Neuro Flashcards
`What do the wall and the lumen of the neural tube give rise to? What about neural crest cells, generally speaking?
- wall: CNS tissue
- lumen: ventricles
- neural crest: PNS tissue
What compound is associated with neural tube defects?
low folate pre-conception
At what point in the process of gestation does low folate lead to neural tube defects?
- pre-conception
- week 4 when neural pore closes
What are two ways to screen for neural tube defects in utero? What is the exception to this?
- elevated alpha-fetoprotein in the amniotic fluid or maternal blood
- elevated acetylcholinesterase in amniotic fluid
- AFP won’t be elevated in cases of spina bifida occult
Anencephaly
- a malformation of the anterior neural tube, which results in the absence of the forebrain and an open calvarium
- associated with maternal type I diabetes and folate deficiency
- presents with a “frog-like” appearance due to enlargement of the eyes but is incompatible with life
- can detect in utero with elevated AFP and polyhydramnios since there is no swallowing center in the brain
Spina Bifida
- failure of the posterior vertebral arch to close, resulting in a vertebral defect
- most often due to failure of the caudal end of the neural tube to close as a result of low folate in the pre-conception period
- spina bifida occulta is the mildest form and presents as a dimple or patch of hair overlying the vertebral defect with the dura still intact
- true spina bifida can present with either a meningocele (protrusion of meninges alone) or meningomyelocele (protrusion of meninges and spinal cord)
What are the three degrees of spina bifida?
- spina bifida occulta: mildest form, presenting as a dimple or patch of hair over the vertebral defect with the dura still intact
- meningocele: moderate form, presenting as a cystic protrusion of just the meninges
- meningomyelocele: severe form, presenting as a cystic protrusion of the meninges and spinal cord
What is the cerebral aqueduct?
the channel that drains CSF from the 3rd to the 4th ventricle
Cerebral Aqueduct Stenosis
- a stenosis of the channel draining CSF from the 3rd to the 4th ventricle
- results in the accumulation of CSF and is the most common cause of hydrocephalus in newborns
- presents with enlarging head circumference due to dilation of the ventricles and the fact that the cranial suture lines are not yet fused
Describe the flow of CSF through the brain.
- CSF is produced by ependymal cells of the choroid plexus lining the lateral ventricles
- it flows into the 3rd ventricle via the interventricular foramen of Monro
- then into the 4th ventricle via the cerebral aqueduct
- from the 4th ventricle, it flows into he subarachnoid space via the foramina of Magendie and Luschka
- finally, it drains into the venous sinuses through the arachnoid granulations
What are the foramina of Magendie and Luschka?
- they are the foramen through which CSF flows out of the fourth ventricle and into the subarachnoid space
- there are two lateral foramen of Luschka situated somewhat anteriorly and one medial foramen of Magendie posteriorly
Dandy-Walker Malformation
- congenital failure of the cerebellar vermis to develop
- presents as a massively dilated fourth ventricle (posterior fossa) with an absent cerebellum, typically accompanied by hydrocephalus
Type II Chiari Malformation
- a congenital downward displacement of cerebellar vermis and tonsils through the foramen magnum
- type II is defined as a displacement that obstructs the flow of CSF, resulting in hydrocephalus
- presents with headaches and cerebellar symptoms
- associated with meningomyelocele
What is the difference between a type I and a type II Chiari malformation?
- type I doesn’t obstruct the flow of CSF and therefore doesn’t result in hydrocephalus like type II does
- furthermore, type I has an associated with syringomyelia while type II has an association with meningomyelocele
Syringomyelia
- a cystic degeneration of the spinal cord
- arises with trauma or in association with a type I Chiari
- usually occurs at C8-T1 and involves the anterior white commissure
- presents as a loss of pain and temperature sensation in the upper extremities bilaterally with sparing of fine touch and position sense (said to have a “cape-like” distribution of deficits)
- may expand to involve and damage the anterior horn (lower muscle signs) or lateral horn (Horner syndrome)
The anterior white commissure is where what fibers cross within the spinal cord?
it is where the second-order neurons of the spinothalamic tract, carrying pain and temperature, cross the midline
What structures will a syringomyelia typically involve once it expands beyond the white commissure? How does this present?
- begins with involvement of the anterior white commissure, which affects the spinothalamic tract carrying pain and temperature
- may expand to involve the anterior horn, which presents with lower motor neuron signs of flaccid paralysis, muscle atrophy, weakness, and impaired reflexes
- may expand to involve the lateral horn, which is home to sympathetic neurons and presents as Horner syndrome
What is Horner syndrome?
