Learning Objectives Week 1 Semester 3

• Micronutrients:

  • Zinc: Important for DNA synthesis and cell division.
  • Thiamine: Essential for energy metabolism in neural tissues.
  • Iron: Crucial for oxygen transport and neurotransmitter synthesis.
  • Copper: Involved in myelination and neurotransmitter release.
  • Iodine: Necessary for thyroid hormone production, affecting brain development.
  • Choline: Important for neurotransmitter synthesis and cell membrane integrity.

• Macronutrients:

  • Carbohydrates: Provide energy for brain function.
  • Fats: Essential for brain structure and function.
  • Proteins: Necessary for neurotransmitter and enzyme production.

• Clinical consequences of deficiencies can include developmental delays, cognitive impairments, and increased risk of neural tube defects.

Anencephaly is caused by the failure of the rostral (cranial) neuropore to close on day 25 of development.

Key features of Encephalocele include protrusion of brain/meninges through the occipital region or other cranial sites, leading to neurological deficits, seizures, and developmental delay.

Craniosynostosis can lead to increased intracranial pressure, developmental delay, and syndromic forms such as Crouzon syndrome.

Iniencephaly is a rare neural tube defect characterized by extreme retroflexion of the head, often associated with anencephaly.

Spina Bifida can result in lower extremity paralysis, hydrocephalus (via Chiari II), and neurogenic bladder and bowel incontinence.

Folic Acid is essential for DNA synthesis and the closure of the neural tube. Its deficiency can lead to neural tube defects (NTDs).

Zinc acts as a cofactor for over 100 enzymes, playing a role in neurogenesis and synaptic signaling. Deficiency can result in poor memory, delayed mental development, and NTDs in utero.

Thiamine (B1) is a cofactor for pyruvate dehydrogenase, crucial for glucose metabolism in neurons. Its deficiency can lead to Wernicke-Korsakoff syndrome, infantile beriberi, and impaired myelination.

Iron is important for myelination, dopamine synthesis, and oxygen transport. Deficiency can cause poor cognitive development, learning deficits, and microcytic anemia.

Copper serves as a cofactor for enzymes involved in neurotransmitter biosynthesis and myelin formation. Deficiency can lead to Menkes disease, characterized by hypotonia, seizures, and neurodegeneration.

Iodine is critical for the synthesis of thyroid hormones (T3/T4), which are essential for brain development. Its deficiency can result in cretinism, leading to intellectual disability and growth retardation.

Choline is a precursor to acetylcholine and plays a role in neurogenesis and cell membrane synthesis. Deficiency can lead to memory deficits and impaired fetal brain development.

Carbohydrates serve as the main energy source for the brain (glucose) and are essential for cell division. Deficiency can lead to hypoglycemia, resulting in seizures and impaired brain growth in infancy.

Fats, particularly DHA, are crucial for myelin synthesis and the structure of neuronal membranes. Deficiency can impair myelination and lead to poor visual and cognitive development.

Proteins provide amino acids necessary for neurotransmitter synthesis, structural proteins, and receptors. Deficiency can result in microcephaly, cognitive delay, and reduced synapse formation.

Major risk factors for NTDs include maternal diabetes, anticonvulsants (such as valproate), and folate deficiency.

Elevated AFP and acetylcholinesterase suggest open neural tube defects such as anencephaly and myelomeningocele.

Periconceptional folic acid may prevent many neural tube defects, which are detectable on prenatal ultrasound.

Normal opening pressure is 90-180 mmH2O. It is elevated in infections like meningitis, subarachnoid hemorrhage (SAH), and tumors, and decreased in CSF leaks.

A turbid appearance of CSF suggests bacterial infection, while xanthochromia indicates red blood cell breakdown, often seen in SAH.

Elevated protein levels (15-45 mg/dL) in CSF are associated with infections, inflammation, and conditions like Guillain-Barré syndrome.

The presence of oligoclonal bands in CSF is associated with Multiple Sclerosis (MS).

A positive India Ink stain in CSF indicates the presence of Cryptococcus neoformans, a fungal infection.

