Congenital neurological disorders: Pathology review

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Case Study0:00–0:40

At the physician’s office, a 30 year old male named Alex came in because of headaches and dizziness for the past few months.
He also often stumbles while walking and recently fell down the stairs. His past medical history is insignificant.
MRI of the brain and spinal cord shows herniation of the cerebellar tonsils. Next to Alex, there’s a mother with her 4 years old child named Evi who had recurrent urinary tract infections.
Evi was born with leg paralysis and leg deformities. Clinical examination reveals a mass on her lower back.

Pathology0:40–1:15

All right, both of them have a congenital neurological malformation, which occurs when there’s a primary defect in the developmental process of the nervous system.
These conditions appear as the baby develops in utero and can vary in severity and presentation, ultimately impacting the infant's health, development, and survival.
The most high yield neurological malformations are neural tube defects, posterior fossa malformations, syringomyelia, and holoprosencephaly.
Okay, let’s take a closer look at these disorders, starting with neural tube defects, or NTDs, which include spina bifida and anencephaly.

Neural Tube Defects 1:15–2:57

They’re relatively common anomalies that develop when a portion of the neural tube - the precursor of the central nervous system- fails to close as it should during the fourth week of gestation.
When the posterior neuropore doesn’t close well, the baby is born with spina bifida, which is Latin for “split spine”. But when the anterior neuropore doesn’t close properly, the forebrain fails to develop, and the baby is born with anencephaly or absence of a major portion of the brain and the skull.
In spina bifida, there’s incomplete closure of the vertebrae and membranes of the spinal cord. A very high yield risk factor for NTD is folate or vitamin B9 deficiency in the mother.
For this reason, folic acid, which is the manufactured form of folate, should be given at least one month prior to conception and during early pregnancy.
Another important concept for the exams is that certain medications can also increase the risk for an NTD because they interfere with folate metabolism.
These include valproic acid and phenytoin, which are antiepileptics; trimethoprim and sulfonamides, which are antibiotics; and methotrexate, which is an anticancer medication.
Finally, other risk factors that increase the risk for NTDs include obesity and maternal diabetes. Okay, now clinical presentation depends on the type of NTD.

Spina Bifida2:57–5:23

Let’s start with spina bifida that has four important subtypes: spina bifida occulta, meningocele, myelomeningocele, and myeloschisis.
The most common and most mild form is spina bifida occulta, where “occulta” is Latin for hidden. This is because the deformities in the tissues of the lower back are tiny.
In this form, the spinal cord and surrounding tissue don’t protrude and no neural tissue is forced into the spaces in between the vertebrae.
Individuals with this form are often asymptomatic, and the condition is only found later in life. At most, individuals can have hair, a dimple, or a birthmark on their lower back above the site of the lesion.
Next is meningocele, sometimes called a meningeal cyst. In this condition, the meninges (but not the spinal nerves) slip into the gaps between the deformed vertebrae.
This is the least common form of spina bifida. Meningocele is an open NTD, but because the spinal cord itself is not damaged, these individuals experience only mild symptoms.
Now, a more serious form of spina bifida is myelomeningocele, also called meningomyelocele. It occurs when the spinal cord and the surrounding meninges protrude out of an opening in the vertebrae and are stuck in a cyst like pouch protruding from the back.
This condition is also an open NTD. But unlike meningocele, myelomeningocele can cause serious damage to the exposed nerves.
There is also an increased risk of infection. Symptoms of myelomeningocele include loss of sensation (or paralysis) in the areas of the body below the damaged site; problems with bladder or bowel movement; seizures; and leg and foot deformities.
Another, even more severe form of open spina bifida, is myeloschisis, also referred to as rachischisis. In this form, the neural tissue protrudes from the back without the meninges or the skin covering it, so it’s exposed completely to the external environment.
Now apart from spina bifida, a very severe form of NTD is anencephaly, where a major part of the brain and skull is absent.