- results from disruption of sympathetic input to the face/head
- presents with ptosis (droopy eyelid), miosis (constricted pupil), and anhidrosis (decreased sweating)
What is ptosis?
drooping of the eyelid
What is miosis?
constriction of the pupil; opposite of mydriasis
What are signs of damage to lower motor neurons?
- flaccid paralysis
- impaired reflexes
- muscle weakness and atrophy
- negative Babinski (down going toes)
What cells reside in the lateral horn of the spinal cord?
sympathetic preganglionic visceral motor neurons
What cells reside in the anterior horn of the spinal cord?
lower motor neurons
Polio damages what neuron population?
lower motor neurons in the anterior horn
Poliomyelitis
- damage incurred by lower motor neurons in the anterior horn due to poliovirus infection
- polio is transmitted via the fecal-oral route and infects the oropharynx and small bowel, replicates in the Peyer’s patches, and eventually spreads to the CNS
- initially, it presents with fever, sore throat, n/v, and abdominal pain; later it presents with asymmetric lower motor neuron signs
- CSF will demonstrate elevated WBC, a slight increase in protein, and no change in CSF glucose
Werdnig-Hoffman Disease
- an inherited, autosomal recessive degeneration of the anterior motor horn
- presents as “floppy baby” with hypotonia and tongue fasciculations
- death occurs within a few years
Amyotrophic Lateral Sclerosis
- a degenerative disorder of the upper and lower motor neurons of the corticospinal tract
- presents with asymmetric upper and lower motor neuron signs; atrophy and weakness of the hands is usually the first indicator; importantly, there is no sensory impairment
- most cases are sporadic and arise in middle age adults
- however, a zinc-copper superoxide dismutase mutation (SOD1) is present in some familial cases and contribute to free radical injury
- treat with riluzole
Louis Gherig (AML) disease affects which neuron populations?
only the upper and lower motor neurons of the corticospinal tract, meaning there are no sensory deficits
What mutation can be associated with familial cases of Amyotrophic Lateral Sclerosis?
a mutation in SOD1, a zinc-copper superoxide dismutase
What are signs of upper motor neuron damage within the corticospinal tracts?
- spastic paralysis
- hyperreflexia
- increased muscle tone
- positive Babinski sign (upward facing toes)
- clasp knife spasticity
What is the Babinski sign? What is a negative finding and what is a positive finding? What does a positive finding indicate?
- it is the plantar reflex to scraping the bottom of the foot
- it is considered positive if the big toe points up
- this is physiologic in neonates but indicative of upper motor neuron injury later
Friedreich Ataxia
- a degenerative disorder of the cerebellum and multiple tracts within the spinal cord
- due to an autosomal recessive, unstable trinucleotide repeat of GAA in the frataxin gene on chromosome 9, which is essential for mitochondrial iron regulation
- loss of this gene results in free radical damage
- presents in early childhood with ataxia, loss of vibratory sense and proprioception, muscle weakness in the lower extremities, and loss of deep tendon reflexes
- additional features include staggering gait, frequent falling, nystagmus, dysarthria, pes cavus, hammer toes, diabetes, and hypertrophic cardiomyopathy
- patients become wheelchair bound within a few years
What mutation leads to Friedreich Ataxia?
an autosomal recessive, unstable trinucleotide repeat of GAA in the frataxin gene
What is the frataxin gene?
a gene important in mitochondrial iron regulation, which may incur an unstable, trinucleotide repeat of GAA, resulting in Friereich Ataxia
Describe the anatomy of the spinothalamic tract, what information it carries and at what level it decussates.
- it carries pain and temperature sensation
- the first order neuron is located in the dorsal root ganglion and synapses on a second-order neuron in the posterior horn
- this second-order neuron then decussates via the anterior white commissure near at the level where it enters
- the second-order neuron then ascends via the spinothalamic tract to the thalamus where it synapses on the third-order neuron
- this third-order neuron projects to the cortex
Describe the anatomy of the corticospinal tract, what information it carries and at what level it decussates.
- upper motor neurons descend and decussate in the medullary pyramids
- they continue to descend and synapse on lower motor neurons in the anterior horn
- these lower motor neurons then project to the NMJ
Describe the anatomy of the hypothalamospinal tract, what information it carries and at what level it decussates.
- first order neurons located in the hypothalamus synapse on the T1 lateral horn
- from there, second-order neurons synapse on the superior cervical ganglion (sympathetic chain ganglion)
- this third-order neuron then projects to the eyelids, pupil, and skin on the face carrying sympathetic input
Describe the anatomy of the dorsal column-medial lemniscus tract, what information it carries and at what level it decussates.
