Chapter 28: CV/Infections/Demyelinating/Degenerative Diseases/Toxic and Acquired Metabolic Diseases Flashcards
Demyelinating diseases of the CNS are acquired conditions characterized by preferential damage to ________ w/ relative preservation of ______.
Demyelinating diseases of the CNS are acquired conditions characterized by preferential damage to myelin w/ relative preservation of axons.
Why is severe cognitive impairment not a usual feature of MS?
Gray matter is relatively spared
Which disease is characterized by distinct episodes of neuro deficits separated in time due to white matter lesion that are separated in space
Multiple Sclerosis
Which MHC halotype increases risk for developing MS?
HLA-DR2
Which T cells are the major players in causing damage to the myelin in persons w/ MS?
CD4+ TH1 and TH17
Which demyelinating disease is associated with lesions that are firmer than the surrounding white matter and contain circumscribed, depressed, glassy, grey-tan, irregularly shaped plaques?
MS
What is seen morphologically in an active plaque of a patient with MS?
- Abundant macrophagescontaininglipid-rich, PAS-positive debris
- Perivascular (small veins) inflammatory infiltrate (mononuclear) at outer edge of plaqe
- Relative preservation of axons within plaque and depletion of oligodendrocytes
A 40 yo woman who presents with chief complaint of unilateral disturbance should raise red flags for which disease until proven otherwise?
MS
What is a frequent initial manifestation of MS?
Unilateral visual disturbances due to involvement of the optic nerve (optic neuritis, retrobulbar neuritis)
The mnemonic for MS is SINS, what are each of these clinical findings?
S = scanning speech
I = intention tremor (incontinence and INO)
N = nystagmus
Internculear opthalmoplegia (INO) often seen in MS is due to damage to what?
Medial longitudinal fasciculus (MLF)
Which Ig is found in increased levels in the CSF of patients with MS?
What is seen on immunoelectrophoresis?
- IgG
- Oligoclonal IgG bands
Infarction of which artery is associated with contralateral homonymous hemianopia?
Posterior Cerebral Artery
Infarction of which artery is associated with UMN-type weakness and cortical-type sensory loss; contralateral hemiplegia initially?
Anterior Cerebral Artery (ACA)
What is the significance of Transient Ischemic Attacks (TIA)?
- Are a warning sign for potentially larger ischemic injury to the brain
- Neurological emergency!
- 15% of TIA pts will have a stroke causing persistent deficits within 3 months; HALF of those within the first 48 hrs
Genes for which interleukin receptors have been associated with an increased risk in developing MS?
IL-2 and IL-7
What are the CSF findings in MS?
- Midly elevated protein
- Moderate pleocytosis in 1/3 cases
- IgG increased
Which condition is characterize by synchronous bilateral optic neuritis and spinal cord demyelination?
Neuromyelitis optica (aka Devic disease)
Neuromyelitis optica is due to antibodies against?
Major channel of which cell?
Aquaporin-4; major water channel of astrocytes
What is commonly found in the CSF of patients with Neuromyelitis Optica?
White cells, often including neutrophils
Although similar to MS, how does Acute Disseminated Encephalomyelitis (ADEM) differ?
When does it occur and what are the clinical manifestations?
- Occurs in younger patients w/ an abrupt onset and may be rapidly fatal
- Is a DIFFUSE monophasic demyelinating disease occuring after a viral infection or viral immunization (rare)
- Signs and symptoms develop 1-2 weeks after the antecedent infection as headache, lethargy, and coma
- In contrast to MS, all of the lesions look similar – monophasic
*MS has focal findings w/ considerable variance in the size of lesions
Acute necrotizing hemorrhagic encephalomyelitis (AKA acute hemorrhagic leukoencephalitis of Weston Hurst) is almost invariable preceded by a recent episode of?
Who is most at risk?
- Upper respiratory infection (URI)
- Young adults and children
Central pontine myelinolysis (aka osmotic demyelination disorder) most commonly arises when?
- 2-6 days after rapid correction of hyponatremia
- Low to high, the pons will die
Which neurodegenerative disorder is characterized by loss of myelin in a roughly symmetric pattern involving the basis pontis and portions of the pontine tegmentum, including myelin loss WITHOUT evidence of inflammation?
