• Arise from incomplete closure of the neural tube
• Neural plate invaginates early in gestation to form the neural tube, which runs along the cranial-caudal axis of the embryo
• The wall of the neural tube forms central nervous system tissue,
• the hollow lumen forms the ventricles and spinal cord canal,
•  the neural crest forms the peripheral nervous system
• Associated w/ low folate levels prior to conception
• Detected during prenatal care by elevated alpha-fetopreotein (AFP) levels in the amniontic fluid and maternal  blood

• Anencephaly
• absence of the skull and brain (distribution of the cranial end of the neural tube)
• leads to a frog-like appearance of the fetus
• results in maternal polyhydramnios since fetal swallowing of amniotic fluid is impaired

• failure of the posterior vertebral arch to close, resulting in a vertebral defect (disruption of the caudal end of the neural tube)
• Spina bifida occulta presents as a dimple or patch of hair overlying the vertebral defect
• spina bifida presents with cystic protrusion of the underlying tissue through the vertebral defect.
• Meningocele-protrusion of meninges
• Meningomyelocele-protrusion of meninges and spinal cord

• Congenital stenosis of the channel that drains CSF from the 3rd ventricle into the 4th ventricle
• Leads to accumulation of CSF in the ventricular space; most common cause of hydrocephalus in newborns
• CSF is prod. by the choroid plexus lining the ventricles
• flows from the lateral ventricles into the 3rd ventricle via the interventricular foramen of Monro
• Flows from the 3rd ventricle into the 4th ventricle via the cerebral aqueduct
• Flows from the 4th ventricle into the subarachnoid space via the foramina of Magendie and Luschka
• Presents w/ enlarging head circumfrence due to dilation of the ventricles (cranial suture lines are not fused)

• Congenital failure of the cerebellar vermis to develop
• Presents as a massively dilated (D=DILATED) 4th ventricle (posterior fossa) w/ an absent cerebellum
• Often accompanied by hydrocephalus

• Congenital extension of cerebellar tonsils through the foramen magnum
• Obstruction of CSF flow can result in hydrocephalus
• May occur in association w/ meningomyelocele and syringomyelia

• Cystic degeneration of the spinal cord
• Arises w/ trauma or in association w/ an Arnold-Chiari malformation
• Usually occurs at C8-T1
• presents as sensory loss of P and T w/ sparing of fine touch and position sense in the upper extremeties (cape-like-distribution) due to involvement of the anterior white commissure of the spinothalamic tract w/ sparing of the dorsal column
• Syrinx expansion results in involvement of other spinal tracts leading to:
•  muscle atrophy and weakness w/ decreased muscle tone and impaired reflexes-due to damage to lower motor neurons of teh anterior horn
• Horner syndrome w/ ptosis (droopy eyelid), miosis (constricted pupil), and anhidrosis (decreased sweating)-- due to disruption of the lateral horn of the hypothalamospinal tract

• Damage to the anterior motor horn due to poliovirus infection
• Presents with lomor motor neuron signs-- flaccid paralysis w/ muscle atrophy, fasciculations, weakness w/ decreased muscle tone, impaired reflexes, and negative Babinski sign (downgoing toes)

• Inherited degeneration of the anterior motor horn; autosomal recessive
• presents as a floppy baby
• Death occurs w/i a few years after birth

• Degenerative disorder of upper and lower motor neurons of the corticospinal tract
• Anterior motor degeneration leads to lower motor neuron signs- flaccid paralysis w/ muscle atrophy, fasciculations, weakness w/ decreased muscle tone, impaired reflexes, and negative Babinski sign
• Lateral corticospinal tract degeneration leads to UMN signs- spastic paralysis w/ hyperreflexia, increased muscle tone, and positive Babinski sign
• Atrophy and weakness of hands is an early sign
• Lack of sensory impairment distinguishes ALS from syringomyelia
• Most cases are sporadic, arising in middle age adults
• Zinc-copper superoxide dismutase mutation (SOD1) is present in some cases; leads to free radical injury in neurons

• Degenerative Disorder of the cerebellum and spinal cord
• Degeneration of the cerebellum leads to ataxia
• Degeneration of multiple spinal cord tracts leads to loss of vibratory sense and proprioception, muscle weakness in the lower extremeties, and loss of deep tendon reflexes
• Autosomal recessive; due to expansion of an unstable trinucleotide repeat (GAA) in the frataxin gene
• Frataxin is essential for mitochondrial iron regulation; loss results in iron buildup w/ free radical damage
• Presents in early childhood; patients are wheelchair bound w/i a few ears
• Associated w/ hypertrophic cardiomyopathy

