformations Facial abnormalities include cyclopia, cebocephaly, and premaxillary agenesis Dxtic: facial x-ray to show deformed anterior craniobasal bones, cytogenetics, MRI. EEG, VER, ABR are generally abnormal.

Disorders of Neuronal Migration Migrating neurons attach to the radial glial fiber and reach their predetermined sites to form the six-layered cerebral cortex Small heterotopias- little or no CM Lissencephaly Schizencephaly severe MR

Lissencephaly(Agyria) Absence of the cerebral convolutions and a poorly formed sylvian fissure (3-4 month fetal brain), numerous gray heterotopia Present with failure to thrive, microcephaly, marked developmental delay, severe seizure disorder, hypoplasia of the optic nerve, microphthalmia Miller-Dieker syndrome: prominent forehead, bitemporal hollowing, anteverted nostrils, prominent upper lip, micrognathia (90% with chromosomal deletions of 17p13.3- lissencephaly I gene)

Lissencephaly

Schizencephaly Unilateral or bilateral clefts within the cerebral hemispheres due to an abnormality of morphogenesis The cleft may be fused or unfused, and is usually surrounded by abnormal brain, microgyria Present with severe MR, intractable Szs, microcephaly, spastic quadriplegia when clefts are bilateral

was noted to be microcephalic w/ sz Porencephalic Cyst Schizencephaly A.M., 2 months old was noted to be microcephalic w/ sz Porencephalic Cyst Schizencephaly Absent Septum Pellucidum Dysgenetic Corpus Callosum Aqueductal Stenosis Neuronal Migration Gestational Age in Months Postnatal 1 2 3 4 5 6 7 8 9

Porencephaly Cysts or cavities within the brain that may or may not communicate with the ventricular system, resulting from vascular or infectious results during late fetal or early infantile life Usually present with hemiparesis and focal seizures during the 1st year of life

Porencephaly

Agenesis of the Corpus Callosum Results from an insult to the commissural plate during embryogenesis When it appears as an isolated phenomenon, the patient may be normal; but those with associated migration defects (heterotopia, microgyria, pachygyria) may present with MR, microcephaly, hemiparesis, diplegia and seizures CT/MRI: widely separated frontal horns with an abnormally high position of the 3rd ventricle

Agenesis of the Corpus Callosum

Agenesis of the Corpus Callosum Aicardi Syndrome Patients are almost all females (may be lethal in males) Characterized by severe MR, intractable seizures with onset between birth and 4 mons of age, and chorioretinal lacunae. Hemivertebrae and costovertebral anomalies are common. EEG: independent activity from both hemispheres as a result of the absence of the CC

Agenesis of the Cranial Nerves II, III(Congenital ptosis), V, VIII, IX, X, XI, XII Marcus Gunn phenomenon: sucking jaw movements causing simultaneous eyelid blinking Mobius syndrome: absence of the VII nerve resulting in bilateral facial weakness, associated with abducens nerve paralysis. Result in feeding difficulties due to poor suck. Immobile or dull facies may be misinterpreted as MR.

Microcephaly HC >3 SDs below the mean for age/sex Primary (genetic) Microcephaly Secondary (non-genetic) Microcephaly Dxtic: mother’s serum phenylalanine, karyotype (abnormal facies, short stature, associated congenital abn), CT/MRI (TORCH), fasting plasma and urine amino acid analysis, serum NH4. Primary microcephaly- due to familial and AD microcephaly, chromosomal syndromes Secondary microcephaly- noxious agents

Hydrocephalus CSF production: 20 ml/hr Total CSF volume: 50 ml (infant) 150 ml (adult) Normal IV pressure: 180 mm H2O Communicating Hydrocephalus Noncommunicating or obstructive hydrocephalus

Hydrocephalus Obstructive HCP Aqueductal stenosis- x-linked recessive trait, associated with spina bifida occulta, NF Aqueductal gliosis- 20 to neonatal meningitis or SAH in PT, intrauterine viral infections, mumps meningoencephalitis Vein of Galen malformation Space occupying lesions in the posterior fossa

Aqueductal Stenosis C. V., 1 month old At 2 weeks of age was noted to have a fast enlarging head Aqueductal Stenosis Neuronal Proliferation Gestational Age in Months Postnatal 1 2 3 4 5 6 7 8 9

Vein of Galen Malformation R.C., 5 months old came in because of enlarge head size

Hydrocephalus Infant: increasing HC, open and bulging AF, dilated scalp veins, broad forehead, setting-sun eye signs, hyperreflexia, spasticity, clonus, bilateral Babinski sign Child: irritability, lethargy, poor appetite, vomiting, headache. Gradual personality change and deterioration in academic performance Serial HC monitoring, Macewen sign Papilledema