Central pontine myelinolysis (aka osmotic demyelination disorder)
What is the clinical presentation of Central pontine myelinolysis (aka osmotic demyelination disorder)?
- Rapidly evolving quadriplegia, which may be fatal
- “Locked-in” syndrome, in which patients are fully conscious yet unresponsive
Following cleavage of APP by either the α-secretase or β-secretase, what is the function of the γ-secreatse complex?
- Performs an intramembranous cleavage
- When paired with first cut by α-secretase, produces a soluble fragment
- When paired with β-secretase cleavage, it generates Aβ (highly prone to aggregation)
Which chromosome is the gene encoding APP located on and why is this significant?
- Chromosome 21
- Lies in the down syndrome region; patients with down syndrome usually develop Alzheimers around age 40
Generation of which peptide aggregates are the critical initiating event for the development of AD?
Aβ first and then tau
Plaques are deposits of aggregated ______ peptides in the _______
Tangles are aggregates of the ________ binding protein tau
Plaques are deposits of aggregated Aβ peptides in the neuropil
Tangles are aggregates of the microtubule binding protein tau
Which 3 diseases do Tau deposits appear in without the appearance of Aβ?
1) Frontotemporal lobar degeneration (Picks disease)
2) Progressive supranuclear palsy
3) Corticobasal degeneration
Which chromosome contains the ApoE locus?
Chromosome 19
A higher number of (plaques/tangles) correlates better with the degree of dementia seen in AD?
Number of neurofibrillary tangles correlates better with the degree of dementia
What are the focal spherical collections of dilated tortous neuritic processes (dystrophic neurites) around an amyloid core seen in AD?
How are they stained?
- Neuritic (senile) plaques
- Amyloid core can be stained w/ congo red; dominant component of amyloid core = Aβ
Grossly how does the brain of a patient with AD look; where are the effects most pronounced?
Which compensatory change is seen?
- Cortical atropy = widening of sulci, narrowing of gyri
- Most pronounced in: frontal, temporal, and parietal lobes
- Compensatory ventricular enlargement –> Hydrocephalus ex vacuo
Which parts of the brain will contain neuritic (senile) plaques associated w/ AD?
Hippocampus, amygdala, and neocortex
Diffuse plaques seen in AD have no _____ and are predominantly made up of Aβ____
Diffuse plaques seen in AD have no amyloid core and are predominantly made up of Aβ 42
Neurofibrillary tangles are seen best with which stain?
Bielschowsky stain (silver stain)
How do neurofibrillary tangles appear in pyramidal neurons vs. in rounder cells?
- Pyramidal = elongated “flame” shape
- Rounder cells = “globose;” basket weave of fibers around nucleus
Structures of which lobe are involved earliest in the AD and are usually severely atrophied in the later stages?
Medial temporal lobe, including hippocampus, entorhinal cortex and amygdala
Neurofibrillary tangles are insoluble and apparently resistant to clearance in vivo, thus remaining visible in tissue sections as _______ or _______ tangles long after the death of the parent neuron.
“Ghost” or “Tombstone” tangles
What are Hirano Bodies and what is their major component?
- Elongated glassy eosinophilic bodies
- Actin = major component
Cerebral amyloid angiopathy (CAA) is an almost invariable accompaniment of _______
AD
The vasuclar amyloid seen in CAA is predominantly of which type?
Aβ40
What is typically the terminal event in a patient with AD?
Intercurrent disease, often pneumonia
How are Frontaltemporal Lobar Degenerations (FTLDs) distinguished from AD in term of clinical manifestations?
Changes in personality, behavior, and language come BEFORE changes in memory
Accumulation of what is seen in FTLD-tau?
- Accumulation of tau and NOT Aβ are characteristic
- Smooth contoured inclusions —> Pick bodies
FTLDs are one of the more common causes of?
Early onset dementia
What is the characteristic pattern of atrophy seen in Pick disease?
- Asymmetric, atrophy of the frontal and temporal lobes w/ sparing of the posterior 2/3 of superior temporal gyrus
- Reduction of gyri to a wafer-thin (“knife-edge”) appearance
What are Pick Cells vs. Pick Bodies?