- first order neurons enter via the dorsal root and ascend within the ipsilateral dorsal column and project to second order neurons located in the medulla
- second order neurons then decussate and ascend via the medial lemniscus to the thalamus where third order neurons are located
- third order neurons finish carry pressure, touch, vibration, and proprioception information to the cortex
Meningitis is an inflammation of which layers of the meninges?
the arachnoid and pia, collectively known as the leptomeninges
Which layers of the meninges are included in the leptomeninges?
the arachnoid and pia
Which organisms are most commonly responsible for instances of meningitis in the following:
- neonates
- children/teenagers
- adults/elderly
- viral
- immunocompromised
- unvaccinated infants
- neonates are commonly infected by Group B Strep (agalactaie), E. coli, or Listeria monocytogenes
- children and teenagers by N. meningitidis
- adults by Strep pneumoniae
- Coxsackievirus is the most common cause of viral meningitis in children
- fungi affect the immunocompromised
- H. influenza is common in unvaccinated infants
Meningitis
- inflammation of the leptomeninges (arachnoid and pia)
- most often due to Group B strep, E. coli, Listeria monocytogeens, N. meningitidis, S. pneumoniae, H. influenza, Coxsackievirus, or fungi depending on the patient’s age and immune competence
- presents with a classic triad of headache, nuchal rigidity, and fever; photophobia, vomiting, or altered mental status are also possible
- diagnosis is made by lumbar puncture and examining the CSF for neutrophils or lymphocytes and determine the CSF glucose level to determine whether it is fungal, viral, or bacterial
- complications are usually seen in those with bacterial meningitis and include death secondary to edema and herniation, hydrocephalus, hearing loss, or seizures
Where is a lumbar puncture performed? What can help you identify this location?
between L4 and L5 at the level of the iliac crest
Why is a lumbar puncture performed between L4/L5?
because the spinal cord ends at L2 but the cauda equina and subarachnoid space continue to S2
Where does the spinal cord end? Where does the cauda equina end?
- spinal cord ends at L2
- cauda equina ends at S2
What would you expect to find via lumbar puncture in someone with bacterial, fungal, or viral meningitis?
- bacterial: you would expect neutrophils and low CSF glucose
- viral: you would expect lymphocytes and normal CSF glucose
- fungal: you would expect lymphocytes and low CSF glucose
What does a lumbar puncture needle pass through on it’s way to sample CSF?
- skin
- supraspinous ligament
- interspinous ligament
- ligamentum flavum
- epidural space
- dura
- arachnoid
- ends in subarachnoid space
What is a normal or expected CSF glucose measurement?
⅔ that of the serum glucose
Which type of meningitis is most often associated with complications? What are those complications?
- bacterial more so than either viral or fungal
- includes death due to edema and herniation, hearing loss, hydrocephalus, and seizures
Through what pathway does N. meningitidis enter the subarachnoid space?
- it enters via the nasopharynx
- then spreads the blood and gets into the CSF
Neurons rely on what energy source?
glucose
Why are neurons particularly susceptible to ischemia?
because they rely almost exclusively on glucose for their energy needs
After what period of ischemia will neurons undergo necrosis?
between 3-5 minutes after initiation
What are four major etiologies for global cerebral ischemia?
- low perfusion (atherosclerosis)
- acute decrease in blood flow (cardiac shock)
- chronic hypoxia (anemia)
- repeated episodes of hypoglycemia (insulinoma)
Mild global cerebral ischemia results in what presentation?
transient confusion with prompt recovery
Severe global cerebral ischemia results in what presentation?
diffuse necrosis and either a vegetative state or death
Moderate global ischemia is most likely to damage which structures and areas within the brain?
watershed areas are vulnerable as are three select groups of neurons:
- pyramidal neurons in layers 3, 5, and 6 of the cortex
- pyramidal neurons of the hippocampus
- purkinje layer of the cerebellum
What is laminar necrosis in the brain?
- necrosis of the pyramidal neurons in layers 3, 5, and 6 of the cerebral cortex, which are particularly susceptible to ischemia
- the result is “laminar” necrosis within the layers of the cortex
Global Cerebral Ischemia
- a state of global ischemia within the brain
- most often due to low perfusion, acute decrease in blood flow, chronic hypoxia, or repeated episodes of hypoglycemia
- presentation depends on the duration and magnitude of the insult
- mild insult results in transient confusion with prompt recovery; severe results in diffuse necrosis and death or a persistent vegetative state; moderate damages watershed areas and particularly susceptible populations of neurons
What is the difference between an ischemic stroke and a TIA (transient ischemic attack)?
- TIAs have symptoms lasting less than 24 hours
- ischemic strokes have focal neurologic deficits lasting more than 24 hours
What are the three major subtypes of ischemic stroke?
- thrombotic
- embolic
- lacunar
Where are thrombotic strokes in the brain most likely to arise?
atherosclerosis usually develops at branch points such as the bifurcation of the internal carotid and the middle cerebral artery in the circle of Willis
What kind of infarct does a thrombotic stroke lead to? Why?
