Week 5: Compressive and Demyelinating Illness in the CNS PDF

Week 5 Tuesday, January 30, 2024 11:56 AM Compressive and Demyelinating Illness in the Central Nervous System Demyelinating Disease – Overview: Demyelination can occur in the peripheral or central nervous system ○ Central – damage to oligodendrocytes or their processes that myelinate axons ▪ Most co...

Week 5 Tuesday, January 30, 2024 11:56 AM Compressive and Demyelinating Illness in the Central Nervous System Demyelinating Disease – Overview: Demyelination can occur in the peripheral or central nervous system ○ Central – damage to oligodendrocytes or their processes that myelinate axons ▪ Most common mechanism of injury – damage to the processes, usually an autoimmune mechanism (multiple sclerosis) ○ Peripheral – damage to Schwann cells; common mechanisms include: ▪ Genetic deficits that impair the ability of Schwann cells to compact or produce myelin sheaths ▪ Autoimmune – self-reactive antibodies, antibody complexes, or cytotoxic T-cells damage Schwann cells Central Nervous System Multiple Sclerosis – Overview: Immune-mediated disease directed against the CNS => loss of myelin and eventual loss of axons ○ Chronic inflammatory findings (typical of autoimmunity) ○ White matter lesions throughout the brain and spinal cord ○ Pathological specimens are firm and indurated in areas of white matter loss (sclerosis) Highly variable ○ can affect almost anywhere in the CNS (brain and spinal cord) ○ Motor, sensory, cognitive, and mood signs/symptoms Multiple Sclerosis – Epidemiology: Most common demyelinating illness ○ Prevalence is ~1/1000 in North America and Europe ▪ 3x more frequent in women ▪ Tends to begin during young adulthood/middle age Peak incidence between 20 and 40 ○ How common is it in Canada? ▪ About 100,000 people affected now By 2031 there will be over 130,000 affected ○ Cost on the Canadian healthcare system => over $16,000/person/year MS – Etiology: Genetic Polygenetic etiology ○ Candidate genes: ▪ HLA-II gene (DRB1/DRB15) Responsible for antigen presentation – responsible for 10% of disease risk, gene most associated with the disease Pathophysiology uncertain ▪ IL-2, IL-7, IL-17 ▪ Genetic variations have not been linked to phenotypic variations (110 genetic variations identified so far) ○ 15X increased risk if a first degree relative, 150X increased risk if a monozygotic twin has it Other factors: Link to viral infections (EBV?) ○ B cells may find their way into the CNS during a viral infection ○ There are often many activated B-lymphocytes found within the CNS that are not specific for myelin – may disrupt immune regulation in the CNS once they’re established Sun exposure and vitamin D ○ Some epidemiological evidence that reduced levels of vitamin D may contribute History of another autoimmune disease MS – Pathogenesis: MS progresses straight to a chronic inflammatory picture with no preceding acute inflammation ○ Typical of most autoimmune diseases Two phases: ○ 1st phase (active plaques): presence of typical leukocytes found during chronic inflammation ▪ Destroy myelin and oligodendrocytes that form it, though new oligodendrocytes can still be generated ▪ Major leukocytes: CD4+ Th (likely mostly Th1 and Th17) and B-cells Macrophages (recruited and derived from microglia) and cytotoxic T-cells 2nd phase (inactive plaques): loss of axons (and eventually neurons) with limited to no leukocytic infiltration and prominent gliosis found during that MS - Gross Pathology: Multiple well-circumscribed, irregularly shaped plaques that are firmer than the surrounding tissues Commonly occur adjacent to the lateral ventricles, optic tracts, brainstem, cerebellum, spinal cord More prominent in areas rich in white matter Over time, a degree of cerebral atrophy may be noted change of s in glia MS Pathogenesis: Active Plaques: Leukocytes are recruited from the circulation, across the BBB (there should be few to no leukocytes in the normal CNS) Helper T-cells initiate an immune response against myelin (likely a component of myelin basic protein) ○ MBP helps to compact the many layers of the myelin sheath These helper T cells recruit other leukocytes into white matter (cytotoxic T-cells, macrophages) and activate them ○ Cytotoxic T-cells seem to attack oligodendrocytes MBP-specific B-lymphocytes are also recruited into the CNS and produce anti-MBP antibodies – these also seem to help destroy the myelin sheath Inflammation in MS Hematoxylin and eosin (H&E) stain shows perivascular infiltration of inflammatory cells These infiltrates are composed of activated T cells, B cells and macrophages ftp.ffd Infiltrates Macrophages MS Pathogenesis: Acute Flares: Flare = period of worsened neurological symptoms ○ build-up of helper T-cells and cytotoxic T-cells in the CNS that attack white matter components and B-cells that produce myelin-specific antibodies ○ In between flares, fewer chronic inflammatory cells detected As flares continue, there seem to be areas where lymphocytes reside “permanently” – these are called lymphocytic follicles ○ Prominent around the meninges and blood vessels MS Pathogenesis: Inactive Plaques: Inactive plaques = plaques without prominent inflammation With loss of myelin and oligodendrocytes, axons tend to degenerate ○ “destabilization” of action potentials (see next slide) ○ Fewer action potentials à reduced trophic support for neurons – leading to neuronal cell death ○ Expression of NMDA receptors on “naked” axons and calcium-mediated cytotoxicity – glutamate is also toxic to oligodendrocytes In many (most?) patients, over time MS can progress with very limited inflammation ○ White matter, axons, and neurons can all be lost in areas with minimal chronic inflammatory findings ○ Prominent gliosis (astrocytes and microglia), no new oligodendrocyte production Following demyelination, additional sodium channels are redistributed along the axon, allowing action potential conduction ○ Changes in temperature and activity can impair the conduction along the demyelinated segment, though – destabilization of APs Non-saltatory (continuous) conduction of APs requires more ATP; may have long-term neuronal metabolism consequences MS - Signs and Symptoms: Most common initial symptoms: Paresthesias in one or more extremities, the trunk, or one side of the face Weakness or clumsiness of a leg or hand Visual disturbances ○ Partial loss of vision and pain due to optic neuritis ○ Diplopia ○ Scotomas ○ Nystagmus and dizziness Double vision InvoluffrySEEmovement Cognitive: Fatigue and depression are common and disabling (~75%) Many patients report that MS impairs (slows) their cognition and has prominent effects on memory Sensory: Paresthesia and loss of any type of sensation ○ Paresthesias include tingling, prickling, “pins and needles” feelings, and are very common ▪ Can also include a restless feeling or feeling like bugs are on or under the skin (formication) Pain, whether as a part of paresthesias or chronic pain, is present in 50% L’hermitte’s phenomenon ○ Sensation of an “electrical shock” running down the back and along the limbs (usually unpleasant) ○ Not sensitive or specific for MS Motor: Bilateral, spastic weakness, mostly in the lower extremities ○ Spasticity is a common spinal cord manifestation Increased deep tendon reflexes Charcot triad: dysarthria, nystagmus, tremor Facial twitching (myokymia) Slurred speech Brainstem and spinal cord findings: Dizziness Bladder dysfunction (e.g. urinary urgency or hesitancy, partial retention of urine, mild urinary incontinence) – very common Constipation Erectile dysfunction in men or genital anesthesia in women Frank urinary and fecal incontinence in advanced cases Other: Heat and activity intolerance ○ May be linked to “action potential destabilization” ○ Uhthoff sign – hot environment or shower => blurry vision ○ Symptoms and signs often worsen in hot environments and with intense activity – can even precipitate flares Lhermitte's phenomenon Sensation of an electrical shock along running back limbs Charcot toad MS – Diagnosis: Clinical diagnosis ○ A symptom and history checklist, known as the MacDonald’s criteria Aided by characteristic lesions on a brain and spinal MRI ○ these lesions are not specific, though they are pretty sensitive Presence of certain types of antibodies in the CSF dysarthria nystagmus tremor criteria Macdonalds at episodes 2t Signs hours last 24 Distinct episodes separatedby Must a month or more MS - MacDonald criteria simplified: Requires: documentation of two or more episodes of symptoms + two or more signs ○ pathology in anatomically noncontiguous white matter tracts of the CNS ○ Symptoms must last for >24 h ○ Must occur as distinct episodes that are separated by a month or more Revision allows for imaging (MRI) to add additional data in place of a second occurrence of 2 signs + 2 symptoms MS – Treatment: In general, the prognosis is better for relapsing-remitting, and worse for primary progressive ○ Many relapsing-remitting patients progress to secondary progressive ○ Secondary proressive is often less responsive to immunomodulatory drugs Mortality is uncommon, but significant functional disability is the norm (likely 30 – 50% even with disease-modifying therapies) relapsing remitting Iffressive Secondary progressive less responsive to immenomodulatory drugs MS Therapies => FYI: … are complicated and some have a pretty much unknown mechanism of action Agents that prevent immune cell migration ○ Natalizumab (anti-integrin) ○ Fingolimod (keeps lymphocytes sequestered in lymph nodes vs. migrating to peripheral tissues, may also shift macrophages to M2 phenotype) ○ interferons (reduces T-cell penetration through the BBB, not sure why) Agents that deplete immune cells ○ Ocrelizumab, rituximab, cladribine, alemtuzumab, mitoxantrone Agents that nobody really understands ○ Copaxone (glatiramer), dimethylfumarate There’s a lot of others Peripheral Neuropathies: Terminology: Neuropathy: functional disturbance and/or pathological change in the PNS Neuralgia: pain in the distribution of a particular nerve, usually in the absence of objective signs Neuritis: inflammation of a nerve Radiculopathy: pain along a dermatome, implying that the problem is at the level of the nerve root Plexopathy: neuropathy of the entire plexus Neuropathies can be sensory, motor, autonomic or a combination Polyneuropathy: often presents as: ○ Symmetrical distal weakness ○ Symmetrical distal sensory loss (stocking & glove) ○ Hyporeflexia Multiple mononeuropathy: involves >1 nerve, but