Causes of Hydrocephalus Chiari malformation Type I: medulla is displaced caudally into the spinal canal, inferior cerebellar hemispheres is herniated through the foramen magnum Type II: medulla, cerebellum and part or all of the 4th ventricle are displaced into the spinal canal, with associated obst hcp and LS spina bifida Type III: features of type I or II plus the entire cerebellum is herniated through the foramen magnum with a cervical spina bifida cystica Type IV: cerebellar hypoplasia with other malformations of the posterior fossa

Chiari Malformation Type I Type II

Hydrocephalus Cause: Dandy-Walker malformation- cystic expansion of the 4th ventricle in the posterior fossa Dxtic: Plain skull x-ray: separation of sutures, erosion of the post clinoids, beaten-silver appearance UTZ/CT/MRI DDx: thickened cranium, metabolic and degenerative disorders producing megalencephaly, gigantism, NF, familial megalencephaly Management: depends on the cause

Dandy Walker Malformation R.B, 2 months old male, noted at birth to have a big head Prosencephalic Period Gestational Age in Months Postnatal 1 2 3 4 5 6 7 8 9

Craniosynostosis Premature closure of the cranial sutures Primary craniosynostosis- closure of one or more sutures probably due to abnormal development of the base of the skull Secondary caniosynostosis- results from failure of brain growth and expansion

Craniosynostosis Scaphocephaly- premature closure of the sagittal suture producing a long and narrow skull, broad forehead, prominent occiput and absent AF Frontal plagiocephaly- premature fusion of a coronal and sphenofrontal suture resulting in unilateral flattening of the forehead, elevation of the ipsilateral orbit and eyebrow, and an ipsilateral prominent ear

Craniosynostosis Type Suture with premature closure Occipital plagiocephaly Lambdoid suture Trigonocephaly Metopic suture Turricephaly Coronal and sphenofrontal and frontoethmoidal Kleeblattschadel deformity Cloverleaf shaped skull

Craniosynostosis Crouzon syndrome: due to bilateral closure of the coronal sutures, char. by underdeveloped orbits, ocular proptosis, hypoplasia of the maxilla and orbital hypertelorism Apert syndrome: Premature fusion of multiple sutures resulting in asymmetric facies, syndactyly, progressive calcification and fusion of the bones of the hands, feet and cervical spine Carpenter syndrome Chotzen syndrome Pfeiffer syndrome

Craniosynostosis Mutations of the fibroblast growth factor receptor (FGFR) gene family Pfeiffer syndrome- FGFR1 on ch8 Apert syndrome- FGFR2 gene Identical mutations of FGFR2 gene may result in both Pfeiffer and Crouzon phenotype Involvement of one suture rarely causes neuro deficit. Surg is indicated for cosmetic purposes. Craniectomy is mandatory for mgt of increased ICP

All of the following statements about spina bifida cystica are true except: A. it is often associated with HCP B. it is fatal if not treated within 24 hrs. C. It may be diagnosed in utero with UTZ D. It can cause urologic problems E. It requires orthopedic management

NEUROMUSCULAR DISORDERS

Neuromuscular Disorders Disorder of the motor unit Motor neuron in the brainstem or ventral horn of the spinal cord Axon -- peripheral nerve Neuromuscular junction All muscle fibers innervated by a single motor neuron

Work-up of the child with a suspected muscular dystrophy or myopathy A. MRI B. ECG C. Nerve conduction velocity or NCV study D. Sural nerve biopsy

Distinguishing Features of Disorders of the Motor System LOCUS OF LESSON FACE ARMS LEGS PROXIMAL-DISTAL DEEP TENDON REFLEXES ELECTRO-MYOGRAPHY MUSCLE BIOPSY OTHER CENTRAL + > OR = NORMAL OR UP NORMAL SEIZURES, HEMIPARESIS, AND DELAYED DEVELOPMENT ANTERIOR HORN CELL LATE ++++ FASCICULATIONS AND FIBRILLATIONS DENERVATION PATTERN FASICULATIONS (TONGUE) PERIPHERAL NERVE +++ < DOWN FIBRILLATIONS SENSORY DEFICIT, ELEVATED CEREBROSAL FLUID PROTEIN, DEPRESSED NERVE CONDUCTION VELOCITY, ABNORMAL NERVE BIOPSY NEURO- MUSCULAR JUNCTION = DECREMENTAL RESPONSE (MYATHENIA); INCREMENTAL RESPONSE AND BSAP (BOTULISM) RESPONSE TO NEOSTIGMINE OR ENDOPHONIUM (MYASTHERIA); CONSTIPATION AND FIXED PUPILS (BOTULISM) MUSCLE VARIABLE ( + TO ++++) ++ > SHORT DURATION,SMALL AMPLITUDE MOTOR UNIT POTENTIALS AND MYOPATHIC POLYPHASIC POTENTIALS MYOPATHIC PATTERN ELEVATED MUSCLE ENZYME LEVELS (VARIABLE)

