Congenital Anomalies of the Central Nervous System

Congenital Anomalies of the Central Nervous

System

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Gestational Age in MonthsPostnatal

Neurulation(3 – 4 wks)

Prosencephalic(2 – 3 mos)

NeuronalProliferation(3 – 4 mos)

NeuronalMigration(3 – 5 mos)

Organization(5 – postnatal years)

Myelination(Birth – Postnatal yrs)

Major Events in Human Brain Developmentand Peak Times of Occurrence (Menkes)

Neural tubeBrain &Spinal cordNeural crestPNS &leptomeninges

Paired cerebralHemispheres,LV, BG,Thalami, OpticNerves/chiasmCC, SP

Full comple-Ment of neu-rons in cerebralhemispheres Formation from

4 layered embryoniccortex 6 layeredadult cortex

Synaptogenesis programmedCell death

Formation of myelin electrical conduction

Transverse sections ofembryos at Different ages to show theDev’t ofthe spinal cord

Early development of the human nervous system

late presomite andearly neural plate stage

early somite and neuralgroove stage

eight-somite andearly neural tubestage

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Neurulation(3 – 4 wks)

Prosencephalic(2 – 3 mos)

NeuronalProliferation(3 – 4 mos)

NeuronalMigration

(3 – 5 mos)

Organization(5 – postnatal years)

Myelination(Birth – Postnatal yrs)

Congenital Anomalies in the different stages Of CNS development

EncephalocoeleMyelomenin-gocoele

Holoprosence-phalyDandy walker Aqueductal

StenosisHydroceph

SchizencephalyColpocephalyLissencephalyAgenesis of corpus callosum

Perinatal InsultsICH/ HIETumorsCNS Infections

Perinatal InsultsICHTumorsCNS Infections

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:RadiationDrugsMalnutrition ChemicalsGenetic 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 DefectsDiagnostic 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 OccultaMidline 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 OccultaSpine 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

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Neurulation Period

S. N., 2 mos old, female

Marked obstructive Hydrocephalussecondary to ARNOLD CHIARI II

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

MeningocoeleDxtic: 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.

MeningocoeleAnterior 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

MyelomeningocoeleMost 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

MyelomeningocoeleMay 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

MyelomeningocoeleRequires 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)

MyelomeningocoelePrognosis:

MR- 10-15% Most deaths occur before age 4 years70% have normal intelligence, but learning

problems and seizure disorders are commonHistory of meningitis or ventriculitis adversely

affect the ultimate IQ

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Neurulation Period

11 mos old, male

EncephalocoeleCranium 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

EncephalocoeleDxtic:

Plain x-ray of the skull and cervical spineCranial utzIn utero: AFP, biparietal diameter

Prognosis:Encephalocoele- at risk for visual problems,

microcephaly, MR, seizuresMeckel-Gruber syndrome: AR condition,

occipital encephalocoele, cleft lip or palate, microcephaly, microphthalmia, abnormal genitalia, polycystic kidneys, and polydactyly

AnencephalyLarge 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

AnencephalyAssociated 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 palateHoloprosencephaly, semilobarMacrogyriaAbsent Septum PellucidumDysgenesis 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

HoloprosencephalyClinically, 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

SchizencephalyUnilateral 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

A.M., 2 months oldwas noted to be microcephalic w/ sz

Porencephalic CystSchizencephalyAbsent Septum PellucidumDysgenetic Corpus CallosumAqueductal Stenosis

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Neuronal Migration

PorencephalyCysts 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


Aicardi SyndromePatients 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.

MicrocephalyHC >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.

HydrocephalusCSF production: 20 ml/hr

Total CSF volume: 50 ml (infant)

150 ml (adult)

Normal IV pressure: 180 mm H2O

Communicating HydrocephalusNoncommunicating or obstructive hydrocephalus

HydrocephalusObstructive 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 malformationSpace occupying lesions in the posterior fossa

C. V., 1 month oldAt 2 weeks of age wasnoted to have a fastenlarging head

Aqueductal Stenosis

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Neuronal Proliferation

R.C., 5 months oldcame in because ofenlarge head size

Vein of Galen Malformation

HydrocephalusInfant: 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 HydrocephalusChiari 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

HydrocephalusCause: 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 appearanceUTZ/CT/MRI

DDx: thickened cranium, metabolic and degenerative disorders producing megalencephaly, gigantism, NF, familial megalencephaly

