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New Treatments for Developmental Neurology

The nervous system is derived wholly from the ectoderm. The dorsal ectoderm thickens around the third week to form the neural plate, and then it rapidly folds itself to form the neural groove and then the neural tube. Prior to this folding, the neural crest cells leave the folds and then gets transferred over to the rest of the area, such as the adrenal medulla. Cranially the neural tube gives rise to the brain and caudally to the spinal cord.

Neural tube formation. On day zero to 18 the three germ layer is formed, then the early neuro plate formation and by day 18 the plate and groove development, and by 23 the neural tube is completely formed. By day 24 the optic vesicles appear and you have brain segmentation. The two things that are important to know is in day 24-26 when the closure of the anterior neuropore and on day 26 or 28 when the posterior neuropore closes.

Major congenital anomalies. The majority of them is unknown etiology. The rest, about 25%, is multifactorial inheritance. Very few actually from chromosomal abnormalities. The brain is affected 10 for every 1,000. Obviously the total brings it up to about 30% but among all of this the brain is much more commonly affected in terms of its malformation.

Anencephaly occurs in about 0.5% to 2.00% of live infants and they account for about 30% of all major abnormal live births. It is increased in diabetic pregnancies. Females are predominantly affected. They are either stillborn or live only a few days. They can be maintained on a respirator because they’ve got the intact brainstem. The etiology is really unknown and they occur in increased frequency in the same family.

Encephaloceles. The incidence is about 0.8 to 3.00% per 10,000. They are ten times less common than meningomyeloceles and they account for 0.07% of all pediatric admissions, and 10% of all cranial spinal malformation. Occipital encephaloceles are much more common in women, but parietal ones are much more common in males. It is the occipital and parietal encephaloceles that are related to neural tube defect.

Holoprosencephaly is a single ventricular system and it is frequently associated with cyclopia. The incidence rate is about 0.4, one in 14,000. They have is a trigonocephalic-type of head with premature closure of the metopic sutures. It is associated with other organ involvement in about 75% of the cases. Usually seen in association with chromosomal abnormalities, especially 13 and 18. Fifty percent are not associated however with chromosomal defects.

Myelodysplasias. There are certain socioeconomic factors that play a role in this disorder. Usually those with low socioeconomic status, females are affected more, spina bifida is much more common, as opposed to anencephaly. The high risks are those in the Irish group. The low risks are in the African-American, Oriental or Ashkenazi Jews, and maternal.

Associated with spina bifida, or other myelodysplasia are other CNS abnormalities. The more common one is Arnold-Chiari malformation, and that’s when you have the type II malformation. You can also have gyral abnormalities of schizencephaly.

Spina bifida occulta does not show any overt sign of skin problems or anything, but is mainly noted in the vertebral column. And it’s found in 10% of all children and is usually an incidental finding when you perform an x-ray. You do not have any herniation of the meninges.

Some course of action that really needs to be done:  The sac should be closed immediately. When children are born with the sac out, and in a hospital that doesn’t have a neurosurgeon and who is not capable of doing surgery, they are transferred right away to get this done. Observe the head size. Once the defect is closed, watch for hydrocephalus because 90% of them will develop hydrocephalus in the next 24-48 hours. Assess the urological status as well. Take good care of the skin, especially after closure in the first week of life, and obviously counseling.

The Miller-Dicker syndrome is a genetic disorder and is noted in chromosome 17. It is basically a lissencephaly type of picture where you have agyria. It’s a deletion or translocation of chromosome 17 and the genus is called LIS-1. Typically the pregnancy is complicated by polyhydramnios. There is decreased fetal movement and poor respiratory drive at birth. The child itself will have severe hypotonia, microcephaly, poor feeding and infantile spasms.

Septo-optic dysplasia, also known as de Morsier’s syndrome. The septum pellucidum is not formed. The columns of the fornix are displaced laterally. The pituitary gland may be hypoplastic or absent, and some of them will have growth hormone deficiencies. they also thyroid function dysfunction and their endocrine status needs to be checked.

