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Questions and Answers
What is the primary consequence of demyelination on neuronal function?
What is the primary consequence of demyelination on neuronal function?
Which of the following patterns of MS progression is characterized by a steady worsening of neurological function over time?
Which of the following patterns of MS progression is characterized by a steady worsening of neurological function over time?
What is the term for a condition characterized by damage to a single nerve?
What is the term for a condition characterized by damage to a single nerve?
Which of the following is a common clinical feature of Guillain-Barre syndrome?
Which of the following is a common clinical feature of Guillain-Barre syndrome?
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What is the primary mechanism by which nerve compression leads to neurological damage?
What is the primary mechanism by which nerve compression leads to neurological damage?
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What is the characteristic of monosodium urate crystals in synovial fluid analysis?
What is the characteristic of monosodium urate crystals in synovial fluid analysis?
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Which of the following is NOT a treatment option for gout?
Which of the following is NOT a treatment option for gout?
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What is the mechanism of action of colchicine?
What is the mechanism of action of colchicine?
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What is the most serious adverse effect of colchicine?
What is the most serious adverse effect of colchicine?
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What is the characteristic of synovial fluid in septic arthritis?
What is the characteristic of synovial fluid in septic arthritis?
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What is the function of Leukocydin produced by Staphylococcus aureus?
What is the function of Leukocydin produced by Staphylococcus aureus?
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Which of the following diseases is NOT caused by Staphylococcus aureus?
Which of the following diseases is NOT caused by Staphylococcus aureus?
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What is the role of Fc receptor proteins in structural defenses?
What is the role of Fc receptor proteins in structural defenses?
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What is the function of Exfoliative toxins produced by Staphylococcus aureus?
What is the function of Exfoliative toxins produced by Staphylococcus aureus?
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What is the name of the toxin produced by Staphylococcus aureus that is associated with Toxic Shock Syndrome?
What is the name of the toxin produced by Staphylococcus aureus that is associated with Toxic Shock Syndrome?
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What is the estimated prevalence of hereditary angioedema?
What is the estimated prevalence of hereditary angioedema?
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What is the primary molecule involved in the pathogenesis of hereditary angioedema?
What is the primary molecule involved in the pathogenesis of hereditary angioedema?
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What is the mortality rate of hereditary angioedema without treatment?
What is the mortality rate of hereditary angioedema without treatment?
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What is the relative risk of bacterial infections in IBD patients on corticosteroids alone?
What is the relative risk of bacterial infections in IBD patients on corticosteroids alone?
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What is the name of the fungal infection of the lung that can occur in patients on systemic glucocorticoids?
What is the name of the fungal infection of the lung that can occur in patients on systemic glucocorticoids?
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Study Notes
Compressive and Demyelinating Illness in the Central Nervous System
Objectives
- Describe the pathophysiologic mechanisms of demyelination and its consequences on neuronal function
- Develop a model of the pathophysiology of MS, incorporating pathological findings, immunological mechanisms, and known etiological factors
- Describe the general epidemiology, common clinical features, and key diagnostic aspects of MS
- Describe the time course of MS, including:
- Three major patterns of MS progression
- Major signs and symptoms typical of early MS
- Differences between clinical features of flares and periods in between flares
- Distinctions between the pathologic appearance of an active and inactive plaque
Definitions
- Neuropathy: a disease or dysfunction of the nerves
- Neuralgia: pain in one or more nerves
- Neuritis: inflammation of a nerve
- Radiculopathy: disease or dysfunction of the nerve roots
- Polyneuropathy: disease or dysfunction of multiple nerves
- Multiple mononeuropathy: disease or dysfunction of multiple individual nerves
Hereditary Sensory and Motor Neuropathies
- Basic epidemiology: frequency and distribution of the condition
- Pathogenesis: development and progression of the condition
- Major clinical features: symptoms and signs of the condition
- Prognosis: predicted outcome of the condition
Guillain-Barre Syndrome
- Basic epidemiology: frequency and distribution of the condition
- Pathogenesis: development and progression of the condition
- Major clinical features: symptoms and signs of the condition
- Prognosis: predicted outcome of the condition
Nerve Compression
- Pathophysiologic mechanisms leading to neurological damage
- Effects of compression on nerve function and structure
Bell's Palsy
- Basic epidemiology: frequency and distribution of the condition
- Pathogenesis: development and progression of the condition
- Major clinical features: symptoms and signs of the condition