DEVELOPMENTAL DISORDERS OF MUSCLE Myotubular Myopathy Congenital Muscle Fiber–Type Disproportion (CMFTD) Nemaline Rod Myopathy Central Core Disease and Minicore Myopathy

Muscular Dystrophies Primary Myopathy Genetic Basis Progressive Cause Degeneration and death of muscle fibers

Duchenne and Becker Muscular Dystrophies Most common hereditary neuromuscular disease Progressive weakness, hypertrophy of calves, intellectual impairment, proliferation of connective tissue in muscle Incidence 1 : 3,600 X-linked recessive M trait Xp21 gene locus

Duchene Muscular Dystrophy Clinical Features Progressive hip girdle weakness Gowers sign Hip waddle Progressive weakness from early childhood Pseudohypertrophy of calves and wasting of thigh muscles Distal muscle function preserved Intact extraocular muscle,anal and urethral sphincter Intellectual impairment

Duchenne Muscular Dystrophy LABORATORY FINDINGS: Electromyography – Myopathic features (no denervation) Cardiac Evaluation – ECG, Echocardiography Blood PCR Muscle Biopsy – diagnostic (Endomysial connective tissue proliferation, scattered degenerating and regenerating microfibers) Most myofibers express no dystrophin.

Duchenne Muscular Dystrophy TREATMENT: No medical cure or way of slowing it’s progression Improve quality of life > good nutritional state > treat pulmonary infections > cardiac decompensation > physiotherapy – may delay contractions > steriods – may decrease rate of apoptosin

Disorders Of Neuromuscular Transmission and Of Motor Neurons Myasthenia Gravis

2004 international Classification of Headache Disorders MIGRAINE Migraine without aura Migraine with aura Typical aura with migraine headache Typical migraine with nonmigraine headache Typical aura without headache Familial hemiplegic migraine Sporadic hemiplegic migraine Basiliar-type migraine Childhood periodic symptoms that are commonly precursors of migraine Cyclic vomiting Abdominal migraine Benign paroxysmal vertigo of childhood Retinal migraine Complications of migraine Chronic migraine Status migraine Persistent aura without infarction Migrainous infarction Probable migraine

Indications for Neuroimaging in a child with headaches Abnormal neurologic signs Recent school failure, behavioral change, fall-off linear growth rate Headache awareness child during sleep, early morning headache, with increase in frequency and severity Periodic headaches and seizures coincide, especially if seizure has a focal onset Migraine and seizure occur in the same episode, and vascular symptoms precede the seizure (20-50 % of tumor or arteriovenous malformation) Cluster headaches in child; any child < 5-6 yr whose principal complaint is a headache Focal neurologic symptoms or signs developing during a headache (i.e. complicated migraine) Focal neurologic symptoms or signs (except classic visual symptoms of migraine) develop during the aura, with fixed laterality; focal signs of the aura persisting or recurring in the headache phase. Visual graying-out occuring at the peak of a headache instead of the aura Brief cough headache in a child or adolescent

Paroxysmal Disorders of the Neonatal Period PAROXYSMAL NONEPILEPTIFORM DISORDERS Jitterness Benign neonatal sleep myoclonus ACUTE SYMPTOMATIC SEIZURES AND OCCASIONAL SEIZURES Hypoxic-Ischemic encephalopathy Intraventricular hemorrhage Acute metabolic disorders Sepsis-meningitis

Paroxysmal Disorders of the Neonatal Period EPILEPTIC SYNDROMES Benign idiopathic neonatal convulsions Familial Symptomatic focal epilepsy Brain tumor Malformations of cortical development Inherited metabolic disease; mitochondrial disorders Early-onset generalized epileptic syndromes with encephalopathy Early myoclonic encephalopathy Early infantile encephalopathic epilepsy

Nonepileptic Paroxysmal Disorders NEONATE Jitteriness Benign neonatal sleep myoclonus INFANT Infantile syncope Cyanotic breath-holding spells Pallid syncope Sleep disorders head banging

Nonepileptic Paroxysmal Disorders CHILDREN Breath-holding spells Migraine and migraine equivalents,recurrent abdominal pain, cyclic vomitting Tic Witholding, constipation Daydreaming, staring spells Sleep Disorders Head banging Somnambulism

Nonepileptic Paroxysmal Disorders ADOLESECENTS Syncope Migraine Daydreaming Sleep disorders Nocturnal myoclonus, hypnic jerks Narcolepsy Somnambulism