How do Pick bodies stain?
- Pick cells = swollen cells
- Pick bodies = cytoplasmic, round to oval, filamentous inclusions that are weakly basophilic and stain strongly with silver
Some patients with clinically diagnosed FTLD have inclusions that contain ______, but DO NOT contain Tau
TDP-43
The most common genetic form of FTLD-TDP is the result of an expansion of a _________ repeat in the 5’ UTR of ________
The most common genetic form of FTLD-TDP is the result of an expansion of a hexanucleotide repeat in the 5’ UTR of C9orf72
In FTLD-TDP, there are inclusions containing TDP-43 which is both ______ and ________
In FTLD-TDP, there are inclusions containing TDP-43 which is both phosphorylated and ubiquinated
There is an extremely strong correlation between the presence of needle like neuronal intranuclear inclusions (NII) and which mutation causing FTLD-TDP?
Progranulin mutations
In the absence of a toxic or other known etiology the presumptive diagnosis of PD can be based on the presence of the central triad of parkinsonism, which includes?
How is this diagnosis confirmed?
1) Tremor
2) Rigidity
3) Bradykinesia
- Confirmed by symptomatic response to L-DOPA replacement therapy
Which compound previosuly found in elicit drugs was found to destroy neurons in the substantia nigra and cause an acute parkinsonian syndrome?
MPTP
What is a characteristic morpological finding in the substantia nigra and locus ceruleus of patients with PD?
Pallor (loss of pigmentation) of the substantia nigra and locus ceruleus
Clinical features of PD can be remembered with mnemonic TRAPS, which includes?
T = tremor (“pill rolling” tremor at rest)
R = rigidity
A = akinesia and bradykinesia
P = postural instability (stooped posture)
S = shuffling gait (festinating gait)
First gene to be identified as a cause of autosomal dominant PD encodes _______
α-synuclein
What is the diagnostic hallmark of PD and what is the major component of this diagnostic indicator?
Lewy body; major component is α-synuclein
Mutations in the gene encoding ______ are a more common cause of autosomal dominant PD
LRRK2 (leucine-rich repeat kinase 2)
Single or multiple cytoplasmic, eosinophilic, round to elongated inclusions that often have a dense core surrounded by a pale halo describes what feature found in PD?
Lewy Bodies
Dementia with Lewy Bodies has which characteristc features?
- Fluctuating course (cognition/alertness)
- Hallucinations
- Prominent frontal signs
*HaLewycinations
In dementia with lewy bodies there is depigmentation of the substantia nigra and locus ceruleus w/ relative preservation of which structures?
Cortex, hippocampus, and amygdala
What is Progressive Supranuclear Palsy and when is it commonly seen?
What is the prognosis?
- A Tauopathy (does not contain Aβ)
- Onset between 5th and 7th decades, with males 2x more affected
- Often fatal within 5-7 years
What are the clinical features of Progressive Supranuclear Palsy (PSP)?
- Trunchal rigidity, disequilibrium w/ frequent falls and difficulty w/ voluntary eye movements
- Also can have: nuchal dystonia, pseudobulbar palsy, and a mild progressive dementia
In PSP there is widespread neuronal loss in what areas of the brain?
What type of tangles are found in these areas and what does ultrastructural analysis reveal?
- Globus pallidus, subthalamic nucleus, substantia nigra, colliculi, periaqueductal gray matter, and dentate nucleus of the cerebellum
- Contain globose fibrillary tangles
- Straight filaments composed of 4R tau
What is the pathologic hallmark of PSP?
Tau-containing inclusion in neurons and glia
What type of hydrocephalus may be seen with AD?
Hydrocephalus ex vacuo
What are the inclusions found in the brain of patients who die of CTE?
Tau
What 2 brain inclusions are associated with Parkinsons Disease?
- Tau
- α-synuclein
Inclusions containing SOD1, TDP-43, and FUS are associated with that neurodegenerative disease?
ALS
Which disease has a clinical pattern noted to be Parkinsonian w/ abnormal eye movements?
Progressive Supranuclear Palsy (PSP)
The 2 loci identified as causes of the majority of early-onset familial AD encode what?