• 1st order neuron=peripheral nerves to posterior horn; cell body is in dorsal root ganglion
• 2nd order neuron:arises from posterior horn, immediately crosses over in anterior white commissure, and ascends via the STT to the thalamus
• 3rd order neuron=thalamus to cortex
• [image]

1. order neuron: peripheral nerves to medulla via dorsal column; cell body is in dorsal root ganglion
2. nd order neuron: Arises from medulla, crosses over, and ascends via the medial lemniscus to thalamus
3. rd order Thalamus to cortex

[image]

1. pyrimadal neurons in cortex descend, cross over in medullary pyramids, and synapse on the anterior motor horn of the cord (upper motor neuron)
2. nd order neuron: arises from the anterior motor horn and synapses on muscle (lower motor neuron)
3. No third order neuron
4. [image]

1. st order neuron: Arises from the hypothalamus and synapses on the lateral horn at T1
2. nd order neuron: Arises from lateral horn at T1 and synapses on the superior Cervical ganglion (sympathetic)
3. rd order neuron: superior cervical ganglion to eyelids, pupil, and skin of face

[image]

• Inflammation of the leptomeninges
• Meninges consist of 3 layers (dura, arachnoid, and pia) that lie between the brain and the skull
• Pia and arachnoid together are termed leptomeninges
• Most commonly due to an infectious agent

1. Group B streptococci, E. coli, and listeria monocytogenes (neonates)
2. N. meningitides (children and teenagers), Streptococcus pneumoniae (adults and elderly), and H. influenza (nonvaccinated infants)
3. Coxsacievirus (children; fecal-oral transmission)
4. Fungi (immunocompromised individuals)

• Presents w/ classic triad of headache, nuchal rigidity, and fever; photophobia, vomiting, and altered mental status may also be present
• Diagnosis is made by lumbar puncture (sampling of CSF)
• Performed by placing a needle between L4 and L5 (level of the iliac crest).  Spinal cord ends at L2, but subarachnoid space and cauda equina continue to S2
• Layers crossed include skin, ligaments, epidural space, dura, and arachnoid

• neutrophils w/ decreased CSF glucose; gram stain and culture often identify the causative organism
• Complications are usually seen with bacterial meningitis
• Death--herniation secondary to cerebral edema
• Hydrocephalus, hearing loss, and seizures-sequelae related to fibrosis

• neurologic deficit due to cerebrovascular compromise; major cause of morbidity and mortality
• Due to ischemia (85% of cases) or hemorrhage (15% of cases)
• Neurons are dependent on serum glucose as an essential energy source and are particularly susceptible to ischemia (undergo necrosis w/i 3-5 minutes)

• global ischemia to the brain
• Major etiologies:

1. Low perfusion (ex atherosclerosis)
2. Acute decrease in blood flow (ex cardiogenic shock)
3. Chronic hypoxia (anemia)
4. Repeated episodes of hypoglycemia (ex insulinoma)

• Clinical features are based on duration and magnitude of the insult
• Mild global ischemia results in transient confusion w/ prompt recovery
• Severe global ischemia results in diffuse necrosis; survival leads to a 'vegetative state'
• Moderate global ischemia leads to infarcts in watershed areas (ex area lying between regions fed by the anterior and middle cerebral artery) and damage to highly vulnerable regions such as:

1. Pyramidal neurons of the cerebral cortex (layers 3, 5, and 6)-- leads to laminar necrosis
2. Pyramidal neurons of the hippocampus (temporal lobe)- important in long term memory
3. Purkinje layer of the cerebellum- integrates sensory perception w/ motor control

• Regional ischemia to the brain that results in focal neurologic deficits lasting> 24 hours
•  If symptoms last <24 hours, the event is termed a TIA

• due to rupture of an atherosclerotic plaque
• Atherosclerosis usually develops at branch points (ex bifurcation of internal carotid and middle cerebral artery in the circle of willis)
• Results in a pale infarct at the periphery of the cortex

• due to thromboemboli
• most common source of emboli is the left side of the heart (ex atrial fibrillation).
• Usually involves the middle cerebral artery
• results in a hemorrhagic infarct at the periphery of the cortex

• occurs secondary to hyaline arteriosclerosis (A complication of htn)
• most commonly involves lenticulostriate vessels, resulting in small cystic areas of infarction
• Involvement of the internal capsule leads to a pure motor stroke
• involvement of the thalamus leads to a pure sensory stroke