- it leads to a pale infarct in the periphery of the cortex
- it is pale since attempts to lyse the thrombus are unsuccessful; if blood flow is momentarily re-established due to lysis, the ruptured plaque just forms a new one
Where is the most common source for emboli that contribute to an ischemic stroke?
the left side of the heart
Embolic strokes most often affect which part of the cerebral vasculature?
the middle cerebral artery
What kind of infarct does an embolic stroke lead to? Why?
- it leads to a hemorrhagic infarct at the periphery of the cortex
- this is because the embolus causes necrosis but can be lysed and then the re-established blood flow fills the necrotic space
Ischemic strokes lead to what sort of necrosis within the brain?
liquefactive necrosis
What is the difference between a thrombotic stroke and an embolic stroke?
- the mechanisms are obviously different
- thrombotic stroke leads to a pale infarct while an embolic stroke leads to a hemorrhagic infarct; this is because the embolus can be lysed and blood flow to the area restored, which isn’t possible after a thrombotic stroke
- thrombotic strokes most often occur at branch points, namely the bifurcation of the internal carotid and middle cerebral artery in the circle of Willis
- embolic strokes most often occur in the middle cerebral artery from clots thrown from the left heart
Lacunar Stroke
- a small stroke that occurs secondary to hyaline arteriolosclerosis, a complication of benign hypertension
- this most commonly involves the lenticulostriate vessels arising from the MCA and serving the deep structures of the brain
- the result is small, cystic areas of infarction
Where are the lenticulostriate vessels?
they arise from the MCA and serve the deep brain structures such as the internal capsule and thalamus
What kind of lacunar stroke would result in only motor symptoms?
one that involves the internal capsule
What kind of lacunar stroke would result in a purely sensory stroke?
one that involves the thalamus
Describe the timeline and histologic changes seen after an ischemic stroke.
- the first thing to arise are eosinophilic, red neurons 12 hours after infarction
- necrosis is seen after 24 hours
- infiltration by neutrophils in 1-3 days
- microglial cell infiltrate in 4-7 days
- gliosis (scarring) in the 2-3 weeks that follow
- the result is a fluid-filled cystic space surrounded by gliosis
What is the first change that can be seen after ischemic injury within the brain?
the presence of eosinophilic, red neurons
Describe the scar that forms after an ischemic stroke.
it is a fluid-filled cystic space surrounded by gliosis
What is a Charcot-Bouchard microaneurysm?
- an aneurysm of the lenticulostriate vessels arising due to hypertension, most often found in the basal ganglia
- not visible on an angiogram
Intracerebral Hemorrhage
- a bleed into the brain parenchyma, classically due to rupture of a Charcot-Bouchard microaneurysm, amyloid angiopathy, vasculitis, or neoplasm
- these aneurysms arise as a complication of hypertension and most often in the basal ganglia
- presents with severe headache, n/v, and eventual coma
- Charcot-Bouchard rupture typically involves the basal ganglia and internal capsule
How are Charcot-Bouchard micro aneurysms treated?
by treating the underlying hypertension
How would a subarachnoid hemorrhage appear on gross examination?
as a large blood clot/pool at the base of the brain
Subarachnoid Hemorrhage
- a bleed into the subarachnoid space
- most frequently due to rupture of a berry aneurysm but it can also be the result of an AV malformation or anti-coagulated state
- presents as a sudden headache, classically described as the worst headache of the patients life, with nuchal rigidity
- lumbar puncture shows xanthochromia, a yellow hue due to bilirubin
- inspection of the brain will reveal a large clot or bloody mass at the base of the brain
- may be followed several days later by vasospasm and ischemic infarct, so provide nimodipine for prevention
- increases risk for developing communicating or obstructive hydrocephalus
- aw/ Marfan and AD-PCKD
Why would a lumbar puncture show xanthochromia?
it is a yellow hue of the CSF due to the presence of bilirubin, arising due to a subarachnoid hemorrhage
What is a berry aneurysm? Where are they most often located? What other disease are they associated with?
- it is an aneurysm lacking a media layer
- most frequently located in the anterior circle of Willis at branch points of the anterior communicating artery; secondarily at the posterior communicating artery or MCA
- associated with Marfan syndrome, Ehlers-Danlos syndrome, and ADPKD
- other risk factors include advanced age, hypertension, smoking, and African American race
Epidural Hematoma
- a collection of blood between the dura and the skull
- classically caused by a fracture of the temporal bone, which ruptures the middle meningeal artery
- must be an artery because a vein doesn’t have enough pressure to open a space between the dura and temporal bone
- often presents with a lucid interval before the onset of neurologic signs and progression indicates an abrupt expansion
- expansion may cause transtentorial herniation with CN III palsy
- seen as a “lens-shaped” lesion on CT which doesn’t cross suture lines
- herniation is the feared, lethal complication
How does an epidural hematoma differ from a subdural hematoma?