Hydrocephalus can be caused by obstruction of CSF flow, overproduction of CSF, or impaired absorption. Types include communicating and non-communicating hydrocephalus.

The production rate of cerebrospinal fluid (CSF) is approximately 500 mL/day, with a total volume of about 150 mL.

The circulation pathway of cerebrospinal fluid (CSF) is as follows:

1. Lateral ventricles
2. Foramen of Monro
3. 3rd ventricle
4. Cerebral Aqueduct
5. 4th ventricle
6. Foramina of Luschka (lateral) and Magendie (medial)
7. Subarachnoid space

The main functions of cerebrospinal fluid (CSF) include:

• Cushioning the brain (buoyancy)
• Removing waste
• Transporting nutrients
• Maintaining ionic homeostasis
• Shock absorption

Hydrocephalus is defined as the abnormal accumulation of cerebrospinal fluid (CSF) in the ventricles, leading to an increase in intracranial pressure (ICP).

Communicating hydrocephalus is characterized by:

• Pathophysiology: Decreased CSF absorption by arachnoid granulations
• Causes: Meningitis, subarachnoid hemorrhage (SAH), post-infectious fibrosis
• Features: Increased ICP, headache, papilledema, and risk of herniation

Non-communicating (obstructive) hydrocephalus is distinguished by:

• Pathophysiology: Obstruction in CSF flow within ventricles or foramina
• Causes: Aqueductal stenosis, tumors (e.g., colloid cyst), Arnold-Chiari malformation, Dandy-Walker malformation
• Features: Enlarged ventricles upstream from the blockage

Normal Pressure Hydrocephalus (NPH) is characterized by a slow increase in CSF with normal opening pressure. Its classic triad of symptoms includes:

• Wet: Urinary incontinence
• Wobbly: Gait disturbances
• Wacky: Dementia

Ex Vacuo Hydrocephalus is characterized by ventricular enlargement due to brain atrophy, often seen in conditions like Alzheimer's disease and advanced neurodegeneration. It differs from true hydrocephalus in that it has normal ICP and is related to atrophy rather than an actual accumulation of CSF.

The congenital anomalies associated with hydrocephalus include aqueductal stenosis (X-linked), Chiari II malformation, and Dandy-Walker malformation. Symptoms may include macrocephaly in infants, sunsetting eyes, and bulging fontanelle.

The alterations in hydrocephalus are as follows:

The mnemonic for the triads of Normal Pressure Hydrocephalus (NPH) is 'Wet, Wobbly, Wacky':

• Wet = urinary incontinence
• Wobbly = ataxic gait
• Wacky = dementia (reversible!)

If only part of the ventricular system is enlarged, it suggests obstruction at that level. If all ventricles are enlarged with no obstruction, consider communicating hydrocephalus or Normal Pressure Hydrocephalus (NPH).

It modulates neurotransmitter release, especially glutamate and GABA, leading to decreased neuronal excitability.

It is effective against focal (partial) seizures, generalized tonic-clonic seizures, and myoclonic seizures.

It has minimal hepatic metabolism and is mostly excreted renally; it does not induce or inhibit CYP enzymes.

Adverse effects include somnolence, fatigue, behavioral changes (agitation, depression), and dizziness.

Valproate increases GABA levels by inhibiting GABA transaminase, blocks voltage-gated Na+ channels, and may inhibit T-type Ca²⁺ channels.

Valproic Acid is effective against generalized tonic-clonic seizures, absence seizures (as a second line if ethosuximide fails), myoclonic seizures, and focal seizures; it is broad-spectrum and useful in mixed seizure disorders.

Valproic Acid inhibits CYP450 enzymes, especially CYP2C9, and carries a risk of hepatotoxicity, particularly in children under 2 or those with mitochondrial disorders.

Adverse effects include GI upset, hepatotoxicity, neural tube defects (teratogenic), pancreatitis, weight gain, tremor, alopecia, and thrombocytopenia.

The mnemonic is 'Valproate = Very broad, but Very Bad for Babies & the liver.'

Short-acting benzodiazepine

It increases the frequency of Cl channel opening, leading to hyperpolarization and CNS depression.