• An ischemic stroke
• Eosinophilic change in the cytoplasm of neurons (red neurons) is an early microscopic finding (12 hours after infarction)
• Coagulative necrosis (24 hours), infiltration by neutrophils (day 1-3) and microglial cells (days 4-7), and granulation tissue (weeks 2-3) then ensue
• Results in formation of a fluid-filled cystic space surrounded by gliosis

• Bleeding into brain parenchyma
• Classically due to rupture of Charcot-Bouchard microaneurysms of the lenticulostriate vessels
• Complication of HTN, treatment of HTN reduces incidence by half
• Basal ganglia is the most common site
• Presents as severe headache, nausea, vomiting, and eventual coma

• bleeding into the subarachnoid space
• presents as a sudden headache "worst headache of my life" with nuchal rigidity
• Lumbar puncture shows xanthochromia (yellow hue due to bilirubin breakdown)
• most frequently (85%) due to rupture of a berry aneurysm; other causes include AV malformations and an anticoagulated state
• Berry aneurysms are thin-walled saccular outpouchings that lack a media layer, increasing the risk for rupture
• Most frequently located in the anterior circle of Willis at branch points of the anterior communicating artery
• Associated w/ Marfan syndrome and autosomal dominant polycystic kidney disease

• Collection of blood between the dura and the skull
• classically due to fracture of the temporal bone with rupture of the middle meningeal artery; bleeding separates the dura from the skull
• Lens-shaped lesion on CT
• Lucid interval may preced neurologic signs
• Herniation is a lethal complication

• Collection of blood underneath the dural blood covers the surface of the brain
• Due to tearing of bridging veins that lie between the dura and arachnoid; usually arises with trauma
• Crescent-shaped lesion on CT
• Presents with progressive neurologic signs
• Increased rate of occurence in the elderly due to age-related cerebral atrophy, which stretches the veins
• Herniation is a lethal complication

• Displacement of brain tissue due to mass effect or increased intracranial pressure
• Tonsillar herniation involves displacement of the cerebellar tonsils into the foramen magnum
• Compression of the brain stem leads to cardiopulmonarry arrest
• Subfalcine herniation involves displacement of the cingulate gyrus under the falx cerebri
• Compression of the anterior cerebal artery leads to infarction
• Uncal herniation involves displacement of the temporal lobe uncus under the tentorium cerebelli
• Compression of Cranial nerve III (oculomotor) leads to the eye moving "down and out" and a dilated pupil
• Compression of posterior cerebral artery leads to infarction of occipital lobe (contralateral homonymous hemianopsia)
• Rupture of the paramedian artery leads to Duret (brainstem) hemorhage

• Myelin insulates axons, improving th espeed and efficiency of conduction
• Oligodendrocytes myelinate the CNS
• Schwann cells myelinate the peripheral nervous system
• Demyelinating disorders are char. by destruction of myelin or oligodendrocytes; axons are generally preserved

• Inherited mutations in enzymes necessary for production or maintenance of myelin

• due to a def. of arylsulfatase (autosomal recessive)
• most common dystrophy
• Myelin cannot be degraded and accumulates in the lysosomes of oligodendrocytes (lysosomal storage disease)

• Due to a def. of galactocerebroside Beta galactosidase (autosomal recessive)
• Galactocerebroside accumulates in macrophages

• impaired addition of coenzyme A to long chain fatty acids (X-linked defect)
• Accumulation of FAs damages adrenal glands and white matter of the brain

• Autoimmune destruction of CNS myelin and oligoendrocytes
• Most common chronic CNS disease of young adults (20-30 years of age) more commonly seen in women
• Associated w/ HLA-DR2
• More commonly seen in regions away from the equator
• Presents w/ relapsing neurologic deficits w/ periods of remission (multiple lesions in time and space). Clinical features include
• Blurred vision in one eye (optic nerve)
• Vertigo and scaning speech mimicking alcohol intoxication (brainstem)
• Internuclear ophthalmoplegia (medial longitudinal fasciculus)
• Hemiparesis or unilateral loss of sensation (cerebral white matter, usually periventricular)
• Lower extremity loss of sensation or weakness (spinal cord)
• Bowel, bladder, and sexual dysfunction (autonomic nervous system)
• Diagnosis is made by MRI and lumbar puncture
• MRI reaveals plaques (areas of white matter demyelination)
• Lumbar puncture shows increased lymphocytes, increased immunoglobulins w/ oligoclonal IgG bands on high resolution electrophoresis, and myelin basic protein
• Gross examination shows gray-appearing plaques in the white matter
• Treatment of acute attacks includes high-dose steroids
• Long-term treatment with interferon beta slows progression of disease