- epidural appears lens-shaped on CT while subdural appears crescent-shaped
- epidural is associated with trauma and fracture of the temporal bone, which injures the middle meningeal artery while subdural is associated with age-related cerebral atrophy and rupture of veins
- epidural hematomas often have a lucid period after the injury followed by the onset of neurologic symptoms while subdurals have no associated lucid period
Subdural Hematoma
- a collection of blood beneath the dura
- due to tearing of the bridging veins that lie between the dura and arachnoid, typically with trauma
- presents with the immediate onset of progressive neurologic signs
- crescent-shaped lesion on CT that crosses suture lines and which is hyperdense if acute and hypodense if chronic
- more common in the elderly as a result of age-related cerebral atrophy stretching the veins that mediate disease
- transtentorial herniation is the feared, lethal complication
Tonsillar Herniation
- displacement of the cerebellar tonsils into the foramen magnum
- results in compression of the brainstem and cardiopulmonary arrest
- the most common form of brain herniation
What is brain herniation?
displacement of brain tissue due to mass effect or increased ICP
Subfalcine Herniation
- displacement of the cingulate gyrus under the fall cerebri
- results in compression of the anterior cerebral artery, leading to infarction –> lower extremity sensory and motor problems
Uncal Herniation
- displacement of the temporal lobe uncus under the tentorium cerebelli
- compresses CN III, leading to a “down and out” positioning of the eye with dilated pupil
- also compresses the PCA, leading to infarction of the occipital lobe with contralateral homonymous hemianopsia with macular sparing
- Kernohan notch (indentation of the contralateral cerebral peduncle) results in a “false localization” sign with paralysis on the side ipsilateral the primary lesion/herniation
Metachromatic Leukodystrophy
- a autosomal recessive deficiency of arylsulfatase, which prevents normal degradation of sulfatides, allowing them to accumulate in oligodendrocyte lysosomes
- leads central and peripheral demyelination with ataxia and dementia
- the most common leukodystrophy
Krabbe Disease
- an autosomal recessive deficiency of galactocerebrosidase, leading to accumulation of galactocerebroside in macrophages
- demyelination presents with peripheral neuropathy, developmental delay, optic atrophy, and globoid cells
Adrenoleukodystrophy
an X-linked defect, which impairs the addition of CoA to LCFAs (long-chain fatty acids), which then accumulate and damage the adrenal glands and white matter
Multiple Sclerosis
- autoimmune destruction of oligodendrocytes and CNS myelin
- risk factors include women with the HLA-DR2 haplotype living far from the equator
- primary symptoms are Charcot’s triad of SIN: scanning speech, intention tremor (also incontinence, internuclear ophthalmoplegia), and nystagmus
- diagnosed by MRI, which reveals plaques that vary in time and space, or a lumbar puncture, which demonstrates lymphocytes, an oligoclonal IgG expansion, and elevated myelin basic protein
- gross examination finds gray-appearing plaques in the white matter
- treatment for acute attacks is high-dose steroids; IFN-B is preferred for long-term treatment to slow progression
What are the major risk factors for MS?
- age 20-30
- women
- HLA-DR2 genotype
- living further from the equator
What are common symptoms of MS and in what region are the associated lesions?
- unilateral blurred vision - optic nerve
- vertigo or scanning speech mimicking alcohol intoxication - brainstem
- internuclear ophthalmoplegia - medial longitudinal fasciculus
- hemiparesis or unilateral loss of sensation - cerebral white matter, most often periventricular
- lower extremity loss of sensation or weakness - spinal cord
- bowel, bladder, and sexual dysfunction - ANS
What procedures are used to diagnose MS? What do we expect to find using these methods?
- MRI is used to identify plaques in the white matter which vary across time and space
- lumbar puncture is expected to reveal lymphocytes, an oligoclonal IgG expansion, and myelin basic protein
How is MS treated?
- long term treatment involves IFN-B to slow progression
- supplemented by high dose steroids during acute attacks
Subacute Sclerosing Panencephalitis
- a progressive encephalitis leading to death
- due to persistent infection of the brain by measles
- the infection occurs in infancy but neurologic signs arise many years later during late childhood
- histology finds viral inclusions within neurons of the grey matter and in oligodendrocytes
Progressive Multifocal Leukoencephalopathy
- a JC virus infection of oligodendrocytes
- arises from reactivation of latent virus in a newly immunosuppressed or immunocompromised patient
- presents with rapidly progressive neurologic signs and death
- there is an increased risk associated with use of natalizumab and rituximab
Central Pontine Myelinolysis
- aka osmotic demyelination syndrome
- a focal demyelination of the pons caused by rapid IV correction of hyponatremia
- results in an acute bilateral paralysis, commonly referred to as “locked in” syndrome because the patient is often only able to move his or her eyes
Degeneration of what part of the brain leads to dementia? Degeneration of what part leads to a movement disorder?