not in a symmetrical fashion ○ Often due to toxins, diabetes, AIDS, chronic inflammatory disease (e.g. RA, SLE) s FEE lathy algia pain Itis inflammation Charcot-Marie-Tooth Disease: AKA Hereditary motor and sensory neuropathy ○ HMSN Autosomal dominant inheritance ○ Penetrance is variable – not the same severity in everyone The most common inherited neurologic disorder ○ Prevalence: 1/2500 (quite common) Pathophysiology: CMT1 – demyelination of peripheral nerves due to abnormal myelin production, damage to nerves, and thickened, palpable myelin sheaths ○ Proteins involved in myelin compaction are defective, resulting in demyelination/remyelination cycles CMT2 – axonal death and degeneration without a primary defect in myelin (less frequent) Clinical Presentation: Both sensory and motor symptoms Slowly progressive distal symmetric muscle weakness and atrophy (champagne bottle legs) ○ Diminished DTRs, foot drop, pes cavus with hammer toes common Proprioception and touch mainly affected ○ Less pain and temperature, since these are unmyelinated Nerves can become enlarged and palpable with cycles of myelination and re-myelination Diagnosis, Treatment, Prognosis: Nerve biopsy and nerve conduction studies, as well as characteristic physical exam, history Treatment: ○ Massage – ROM to prevent contractures ○ Anti-inflammatories, analgesics Most have normal life expectancy ○ Involvement of phrenic nerve or cranial nerves is very rare ○ For reasons not well understood, usually exclusively affects the lower leg Guillain-Barre Syndrome (GBS): Acute onset immune-mediated demyelinating neuropathy Uncommon disease, but most common cause of acute flaccid paralysis ○ 1.5/100,000/year Pathogenesis: ○ Typically occurs after an infection (2/3 of cases involve identifiable previous flu-like symptoms) ○ Infections with Campylobacter jejuni, cytomegalovirus, Epstein-Barr virus, and Mycoplasma pneumoniae, or prior vaccination are shown to be associated Pathogenesis cont… T-lymphocytes that presumably recognize myelin cause a segmental demyelination ○ Macrophages are also found within lesions and are thought to aid destruction of nerves ○ Antibodies also likely mediate some damage; plasmapheresis improves symptoms Clinical features: Acute, rapid, progressive inflammatory polyradiculopathy ○ Unlike other conditions discussed previously, develops rapidly and typically involves predominantly motor symptoms Ascending symptoms – weakness starts in the lower limbs, progresses to higher regions of the body ○ Sensory loss can also occur but weakness is prominent ○ Flaccid paralysis that can threaten life if it progresses to involve the phrenic nerve (C3, C4, C5) Sphincters tend to be spared Diagnosis, treatment, prognosis: Diagnosis mostly made by history and physical, EMG and nerve conduction studies are helpful Treatment – severe disease, can progress to loss of function including cervical spinal cord ○ Protect airway, ventilation ○ Plasmapheresis – removal of antibodies from the blood ○ IV immunoglobulins If patients survive the initial disease, prognosis is good ○ Some have prolonged functional deficits for 2 years or more ○ If not recognized and treated, very high mortality Flaccid paralysis loss of musile function reduced muscle tone Compressive Neurological Damage: In the peripheral nervous system, compression of a nerve often leads to: ○ Pain – very common, feature of most compressive neuropathies ○ Reduction or loss of function ▪ Loss of motor function => weakness or flaccid paralysis Sometimes loss of autonomic nervous system function (i.e. urinary retention, erectile dysfunction) ○ Loss of sensory function => numbness (anaesthesia) or tingling, pins-and-needles sensation (dysaesthesia) Compressive Neurological Damage – General Pathophysiology: Theories of compressive nerve damage: Direct mechanical damage to the nerve => loss of axonal function (crush injury) ○ Death of the nerve likely only in severe cases ○ Less severe => compressive defects in axonal transport necessary for transporting proteins from cell body to axon Ischemia: ○ Compression of the vessels in the perineurium => decreased blood flow and reduced function in the nerve ▪ Usually nerve survives unless compression is severe ▪ Likely the most important mechanism of damage ▪ Impingement of the nerve => inability to “glide” along its course may explain symptoms that are dependent on position Direct Mechanical Damage loss of axonal function Ischesi Common Compressive Disorders – Peripheral Nerves: FYI – to be covered in your Biomed/Phys Med class: ○ Carpal tunnel syndrome ○ Ulnar nerve entrapment ○ Thoracic outlet syndrome ○ Suprascapular nerve entrapment ○ Disk herniation => radiculopathy ○ Sciatica ○ Meralgia paresthetica ○ Peroneal nerve compression the perineurium Bell’s Palsy: Idiopathic paralysis of the facial nerve, most common cause of unlateral facial paralysis ○ 23/100,000/year (close to MS incidence; common) ○ Tends to occur in adults (slightly more common in older adults) Thought to be compression of the facial nerve caused by edema/inflammation caused by herpes virus ○ Herpes virus normally lies dormant in the cell body of neurons ○ Pathophysiology: ▪ Herpes virus reactivation à Edema of the facial nerve (CN7) during inflammation à compression