BMS 200 - Cardiology MCQs PDF

BMS 200 – Cardiology 9 Pericarditis, Myocarditis, Endocarditis Orthostatic and vasovagal syndromes Outcomes Briefly describe the pathogenesis, major clinical features, and prognosis of the following clinical classifications of pericarditis: acute pericarditis, subacute pericarditis,...

BMS 200 – Cardiology 9 Pericarditis, Myocarditis, Endocarditis Orthostatic and vasovagal syndromes Outcomes Briefly describe the pathogenesis, major clinical features, and prognosis of the following clinical classifications of pericarditis: acute pericarditis, subacute pericarditis, constrictive pericarditis Briefly describe the pathogenesis, major clinical features, and prognosis of infectious and non-infectious forms of myocarditis Briefly describe the pathogenesis, major clinical features, and prognosis of acute and subacute bacterial endocarditis Describe the biology, life cycle, major virulence factors, diagnosis, and clinical manifestations of infection for the following: Borrelia burgdorferi, trypanosoma cruzi, ehrlichia chaffeensis Outcomes Briefly describe the biology, major virulence factors, diagnosis, and clinical manifestations of coxsackie virus and echovirus Briefly describe the cardiac complications of COVID19 coronavirus Briefly describe the biology, major virulence factors, diagnosis, and clinical manifestations of HACEK group of bacteria Staph epidermidis and viridans streptococci Describe the pathophysiology of postural-tachycardia syndrome (POTS) and relate it to clinical features Inflammation of the structures of the heart Pericarditis ▪ Acute, subacute, and constrictive Myocarditis ▪ Infectious causes ▪ Overview of inflammatory causes Endocarditis ▪ Acute and subacute bacterial endocarditis Pericardium - Recall Double-walled sac that contains the heart How much and the roots of the great vessels pericardial ▪ Fibrous layer - Tough, inelastic dense irregular CT fluid is normal? ▪ Serous layer - Thinner, more delicate 15 – 50 mL double layer composed of mesothelium Visceral layer of pericardium ▪ aka epicardium Parietal layer of pericardium Functions: ▪ Anchors and protects the heart ▪ Prevents overfilling of heart with blood ▪ Allows heart to work in friction-free environment Note – epicardium also contains coronary vessels, nerves, and fat Acute pericarditis Most common pathologic process impacting the pericardium ▪ Between 1% and 5% of cases of acute chest pain more likely in younger patients Major causes are: ▪ Viral causes – coxsackie virus A and B, echovirus, other less common organisms ▪ Bacterial, fungal causes – as extensions from pneumonia Many – streptococcal, staphylococcal, TB, opportunistic fungal infections ▪ Rheumatic fever & autoimmune disorders (RA, SLE, AS) ▪ Cancer (invasion of the pericardium) and CKD (increased filtration 🡪 excess pericardial fluid) Acute pericarditis – general pathogenesis If extracellular fluid volume increases over long periods of time (CHF, CKD) then fluid can accumulate and there may be limited inflammation ▪ Pericardial effusion instead of pericarditis – very little protein, very few leukocytes Inflammatory damage/responses can be caused by all of the etiologies in the last slide ▪ Particular type of inflammation known as fibrinous inflammation – the normally smooth surface of the heart is covered by a shaggy-looking inflammatory exudate with deposition of fibrin Leukocytes (mostly macrophages), Acute pericarditis – clinical features Chest pain – especially in infectious, idiopathic or autoimmune causes ▪ Tends to be severe and sharp – sometimes is pleuritic in nature (often accompanied by pleural inflammation) Pleuritic pain? ▪ Located retrosternally/precordially, can have similar radiation to ischemic chest pain – often confused with angina Tends to be better sitting up + leaning forward than lying down Troponin and ECG can be confusing – troponin can be elevated with epicardial inflammation/damage and the ECG will often exhibit non-specific ST-elevation in a non-vascular distribution Pericardial friction rub – a raspy, “scratchy” sound that can be present during systole and diastole ▪ However, this finding can be transient as more fluid accumulates – Acute pericarditis – ECG & auscultatory findings (FYI) Note the “everywhere” ST elevation – that’s weird for an MI ▪ No one coronary artery would cause ST elevation in that many leads Acute pericarditis – diagnosis, treatment, prognosis Echocardiography is the main method of diagnosis 🡪 ▪ CT or MRI can also contribute and provide detail about pericardial thickening Most cases of idiopathic or viral pericarditis are self-resolving, and anti-inflammatory medications are helpful for symptom resolution ▪ High-dose aspirin, NSAIDs, colchicine, steroids ▪ Depending on the cause, a significant minority will have recurrences Complications – constrictive pericarditis, recurrences, cardiac tamponade Acute pericarditis – additional info Most cases of acute pericarditis