- the cortex leads to dementia
- degeneration of deep structures like the brainstem and in particular the basal ganglia lead to movement disorders
Alzheimer Disease
- a degenerative disease of the cortex, causing dementia
- arises due to B-secretase degradation of the APP protein, which can’t be processed like the A-secretase product and is deposited in the brain tissue instead
- presents with slow-onset memory loss (beginning with short-term loss and then long-term), progressive disorientation, loss of learned motor skills and language, and changes in behavior or personality
- patients often become mute and bedridden to die later of infection
- may be complicated by cerebral amyloid angiopathy
- degree of dementia correlates with the number of neurofibrillary tangles
- most cases are sporadic and arises in the elderly (risk doubles every 5 years after age 60) but early onset AD is seen in association with presenilin 1 and 2 mutations as well as in those with Down syndrome
- gross examination of the brain reveals central atrophy, narrowing of the gyri, widening of the sulci, and dilation of the ventricles
- histology reveals neuritic plaques with an AB amyloid and entangled neuritic processes in addition to the presence of intracellular, hyperphosphorylated tau protein deposits
- it is a clinical diagnosis and can only be confirmed by histology at autopsy
What is the most common cause of dementia?
Alzheimer’s disease
What is the pathogenesis of Alzheimer’s disease?
- normally a-secretase degrades the APP gene product to a structure that can be turned over by cells and properly handled
- in those with Alzheimer’s B-secretase has degraded the APP protein to a different product that can’t be properly handled and is instead deposited as AB-amyloid
What genetic associations are there with Alzheimer’s disease?
- the ApoE4 allele increases risk while the ApoE2 allele lowers it
- the presenilin 1 and 2 genes are associated with familial, early onset Alzheimer’s
- most with Down syndrome have Alzheimer’s by age 40
What is cerebral amyloid angiopathy?
a vascular disease of the brain seen in patients with Alzheimer’s disease as AB amyloid is deposited around vessels, increasing the risk for hemorrhage
Vascular Dementia
- a dementia that arises from multifocal infarction and injury secondary to hypertension, atherosclerosis, or vasculitis
- constituting the second most common cause of dementia
Why is it important to recognize a vascular dementia?
because you can treat the underlying condition and slow or stop the progression of the dementia
Pick Disease
- a degenerative disease of the frontal and temporal lobes
- presents primarily with behavioral and language symptoms in the early stages and then progresses to dementia
- characterized histologically by round aggregates of tau protein in neurons of the cortex
What is tau protein? Why is it clinically significant?
- it is a microtubule-associated protein that normally helps organize microtubules
- it is clinically important because when it becomes hyperphosphorylated, it is a marker or mediator of Alzheimer’s disease
- it is also the protein that forms Pick bodies
How do the tau tangles of Alzheimer’s differ from the tau aggregates seen in those with Pick disease?
- in Alzheimer’s they form whispy, flame-like intracellular structures
- in Pick disease they form actual aggregates
Hyperphosphorylated tau proteins are a feature of which CNS disorders?
Alzheimer’s disease and Pick disease
Parkinson Disease
- the degenerative loss of dopaminergic neurons in the substantia nigra of the basal ganglia, which is partly responsible for initiating movement
- related to aging or in rare cases to MPTP exposure
- presents with TRAP: tremor (pill rolling), rigidity (cog wheel), akinesia (or bradykinesia), and postural instability with shuffling gait
- dementia is a feature of late disease
- histology reveal the loss of the neuromelanin-pigmented neurons as well as Lewy bodies (eosinophilic inclusions of a-synuclein)
Which cell population is the focus of Parkinson disease?
the dopaminergic neurons in the substantia nigra of the basal ganglia
Exposure to MPTP brings about what sort of neurodegenerative disorder?
a disorder resembling Parkinson disease
Describe the tremor associated with Parkinson disease.
it is called a pill rolling tremor and it appears at rest, disappearing with movement
Describe the rigidity associated with Parkinson disease.
it is called cogwheel rigidity and it is a rigidity that can be observed with passive movement of the limbs
What do we call the pigment that is derived from catecholamines and stains the substantia nigra?
neuromelanin
What are Lewy bodies?