Anencephaly5:23–7:38

A high yield concept about anencephaly is that the part of the brain that is responsible for neural control of swallowing is absent.
As a result, the fetus can’t properly swallow amniotic fluid and so excess fluid builds up in the amniotic sac. This is known as polyhydramnios, and it increases the risk of complications such as fetal malposition, premature birth, and placental abruption.
Due to the severe nature of the condition, the risk of stillbirth is high and surviving infants only survive hours to days after birth.
Okay now, prenatal diagnosis of neural tube defects is comprised of two approaches: ultrasound examination and measurement of maternal serum alpha-fetoprotein.
Ultrasound detects most of the defects and classifies them as open or closed based on whether the spinal cord is exposed.
Next, Alpha-fetoprotein synthesized by the fetal yolk sac, gastrointestinal tract, and liver, is usually increased in NTDs except in spina bifida occulta, where AFP is normal.
Serum testing is performed at 16 to 18 weeks of gestation. Elevated levels of acetylcholinesterase in amniotic fluid can also confirm the diagnosis of an NTD.
After birth, diagnosis is clinical, but an MRI is needed to better define the extent of the defect and exclude other central nervous system abnormalities.
Treatment of NTDs depends on the type and severity of the condition and on the presence of complications. Surgery aims to close the defect, but in the more severe forms of NTD (like anencephaly), life expectancy is just past birth.
Now, let’s move onto posterior fossa malformations, which occur when there’s a defect in the development of the posterior fossa of the skull during fetal development.

Post. Fossa Malformation7:38–7:56

They can be further divided into Chiari malformations and Dandy-Walker syndrome. Chiari malformations are a group of conditions where parts of the cerebellum slip down through the foramen magnum and into the upper spinal canal.

Chiari Malformation7:56–14:02

This results in the blockage of the normal flow of cerebrospinal fluid. These malformations are usually caused by underdevelopment of the posterior fossa of the skull.
As the cerebellum continues to develop within the confined space of the malformed posterior fossa, it eventually gets pushed down through the foramen magnum.
Now, there are two main types called the type I Chiari malformation and a type II Chiari malformation, and they differ in terms of what parts of the cerebellum herniates.
A type I Chiari malformation occurs when only the cerebellar tonsils herniate down into the foramen magnum. As a result, the displaced cerebellum can compress the fourth ventricle and block the normal flow of cerebrospinal fluid from the ventricles into the subarachnoid space.
Consequently, cerebrospinal fluid builds up in the ventricles, which is called hydrocephalus, and leads to increased intracranial pressure.
Typically, type I Chiari malformations are asymptomatic, or symptoms only appear later in life during adolescence or adulthood.
Now, cerebrospinal fluid can also build up in the spinal canal, eventually causing it to widen. This can lead to a high yield disorder called syringomyelia.
Remember for your exams that Type I Chiari malformation is the main cause of syringomyelia. You’ll also have to know that syringomyelia disrupts an area of white matter called the anterior white commissure.
This is where the fibers of the lateral spinothalamic tract decussate or cross to the opposite side of the spinal cord. The lateral spinothalamic tract is responsible for sensing pain, pressure, and temperature.
As a result, there’s bilateral loss of pain and temperature, especially in the upper extremities and back. This is often described as a "cape-like" distribution due to damage at the level of C4-C6.
Although it sounds nice to not feel pain, this can lead to neuropathic arthropathy or Charcot joints, which is when there’s repeated trauma and inflammation in a joint because there’s no pain response.Another high yield fact is that syringomyelia can affect the motor neurons in the ventral horns and this can lead to muscle weakness, paralysis, and atrophy typically of the muscles of the hand.
Syringomyelia usually spares the dorsal column, so sensations of pressure, vibrations, fine touch, and proprioception typically remain intact.
Lastly, the widening of the spinal canal can also lead to scoliosis, which is a sideways curvature of the spine. Now moving onto type II Chiari malformation (which is the classic Chiari malformation), also called an Arnold-Chiari malformation.
It’s much more severe and is therefore more readily apparent in childhood. Like in type I, there is herniation of the cerebellar tonsils, but a type II Chiari malformation includes the herniation of the cerebellar vermis as well.
As a result, type II Chiari malformations are almost always associated with non-communicating, or obstructive, hydrocephalus.
Furthermore, type II Chiari malformations are commonly associated with myelomeningocele. Now the symptoms of Chiari malformations depend on which structures of the brain and spinal cord are affected.
For the exams, it’s important to remember that type I Chiari malformation is often asymptomatic or symptoms develop in adolescence or adulthood.
Individuals typically present with severe headaches and signs of cerebellar dysfunction like vertigo or dizziness, nystagmus (or irregular eye movements), and ataxia (or an unsteady gait).
By comparison, a type II Chiari malformation is much more severe, which makes it easier to detect earlier in life. It’s often symptomatic from the neonatal period, causing headaches and cerebellar dysfunction.
In addition, if there’s excessive crowding in the posterior fossa, excess pressure on the medulla oblongata can impair the cough and gag reflexes as well as cause difficulty breathing and sleep apnea.
Chiari malformations are usually diagnosed after birth with an MRI where the cerebellar structures are seen more than 5 millimeters below the foramen magnum.
Okay, moving onto treatment. If a person with a Chiari malformation has neurological symptoms, posterior fossa decompression surgery can be done.
That’s a type of craniotomy where a portion of the back of the skull is removed in order to widen the foramen magnum and help release the buildup of pressure within the brain and restore normal cerebrospinal flow.
Similarly, the dura (the stiff, outermost membrane of the spinal cord and brain) can also be incised to relieve additional tension.
If hydrocephalus is present, a ventriculoperitoneal shunt can be used, which connects the ventricular system to the peritoneal cavity in the abdomen in order to allow fluid to drain out and reduce the intracranial pressure.Okay, moving onto another posterior fossa malformation, Dandy–Walker syndrome.