are presumed to be viral – usually an organism can’t be found ▪ Typically occurs 10 – 12 days of a presumed viral infection ▪ Fever and near-simultaneous development of sharp chest pain is the typical presentation Acute pericarditis can transition to subacute and constrictive pericarditis ▪ Aren’t really clear definitions for subacute pericarditis - usually means symptoms/effusions for > 4-6 weeks ▪ With long-term inflammation, can progress to constrictive pericarditis ▪ Longer-term, slower development of effusions are better tolerated by a patient – slow accumulation of up to 2 L of fluid can occur before tamponade emerges – metastases to the pericardium are a common cause In those that experience recurrence, a hole (pericardiotomy) may need to be left in the pericardium for fluid to drain Constrictive pericarditis Sometimes after acute pericarditis the pericardium “scars” ▪ Often obliteration of the pericardial cavity with chronic inflammation of the visceral pericardium – can even calcify ▪ Can greatly restrict cardiac filling – therefore known as constrictive pericarditis ▪ Causes include TB pericarditis, post-traumatic/surgical/radiation pericarditis, neoplastic disease, CKD, or idiopathic Kind of looks like a restrictive cardiomyopathy: ▪ congestion in the venous system with relatively preserved stroke volume (still reduced though) and reduced EDV ▪ fatigue, neck vein distention, hepatosplenomegaly Uncommon complication of acute pericarditis ▪ Can be diagnosed by US or MRI ▪ Pericardial resection is the treatment Pericardial tamponade Accumulation of fluid in the pericardial space that is severe enough that it acutely obstructs flow into the ventricles – usually acute accumulation ▪ Cause of obstructive shock, and can be rapidly fatal ▪ Thankfully uncommon ▪ Causes include ruptured ventricular aneurysm, severe acute pericarditis, cardiac trauma, aortic dissection ▪ As little as 250 mL in the pericardium, if it develops acutely, can cause death Clinical features: ▪ Hypotension, muffled heart sounds, distended neck veins 🡪 shock Emergent removal of fluid from the pericardial space (pericardiocentesis) is necessary ▪ More later in Emerg Med Myocarditis Inflammation of the heart which can lead to: ▪ Dilated cardiomyopathy 🡪 heart failure ▪ Conduction blocks (or sometimes a predisposition to ventricular tachycardia) ▪ Rarely sudden cardiac death (likely due to dysrhythmia) We’ll focus on infectious causes of myocarditis today – typical etiologic agents include: ▪ Viral causes – echovirus and coxsackie virus (common in this part of the world) ▪ Lyme disease – Lyme myocarditis is usually fairly benign, but rarely it can cause serious myocarditis ▪ Trypanosomiasis cruzi – a parasite common in South America that causes serious myocarditis ▪ Ricketsia ricketsii, ehrlichia chaffeensis – uncommon causes of myocarditis, but can be deadly Myocarditis – Pathogenesis How can infection damage the myocardium? ▪ Invasion of the myocardium – for example, when a virus invades a myocyte and causes lysis ▪ Early cytokine release in response to infection can depress myocardial function, but does not in itself cause damage ▪ Adaptive immune response 🡪 Granuloma formation Prolonged release of cytokines 🡪 fibrosis and damage to the ECM 🡪 dilation ▪ May develop into long-term attack of the heart Myocarditis - Pathogenesis Clinical Features, Diagnosis Acute viral myocarditis can present with symptoms and signs of acutely-developing heart failure ▪ Can also present with chest pain and ECG changes suggestive of pericarditis or acute myocardial infarction ▪ May present with atrial or ventricular tachyarrhythmia Typical patient picture: young to middle-aged adult with progressive dyspnea and weakness ▪ few days or weeks after a viral syndrome that was accompanied by fever and myalgias ECG, echocardiogram, and troponin are the initial diagnostic options ▪ MRI can often visualize soft tissues like the heart quite well – may provide info re: inflammation and scarring within the heart Bacterial endocarditis – a quick overview Typical pathologic sequence: ▪ Damaged endocardium or abnormal surface within the heart (i.e. a device or prosthetic valve) forms a thrombus ▪ Bacteria that have virulence factors that allow thrombus invasion colonize the thrombus ▪ The resulting inflammatory mass can: Damage the endocardium, in particular heart valves Break off and cause strokes or other thromboembolic arterial obstructions that can result in inflammation at the site of obstruction Cause unique “weird” hemorrhagic/ischemic findings Acute bacterial endocarditis Vegetation = mass of platelets, fibrin, microorganisms, and some inflammatory cells ▪ Usually involves a valve, but can occur on a device or area of endocardium near turbulent flow or that has suffered damage ▪ Vegetations are weak and friable, and can break off and spread Most common etiologies: ▪ Large bacterial loads – dental/gingival disease, people who inject