of the nerve in the very narrow compartment of the petrous portion of the temporal bone where the nerve runs ▪ Studies suggest that this compartment is more narrow on the affected side than on the contralateral side Clinical Features: Acute onset of unilateral upper and lower facial paralysis (over a 48 hour period) Posterior auricular pain, earache Decreased tearing or epiphora Hyperacusis Taste disturbances Otalgia Poor eyelid closure Diagnosis, treatment, prognosis: Diagnosis is mainly clinical (signs and symptoms) Steroids and antivirals have limited value ○ Surgery in stubborn cases Tends to self resolve (>80% of cases) over time Nucleotide metabolism: Crystal Arthropathies Review: Purines – De novo synthesis Glutamine is used to transfer an N to PRPP ○ Results in a phosphoribose (sugar+P) with an added N ○ Still need a base to make a nucleotide ○ Base (2 rings) is built on this N ▪ Other amino acids, CO2 and folate (?) coenzymes supply the C, H, O and N ○ The nucleotide product is inosine monophosphate (IMP) ▪ What, therefore, is the purine base that was made? IMP can then be used to make AMP or GMP ○ These pathways also use: ▪ GTP to make AMP ▪ ATP make GMP ○ This allows for reciprocal control: when ATP is high you make GMP, when GTP is high is make AMP ▪ Why do you think is type of control is useful? Purine – Salvage pathway: Important to have, as de novo uses lots of energy Uses hypoxanthine, guanine, and adenine bases that already exist ○ Where do they come from? ○ What do you still need to add to get a nucleotide? Enzymes: ○ Hypoxanthine-guanine phosphoribosyl transferase (HGPRT) ▪ Catalyzes the addition of phosphoribose (sugar+P) from PRPP to: Hypoxanthine to make IMP Guanine to make GMP ○ Adenine phosphoribosyltransferase (APRT) ▪ Catalyzes the addition of phosphoribose (sugar+P) from PRPP to: Adenine to make AMP Pyrimidine Nucleotide Synthesis: De novo pathway, involves making an intermediate pyrimidine ring first, then attaching a ribose-5-P (via PRPP) ○ Opposite to purines, where the ring is constructed directly on the ribose-5-P Substrates for ring are: ○ Carbamoyl phosphate (made from glutamine, ATP, CO2) ▪ What other use do you know for carbamoyl phosphate? ○ Aspartate Pyrmidine Nucleotide Synthesis: To make CTP: ○ UMP is phosphorylated via kinases to make UTP ○ UTP is aminated to make CTP ▪ Glutamine supplies the N To make dTMP (what does “d” mean?): ○ UMP is first phosphorylated (kinase) to make UDP, then converted to dUMP ○ dUMP is methylated to dTMP using a folate coenzyme Catabolism and clinical correlations General: Nucleotidases remove P’s from nucleotides to release nucleosides ○ Sugar removed to release bases ▪ Pyrimidine bases degraded: Cytosine to uracil and ultimately alanine FYI: Thymine to aminoisobutyrate ▪ Purine bases degraded: First to xanthine, then uric acid ○ Uric acid is eventually excreted in urine ▪ Elevated levels can lead to hyperuricemia and gout Conversion of hypoxanthine to xanthine, and xanthine to uric acid, uses the enzyme xanthine oxidase Gout: Can be due to underexcretion (most common) or overproduction (less common) of uric acid à hyperuricemia Hyperuricemia can lead to gout ○ Deposition of monosodium urate crystals in the joints à immune cells mount an inflammatory response to crystals ▪ Known as gout (gouty arthritis) ○ Nodular masses of monosodium urate crystals (tophi) may be deposited in soft tissues ▪ Known as chronic tophaceous gout ○ Uric acid stones can form in the kidneys (urolithiasis) Humans lack uricase, the enzyme responsible for the degradation of uric acid in other mammals ○ Uric acid is also highly reabsorbed in the urine ○ Major modifiable risk factors include diets rich in alcohol (beer has quite a few purines) and meat (especially organ meats), asparagus ▪ Non-modifiable include male sex (much more common in guys) and decreased renal excretion Gout = joint inflammation due to deposition of urate crystals Gout – Epidemiology & Etiology: Epidemiology: 10% - 20% of the population of the Western hemisphere has hyperuricemia, but not all develop gout ○ 1 – 4% of the general population develop gout Etiology: Increased uric acid production: ○ Enzyme defects in degradation of uric acid ○ Rapidly-dividing cancers – i.e. leukemia Decreased uric acid excretion (in the kidneys) ○ Idiopathic ○ Chronic kidney disease Gout – Pathophysiology: Acute: Monosodium urate crystal precipitation results in acute gouty arthritis ○ Local anatomical factors that increase the likelihood of arthritis include: ▪ temperature, pH, trauma, joint hydration Urate crystals are phagocytosed by macrophages, activating them ○ They then release chemokines that attract neutrophils into the joint, found within the synovial fluid ▪ Neutrophils mediate joint inflammation Complement activation via the alternative pathway also contributes to neutrophil recruitment. Phagocytosis by macrophages results in activation of the inflammasome ○ Secretion of IL-1 ○ Further promotes accumulation of neutrophils and macrophages within the joint ▪ Release cytokines, free radicals, proteases, & arachidonic acid metabolites ○ This is a vicious cycle! Phagocytosed crystals will induce rupture of phagolysosomes and lysis of neutrophils. ○ Futher release of proteases and inflammatory