- Prognosis: predicted outcome of the condition
Nucleoside Structure
- Nucleoside consists of a sugar molecule and a nitrogenous base (pyrimidine or purine)
- The sugar molecule can be either 5-carbon ribose (in RNA) or deoxyribose (in DNA)
- Adenosine, a nucleoside, is composed of adenine and sugar
Nucleotide Bases
- Nucleotide bases to know: cytosine, thymine, adenine, guanine, and uracil
- Nucleoside names have "ine" endings (e.g., cytidine) which change to "dine" endings (e.g., cytosine) when referring to nucleosides
- Purine biosynthesis occurs via two main pathways: de novo synthesis and the salvage pathway
Gout
- Gout is a joint inflammation caused by the deposition of urate crystals
- Humans lack uricase, the enzyme responsible for degrading uric acid
- Uric acid is highly reabsorbed in the urine, leading to hyperuricemia
- Risk factors for gout include diets rich in purines, meat, and alcohol, as well as decreased renal excretion
- Non-modifiable risk factors include male sex and decreased renal excretion
Gout Epidemiology and Etiology
- 10% to 20% of the Western hemisphere population has hyperuricemia, but not all develop gout
- 1% to 4% of the general population develops gout
- Primary gout is caused by diet, idiopathic overproduction, or under-secretion of uric acid
- Secondary gout is caused by an identified disorder, such as chronic kidney disease
Gout Pathophysiology
- Acute gout is caused by monosodium urate crystal precipitation
- Local anatomical factors, such as temperature, pH, and joint hydration, increase the likelihood of arthritis
- Urate crystals are phagocytosed by macrophages, activating them and releasing chemokines that attract neutrophils
- Neutrophils mediate joint inflammation, and complement activation via the alternative pathway contributes to neutrophil recruitment
Gout Pathophysiology: Acute
- Phagocytosis by macrophages results in activation of the inflammasome, leading to secretion of IL-1 and further accumulation of neutrophils and macrophages
- Release of cytokines, free radicals, proteases, and arachidonic acid metabolites perpetuates the inflammatory cycle
- Phagocytosed crystals can induce rupture of phagolysosomes and lysis of neutrophils, releasing proteases and inflammatory mediators
Gout Pathophysiology: Chronic
- After the first attack, people enter an inter-critical phase with a varying number of acute attacks
- Chronic gout leads to chronic arthritis with joint erosion, chronic inflammation, and development of pannus and tophi
- Urate crystals encrust the articular surface of the joint, forming deposits in the synovium
Gout Clinical Findings
- 90% of affected individuals experience acute attacks in the first metatarsal-phalangeal joint, insteps, ankles, and heels
- Acute gout attacks are characterized by excruciating pain, inflamed joints, and redness
- In the absence of appropriate therapy, attacks recur at shorter intervals and frequently become polyarticular
Lesch-Nyhan Syndrome
- Deficiency of HGPRT (hypoxanthine-guanine phosphoribosyltransferase) leads to hyperuricemia
- Accumulation of hypoxanthine and guanine breaks down into uric acid
Synovial Fluid Analysis
- Monosodium urate crystals are birefringent, needle-shaped, and diagnostic for gout
- Calcium pyrophosphate crystals are non-birefringent, cuboidal, and diagnostic for pseudogout
Anti-Gout Agents
- Therapeutic options include targeting inflammation, analgesics, decreasing uric acid production, and increasing uric acid excretion
- Colchicine is a specific anti-gout agent that targets inflammation
- Allopurinol decreases uric acid production, while uricosurics (e.g., probenecid and sulfinpyrazone) increase uric acid excretion
Colchicine
- Mechanism of action: binds tubulin and prevents microtubule polymerization
- Reduces frequency of attacks prophylactically and can terminate an attack acutely
- Adverse effects include bone marrow depression
Otitis Media
- Otitis media is a type of infection that affects the middle ear, and can cause complications such as acute mastoiditis, meningitis, and brain abscesses.
- According to estimates, 21000 deaths occur annually due to AOM, and 30 per 10,000 individuals experience hearing loss.
- Perforation of the tympanic membrane is another possible complication.
Epidemology of Otitis Media
- Incidence and prevalence of otitis media have been difficult to establish.
- Acute otitis media (AOM) is a common infection, especially in children.
- Otitis media with effusion (OME) is another type of otitis media, and its epidemiology is not well understood.
- Chronic suppurative otitis media (CSOM) is a chronic infection that can cause complications such as hearing loss.
Causal Pathways for Otitis Media
- Eustachian tube anatomy plays a crucial role in the development of otitis media.
- The common otopathogens that cause otitis media include Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Pseudomonas aeruginosa.
Streptococcus pneumoniae
- Streptococcus pneumoniae is a common otopathogen that can cause otitis media.
- Virulence factors of Streptococcus pneumoniae include polysaccharide capsule, fimbriae, and surface proteins that inhibit activation of complement.
Haemophilus influenzae
- Haemophilus influenzae is another common otopathogen that can cause otitis media.
- Virulence factors of Haemophilus influenzae include adhesins, polysaccharide capsule, lipid A chains/lipooligosaccharides, fimbriae, and IgA protease.
Moraxella catarrhalis
- Moraxella catarrhalis is a gram-negative, diplococcus, aerobic bacteria that can cause otitis media.
- Virulence factors of Moraxella catarrhalis include antibiotic resistance, outer membrane proteins, iron-regulated proteins, and lipid A chains/lipooligosaccharides.
Pseudomonas aeruginosa
- Pseudomonas aeruginosa is an opportunistic pathogen that can cause otitis media and otitis externa.
- Virulence factors of Pseudomonas aeruginosa include fimbriae and adhesins, formation of biofilms, production of enzymes like elastase, and pyocyanin.