• progressive, debilitating encephalitis leading to death
• Due to slowly progressing, persistent infection of the brain by measles virus
• infection occurs in infancy; neurologic signs arise years later (during childhood)
• Char. by viral inclusions w/i neurons (gray matter) and oligodendrocytes (white matter)

• JC virus infection of oligodendrocytes (white matter)
• Immunosuppression (ex AIDS or leukemia) leads to reactivation of the latent virus
• Presents with rapidly progressive neurologic signs (visual loss, weakness, dementia) leading to death

• Focal demyelination of the pons (anterior brain stem)
• Due to rapid intravenous correction of hyponatremia
• Occurs in severely malnourished patients (ex alcoholics and patients with liver disease)
• Classically presents as acute bilateral paralysis (locked in syndrome)

• Char. by loss of neurons w/i the gray matter; often due to accumulation of protein which damages neurons
• Degeneration of the cortex leads to dementia
• Degeneration of the brainstem and basal ganglia leads to movement disorders

• Degenerative disease of cortex; most common cause of dementia
• clinical features
• Slow-onset memory loss (begins w/ short-term memory loss and progresses to long-term memory loss) and progressive disorientation
• Loss of learned motor skills and language
• changes in behavior and personality
• Patients become mute and bedridden; infection is a common cause of death
• Focal neurologic deficits are not seen in early disease
• Most cases ~95% are sporadic and seen in the elderly
• Risk increased w/ age (doubles every 5 years after the age of 60)
• E4 allele of apolipoprotein E (APOE) is associated w/ increased risk, E2 allele w/ decreased risk
• Early onset AD is seen in
• Familial cases-associated w/ presenilin 1 and presenilin 2 mutations
• Down syndrome commonly occurs by 40 years of age
• Morphological features include
• Cerebral atrophy w/ narrowing of the gyri, widening of the sulci, and dilation of the ventricles
• neuritic plaques- extracellular core comprised of Alphabeta amyloid with entangled neuritic processes
• AB amyloid is derived from amyloid precursos Protein (APP), which is coed on chromosome 21.  APP normally undergoes alpha cleavage; beta cleavage resultsin Alpha beta amyloid
• amyloid may also deposit around vessels, increasing the risk of hemorrhage
• neurofibrillary tangles-intracellular aggregates of fibers composed of hyperphosphorylated tau protein
• Tau is a microtubule-associated protein
• Loss of cholinergic neurons in the nucleus basalis of Meynert
• Diagnosis is made by clinical and pathological correlation
• Presumptive diagnosis is made clinically after excluding other causes
• Confirmed by histology at autopsy (when possible)

• Multifocal infarction and injury due to HTN, atherosclerosis, or vasculitis
• 2nd most common cause of dementia

• Degenerative disease of the frontal and temporal cortex; spares the parietal and occipital lobes
• car. by round aggregates of tau protein (Pick bodies) in neurons of the cortex
• behavioral and language symptoms arise early; eventually progresses to dementia

• Degenerative loss of dopaminergic neurons in the substantia nigra of the basal ganglia
• Nigrostriatal pathway of basal ganglia uses dopamine to initiate movement
• common disorder related to aging; seen in 2% of older adults
• Unknown etiology; historically, rare casese were related to MPTP exposure (a contaminant in illicit drugs)
• Clinical features (TRAP)
• Tremor- pill rolling tremor at rest; disappears w/ movement
• Rigidity- cogwheel rigidity in the extremeties
• Akinesia/Bradykinesia- slowing of voluntary movement; expressionless face
• Postural instability and shuffling gait
• Histology reveals loss of pigmented neurons in the substantia nigra and round, eosinophilic inclusions of alpha-synuclein (lew bodies) in affected neurons
• Dementia is a common feature of late disease
• Early-onset dementia is suggestive of Lewy body dementia, which is char. by dementia, hallucinations and parkinsonian features; histology reveals cortical Lewy bodies

• Degeneration of GABAergic neurons in the caudate nucleus of the basal ganglia
• Autosomal dominant disorder (chromosome 4) char. by expanded trinucleotide repeats (CAG) in the huntingtin gene
• Further expansion of repeats during spermatogenesis leads to anticipation
• Presents w/ chorea that can progress to dementia and depression; average age at presentation is 40 years
• Suicide is a common cause of death