mediators Eventually (within days to weeks) there will be spontaneous remission Gout – Pathophysiology: Chronic: After the first attack, people enter an inter-critical phase with a varying number of acute attacks ○ Many people will have attacks every few months Chronic gout leads to chronic arthritis with joint erosion, chronic inflammation, development of pannus, and development of tophi ○ Urate crystals encrust the articular surface of the joint forming deposits in the synovium ○ Synovium becomes hyperplastic, fibrotic, and thickened with inflammatory cells (ie. pannus formation) ○ Destruction of underlying cartilage leads to bone erosion ○ In severe cases a fibrous or bony ankylosis can form, resulting in loss of joint function. Tophi – pathognomonic hallmark of gout ○ Large, inflammatory bodies that surround areas of crystal deposition ▪ form foreign-body giant cells ▪ Consist of macrophages and lymphocytes ▪ Occur in articular cartilage, ligaments, tendons, and bursae ○ Can invade joint and surrounding soft tissues or kidneys ▪ Earlobes, fingertips Presence of urate crystals or tophi in kidneys can result in renal complications (urate nephropathy) Gout – Clinical Findings: Clinical findings - acute: ○ 90% of affected individuals experience acute attacks in the following locations (in descending order of frequency): ▪ st metatarsal-phalangeal joint, insteps, ankles, heels ▪ Knees, wrists, elbows ▪ Fingers ▪ Lower limbs are more often affected than upper ○ Excruciatingly painful, inflamed joints (redness, swelling) characterize acute gout attacks ▪ Untreated, acute gouty arthritis may last for hours to weeks Clinical findings – Chronic: ○ In the absence of appropriate therapy, the attacks recur at shorter intervals and frequently become polyarticular ○ Eventually, over the span of years, disabling chronic tophaceous gout develops ▪ Average of 12 years between the initial acute attack and the appearance of chronic tophaceous arthritis Lesch-Nyhan Syndrome: Can lead to hyperuricemia ○ Deficiency of HGPRT (what does this enzyme do?) ▪ Leads to accumulation of hypoxanthine and guanine, which break down into ? ▪ PRPP also accumulates and stimulates production of purine nucleotides, which ultimately break down into ? ○ Hyperuricemia frequently results in urolithiasis and gouty arthritis ○ Severe neurological problems Calcium pyrophosphate crystal deposition disease (CPPD) – Epidemiology & Etiology: Also known as pseudogout: Epidemiology: Common, prevalence increases with age (reported to be present in 30 – 60% in those older than 85) Etiology: Most cases are sporadic ○ Some have a genetic component (autosomal dominant) ○ Can be caused by hyperparathyroidism, hemochromatosis, diabetes, hypothyroidism ○ Some medications may trigger pseudogout – this is poorly-defined, though Calcium pyrophosphate crystal deposition disease (CPPD) - Pathology: Pathology: ○ Crystals deposit in matrix of menisci, connective tissue of joint ○ Rupture, eliciting inflammation as macrophages phagocytose the crystals ○ Recruit neutrophils, which are thought to mediate inflammatory damage Calcium pyrophosphate crystal deposition disease (CPPD) – Clinical Features: Clinical presentation: ○ Can be asymptomatic – can mimic osteoarthritis or rheumatoid arthritis ○ Asymmetric, can be monoarticular or polyarticular ○ Commonly affects knees, less common sites are wrists, shoulders, elbows, ankles ○ Eventually 50% have significant joint damage (affects mobility) Treatment: ○ No therapy is effective in preventing damage, symptomatic treatment Synovial Fluid Analysis: Why is it done? ○ It is not always easy to distinguish between septic arthritis, gout, pseudogout, hemarthroses and rheumatic joint diseases ▪ Septic arthritis must be managed urgently ▪ Hemarthrosis and gout should also be managed (semi-urgently) ○ It’s a good test at distinguishing between an acute flare of gout or pseudogout and septic arthritis ▪ Poorer sensitivity and specificity when it’s more difficult to visualize crystals (between flares) ○ For an acutely swollen, painful joint, it can change management When is it done? ○ Suspicion of an infectious arthritis, flare of crystal arthritis, or hemarthrosis ▪ Monoarthritis (with or without a prior history of arthritis of other joints) ▪ trauma to a joint with effusion You analyze the three C’s: ○ Crystals – seen under microscopy with gout and pseudogout ○ Cells – red blood cells? Leukocytes (neutrophils or lymphocytes) ○ Culture – any microorganisms growing in there? ▪ (takes some time) Disorder Normal Gout Pseudogout Septic Arthritis Hemarthrosis Inflammatory Arthritis Osteoarthritis Cells Crystals < 200/ul (low) Negative > 2000/uL (high, but not as high as septic) Birefringent, needleshaped > 2000/uL (high, but not as high as septic) Non-birefringent, cuboidal > 50,000/uL (very high) Negative Lots of RBCs Negative > 2000/uL (high) Negative < 2000/uL (medium) Negative Anti-gout agents: Possible therapeutics options include: ○ Target the inflammation ▪ General: Corticosteriods (previous lecture) ▪ Specific to gout: Colchicine ○ Analgesics ▪ NSAIDs (ex aspirin) (previous lecture) Most common treatment ○ Decrease uric acid production ▪ Allopurinol ○ Increase uric acid excretion ▪ Uricosurics (probenecid and