Staphylococcus aureus
- Staphylococcus aureus is a salt-tolerant, facultative anaerobe that can cause otitis externa.
- Virulence factors of Staphylococcus aureus include enzymes like coagulase, hyaluronidase, and lipase, structural defenses like capsule/slime layer, and toxins like cytolytic toxins and leukocydin.
Other diseases caused by Staphylococcus aureus
- Staphylococcus aureus can cause a range of diseases, including skin diseases, reproductive system diseases, systemic infections, cardiovascular diseases, respiratory system diseases, and gastrointestinal system diseases.
Primary Immune Deficiencies
- Most primary immune deficiencies are relatively rare, but they are the most common among the 1° immunodeficiencies.
- The table is not comprehensive, and there are exceptions to the general rules presented.
B Cell Deficiencies
- Isolated IgA deficiency: 1 in 600 people, very common among Caucasians.
- Common variable immunodeficiency: 1 in 50,000 people, characterized by defects in most classes of antibody secretion, inability of helper T-cells to amplify antibody production, and reduced cytotoxic T-cell activity.
- X-linked agammaglobulinemia (Bruton's): 1 in 250,000 people, characterized by an inability of Pro-B cells to differentiate into Pre-B cells due to a lack of a tyrosine kinase that initiates recombination and antibody formation.
- Hyper IgM syndrome: 1 in 1,000,000 people, characterized by an inability of helper T-cells to activate B-cells and macrophages, resulting in difficulty producing IgG, IgA, and IgE.
Clinical Features of B Cell Deficiencies
- X-linked agammaglobulinemia (Bruton's): recurrent respiratory infections, usually only affects males, and diagnosis is made by the absence or decrease of B-cells, depressed immunoglobulins, and underdeveloped B-cell areas of lymphatic tissues.
- Common variable immunodeficiency: resembles XLA, recurrent sinopulmonary infections, giardiasis, and serious enterovirus infections, and 20% rate of autoimmune disease.
- Isolated IgA deficiency: asymptomatic, symptoms if recognized are usually not recognized until adulthood, history significant for recurrent otitis media, sinusitis, bronchitis, pneumonia, and GI tract infections, increased incidence of autoimmunity, and potentially deadly complication of life-threatening anaphylaxis post-blood transfusion.
- Hyper IgM syndrome: recurrent pyogenic infections, many viral infections, high IgM, low on other antibodies, decreased neutrophils, and decreased CD40L on T-cells.
Treatment and Prognosis of B Cell Deficiencies
- X-linked agammaglobulinemia (Bruton's): IVIG therapy, prognosis is good, but most died in childhood before IVIG therapy.
- Common variable immunodeficiency: IVIG therapy, prognosis is good, 20-year survival is high.
- Isolated IgA deficiency: prognosis is good, but potentially deadly complication of life-threatening anaphylaxis post-blood transfusion.
- Hyper IgM syndrome: IVIG and intense antibiotic prophylaxis, prognosis is guarded, 20% survival rate in those 25 and older.
DiGeorge Syndrome (22q11 deletion)
- Relatively common: 1-2 in 2000 people, characterized by a T-cell deficiency, most immunodeficiencies involve primarily B-cell defects.
- Clinical features: immunodeficiency, thymic hypoplasia, increased fungal and viral infections, increased autoimmunity, cardiac abnormalities, craniofacial abnormalities, developmental delay, and hypoparathyroidism.
- Treatment: avoid blood products, can result in graft-vs-host disease, infectious disease specialist for immunotherapy, antibiotic prophylaxis, and prognosis varies greatly.
Severe Combined Immunodeficiency (SCID)
- A multitude of etiologies, defined by recurrent, severe infections by a wide range of pathogens, very severe, and need bone marrow transplant or stem-cell therapies or death ensues at a young age.
- Occurs in ~1 in 75,000 live births.
- 50-60% of SCID is X-linked, due to a mutation in the gamma-chain of a variety of cytokine receptors, and the remainder is autosomal recessive.
Innate Immunodeficiencies
- Complement defects: C2 deficiency, increased risk of SLE, and deficiencies of other components.
- Hereditary angioedema: autosomal dominant disorder, deficit in C1 inhibitor, results in unchecked activation of the classical complement pathway, increased bradykinin production, and increased activation of certain components of the clotting cascade.
- Clinical features: episodic, attacks usually become progressively more severe, severe abdominal pain, vomiting, diarrhea, swelling of face, hands, legs, groin, and life-threatening airway involvement.
- Treatment and Prognosis: can treat with C1 inhibitor from blood products, greatly improved prognosis, and mortality used to range between 20 – 30%.
Infectious Diseases Risk of Systemic Glucocorticoid Use
- Systemic use of glucocorticoids can increase risk of infections, especially with higher doses and for greater than 2-4 weeks.
- Specific Infections: Pneumocystis jiroveci pneumonia, fungal infection of the lung, and combination antibiotics prophylactically or treatment.
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Description
This quiz covers the pathophysiological mechanisms of demyelination, its effects on neuronal function, and the epidemiology of Multiple Sclerosis (MS). It also delves into the clinical features and diagnostic aspects of MS.