- cytoplasmic eosinophilic inclusions of a-synuclein that are visible on histology
- seen in those with Lewy body dementia (cortical) and Parkinson disease (substantia nigra)
- have a halo surrounding them
How can Lewy body dementia and Parkinson disease be differentiated?
dementia is a late feature of Parkinson disease whereas Lewy body has parkinsonian features with early onset dementia and hallucinations
Lewy Body Dementia
- a degenerative disorder most similar to Parkinson disease
- presents with early-onset dementia (which distinguishes it from Parkinson disease), Parkinsonian features, and hallucinations
- histology reveals cortical Lewy bodies
Huntington Disease
- a degeneration of GABAergic neurons in the caudate nucleus of the basal ganglia
- due to an autosomal dominant trinucleotide expansion of CAG in the huntingtin gene on chromosome 4
- this repeat demonstrates anticipation, specifically in spermatogenesis
- presents at age 40 with chorea, including athetosis, and can progress to dementia and depression
- suicide is a common cause of death
- grossly, you can identify atrophy of the caudate and putamen with hydrocephalus ex vacuo
What population of neurons are affected by Huntington disease?
GABAergic neurons in the caudate nucleus of the basal ganglia
What mutation is associated with Huntington disease?
a CAG trinucleotide repeat in the huntingtin gene on chromosome 4, which demonstrates anticipation in spermatogenesis
Normal Pressure Hydrocephalus
- an increase in CSF that results in dilated ventricles, which subsequently stretches the surrounding corona radiata
- presents in the elderly with triad of urinary incontinence, gait instability, and dementia (“wet, wobbly, and wacky”)
- have a characteristic gait known as “magnetic gait” because their feet appear stuck to the floor
- characteristically, lumbar puncture improves symptoms and treatment is ventriculoperitoneal shunting
Which form of dementia typically improves at the time of a lumbar puncture?
normal pressure hydrocephalus
Spongiform Encephalopathy
- a group of degenerative diseases due to prior protein
- this protein is normally expressed in an a-helical configuration but disease arises with conversion to a B-pleated conformation
- the resulting protein cannot be degraded and converts normal protein into the pathologic form, damaging neurons and glial cells
- can be sporadic, inherited, or transmitted
- Creutzfeld-Jakob disease is the most common but familial fatal insomnia is an inherited form
- histology reveals spongy degeneration (intracellular vacuoles)
What is familial fatal insomnia?
an inherited form of prion disease/spongiform encephalopathy characterized by severe insomnia and an exaggerated startle response
Creutzfeldt-Jakob Disease
- the most common spongiform encephalopathy
- usually sporadic but can arise from exposure to prion-infected human tissue via human GH or corneal transplant
- presents as a very rapidly progressing dementia associated with ataxia and startle myoclonus
- death arises within one year
- “spike wave” complexes are seen on EEG
- variant CJD is a special form known as “mad cow” disease which arises from exposure to prion-infected bovine tissue
What is the most rapidly progressing neurodegenerative disorder?
Creutzfeldt-Jakob Disease
How can metastatic brain tumors often be differentiated from primary tumors?
metastatic tend to be multiple, well-circumscribed lesions located at the gray-white junction
What are the most common origins for metastases to the brain?
lung, breast, and kidney
How do brain tumors differ between adult populations and child populations?
- adults tend to have supratentorial primary tumors
- children tend to have infratentorial primary tumors
Glioblastoma Multiforme
- a malignant, high-grade, GFAP-positive astrocyte tumor
- characteristically crosses the corpus callosum, forming a “butterfly lesion”
- histologically there are regions of pseudopalisading with tumor cells surrounding areas of necrosis
- the most common primary malignant CNS tumor in adults and they have a poor prognosis
Meningioma
- a benign tumor of arachnoid cells
- the most common benign CNS tumor in adults and more common in women than men
- presents with seizures since the tumor compresses, but does not invade, the cortex
- imaging reveals a round mass attached to the dura
- histology shows a very distinctive whorled pattern with psammoma bodies
Schwannoma
- a benign tumor of Schwanna cells
- can involve cranial nerves, spinal nerves, or CNS tissue
- most frequently involves CN VIII at the cerebellopontine angle and presents with a loss of hearing and tinnitus
- tumor cells stain S-100+
- bilateral tumors are a feature of neurofibromatosis 2
Oligodendroglioma
- a malignant tumor of oligodendrocytes
- a slow growing, calcified tumor in the white matter, most often involving the frontal lobe
- histology reveals cells with a “fried egg” appearance and a “chicken-wire” pattern of capillaries
- may present with seizures
Pilocytic Astrocytoma
- a benign tumor of astrocytes
- this is the most common CNS tumor in children and is typically located in the cerebellum
- arises as a cystic lesion with a mural nodule, which is easily identifiable on imaging
- histology shows Rosenthal fibers and eosinophilic granular bodies
- the section will be GFAP positive
Medulloblastoma
- a malignant tumor derived from the granular cells of the cerebellum, which are neuroectoderm
- usually arises in children
- histology reveals small, round but cells forming Homer-Wright rosettes
- the tumor grows rapidly and spreads via the CSF; therefore it has a poor prognosis
- a metastasis to the cauda equina is known as a “drop metastasis”
Ependymoma
- a malignant tumor of the ependymal cells lining the ventricles
- most often in the fourth ventricle of children
- may present with hydrocephalus if the tumor forms an obstruction
- histology reveals perivascular pseudorosettes
Craniopharyngioma
- a tumor arising from the epithelial remnants of Rathke’s pouch (oral ectoderm) left behind on it’s way to form the anterior pituitary
- presents as a supratentorial mass in a child or young adult and may compress the optic chasm leading to a bitemporal hemianopsia
- calcifications can be seen on imaging and cholesterol crystals are found in “motor oil-like” fluid within the tumor
- most common childhood supratentorial tumor
- although benign, it tends to recur
What is a “drop metastasis”?