• Status epilepticus (acute seizures) (IV/IM) - Sedation for procedures - Anesthesia induction

• Rapid onset, short half-life (good for procedures) - High lipid solubility for quick CNS entry - Metabolized by CYP3A4 in the liver

• Respiratory depression (especially with opioids) - Hypotension - Amnesia - Paradoxical agitation (especially in elderly/kids)

Flumazenil - a competitive GABA-A antagonist, but carries a risk of seizures if the patient is benzodiazepine-dependent.

It enhances GABA-A receptor activity, leading to increased chloride ion influx, resulting in CNS depression.

It is used for acute seizures, particularly in status epilepticus.

Midazolam is metabolized by CYP3A4 in the liver.

Key side effects include respiratory depression and amnesia, which are significant compared to other drugs like Levetiracetam and Valproic Acid.

A seizure is a transient, abnormal excessive or synchronous electrical discharge of neurons in the brain, which can be provoked or unprovoked. Epilepsy is a chronic disorder characterized by having ≥2 unprovoked seizures >24 hours apart, or one unprovoked seizure with a high risk of recurrence due to underlying brain dysfunction.

Clinical features of focal seizures include:

• Jacksonian march (motor spread)
• Déjà vu or rising epigastric sensation
• Automatisms (e.g., lip smacking, hand wringing)
• An aura is often present.

Generalized seizures include:

• Tonic-clonic (grand mal): characterized by stiffening followed by convulsions.
• Absence: presents as a blank stare with a 3Hz spike on EEG.
• Myoclonic: involves brief jerks.
• Atonic: results in a sudden loss of muscle tone.

EEG findings can be frequent in focal epilepsy, commonly associated with etiologies such as stroke, tumor, trauma, and cortical dysplasia.

Common etiologies include genetic epilepsy syndromes, metabolic derangements, and idiopathic causes, with generalized discharges like 3 Hz spike-and-wave seen in absence seizures occurring multiple times daily.

The treatment approach involves narrow-spectrum drugs such as:

1. Carbamazepine
2. Phenytoin
3. Gabapentin
4. Phenobarbital
5. Lacosamide

The treatment approach involves broad-spectrum drugs such as:

1. Valproic acid
2. Levetiracetam
3. Lamotrigine
4. Topiramate
5. Ethosuximide (for absence only)

The mnemonic 'TAMAA' stands for:

• Tonic-clonic: full body convulsion
• Absence: 3 Hz, blank stare
• Myoclonic: quick jerks
• Atonic: drop attacks
• Atonic: Associated with Lennox-Gastaut

Glucose levels in CSF are approximately 60% of serum glucose. They decrease in bacterial, fungal, and TB meningitis but remain normal in viral meningitis.

Increased WBCs in CSF indicate bacterial infections if polymorphonuclear cells (PMNs) are elevated, and viral, TB, or fungal infections if lymphocytes are elevated.

Structure of Dura Mater:

• Outermost and toughest layer of the meninges.
• Composed of dense irregular connective tissue.
• In the cranial cavity, it has two layers:
  • Periosteal layer: Adheres to the inner surface of the skull.
  • Meningeal layer: Deeper layer, continuous with the spinal dura.
• In the spinal canal, only the meningeal layer is present.
• Contains venous sinuses between the two layers in the cranial cavity (e.g., superior sagittal sinus).

Functions of Dura Mater:

• Provides mechanical protection to the CNS.
• Forms infoldings (dural reflections) that separate parts of the brain:
  • Falx cerebri: Separates the cerebral hemispheres.
  • Tentorium cerebelli: Separates the cerebrum from the cerebellum.

The falx cerebelli separates the cerebellar hemispheres and encloses venous sinuses that drain cerebral blood. It is innervated by the trigeminal nerve (CN V) and is pain-sensitive.

An epidural hematoma is usually due to the rupture of the middle meningeal artery between the skull and dura mater. It appears as a biconvex/lentiform hyperdensity on CT imaging.

A subdural hematoma is caused by the tearing of bridging veins between the dura and arachnoid. It is characterized by a crescent-shaped hemorrhage on imaging.

Arachnoid villi (or granulations) protrude into dural venous sinuses, facilitating the absorption of cerebrospinal fluid (CSF) into the venous system.