Pachygyria is a thick and more completely developed gyri, but it is just thick and usually there is relative sparing of the temporal lobe. The temporal lobes tend not to be affected. It’s much more common typically in the parietal occipital region.

Polymicrogyria is the occurrence of abnormal indentations along the brain surface. The histology on sectioning is abnormal. They can be seen in only one side of the hemisphere but can be on both. There are a decreased number of gyri; however, they are broad.

Gray matter atretopsias is gray matter displaced in areas where it shouldn’t be and  most commonly has a small nest of cells adjacent to the lateral ventricle. Clinically they present with seizures. MRI tends to be iso-intensive to the gray matter.

Dandy-Walker malformation is dysgenesis or agenesis of the vermis and a cystic dilatation of the fourth ventricle. They are commonly associated with hypoplasia of the cerebellum as well, and scalloping of the inner tabia of the occipital bone occurs.

Some of the conditions that can cause agenesis of the cerebellar vermis include, again, Dandy-Walker syndrome, Joubert’s syndrome is something you need to know because these patients basically have atrophy of the cerebellum and they present more or less with ataxia and developmental delay and mild mental retardation. Joubert. And they may also present with respiratory difficulties as well. Dandy-Walker, Warburg’s syndrome, this is a type II lissencephaly again. They are associated with retinal dysplasias and other ocular findings as well. Acardia syndrome is another thing. Goldenhar’s syndrome as well. Goldenhar’s syndrome is

Some teratogens that can cause fetal problems and developmental anomalies are obviously your antiepileptic medications. Vitamin A can cause hydrocephalus or ear and heart abnormalities. A retinoic acid can cause CNS migrational disorder. Obviously this is something that is being used a lot for acne. Your benzodiazepine is fully defined but there are some vague abnormalities

Craniosynostosis. You have proptosis. These are the kids with the proptotic eye. Apert’s syndrome is when you have fused digits. So usually they have the first four digits fused. Sort of like the mitten-glove type of hand is what they have. Pfeiffer’s syndrome is associated with

Developmental reflexes are when certain things occur and when certain things disappear. The adductive spread of the knee jerk. Obviously in an adult we consider that, the cross-adductive reflex, as being abnormal. But it’s normal until eight months of age. The Landau reflex begins at

EEG is useful in helping to determine gestational age. There are specific patterns seen in the different age groups in infancy. Usually at less than 36 weeks of age you have a discontinuous pattern and there is no cycling or reactivity to it. Fasse (?) discontinua is basically a burst of 0.5 to 4.00 hertz at 50 to 300 microvolts and alternating with inactive background. You usually see

Their sleep EEG spindles begin at about 3-4 months of age. They may initially be noted asymmetrically. Vertex sharp waves begin at about 5-6 months of age and your K complex

Myelination begins in the peripheral nervous system, motor first and then sensory. In terms of the sensory tract it’s the central sensory tract first and then also the central motor tracts. Then you get the associated areas, the cerebral commissures and then the intra-cortical neuropil is the last to myelinate. And that’s usually at about 3-5 years of age. On MRI myelin appears black on

Now we’ll talk about developmental milestones. I’m sure for all of you, those of you who have kids, this is probably what you want to do is use the TV milestones and use the VCR as your guide. Unfortunately this is not what the Boards want’s us to do. So, typically in the first year of

Certain things that occur in the different age groups, and what we would call as pathological. At 2-3 months of age they should be able to support their head. So they lift their head up. They tend to have a social smile and they make babble sounds. They begin to sort of coo. They start to have a lot of movements of the extremities as well. And you can

At four months of age they definitely should have good head control by then. By this time also they should be able to put themselves into a tripod position. That usually happens about three months of age. At four months of age they should be able to turn to sounds and recognize familiar voices. By about five or six months of age, that’s when your

By nine months of age, if they are still not sitting alone, you have a problem there. Nine months of age, some of them will start beginning to crawl. Some parents will swear that their kid never crawled and just started walking. If they are walking at nine months, that’s great. I’ve seen a kid that walked at nine months in my office. So that can happen. But they will tend to crawl. They may also begin "cruising" onto furniture or pulling themselves up to