Presenilin-1 and Presenilin-2
Which disease is characterized by extrapyramidal rigidity, asymmetric motor disturbances (jerking movements of limbs), and imparied higher cortical functioning?
Corticobasal Degeneration (CBD)
Clusters of tau-positive processes around astrocytes (“astrocytic plaques”) and the presence of tau-positive threads in gray and white matter are specific pathologic findings for which disease?
Corticobasal Degeneration (CBD)
Multiple System Atophy (MSA) is characterized by cytoplasmic inclusions of ________ in oligodendrocytes (glial cells)
Multiple System Atophy (MSA) is characterized by cytoplasmic inclusions of α-synuclein in oligodendrocytes
What are the 3 distinct neuroanatomic circuits commonly involved in MSA; what does disruption of each lead to?
- Striatonigral: parkinsonism
- Olivopontocerebellar: ataxia
- ANS: autonomic dysf. w/ orthostatic hypotension as prominent component
What is the primary pathologic event occuring in MSA?
Glial cytoplasmic inclusions (aka α-synuclein inside of oligodendrocytes)
How are the diagnostic glial cell inclusions in MSA stained?
Silver stain; show glial inclusions mainly in oligodendrocytes containing α-synuclein and ubiquitin
What is the prognosis of Huntington Disease?
Relentlessly progressive and uniformly fatal, average course of 15 years
What chromosome is the HTT gene encoding the protein huntingtin found on?
Chromosome 4p16.3
Huntington Disease is the prototype of?
Polyglutamine trinucleotide repeat expansion diseases (CAG)
Repeat expansions of CAG associated with Huntington Disease occur when?
Spermatogenesis; paternal transmission associated w/ early onset in next generation
In Huntington Disease there is striking atrophy of?
Caudate nucleus; globus pallidus may atrophy secondarily
What is the age of onset most commonly seen with Huntington Disease?
Fourth and fifth decades (30-50 yo)
Huntington Disease patients are at an increased risk of suicide, but the most common cause of death is?
Intercurrent infection
Which 2 spinocerebellar degeneration disorders are Autosomal Recessive?
- Friedreich ataxia
- Ataxia Telangiectasia
Friedreich ataxia is associated with what expansion?
GAA trinucleotide repeat of gene on chromosome 9q13 that encodes frataxin
When is the onset of Friedreich Ataxia and how does it manifest?
How do the symptoms progress and what do most affected individuals develop?
- First decade of life beginning with gait ataxia, followed by hand clumsiness and dysarthria
- DTRs are depressed or absent, but extensor plantar reflex is typically present
- Joint position and vibratory senses impaired
- Most will develop pes cavus and kyphoscoliosis
- Cardiomyopathy later in life associated w/ arrhythmia and CHF
Loss of axons and gliosis are seen where in Friedreich Ataxia?
- Posterior columns
- Corticospinal tracts
- Spinocerebellar tracts
How long do patients with Friedreich Ataxia live and what are common causes of death?
- Most patients are wheelchair-bound within 5 years and live to about 40-50 yo
- Intercurrent pulmonary infections and cardiac death = cause of death
Which chromosome is the mutated ATM gene associated with Ataxia-Telangiectasia located on?
Function of this gene?
- Chromosome 11q22-q23
- Encodes kinase critical for repair of double-stranded DNA breaks
- Fails to remove cells with DNA damage
When is the onset of Ataxia-Telangiectasia?
What are the common symptoms?
- Ataxic-dyskinetic syndrome beginning in early childhood w/ recurrent sinopulmonary infections and unsteadiness in walking
- Later on, dysarthria and eye movement abnormalities
- Subsequent development of telangiectasias in the conjunctiva and skin along w/ immunodeficiency
What is the prognosis of Ataxia-Telangiectasia and how do most of these patients die?
- Relentlessly progressive –> death early in second decade
- Many develop lymphoid neoplasms (often T cell leukemias), gliomas, and carcinomas
In which condition do various cells, including Schwann cells in DRG and peripheral nerves, endothelial cells, and pituicytes show bizarre enlargement of the nucleus to 2-5x normal size and are referred to as amphicytes?