a medulloblastoma metastasis to the cauda equina via the CSF
What are the most common primary CNS tumors seen in children?
- pilocytic astrocytoma
- ependymoma
- medulloblastoma
What are the most common primary CNS tumors seen in adults?
- glioblastoma multiforme
- meningioma
- Schwannoma
What are two possible causes for bitemporal hemianopsia?
- pituitary adenoma
- craniopharyngioma
What is the notochord?
a portion of mesoderm, which induces overlying ectoderm to differentiate into neuroectoderm and later gives rise to the nucleus pulposus
What are the alar and basal plates of the neural tube?
- alar: dorsal portion, which is associated with sensory information
- basal: ventral portion, which is associated with motor activity
List the primary vesicles of the brain and the secondary vesicles they give rise to.
- prosencephalon gives rise to the telencephalon and diencephalon
- mesencephalon to the mesencephalon
- rhombencephalon to the metencephalon and myelencephalon
List the secondary vesicles of the developing brain and the adult structures to which they give rise.
- telencephalon: cerebral hemispheres and lateral ventricles
- diencephalon: thalamus, hypothalamus, and third ventricle
- mesencephalon: midbrain and aqueduct
- metencephalon: pons, cerebellum, and upper part of 4th ventricle
- myelencephalon: medulla and lower part of the 4th ventricle
What adult cell populations are derived from neuroectoderm?
- CNS neurons
- ependymal cells
- oligodendroglia
- astrocytes
What adult neural cell populations are derived from neural crest?
PNS neurons and Schwann cells
What adult neural cell population is derived from mesoderm?
microglia (macrophages)
Holoprosencephaly
- a failure of the left and right hemispheres to separate, usually during weeks 5-6 of gestation
- thought to be related to mutations in the sonic hedgehog signaling pathway
- moderate form presents with a cleft lip/palate and the most severe form results in cyclopia (failure of the eye to separate)
- seen in associate with Patau syndrome (trisomy 13) and fetal alcohol syndrome
Describe development of the tongue, including the structures it arises from and it’s innervation.
- the anterior tongue is derived from the 1st and 2nd arches, thus sensation is mediated by CN V3 and taste by CN VII
- the posterior ⅓ is derived from the 3rd and 4th arches, thus sensation and taste are mediated by CN IX (and X in the most posterior aspect)
- motor innervation is via CN X to the palatoglossus and via CN XII to the hyoglossus, genioglossus, and styloglossus
The tongue is derived from what embryonic structures?
- the anterior tongue from branchial arches 1 and 2
- the posterior tongue from branchial arches 3 and 4
Which nerves are responsible for taste, sensation, and motor innervation of the tongue?
- taste: CN VII, IX, X
- sensation: CN V3, IX, X
- motor: CN X, XII
List the four muscles of the tongue, their innervation, and their function.
- hyoglossus (XII): retracts and depresses tongue
- genioglossus (XII): protrudes tongue
- styloglossus (XII): draws sides of tongue upward to create a trough for swallowing
- palatoglossus (X): elevates posterior tongue during swallowing
What is a Nissl stain?
a stain for RER used to identify neuronal cell bodies and dendrites (the axon does not contain any RER)
What is Wallerian degeneration?
axonal degeneration distal to an injury with axonal retraction proximal to the injury, which allows for potential regeneration of the axon if in the PNS
What are the functions of astrocytes?
- component of the BBB
- supply glycogen fuel buffer
- mediate reactive gliosis
- provide physical support
- repair
- potassium metabolism
- remove excess NT
What is GFAP?
an intermediate filament expressed by astrocytes and ependymal cells, which can be used for immunohistochemical purposes