sulfinpyrazone) Colchine: Mechanism of action: ○ Binds tubulin and prevents microtubule polymerization ▪ How does effect inflammation? ▪ What other condition do you think it was considered as a treatment for? Found to be too toxic ○ Prophylactically, can reduce frequency of attacks ▪ FYI: : 0.5mg/day, 3-4 days per week ○ Acutely, can terminate an attack if taken at first sign of inflammation ▪ FYI: 1-1.2 mg every hour until attack abates or diarrhea occurs Adverse effects: ○ Most serious is bone marrow depression ▪ Why would it potentially cause this? ▪ Requires patient blood count monitoring ▪ Requires monitoring for less serious adverse effects Ex nausea, vomiting, abdominal pain, diarrhea ○ If appear, drug should be discontinued for at least 3 days to prevent cumulative toxicity leading to more serious effects Allopurinol and Uricosurics: Allopurinol: ○ Competitive inhibitor of xanthine oxidase (?) ○ Do you think it is useful prophylactically, acutely, or both? ○ Can precipitate an attack of gout at the beginning of therapy – why? ▪ As uric acid concentrations go down, crystals start to dissolve and the immune system responds Typically give aspirin at beginning of allopurinol therapy to reduce pain Uricosurics: ○ Block tubular reabsorption of uric acid, increasing excretion ○ Do you think it is useful prophylactically, acutely, or both? ○ Do you think it can precipitate an attack of gout at the beginning of therapy? OTITIS MEDIA/EXTERNA: PATHOGENESIS, EPIDEMIOLOGY and TREATMENT Otitis Media (OM): Acute Otitis Media (AOM): ACUTE OTITIS MEDIA (AOM): Complications: Suppurative complications of AOM ○ Acute mastoiditis ○ Meningitis ○ Brain abscesses 21000 deaths from AOM per year 30 per 10,000 individuals: hearing loss Perforation of tympanic membrane Otitis Media w/ Effusion: Chronic suppurative otitis Media (COM/CSOM): Acute otitis Media (AOM): Epidemiology: OTITIS MEDIA With EFFUSION (OME) - EPIDEMIOLOGY: Incidence and prevalence have been difficult to establish CHRONIC SUPPURATIVE OTITIS MEDIA – EPIDEMIOLOGY: CAUSAL PATHWAYS FOR OTITIS MEDIA: EUSTACHIAN TUBE ANATOMY: THE COMMON OTOPATHOGENS: Streptococcus pneumoniae (Pneumococcal conjugate vaccine?) Haemophilus influenzae Moraxella catarrhalis Pseudomonas aeruginosa HAEMOPHILUS INFLUENZA: Haemophilus influenzae: VIRULENCE FACTORS: Adhesins Polysaccharide capsule Lipid A chains/lipooligosaccharides Fimbriae IgA protease Biofilms Moraxella catarrhalis: Gram –ve, diplococcus, aerobic bacteria Common for URT, middle ear, eye infections Commonly resistant to beta lactam drugs Part of normal microbiota of ~3% of people. (children more) Variable rates of colonizations in communities. Moraxella catarrhalis: VIRULENCE FACTORS: Antiobiotic resistance (b-lactamase resistance) Outer Membrane Proteins ○ uspA1-A2, Pili Iron-Regulated Proteins ○ Transferrin-Binding proteins ○ Lactoferrin-binding proteins Lipid A chains/lipooligosaccharides Streptococcus pneumoniae: VIRULENCE FACTORS: Polysaccharide capsule Fimbriae Surface proteins that inhibit activation of complement PSEUDOMONAS infections: Caused by Pseudomonas aeruginosa – an opportunistic pathogen that becomes an infectious agent following the burning away of skin; can also cause otitis externa PSEUDOMONAS aeruginosa: VIRULENCE FACTORS: Fimbriae and adhesins to improve attachment Formation of biofilms Produce enzymes like elastase, which breaks down elastic fibres, degrades complement system, cleaves IgG and IgA antibodies Pyocyanin with triggers free radical accumulation (this is what causes tissue damage) PSEUDOMONAS AERUGINOSA: EPIDEMIOLOGY: P. aeruginosa is found mostly in soil; not a component of regular microbiota Cannot penetrate epidermal layer independently – good news! Common nosocomial infection agent (10% of hospital infections) STAPHYLOCOCCUS AUREUS: Salt tolerant, facultative anaerobe, resistant to dessication, UV radiation and heat Along with Staphylococcus epidermidis, make up ~90% of microbiota of skin. Common cause of otitis externa Virulence factors Staphylococcus aureus: 1. ENZYMES: Coagulase, Hyaluronidase, Staphylokinase Lipase, beta-lactamase 2. STRUCTURAL DEFENSES: Capsule/slime layer glycocalyx Binding IgG antibody stem regions 3. Toxins: Cytolytic toxins to disrupt membranes of a large number of cell types Leukocydin – kills leukocytes (another means of avoiding phagocytosis) Epidermal Cell Differentiation Inhibitors – produces large holes in the lining of blood vessels Exfoliative toxins (Toxic Shock Syndrome Toxin) Some other diseases caused by Staphylococcus aureus: Primary Immunodeficiencies Immunodeficiencies: Any defect in the immune response that renders an individual more susceptible to infectious diseases that would be cleared by someone who was healthy Patients with immunodeficiency diseases are more prone to contracting infections and these infections are more likely to end in long-term debilitation or death. ○ They also have higher risk for developing autoimmunity or cancer. Primary Immunodeficiencies: ○ Mostly inborn (genetic) and often detected in infancy or childhood (though some are detected in adulthood) Secondary Immunodeficiencies: ○ Acquired due to external factors (e.g. infection, chemotherapy, medications…) How do people with immunodeficiencies present? The