Cerebral Dysgenesis

Jeffrey Bolton

Jurriaan M. Peters

Annapurna Poduri

DISORDERS OF NEURULATION

OVERVIEW: Failure of the embryonic neural tube to close during fetal development results in the group of disorders classified as neural tube defects. The specific disorder largely depends on the site at which fusion is disrupted. Rostral defects cause anencephaly or encephalocele, and caudal defects lead to spina bifida and similar conditions.

Anencephaly

DEFINITION: Congenital absence of both cerebral hemispheres with accompanying cranial vault defect. A soft, angiomatous mass of neural tissue is covered by skin with no overlying skull. The forebrain and upper brainstem are present.

PATHOPHYSIOLOGY: Failure of closure of the rostral neural tube occurs between days 21 to 26 of gestation. Exact mechanism is unclear, but may be associated with low maternal folate levels. Other associations include maternal hyperthermia, infection, low socioeconomic status, chromosomal abnormalities, and extremes of maternal age.

DIAGNOSIS: Prenatal ultrasound, prenatal MRI, increased alpha-fetoprotein (AFP).

MANAGEMENT: Prenatal folate supplementation may decrease incidence in at-risk populations. Spontaneous abortions or stillbirths are common (75%). If delivered, will die shortly after birth.

Encephalocele

DEFINITION: Herniation of intracranial contents through a midline skull defect. Three subsets based on location: sincipital (orbit, nose, or forehead), basal, or occipital (most common form). There is accompanying hydrocephalus in about 50% of cases and strong association with agenesis of the corpus callosum.

PATHOPHYSIOLOGY: Largely unknown and likely multifactorial. Hyperthermia around days 20 to 28 has been implicated. Rare associations with known genetic syndromes, such as Meckel syndrome and Walker-Warburg syndrome.

DIAGNOSIS: Prenatal ultrasound, fetal MRI, increased AFP.

TREATMENT/OUTCOME: Surgical intervention to repair the deficit in the neonatal period. Endocrinologic evaluation for those with the basal form. Hydrocephalus, if present, may also require surgical intervention. Majority of children have some degree of neurologic deficit, many quite severe. Frontal form tends to have better neurologic outcome than occipital form. Outcome is also dependent on any genetic association.

Myelomeningocele (MMC)

DEFINITION: Incidence ˜0.5 to 2.5 per 1,000 live births. Spinal neural tube defect with cleft in the vertebral column, exposing spinal cord and meninges; may be covered by thin membrane. Up to 80% have lumbosacral involvement. Majority are associated with hydrocephalus, particularly with thoracolumbar location.

PATHOPHYSIOLOGY: Similar to encephalocele, though with defect occurring in the caudal neural tube closure. Low maternal folate levels are implicated as one etiology. Other factors include chromosomal abnormalities, teratogens (valproic acid, thalidomide), and maternal hyperthermia and obesity.

DIAGNOSIS: Prenatal ultrasound, fetal MRI, elevated levels of alpha-fetoprotein. Prevention with prenatal folate supplementation.

MANAGEMENT: Great advances in fetal surgery have led to push for prenatal surgical repairs, with good outcomes. Delivery should be via planned C-section with close attention to infection prevention, followed by early postnatal closure. Children should be closely followed for hydrocephalus, and require long-term multidisciplinary follow-up by neurology, neurosurgery, renal, and orthopedics. Many patients will have impaired gait and bowel/bladder function. Most have normal cognition.

Occult Dysraphic States

DEFINITION: Subtle anomalies of caudal neural tube formation accompanied by overt dermal and vertebral abnormalities, due to nondysjunction of overlying ectoderm from the neural tube. Neural injury results from both tethering, i.e., traction injury to the cord from differential growth of vertebrae and spinal cord, as well as fixation, leading to limitation of the lower spinal cord mobility and injury upon flexion and extension of the trunk. See Table 11.1 for more details.

DISORDERS OF PROSENCEPHALIC DEVELOPMENT

OVERVIEW: After caudal neural tube closure, a single prosencephalic vesicle is formed. This is the precursor of the cerebral hemispheres and deep nuclei. Various errors may occur between weeks 4 to 20 of gestation in the development of the prosencephalon. This includes defects in formation of the prosencephalon (wk 4-5), prosencephalic cleavage (wk 5-6), and midline prosencephalic development (wk 7-12, corpus callosum wk 9-20). These disorders are often accompanied by significant facial/midline abnormalities. (See Table 11.2.)