Ataxia-Telangiectasia
What is the morphology of the LNs, thymus, and gonads in Ataxia-Telangiectasia?
Hypoplastic
Progressive disease marked by loss of UMN in cerebral cortex and LMNs in spinal cord and brainstem w/ evidence of toxic protein accumulation
Amyotrophic lateral sclerosis (ALS)
Which missense mutation and on what gene is the most common cause of ALS in the US?
A4V mutation of SOD1 on chromosome 21
What is the age of onset for ALS and the earliest symptoms?
Symptoms progress to?
- Asymmetric weakness of hands – dropping objects + difficulty performing fine motor tasks
- Cramping + spasticity of the arms and legs
- Fasciculations
- Respiratory infections
Mutations in SOD1 associated with ALS are loss or gain of function?
Leads to?
- Gain of function associate w/ mutant SOD1 protein
- Forms aggregates
What are characteristic morphological findings on the spinal cord and brain in ALS?
- Anterior roots are thin
- Reduction in anterior horn neurons
- Precentral motor gyrus in the cortex may be atrophic
What do the remaining neurons in ALS contain?
PAS-positive cytoplasmic inclusions called Bunina bodies (remnants of autophagic vacuoles)
What is progressive musclar atrophy vs. primary lateral sclerosis in terms of findings in patients w/ ALS?
- Progressive muscular atrophy: applied to uncommon cases where LMN involvement predominates
- Primary lateral sclerosis: cases where UMN involvement predominates
What is progressive bulbar palsy (Bublar ALS) associated with some patients with ALS?
Prognosis?
- Some pts will have degeneration of the lower brainstem cranial motor nuclei occuring early and rapidly progessing
- Problems with deglutination and phonation dominate; clinical course is inexorable during 1-2 year period; 50% alive at 2 years
Which cerebral disease is ALS most often associated with?
FTLD; most often w/ TDP-43 inclusions
Spinal and Bulbar Muscular Atrophy (Kennedy Disease) is due to what mutation?
X-linked polyglutamine repeat expansion in the androgen receptor gene
What are common findings of Spinal and Bulbar Muscular Atrophy (Kennedy Disease)?
- Distal limb amyotrophy and bulbar signs –> atrophy and fasciculations of the tongue and dysphagia
- Androgen insensitivity, gynecomastia, testicular atrophy, and oligospermia
What is the most severe form w/ the earliest onset of Spinal Muscular Atrophy?
Onset and prognosis?
- SMA type 1, Werdnig-Hoffmann disease
- Onset during first year of life w/ death by 2
All forms of spinal muscular atrophy (SMA) are associated with what genetic mutation?
Common clinical course?
- Disruption of SMN1 (usually deletion)
- Marked loss of LMN –> progressive weakness
Increased levels of which toxic product are seen in Krabbe disease?
Galactosylsphingosine
When is the onset of Krabbe disease and what are the clinical findings?
- Between 3-6 months of age; rapidly progressive motor signs of stiffness and weakness
- Fatal by age 2
Aggregation of engorged macrophages called globoid cells is a diagnostic feature of which disease?
Krabbe disease
In Metachromatic Leukodystrophy there is an accumulation of what?
What does this accumulation lead to?
Sulfatides —> white matter injury, inhibiting differentiation of oligodendrocytes, inflammatory response from microglia and astrocytes
Metachromatic Leukodystrophy can be observed using what stain?
What is a sensitive method of establishing diagnosis?
- Toluidine blue
- Metachromatic material in the urine = sensitive
Which disease is characterized by the inability to catabolize VLCFAs and increased levels in the serum?
Adrenoleukodystrophy
Who is most commonly affected by Adrenoleukodystrophy?
What is the typical presentation?
- Young males
- Present w/ behavioral changes and adrenal insufficiency
What occurs in Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS)?
- Episodes of acute neuro dysf., cognitive changes, and evidence of muscle involvement w/ weaknss and lactic acidosis
- Stroke like episodes often associated w/ reversible deficits
The most common mutation in Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS) is in what?
Gene encoding mitochondrial tRNA-leucine (MTTL1)
What are the symptoms and classic findings in Myoclonic Epilepsy and Ragged Red Fibers (MERRF)?