Dandy-Walker Syndrome14:02–15:56

There are three main defects. First, there’s a cyst in the fourth ventricle, which causes the ventricle to enlarge.
As a result, it presses against the cerebellum, interfering with cerebellar function. Secondly, the posterior fossa space is enlarged.
Thirdly, the cerebellar vermis, which divides the cerebellum into its hemispheres, is either smaller than usual or absent altogether.
As a result of these features, flow of cerebrospinal fluid is blocked from the fourth ventricle into the subarachnoid space.
The cerebrospinal fluid builds up in the ventricles resulting in non-communicating hydrocephalus, increased intracranial pressure, as well as macrocephaly (or an enlarged head circumference).
In addition, Dandy-Walker syndrome can be associated with spina bifida. The symptoms of Dandy–Walker syndrome typically present at birth or soon after birth.
They include irritability, vomiting, and seizures. Over time, infants can have delays in motor skills such as crawling and walking.
The cerebellar dysfunction can lead to ataxia, nystagmus, muscle paralysis, or spasticity, and abnormal breathing patterns.
Dandy–Walker syndrome is often diagnosed prenatally via ultrasound and can be confirmed after birth with an MRI. Treatment for Dandy-Walker syndrome typically involves the placement of a ventriculoperitoneal shunt.
In addition, individuals often benefit from physiotherapy to help them develop their motor skills.Finally, another high yield congenital malformation is holoprosencephaly that occurs when there’s failure of the prosencephalon (the forebrain of the embryo) to divide into the two hemispheres.

Holoprosencephaly15:56–17:32

The result is a single-lobed brain structure with skull and facial defects. Normally, the division occurs during the fifth week of gestation.
Holoprosencephaly can be due to mutations in the sonic hedgehog signaling pathway. For the exams, remember that it can be seen in trisomy 13 (or Patau syndrome), trisomy 18 (or Edwards syndrome), and fetal alcohol syndrome.
Now, moderate forms of holoprosencephaly can present with facial defects like cleft lip and palate, which are openings in the upper lip or roof of the mouth.
More severe forms present with cyclopia (or a single eye at the center of the forehead). This can occur because when the forebrain fails to divide into the two hemispheres, the two orbits don’t divide into two cavities either, remaining in a single cavity.For diagnosis, a brain MRI reveals fused cerebral hemispheres and a single ventricle.
Also, there’s fusion of the basal ganglia and absence of the olfactory nerves. Treatment of the moderate forms includes surgery to repair defects.
The severe forms of holoprosencephaly are fatal. All right, as a quick recap...

Review 17:32–18:15

Congenital neurological malformations include neural tube defects (like spina bifida and anencephaly) and posterior fossa malformations (like Chiari malformations and Dandy-Walker syndrome) Both of the posterior fossa malformations can lead to syringomyelia.
Finally, there’s holoprosencephaly, where the prosencephalon doesn’t divide normally. Diagnosis of these disorders are made with imaging tests such as ultrasound or brain MRI.
For NTDs, laboratory tests such as measurement of maternal serum alpha-fetoprotein are a useful screening tool.Okay, back to the patients!

Summary18:15–18:49

Alex had headaches and symptoms of cerebellar dysfunction that appeared recently. MRI showed cerebellar herniation, and this is concurrent with type I Chiari malformation where symptoms appear later in life.
For Evi, due to the presence of leg paralysis, leg deformities, and a mass on her lower back, Evi most likely has a myelomeningocele.
Myelomeningocele can also cause bladder problems and lead to recurrent