above is a generalization re: how primary immunodeficiencies affect the patient: There are exceptions to the general rules presented above The table is also not comprehensive Primary immune deficiencies: Most of these are relatively rare, but they are the most common among the 1° immunodeficiencies: B Cell Deficiencies: ○ Isolated IgA deficiency 1/600 ○ Common variable immunodeficiency 1/50,000 ○ X-linked agammaglobulinemia (Bruton’s) 1/250,000 ○ Hyper IgM syndrome 1/1,000,000 DiGeorge syndrome 1-2/2000 Severe combined immunodeficiency 1/75,000 Innate Immunodeficiencies: ○ Complement Deficiencies 1/20,000 ○ Hereditary Hemangioma 1/50,000 X-linked agamaglobulinemia: Not very common – 1/250,000 population ○ Very few of the primary immune deficiencies are common, though Pathophysiology: ○ Inability of Pro-B cells to differentiate into Pre-B cells ▪ They can make a heavy chain variable region, but not a light chain, so they’re unable to make antibodies ▪ Due to lack of a tyrosine kinase that initiates recombination and antibody formation XLA (Bruton’s agammaglobulinemia): Clinical features: ○ Usually only males are affected (X-linked) ▪ When females express this disease, other genetic defects are thought to be in play ○ Recurrent respiratory infections call attention to the disease ▪ Pharyngitis, sinusitis, bronchitis, pneumonia ▪ Most are gram positive bacteria that are usually destroyed by IgG opsonization and phagocytosis Diagnosis: ○ B-cells are absent or very much decreased ○ All immunoglobulins are depressed ○ B-cell areas of lymphatic tissues are underdeveloped Treatment – IVIG: ○ Prognosis: in the past, most died in childhood ▪ IVIG therapy allows most people to live into their 40’s… it’s absolutely key to diagnose it and treat it early Common Variable Immunodeficiency: Numerous immunological issues can be present ○ defects in most classes of antibody secretion, ○ inability of helper T-cells to amplify antibody production, ○ reduced cytotoxic T-cell activity, and assorted defects in the innate immune system may be present Common feature is hypogammaglobulinemia, usually involving all antibody classes but sometimes only IgG ○ Other diagnostic criteria – reduced B-lymphocytes, recurrent bacterial infections Uncommon—1/50,000 of the population ○ Not necessarily a single disease, but a diagnosis of exclusion Clinical Features: ○ Resembles XLA – recurrent sinopulmonary infections, giardiasis, and serious enterovirus infections ▪ Can also have recurrent, severe herpes infections ▪ 20% rate of autoimmune disease Diagnosis: ○ No other B-cell abnormality (isolated IgA, XLA) detected ○ Reduced (but not absent) immunoglobulins (not as severely reduced as XLA) ○ B-cell areas of lymphatic tissues are hyperplastic, usually Treatment: ○ IVIG ○ Prognosis: 20-year survival is high, people can live for quite a while with therapy Isolated IgA deficiency: Very common – 1 in 600! ○ Your only common primary immunodeficiency ○ Much, much more common in Caucasians Pathogenesis: ○ No one knows… defects in a receptor for a B-cell activating cytokine? ○ Reduced amounts of IgA in serum, very little in secretions, but normal levels of other antibodies and lymphocytes ○ Lymphatic tissues look pretty much normal under a slide Clinical Features: ○ Most are asymptomatic – symptoms, if they are recognized, are usually not recognized until adulthood ○ History significant for recurrent otitis media, sinusitis, bronchitis, pneumonia, GI tract infections ▪ Like many other B-cell deficiency diseases – however, the immunodeficiency and subsequent infections are not nearly as severe ▪ Also increased incidence of autoimmunity, particularly lupus and RA ○ A potentially deadly complication is life-threatening anaphylaxis post-blood transfusion ▪ Recognize transfused IgA as foreign ○ Clinical pearl – the serology for detecting celiac disease is based on detection of IgA antibodies to enzymes that are involved in metabolizing gliadin ▪ IgA deficiency can result in false negatives in these celiac patients Prognosis is good Hyper-IgM Syndrome: Patients make IgM but have difficulty producing IgG, IgA, and IgE ○ Inability of helper T-cells to activate B-cells and macrophages ▪ CD40L deficit or lack of function ▪ Gene is on the X-chromosome, thus is X-linked and usually affects ??? ▪ 30% of patients have other defects – inheritance pattern is autosomal recessive in these instances ○ Very uncommon - 1/1,000,000 live births Clinical features: ○ Recurrent pyogenic (purulent) infections ▪ Can be in the CNS, respiratory tract, and GI tract ○ Many viral infections ▪ Hepatitis, gastroenteritis, encephalitis, pulmonary infections ○ These people are very immunodeficient – neutrophil counts are also decreased for unknown reasons ▪ High IgM, low on other antibodies, decreased neutrophils, decreased CD40L on T-cells can be used to diagnose ○ Treatment & Prognosis ▪ IVIG and intense antibiotic prophylaxis ▪ Prognosis is guarded… meaning often not good (20% survival rate in those 25 and older) 22q11 deletion (DiGeorge) syndrome: T-cell deficiency – most of the immunodeficiencies involve primarily B-cell defects (at least clinically) ○ 3rd and 4th pharyngeal pouches don’t develop… ▪ So you’re short on a thymus, parathyroid glands, some thyroid tissue ▪ Can also have heart and great vessel defects ▪ Hypothesized that the T-box family of transcription factors is absent or does not function – important transcription factor for branchial/pharyngeal arch development and large vessels ▪ Loss of genetic material on chromosome 22, on the long arm Relatively common – 1-2/2000 population Clinical Features: ○ Immunodeficiency: thymic hypoplasia results in variable loss of T-lymphocytes – low in blood and in lymphatic tissue ▪ Increased fungal and viral infections ▪ Increased autoimmunity (RA, thyroiditis) ○ Cardiac abnormalities (especially associated with the great vessels) ○ Craniofacial abnormalities – cleft palate, high and broad nasal bridge, long face, narrow palpebral fissures, and micrognathia ○ Developmental delay ○ Hypoparathyroidism… what electrolyte abnormality would this be associated with??? ○ Very complex disorder, usually diagnosed in childhood when cardiac abnormalities are identified and treated surgically Treatment: ○ Avoid blood products, can result in graft-vs-host disease ▪ GVD will be discussed later on ○ Infectious disease specialist for immunotherapy, antibiotic prophylaxis ○ Prognosis varies greatly – not everyone has every manifestation Severe Combined Immunodeficiency (SCID): A multitude of etiologies, defined by: ○ recurrent, severe infections by a wide range of pathogens ▪ C. albicans, P. jiroveci, Pseudomonas, CMV, varicella, and a ton of different types of bacteria ▪ Very severe – need bone marrow transplant or stem-cell therapies or death ensues at a young age ▪ defects in both cell-mediated and humoral immunity ○ Occurs in ~ 1/75,000 live births 50-60% of SCID is X-linked, due to mutation in the gamma-chain of a variety of cytokine receptors ○ signal-transducing component of the receptors for IL-2, IL-4, IL-7, IL-9, IL-11, IL-15, and IL-21 ○ very few T-lymphocytes or NK cells… yikes Remainder is autosomal recessive ○ due to a mutation in adenosine deaminase ▪ accumulation of deoxyadenosine and its derivatives are thought to be toxic to rapidly dividing lymphocytes ○ RAG mutations (interferes with somatic recombination)– B- and T-cell development blocked Pathological and clinical features: ○ Pathology: ▪ small thymus with very few lymphocytes ▪ depletion of T-cell areas of other lymphatic tissues ○ Signs and symptoms: ▪ Presents very early in life with recurrent severe infections ▪ Occasionally the mother’s T-cells are transferred across the placenta and cause graft-versus-host-disease (mom’s lymphocytes attack baby’s tissues), shows up as a generalized, morbilliform rash Innate Immunodeficiencies: Complement defects: ○ C2 deficiency – most common deficiency ▪ increased bacterial or viral infections, though many have no increased incidence of infection alternative pathway is adequate for most cases ○ Increased risk of SLE ○ Deficiencies of other components ▪ properdin, factor D, C3, and ? deficiencies are uncommon, but result in more severe immunosuppression Hereditary angioedema ○ Autosomal dominant disorder, less common than the complement deficiency disorders (1 in 50,000, so still not that common) ○ deficit in C1 inhibitor – results in: ▪ unchecked activation of the classical complement pathway ▪ increased bradykinin production (seems to be the most important molecule in pathogenesis) ▪ increased activation of certain components of the clotting cascade ○ Clinical features: ▪ episodic, attacks usually become progressively more severe can be precipitated by minor trauma (pressure), stress ▪ Symptoms: severe abdominal pain – can be mistaken for serious abdominal pathology ○ vomiting and diarrhea can also be present swelling of face, hands, legs, groin – can be life-threatening if airway is involved pleural effusions and seizures rarely occur ○ Treatment and Prognosis: ▪ can treat with C1 inhibitor from blood products – greatly improved prognosis ▪ mortality used to range between 20 – 30% Infectious Diseases Risk of Systemic Glucocorticoid Use: Systemic use of glucocorticoids can increase risk of infections ○ Increased risk with higher doses (e.g. 15-30g prednisone) and for greater than 2-4 weeks ○ E.g. in IBD patients on corticosteroids alone, ▪ the relative risk of bacterial infections was found to be 5-fold higher ▪ 4-fold higher for other infections like strongyloidiasis and tuberculosis ▪ 1.5 fold higher for viral infections Specific Infections: ○ Pneumocystis jiroveci pneumonia ▪ Fungal infection of the lung ▪ Combination antibiotics prophylactically or treatment Herpes Zoster (Shingles): ○ Reactivation of varicella zoster virusà painful rash ○ Vaccinations or antiviral Tuberculosis: ○ Conversion of latent TB to active formà usually affects lungs ○ Should be tested for before glucocorticoid treatment and treated with antibiotic (isoniazid) beforehand Strongyloidiasis: ○ A chronic parasitic infection, usually acquired through direct contact with contaminated soil (can be asymptomatic) ○ Can persist for several decades and can reactivate with glucocorticoid exposure. Treated with antiparasitic Other opportunistic infections? ○ Aspergillosis, nontuberculous mycobacterial disease, candidiasis, and cryptococcosis ○ Evidence for these is less robust Culture Negative Negative Negative Positive Negative Negative Negative