Holoprosencephaly (HPE)

DEFINITION: Incidence ˜1:10,000 live births. Characterized by failure of prosencephalic cleavage. Divided into 3 subtypes. Alobar HPE is characterized by a single spheroid cerebral structure with common ventricle, fused basal ganglia and thalamus, membranous roof of the 3rd ventricle with posterior cystic extension, agensis corpus callosum (ACC), absent olfactory system, and a hypoplastic or single optic nerve. Limbic characteristics of cortical architecture and absent supralimbic cortex. Often associated with neuronal migration disorder. Semilobar HPE is characterized by anterior fusion with some cleavage present posteriorly, less fusion of the deep nuclei, and ACC. Lobar HPE is the mildest form and is characterized by near or total separation of cerebral hemisphere with fusion of only the most rostral
and ventral aspects. The majority of the corpus callosum is formed, except for the genu.

TABLE 11.1 Disorders of Neurulation

D/o, Mechanism, Timing

Anatomy/Pathology

RF, Genetics, Associations

Management/Outcome

Cranioraschisis totalis

Total failure of neurulation ˜D20-22

Anencephaly plus myeloschisis

Possible link to planar cell polarity pathway¹

Dx: routine US Miscarriage, death in utero

Anencephaly

Failure of anterior NT closure, ˜D24

Soft angiomatous mass of neural tissue covered by skin with no overlying skull

Forebrain and upper brainstem present

Positive family history, ↓ SES, Caucasian, female, young/old maternal age

Dx: routine US 2nd trimester, increased AFP levels

75% die in utero, 25% in neonatal period Prevention with folic acid prior to conception

Myeloschisis

Failure of posterior NT closure, ˜D24

Neural plate-like spinal cord with flat, velvety structure and no vertebral or dermal covering

Overlap with more restricted NT defects, e.g., myelomeningocele

Dx: routine US 2nd trimester, increased AFP

Most are stillborn

Encephalocele Restricted disorder of neurulation involving anterior NT closure, ˜D26

Later closure defects have no neural elements involved, termed meningocele

Typically protruding occipital mass with cortex and white matter 3 types Sincipital (frontoethmoidal)

Basal Occipital ± hydrocephalus 50% Chiari III: low occipital-type encephalocele with Chiari II (see below), cerebellar abnormalities, ± agenesis corpus callosum (2/3), abnormal venous drainage (1/2)

AR inheritance, maternal hyperthermia D20-28

Subependymal nodular heterotopia Meckel syndrome: encephalocele, microcephaly, microphthalmia, cleft lip/ palate, Polydactyly, polycystic kidneys, ambiguous genitalia

Walker-Warburg syndrome (see below)

Dx: routine US 2nd trimester

Surgical interventions when appropriate, variable neurological outcome

Sincipital form has better outcomes

MMC

Restricted disorder of neurulation involving posterior NT closure, ˜ D26 (0.5-2.5 per 1,000 live births)

Chiari II Malformation

Dorsally displaced neural plate or neural tube-like structure, resulting in sac on the back

Defects in axial skeleton, dermal covering

80% lumbar involvement (lumbar, thoracolumbar, or lumbosacral) Hydrocephalus 85%-90% with lumbar involvement, less with others. Etiology Chiari II (blocked 4th V. or flow through posterior fossa) > aqueductal stenosis

Chiari II: (1) inferior displacement medulla and 4th V. into upper cervical canal, (2) herniation cerebellum through foramen magnum, (3) elongation, embryonic angulation, and thinning upper medullar, lower pons, (4) variable defects foramen magnum, occiput, upper cervical vertebrae, (5) MMC

Chiari II is associated with cortical dysgenesis in 92% (40% polymicrogyria, 44% neuronal heterotopia, 8% other)

Genetics & environmental etiology: see anencephaly, plus maternal DM, obesity, hyperthermia, low B₁₂, folate

Other causes: (1) multifactorial inheritance, (2) single mutant genes (e.g., Meckel syndrome autosomal recessive), (3) chromosomal abnormal incl. trisomies and duplications, (4) specific rare syndromes of uncertain mode of transmission, (5) teratogens (e.g., valproate, carbamazepine, thalidomide), (6) specific phenotypes of uncertain etiology (e.g., cloacal exstrophy and myelocystocele)

Deficits in motor, sensory, sphincter function, reflexes ˜segmental innervations

Hydrocephalus

Brainstem dysfunction: stridor, central, or obstructive apnea, cyanotic spells, reflux, aspiration, feeding difficulties

Cognitive impairment, seizures 20%—25%

Scoliosis Urologic complications (retention, incontinence, recurrent UTI)