The arachnoid mater is the middle meningeal layer, thin and avascular, lying just deep to the dura mater. It encloses the subarachnoid space, which contains cerebrospinal fluid (CSF) and cerebral arteries and veins. It is connected to the pia mater via fine, web-like arachnoid trabeculae and does not follow the contours of sulci but bridges over them.

Subarachnoid hemorrhage is bleeding into the subarachnoid space, often from ruptured berry aneurysms, particularly in the Circle of Willis. It typically presents with a sudden, severe headache known as a 'thunderclap headache'.

A lumbar puncture involves accessing cerebrospinal fluid (CSF) from the subarachnoid space at the L3-L4 or L4-L5 levels of the spine.

Hydrocephalus can occur if the arachnoid villi are damaged, such as from post-infectious scarring, leading to impaired CSF reabsorption and resulting in communicating hydrocephalus.

The pia mater is the innermost meningeal layer, delicate and highly vascularized, closely adhering to the surface of the brain and spinal cord, and following the contours of gyri, sulci, and fissures.

The pia mater provides a supportive layer for blood vessels supplying the brain and spinal cord, helps form the perivascular (Virchow-Robin) spaces, and in the spinal cord, continues as the filum terminale, anchoring the cord to the coccyx.

Meningitis is the inflammation of the pia and arachnoid (leptomeninges) and can be caused by bacterial, viral, or fungal infections.

The epidural space is located between the skull and dura mater; it is only a potential space in the cranium but is a real space in the spinal canal.

The subdural space is a potential space between the dura and arachnoid layers, which becomes a real space in cases of subdural hemorrhage.

The subarachnoid space is a real space located between the arachnoid and pia mater. It contains cerebrospinal fluid (CSF), blood vessels, and cranial nerves.

The surface ectoderm gives rise to several structures, including:

1. Epidermis of skin, hair, nails
2. Sebaceous, sweat, and mammary glands
3. Lens of the eye
4. Anterior pituitary (from Rathke pouch)
5. Inner ear structures (including external auditory meatus and tympanic membrane - outer layer)
6. Oral epithelium, including enamel of teeth
7. Anal canal above the pectinate line

The derivatives of the neuroectoderm include:

1. CNS neurons and glia (brain and spinal cord)
2. Retina and optic nerve
3. Pineal gland
4. Posterior pituitary
5. Oligodendrocytes and astrocytes
6. Ependymal cells (line ventricles and central canal)

Neural crest cells give rise to a variety of structures, including:

• Peripheral nervous system:
  • Dorsal root ganglia
  • Autonomic ganglia
  • Schwann cells
  • Sensory neurons
• Adrenal medulla (chromaffin cells)
• Melanocytes (pigment cells)
• Parafollicular (C) cells of the thyroid
• Pia and arachnoid mater
• Bones/cartilage of the face and skull (e.g., maxilla, mandible)
• Odontoblasts (form dentin of teeth)

The aorticopulmonary septum contributes to the outflow tract of the heart by dividing the truncus arteriosus and bulbus cordis.

Hirschsprung disease is caused by the failure of the enteric nervous system, specifically the Meissner and Auerbach plexuses, to migrate properly during development.

The mesoderm is divided into four main divisions:

1. Paraxial mesoderm
2. Intermediate mesoderm
3. Lateral plate mesoderm
4. Axial mesoderm (notochord)

The derivatives of the paraxial mesoderm (somites) include:

1. Skeletal muscles (except head and some pharyngeal arch muscles)
2. Axial skeleton (vertebrae and ribs)
3. Dermis of skin (dorsal)

The intermediate mesoderm primarily gives rise to the urogenital system, which includes the kidneys and ureters.

The derivatives of the lateral plate mesoderm include:

1. Cardiovascular system:

   • Heart (including myocardium)
   • Blood vessels

2. Lymphatics

3. Body wall (parietal layer)

4. Smooth muscle of GI and respiratory tract

5. Serous linings (pleura, pericardium, peritoneum)

6. Spleen (intraperitoneal mesoderm-derived organ)

7. Adrenal cortex

The notochord, which is part of the axial mesoderm, plays a crucial role in development by:

• Inducing neural tube formation.
• Its remnants become the nucleus pulposus of intervertebral discs.