Management: depends on the cause

Dandy WalkerMalformation

R.B, 2 months oldmale, noted at birthto have a big head

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Prosencephalic Period

CraniosynostosisPremature 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

CraniosynostosisScaphocephaly- 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

CraniosynostosisType Suture with premature

closure

Occipital plagiocephaly Lambdoid suture

Trigonocephaly Metopic suture

Turricephaly Coronal and sphenofrontal and frontoethmoidal

Kleeblattschadel deformity

Cloverleaf shaped skull

CraniosynostosisCrouzon 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

CraniosynostosisMutations of the fibroblast growth factor

receptor (FGFR) gene familyPfeiffer syndrome- FGFR1 on ch8Apert syndrome- FGFR2 geneIdentical 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 DisordersDisorder 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 LOCUS OF LESSONLESSON

FACEFACE ARMS ARMS LEGSLEGS PROXIMALPROXIMAL-DISTAL-DISTAL

DEEP DEEP TENDON TENDON

REFLEXESREFLEXES

ELECTRO-ELECTRO-MYOGRAPHYMYOGRAPHY

MUSCLE BIOPSYMUSCLE BIOPSY OTHEROTHER

CENTRALCENTRAL 0 0 ++ ++ > OR => OR = NORMAL NORMAL OR UPOR UP

NORMALNORMAL NORMALNORMAL SEIZURES, SEIZURES, HEMIPARESIS, AND HEMIPARESIS, AND DELAYED DELAYED DEVELOPMENTDEVELOPMENT

ANTERIOR ANTERIOR HORN CELL HORN CELL

LATELATE ++++++++ ++++++++ > OR => OR = 00 FASCICULATIONS FASCICULATIONS AND FIBRILLATIONSAND FIBRILLATIONS

DENERVATION DENERVATION PATTERNPATTERN

FASICULATIONS FASICULATIONS (TONGUE)(TONGUE)

PERIPHERAL PERIPHERAL NERVENERVE

00 ++++++ ++++++ << DOWNDOWN FIBRILLATIONS FIBRILLATIONS DENERVATION DENERVATION PATTERNPATTERN

SENSORY DEFICIT, SENSORY DEFICIT, ELEVATED ELEVATED CEREBROSAL FLUID CEREBROSAL FLUID PROTEIN, DEPRESSED PROTEIN, DEPRESSED NERVE CONDUCTION NERVE CONDUCTION VELOCITY, ABNORMAL VELOCITY, ABNORMAL NERVE BIOPSYNERVE BIOPSY

NEURO-NEURO-

MUSCULAR MUSCULAR JUNCTIONJUNCTION

++++++ ++++++ ++++++ == NORMALNORMAL DECREMENTAL DECREMENTAL RESPONSE RESPONSE (MYATHENIA); (MYATHENIA); INCREMENTAL INCREMENTAL RESPONSE AND RESPONSE AND BSAP (BOTULISM)BSAP (BOTULISM)

NORMALNORMAL RESPONSE TO RESPONSE TO NEOSTIGMINE OR NEOSTIGMINE OR ENDOPHONIUM ENDOPHONIUM (MYASTHERIA); (MYASTHERIA); CONSTIPATION AND CONSTIPATION AND FIXED PUPILS FIXED PUPILS (BOTULISM)(BOTULISM)

MUSCLEMUSCLE VARIABLEVARIABLE

( + TO +++( + TO ++++)+)

++++ ++ >> DOWNDOWN SHORT SHORT DURATION,SMALL DURATION,SMALL AMPLITUDE MOTOR AMPLITUDE MOTOR UNIT POTENTIALS UNIT POTENTIALS AND MYOPATHIC AND MYOPATHIC POLYPHASIC POLYPHASIC POTENTIALS POTENTIALS

MYOPATHIC MYOPATHIC PATTERNPATTERN

ELEVATED MUSCLE ELEVATED MUSCLE ENZYME LEVELS ENZYME LEVELS (VARIABLE)(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


CHILDREN

Breath-holding spells

Migraine and migraine equivalents,recurrent abdominal pain, cyclic vomitting

Tic

Witholding, constipation

Daydreaming, staring spells

Sleep Disorders Head bangingSomnambulism


ADOLESECENTS

Syncope

Migraine

Daydreaming

Sleep disordersNocturnal myoclonus, hypnic jerks NarcolepsySomnambulism

Congenital Anomalies of the Central Nervous System

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