Perinatally. Premature birth, low birth weight in relation to gestational age, very commonly seen in mothers who smoke heavily during pregnancy. Post-term birth, those deliveries that are prolonged, precipitous or instruments requiring forceps, or vacuum. Birth asphyxia, jaundice or other congenital anomalies. Some of the more common ones, in

The workup for mental retardation consists of amino acid, both serum and urine, and organic acid. Chromosomal studies, thyroid function test, even though the newborn screen may have done the thyroid function test, during my days in New York. Some of

Cerebral palsy is a group of disorders. There are multiple etiologies. It is early onset. By definition cerebral palsy is actually something that happened at the time of birth. We tend to generalize it and even if it occurs at six months of age, for example from drowning, we still call that cerebral palsy when they have hypoxic ischemic injury from that. But for

Autism is a disorder affecting three main areas. They have a restricted repertoire. They tend to be fascinated with spinning objects. They have language problems. They usually may develop normally until about two years of age and then regressing in their language, and they have social interaction problems as well. Those are the three main key features that one has to think about when you think of autism. And they appear in the first three years of life. The incidence is about 15:1,000. For some reason males are much more commonly affected. The main differential diagnosis for this is really going to be pervasive developmental disorder. The main difference is that there is no significant language delays, with Asperger’s syndrome rather. So this was a Board question, where they gave a good case scenario with behavioral disorders, some restricted repertoires, some social problems with interaction, sort of aggressive behavior sometimes. Sometimes subdued. But language was normal. Think of Asperger’s. So anything that doesn’t fit Asperger’s and autism is called pervasive developmental disorder.

Rett’s syndrome is x-linked dominant, males are either spontaneously aborted or they are stillborn. The classical one, the seizures, the early onset seizures, the atypical one you see seizures come on later on and there are a whole bunch of other things that happen. And

Some other supporting criteria that would help you diagnose Rett’s is breathing irregularity. These kids at about four years of age start having respiratory difficulties. They may have hyperpnea, they may have apnea or other kinds of respiratory difficulties. Then they have bruxism as well. They develop scoliosis later on. They can have some feet disturbances, bloating, gait apraxia, EEG may be abnormal, and then they have growth retardation. They

ADHD. About 5% of the general population. In specialty clinics is occurs in about nine to one, but in the general population it is more four to one. There is possibly some genetic predisposition. The key is, the symptoms begin before the age of seven. It has to be there for

Microcephaly is the most common cause genetic. Chromosomal abnormalities is the next most common cause. You also have to look at defective neurulation obviously, holoprosencephaly

Megalencephaly: again, the most common cause of this is going to be familial so you always need to measure the father or the mother’s head size and see whether they’ve got a big head. Then you need to look at other neurologic abnormalities such as hydrocephalus or other types

Hydrocephalus, the communicating type. You have achondroplasia, your basilar impression. You have the benign enlargement of subarachnoid spaces, also called benign external

Some common features of chromosomal disorder include mental retardation, congenital anomalies, abnormal growth, subcutaneous signs, dysmorphic features, obviously have a family history, and developmental abnormality. Down syndrome is associated with increasing maternal age. The incidence is about 1:1,000. There is no sex predilection. They have

Prader-Willi syndrome, again 1:25,000. It can present in the neonatal period with neonatal hypotonia. They may have hypogonadism and small hands and feet. The polyphagia, obesity, short stature and mental retardation comes later on. Usually about nine or

Turner’s syndrome, seen in females. They have webbed neck. They have coarctation of the aorta. They have mild mental retardation and perceptive hearing loss. The

Fragile X syndrome is the second most common recognizable cause of mental retardation. So they have delayed speech, they may have echolalia as well. The craniofacial … the large protruding ears - believe it or not, I have not really seen anybody with that

The XYY syndrome. It’s 1:1,000. They have behavior and learning disabilities. They have large teeth, severe acne. They have normal secondary sexual development. They have a lot of temper outbursts which actually leads them to be