The VACTERL association refers to a group of congenital anomalies that include:

• Vertebral defects
• Anal atresia
• Cardiac defects
• Tracheoesophageal fistula
• Renal anomalies
• Limb anomalies

This association is significant as it highlights the impact of mesodermal derivatives in developmental anomalies.

The endoderm forms the epithelial lining of internal structures and contributes to some glands, playing a vital role in the development of the gastrointestinal and respiratory systems.

The key derivatives of the endoderm germ layer include:

• Epithelial lining of the GI tract (except mouth and anal canal below pectinate line)
• Epithelial lining of the lower respiratory tract (trachea, bronchi, alveoli)
• Bladder (except trigone) and urethra
• Auditory tube and middle ear cavity
• Parenchyma of the liver
• Parenchyma of the pancreas (both exocrine and endocrine)
• Thyroid follicular cells
• Parathyroid glands
• Submandibular and sublingual glands
• Thymus
• Eustachian tube

The key derivatives of the ectoderm (surface) germ layer include:

• Epidermis
• Hair
• Nails
• Lens of the eye
• Anterior pituitary

• Occurs in the ampulla of the fallopian tube.
• Sperm binds to the zona pellucida of the oocyte (glycoproteins ZP2 and ZP3 are involved).
• Triggers the acrosomal reaction, allowing sperm to penetrate zona pellucida.
• Fusion of sperm and oocyte membranes allows sperm nucleus to enter the oocyte.
• Cortical reaction (release of calcium) prevents polyspermy by hardening the zona pellucida.
• Oocyte completes meiosis II to form the ovum and second polar body.
• Male and female pronuclei fuse to form a diploid zygote (2n, 2c).

ZP3 is a major sperm-binding glycoprotein located on the zona pellucida, which facilitates the binding of sperm to the egg during fertilization.

The calcium wave inside the oocyte is triggered by PLCζ (phospholipase C zeta), a sperm factor that initiates this process.

Maternal mRNA and proteins regulate early zygotic processes until the embryonic genome activates.

Cleavage involves a series of mitotic divisions of the zygote without an increase in overall size, resulting in cells called blastomeres. It transitions from 2-cell to 4-cell to 8-cell to 16-cell (morula) stages.

During compaction at the 8-cell stage, cell-cell adhesion increases via E-cadherin, leading to the differentiation of cells into the inner cell mass (embryoblast) and outer trophoblast around the 16-cell stage.

Zygotic genome activation (ZGA) begins around the 8-cell stage in humans, marking a transition in genetic regulation during early development.

Blastulation occurs approximately 5 days after fertilization, during which a fluid-filled cavity (blastocoel) forms inside the morula, creating the blastocyst.

The blastocyst consists of the inner cell mass (ICM), which develops into the embryo proper, and the trophoblast, which forms the placenta.

The zona pellucida is degraded to allow for implantation into the endometrium.

The trophoblast differentiates into:

1. Cytotrophoblast: Mononuclear and mitotically active.
2. Syncytiotrophoblast: Multinucleated, invasive, and produces hCG.

The genetic factors crucial for maintaining pluripotency of the inner cell mass are OCT4, SOX2, and NANOG.

Gastrulation is initiated by the formation of the primitive streak on the epiblast surface, converting the bilaminar disc into a trilaminar disc with ectoderm, mesoderm, and endoderm.

During gastrulation, epiblast cells migrate toward the primitive streak and invaginate, with the first wave displacing the hypoblast to become the definitive endoderm.

The notochord induces the overlying ectoderm to form the neural plate, which is the first step in the process of neurulation.

Key genetic factors involved in mesoderm formation include:

• Nodal (TGF-ß family): Promotes mesoderm and endoderm formation.
• BMP4: Promotes ventral mesoderm; antagonized by chordin and noggin to allow dorsal structures.
• Goosecoid, Brachyury (T gene): Organize mesodermal patterning and notochord formation.
• FGF8: Drives cell migration through the primitive streak.