Dx: routine US, increased AFP levels

Prevention with folic acid prior to conception

Intrauterine surgical repair more common, good results

Delivery by C-section

Early postnatal closure and broad-spectrum antibiotics <24-72 h (infection, outcome—both controversial)

Hydrocephalus (late, insidious), common at 2-3 wk, 80% at 6 wk; should be followed by serial US

Early ventriculoperitoneal shunting

Brainstem dysfunction: supportive care

Orthopedic and urological complications: specialty care

Occult dyspraphic states Subtle anomalies of caudal NT formation accompanied by overt dermal and vertebral abnormalities, due to nondysjunction of overlying ectoderm from NT

Myelocystocele—cystic dilation of central canal of caudal neural tube. Association with cloacal exstrophy, omphalocele, imperforate anus, severe vertebral defects, and others

Diastematomyelia, diplomyelia— bifurcation of the spinal cord

Meningocele-lipomeningocele— rare as an isolated lesion, not a disorder of neurulation. Association with fibrofatty tissue contiguous with subcutaneous lipoma

Lipoma, teratoma, others—tumors originating from germinative caudal tissue

Dermal sinus ± (epi)dermoid cyst—lumbosacral cutaneous dimple with sinus tract ± cyst, can infect, tether, or compress

Tethered cord (isolated)—prolonged conus, fatty fibrous filum and fibrous bands fixing caudal cord

Vertebral defects >85% (laminae, sacrum, widened spinal canal)

Dermal findings 80% (hair tufts, subcutaneous mass, cutaneous dimples or tracts, superficial cutaneous hemangioma, skin tag, pigmented macule)

Later: gait problems, abnormal sphincter function, pes cavus or equinovarus, pain, motor and sensory deficits, scoliosis, recurrent meningitis (rare)

Spinal X-ray insensitive

US sufficient if no neurological abnormalities

If clinically suspect or equivocal US, perform MRI (superior)

Early microsurgical repair with electrophysiologic intra-op monitoring of cord function to prevent neurological symptoms

Sudden deterioration: consider vascular compromise

ACC, agenesis of corpus callosum; AFP, alpha-fetoprotein; D, day of gestation; MMC, meningomyelocele; MRI, magnetic resonance imaging; NT, neural tube; US, ultrasound; UTI, urinary tract infection.