- Myoclonus, a seziure disorder, and evidence of myopathy
- Ataxia due to neuronal loss in cerebellar system also common
- Characterized by ragged red fibers on muscle biopsy
How is Myoclonic Epilepsy and Ragged Red Fibers (MERRF) transmitted and what is due to mutation in what?
- Maternally transmitted disease (mitochondrial)
- Mutations in tRNA; distinct from MELAS
When is the onset of Leigh syndrome and what are the common signs/symptoms?
- Disease of infancy – mitochondrial encephalopathy
- Poor psychomotor development
- Lactic acidemia, feeding problems, SEIZURES, and weakness w/ hypotonia
What is seen histologically in the brain tissue of an infant with Leigh Syndrome?
- Multifocal regions of destruction to brain tissue
- SPONGIFORM appearance w/ vascular proliferation
What is the underlying mutation that causes Leigh Syndrome?
Genetic mutation in one of the genes coding for enzymes in oxidative phosphorylation pathway
What are the signs of Wernicke encephalopathy; caused by?
How can it be alleviated?
- Thiamine (B1) deficiency
- Acute; psychotic symptoms or opthalmoplegia
- May reverse w/ Thiamine
What is Korsakoff syndrome and the main signs/symptoms?
Is damage reversible?
Caused by?
- Disturbances of short term memory and confabulation
- Irreversible
- Thiamine deficiency –> Chronic alcohol; also gastric disorders (carcinoma), chronic gastritis or persistent vomiting
Wernicke encephalopathy is characterized by foci of hemorrhage and necrosis where?
With time there is infiltration by?
- Mammillary bodies and walls of the 3rd and 4th ventricles
- Hemosiderin-laden macrophages
B12 deficiency causes what?
- Subacute combined degeneration of the spinal cord –> defect in myelin formation
- Degeneration of both ascending and descending spinal tracts
What are the initial signs/symptoms of B12 deficiency?
- Bilateral symmetrical numbness, tingling, and slight ataxia in the lower extremities
- May progress to include spastic weakness of the lower extremities
Glucose deprivation (hypoglycemia) initially causes selective injury to which areas of the brain?
- Large pyramidal neurons of cerebellar cortex
- Hippocampus; especially Sommer sector (CA1)
- Purkinje cells of the cerebellum
- If severe, PSEUDOLAMINAR necrosis of the cortex
What occurs to someone suffering from clinical hyperglycemia and what precautions must be taken clinically?
- Pt becomes dehydrated and develops confusion, stupor, and eventually coma
- Fluid depletion must be corrected slowly; otherwise, severe cerebral edema may follow
*From high to low, the brain may blow!
What type of response in the CNS accompanies hepatic encephalopathy?
Critical mediators?
Which cells appear in the basal ganglia and cerebral cortex?
- Impaired liver function accompanied by glial response in the CNS
- Mediators = ELEVATED ammonia levels as well as proinflammatory cytokines
- Alzheimers type II cells
Carbon monoxide poisoning causes selective injury to which areas of the CNS?
- Layers III and V of the cerebral cortex
- Sommer sector of hippocampus
- Purkinje cells
- BILATERAL NECROSIS of the globus pallidus may also occur
Methanol toxicity preferentially damages what structure?
Which structures in brain may be damaged?
- Retina
- Degeneration of retinal ganglion cells may cause blindess
- Selective bilateral necrosis of the putamen
1% of chronic alcoholics will develop a clinical syndrome with what findings?
- Truncal ataxia
- Unsteady gait
- Nystagmus
In chronic alcoholics who suffer from cerebellar dysfunction where is atrophy and loss of granule cells mainly seen?
Anterior vermis
What is Bergmann gliosis and who is it seen in?
- Advanced cases of chronic alcoholism
- Loss of purkinje cells and proliferation of adjacent astrocytes = Bergmann gliosis
What are the pathologic findings in the CNS following exposure to high doses of radiation (>10 Gy)
- Large areas of coagulative necrosis, primairly in white matter, and adjacent edema
- Vessels will have thickened walls w/ intramural fibrin-like material
Radiation may induce tumors years after therpay, and include what 3 types?
- Sarcomas
- Gliomas
- Meningiomas