The process of neural tube formation during neurulation involves the following steps:

1. The notochord induces the ectoderm to form the neural plate.
2. The neural plate folds inward to create the neural groove.
3. The edges of the neural groove elevate and fuse to form the neural tube, which will develop into the brain and spinal cord.
4. Neural crest cells form at the lateral edges and migrate throughout the embryo.

Neural tube closure occurs in a cranial to caudal direction. The key time points are:

• Cranial neuropore closes around day 25.
• Caudal neuropore closes around day 27.

Sonic Hedgehog (SHH), produced by the notochord, plays a crucial role in neural development by inducing the formation of the floor plate and promoting the development of motor neurons.

BMP4 promotes dorsal neural tube structures such as sensory neurons and is derived from the ectoderm.

Noggin and Chordin are BMP antagonists that facilitate neural induction by inhibiting BMP signaling.

Folic acid is critical for neural development; its deficiency can lead to neural tube defects such as anencephaly and spina bifida.

HOX genes are crucial for patterning the anterior-posterior axis during organogenesis; mutations can lead to homeotic transformations.

FGFs (Fibroblast Growth Factors) are involved in the development of limbs and the brain, playing a key role in signaling during organogenesis.

Wnt signaling is essential for limb and axis formation, influencing various developmental processes during organogenesis.

Retinoic acid regulates the expression of HOX genes, which are vital for proper patterning and development during organogenesis.

Apoptosis genes, such as the Bcl-2 family, are important for sculpting structures like fingers by removing interdigital webbing during development.

1. Neural induction (Day 18-19): The notochord and prechordal mesoderm secrete Sonic Hedgehog (SHH), inducing the ectoderm to form the neural plate. BMP4 is inhibited by noggin, chordin, and follistatin, allowing ectodermal cells to adopt a neural fate.

2. Neural plate shaping and folding (Day 19-21): The neural plate elongates, median hinge points (MHP) form at the midline, and the lateral edges elevate to form neural folds, assisted by dorsolateral hinge points (DLHPs).

3. Convergence and closure (Day 22-28): Neural folds meet and fuse at the midline, forming the neural tube, starting in the cervical region. The anterior neuropore closes around day 25, and the posterior neuropore closes by day 27.

4. Neural crest cell migration: Neural crest cells delaminate from the neural folds and migrate to form various structures, including dorsal root ganglia and Schwann cells.

• Sonic Hedgehog (SHH): Promotes ventral patterning and motor neuron development; secreted by notochord.
• BMP4: Promotes dorsal neural tube identity; inhibited for induction of neuroectoderm.
• Noggin, chordin, follistatin: BMP antagonists that allow neural fate.
• PAX3: Involved in neural crest development and neural tube closure.
• VANGL2 and PCP pathway genes: Guide cell polarity and movement required for proper tube closure.

Disruptions during gastrulation can lead to major congenital anomalies, including:

• Neural tube defects (NTDs): Resulting from neurulation defects.
• Structural birth defects: Such as congenital heart disease and limb malformations, caused by errors in organogenesis.

Grhl2 and Grhl3 are the transcription factors involved in surface ectoderm closure.

Folic acid (vitamin B9) is critical for DNA synthesis and methylation; deficiency increases the risk of neural tube defects (NTDs).

Neural tube defects can be classified as open (neural tissue exposed) or closed (covered by skin).

Risk factors for neural tube defects include folate deficiency, maternal diabetes, anti-folate drugs (e.g., methotrexate, valproic acid), and genetic mutations in closure-related genes.

Spina bifida occulta is a failure of vertebral arch fusion without herniation; the skin is intact, and it may present with a tuft of hair or dimple, often asymptomatic.

Elevated maternal serum alpha-fetoprotein (AFP) and acetylcholinesterase (AChE) in amniotic fluid are indicative of neural tube defects, except in spina bifida occulta; diagnosis is confirmed by prenatal ultrasound.

Treatment includes prenatal folic acid supplementation (400-800 mcg daily; 4 mg if high-risk), surgical closure (postnatal or in utero), shunt placement for hydrocephalus, and multidisciplinary care including neurosurgery, neurology, orthopedics, and physical therapy.