TABLE 11.2 Disorders of Prosencephalic Development

Mechanism, Timing	Anatomy	Etiology and Associations	Management
Aprosencephaly and atelencepaly Total failure of prosencephalic formation, absence of diencephalon and telencephalon, wk 4-5	Small cranium with minimal volume above supraorbital ridge, but with intact skull and dermal coverings Facial anomalies, including cyclopia or absence of eyes Anomalies of limbs and genitalia	Unknown. May be postneurulation encephaloclastic event	Lethal, rarely make it to neonatal stage
HPE and holotelencephaly Failure of prosencephalic cleavage with marked abnormalities of (diencephalon and) telencephalon, wk 5-6 Etiologies: Chromosomal anomalies 60% (chr 13 > 18 > 2,3,7,21) Monogenic syndromes 25% (Smith-Lemli-Opitz, pseudotrisomy 13, Pallister—Hall, Meckel, velocardiofacial) Monogenic nonsyndromic 15%-20% (SHH, PTCH, GLI2, TGIF, TDGF, FAST1, Z1C2) Teratogenic: maternal diabetes, others disputed Sporadic	Alobar: single spheroid cerebral structure with common ventricle, fused basal ganglia and thalamus, membranous roof 3rd ventricle with posterior cystic extension, absence CC, absence olfactory system, hypoplastic or single optic nerve. Limbic characteristics of cortical architecture and absence of supralimbic cortex. Often also neuronal migration d/o. Semilobar: anterior fusion, presence of some cleavage posterior, less fused deep nuclei, absent anterior CC Lobar: Near or total separation of cerebral hemispheres and deep nuclei, small anterior CC Syntelencephaly: Fusion of onormaly posterior frontal and parietal cerebrum, abnormal body CC	Alobar: thalamic fusion with aqueductal stenosis leads to hydrocephalus, large dorsal 3rd ventricular cyst Semilobar and lobar: microcephaly Facial anomalies: absent, rudimentary, or malformed nose, absent, single, or hypoteloric eye(s), cleft lip/palate with absent philtrum. Severe facial abnormality indicates severe HPE, while severe HPE can have normal face Other anomalies: cardiac, skeletal, GU, GI Neurological: wide range of cognitive deficits, motor abnormalities incl dystonia, hypothalamic endocrinopathies, seizures, neonatal apnea, and stimulus-sensitive tonic spasms Mild cases are detected later Etiologies: see left panel. Detailed examination of parents and relatives for detection of hypotelorism, coloboma, single incisor, microcephaly, mild cognitive deficits; may indicate autosom dominance	Neurological management of seizures, motor abnormalities, development not specific Multiple systems affected (neurological, cardiac, skeletal, GU, GI, endocrine) requires coordinated effort of clinical care
ACC,wk 9-20 ASP, wk 20 SOD SOHD Disorders of midline prosencephalic development with failure of development of commissural, chiasmatic and hypothalamic plates	ACC: everted cingulate gyri, crescentric lateral ventricles lined by uncrossed Probst bundles. Partial ACC is typically posterior (except in HPE, see above). On imaging superiorly displaced 3rd V., colpocephaly, longitudinal Probst bundles, radial orientation of gyri (“sunburst”) ASP: virtually never isolated. HPE, ACC, SOD, hydrocephalus, Chiari II, porencephaly/hydranencephaly from encephaloclastic event in utero, schizencephaly (see panel on right), basilar encephalocele SOD/SOHD: often associated with hypothalamic-pituitaryendocrinopathies	ACC: assoc with Chiari II, vermian hypoplasia, encephalocele, d/o of neuronal migration 25%—45% Aicardi syndrome (female with ACC, periventricular nodular heterotopia, polymicrogyria, and chorioretinal lacunae): infantile spasms, other seizures, mental retardation, X-linked ASP: syndrome of ASP with schizencephaly: uni > bilat cerebral cleft or narrowing at level of primary fissures, heterotopias, gyral abnormal’s (hemi- or quadriparetic, seizures, mental retardation) Cavum septum pellucidum ± mild cognitive deficits (doubtful, usually coincidental finding) SOD/SOHD: hypothalamic-pituitary endocrinopathies 72% (multiple, DI, hypogonadism, neonatal hypoglycemia). Seizures, cognitive deficits ± neuronal migration d/o	As a rule: neuronal migration occurs concurrently and d/o should be suspected MRI better than US and CT Neurological management of seizures, motor abnormalities, development not specific Multiple systems affected (neurological, cardiac, skeletal, GI, endocrine, GU) requires coordinated effort of clinical care
ACC, agenesis corpus callosum; ASP, agenesis of septum pellucidum; CC, corpus callosum; CT, computed tomograph; DI, diabetes insipidus; d/o, disorder; GI, gastrointestinal; GU, genitourinary; HPE, holoprosencephaly; MRI, magnetic resonance imaging; SO(H)D, septo-optic (hypothalamic) dysplasia; US, ultrasound; wk, week of gestation.

PATHOPHYSIOLOGY: Over 60% of HPE cases are due to underlying chromosomal/genetic causes. Maternal factors also play a role, including alcohol, retinoic acid exposure, and maternal diabetes. Common chromosomal abnormalities include trisomy 13 and 18. Monogenic syndromes such as Smith-Lemli-Opitz and Pallister-Hall syndrome and nonsyndromic monogenic mutations in SHH (7q36), PTCH (9q22), and TGIF(18p11) genes have been implicated.

DIAGNOSIS: Prenatal ultrasound may detect alobar HPE, but is not sensitive for the more mild forms. Fetal MRI can better characterize the malformation if ultrasound is suggestive. Prenatal genetic testing is available for families with prior children with HPE. After birth, mild cases may be diagnosed with MRI after clinical concerns arise.

MANAGEMENT: Large majority have severe neurologic impairment as well as epilepsy. There may be endocrinologic abnormalities which need to be closely monitored. Due to the medical complexity of these patients, a multidisciplinary approach is suggested. Many will require long-term support such as gastrostomy tubes and in-home nursing care.

Agenesis of the Corpus Callosum (ACC)

DEFINITION: Corpus callosum fails to develop. May range from complete to partial agenesis. Partial agenesis may refer to either thinning of the full structure or segmental loss. Often associated with Chiari II malformation, but seen in wide array of genetic and metabolic syndromes.

PATHOPHYSIOLOGY: Thought to be due to disruption in prosencephalic segmentation around week 10 to 20 gestation.

DIAGNOSIS: Prenatal US (should be visualized by 20 wk), fetal MRI; if partial, may be diagnosed later in life via MRI.

MANAGEMENT: Isolated ACC

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