• Increased CSF resulting in dilated ventricles
• Can cause dementia in adults; usually idiopathic
• Presents as triad of urinary incontinence, gait instability, and dementia ("wet, wobbly, and wacky")
• Lumbar puncture imporves symptoms; treatment is ventriculoperitoneal shunting

• Degenerative disease due to prion protein
• Prion proetein is normally expressed in CNS neurons in an alpha helical configuration PrPc
• Disease arises w/ conversion to a beta pleated confirmation PrPsc
• Conversion can be sporadic, inherited (familial forms of disease), or transmitted
• Pathologic protein is not degradable and converts normal protein into the pathologic form, resulting in a vicious cycle
• Damage to neurons and glial cells is char. by intracellular vacuoles (spongy degeneration)

CJD

• most common spongiform encephalopathy
• usually sporadic; can arise due to exposure to prion-infected human tissue (ex human growth hormone or corneal treansplant)
• Presents as rapidly progressive dementia associated w/ ataxia (cerebellar involvement) and startle myoclonus
• Spike-wave complexes are seen on EEG
• results in death, usually in <1 year
• Variant CJD is a special form of disease that is related to exposure to bovine spongiform encephalopathy ('mad cow')
• Familial fatal insomnia is an inherited form of prion disease char. by severe insomnia and an exaggerated startle response

• can be metastatic (50%) or primary (50%)
• metastatic tumors char. present as mult. well-circ. lesions at the gray-white junction
• lung, breast, adn kidney are common sources
• primary tumors are classified according to cell type of origin (astrocytes, meningothelial cells, ependymal cells, oligodendrocytes, or neuroectoderm).
• In adults, primary tumors are usually supratentorial
• most common tumors in adults are glioblastoma multiforme, meningioma, and schwannoma
• in children, primary tumors are usualy infratentorial
• Most common tumors in children are pilocytic astrocytoma, ependymoma, and medulloblastoma
• Primary malignant CNS tumors are locally destructive, but rarely metastasize

• Malignant, high-grade tumor of astrocytes
• most common primary malignant CNS tumor in adults
• usually arises in the cerebral hemisphere; char. crosses the corpus callosum=butterfly lesion
• Char. by regions of necrosis surrounded by tumor cells (pseudopalisading, and endothelial cell proliferation; tumor cells are GFAP +
• Poor prognosis

• Benign tumor of arachnoid cells
• Most common benign CNS tumor in adults
• More commonly seen in women; rare in children
• may present as seizures; tumor compresses, but does not invade, the cortex
• Imaging reveals a round mass attached to the dura
• Histology shows a whorled pattern; psammoma bodies may be present

• Benign tumor of schwann cells
• Involves cranial or spinal nerves; w/i the cranium, most freq. involves cranial nerve VIII at the Cerebellopontine angle (presents as loss of hearing and tinnitus)
• Tumor cells are S-100 +
• Bilateral tumors are seen in neurofibromatosis type 2

• Benign tumor of Schwann cells
• Involves cranial or spinal nerves; w/i the cranium, most freq. involves CN VIII at the cerebellopontine angle (presents as loss of hearing and tinnitus)
• Tumor cells are S-100 positive
• Bilateral tumors are seen in neurofibromatosis type 2

• Malignant tumor of oligodendrocytes
• Imaging reveals a calcified tumor in the white matter, usually involving the frontal lobe; may present w/ seizures
• Fried-egg appearance of cells on biopsy

• Benign Tumor of astrocytes
• Most common CNS tumor in kids; usually arises in the cerebellum
• imaging reveals a cystic lesion w/ a mural nodule
• biopsy shows Rosenthal fibers (thick eosinophilic processes of astrocytes, and eosinophilic granular bodies; tumor cells are GFAP +

• Malignant tumor derived from the granular cells of the cerebellum (neuroectoderm)
• Usually arises in children
• histology reveals small, round blue cells; Homer Wright rosettes may be present
• Poor prognosis; tumor grows rapidly and spreads via CSF
• Metastasis to the cauda equina is termed 'drop metastasis'

• Malignant tumor of ependymal cells; usually seen in kids
• Most commonly arises in teh 4th ventricle; may present w/ hydrocephalus
• Perivascular pseudorosettes are a char. finding on biopsy

• Tumor that arises from epithelial remnants of Rathke's Puch
• Presents as a supratentorial mass in a child or young adult; may compress the optic chiasm leading to bitemporal hemianopsia
• Calcifications are commonly seen on imaging (derived from "tooth-like" tissue)
• Benign, but tends to recur after resection