drugs (often right-sided valves involved) ▪ Valvular damage or recent valvular surgery ▪ Congenital heart disease (in particular VSD) Acute bacterial endocarditis The type of infectious agent causing the problem tends to determine whether the presentation is acute and immediately life-threatening/valve-destroying or whether it follows a less stormy, subacute course ▪ Nasty acute bugs – staphylococcus aureus, streptococcal species, rarely pneumococcus ▪ More slow-growing, “less damaging” bugs – HACEK group, enterococcus Terminology: ▪ NBTE – non-bacterial thrombotic endocarditis – often the first step to an infected vegetation ▪ NBTE most commonly develops in those with mitral regurgitation, aortic stenosis, aortic regurgitation, VSDs and other congenital heart disease Signs and symptoms of infective endocarditis Clinical Feature Frequency Fever, chills, sweats: 80 – 90% Acute – high fevers Subacute – lower fevers that spike intermittently Anorexia, weight loss, malaise (subacute most noticeable) 40 – 75% Myalgias, arthralgias, back pain 15 – 30% Heart murmur (may not present until some time after onset) > 80% Arterial emboli 20 – 50% Splenomegaly 15 – 50% Nail clubbing 10 – 20% Neurologic manifestations (CVAs) 20 – 40% Peripheral manifestations 2 – 15% Infective endocarditis Assorted endocarditis info: ▪ Peripheral manifestations include Osler nodes (painful raised papules – nodules on digits), Janeway lesions (painless hemorrhagic pustular lesions on soles or palms) and Roth spots (retinal hemorrhages with a pale centre ▪ FYI – Duke criteria (see next slide) used to diagnose infective endocarditis Subacute bacterial endocarditis ▪ Present for weeks – months with a gradual progression, usually slow and limited valvular damage Exception 🡪 valve rupture/serious damage or a major embolic event Duke criteria - FYI Microbes that impact the heart Borrelia burgdorferi (Lyme disease) Endocarditis-causing microbes: ▪ Coagulase-negative staphylococci, streptococcus viridans, enterococcus faecalis, HACEK organisms Myocarditis-causing microbes: ▪ Coxsackie virus and echovirus ▪ SARS-CoV2 ▪ Ricketsia ricketsii ▪ Trypanosoma cruzi, ehrlichia chaffeensis Lyme disease – a quick overview Caused by Borrelia burgdorferi, a tick-borne spirochete that is quite common in the Northern Hemisphere ▪ 30,000 new cases in US/year Structure – inner membrane with a peptidoglycan layer in the middle, and then an outer membrane ▪ Flagella are present between the two membranes and allow the bacterium to move through host tissues Fastidious microbes that require a complex medium to culture ▪ lack the ability to synthesize amino acids, fatty acids, nucleotides and enzyme cofactors Lyme disease – life cycle and virulence factors Humans aren’t required for the life cycle of Lyme disease (see next slide) ▪ Certain mice maintain B. burgdorferi in nature ▪ Ticks 🡪 tick can’t the bacteria to their offspring, so it travels from tick 🡪 reservoir animal ▪ The “baby ticks” (nymphs) are better at transmitting the disease than adult ticks – hence most cases of Lyme disease occur in the spring Virulence factors ▪ Seem to be able to bind to complement regulatory proteins, which may protect it from attach via the complement system ▪ Constantly changes the sequence or type of their surface proteins – an immunologic “moving target” ▪ They like to hide and divide in avascular areas (tendons, joints, etc.) The natural cycle of Lyme disease. Ixodes ticks undergo a 2-year cycle that encompasses four stages: eggs, larvae, nymphs, and adults. In the summer, larvae hatch in an uninfected state and then acquire Lyme borreliae by feeding on infected rodents. Lyme borreliae survive in the midgut as the larvae molt into nymphs in the fall and are dormant through the winter. Infected nymphs feed on rodents in the late spring and early summer, resulting in the chronic infection of this natural reservoir of Lyme borreliae. The population of chronically infected rodents transmits Lyme borreliae to the next generation of ticks. Nymphal ticks can also feed on humans, giving rise to the peak of human Lyme disease in the late spring and summer. 2018 – cases of reported Lyme disease in the US Stages of Lyme infection in humans Stage 1 – erythema migrans skin rash ▪ Spreading rash that reflects the ability of the spirochete to spread through the skin ▪ Uncommon rash that is fairly specific for Lyme disease The rash itself if not painful or itchy, but is often accompanied by: ▪ Arthralgias and myalgias ▪ Fever, fatigue, headaches This is the optimal time for antibiotic therapy to clear the infection Stages of Lyme infection in humans Stage 2 – disseminated infection that is likely due to the bacterium infiltrating walls of blood vessels, occurs weeks – months after initial infection ▪ Can invade a wide range of organs including: Central nervous system – fatigue, aseptic meningitis, and cranial nerve palsies (in particular Bell’s palsy) Heart – one of the less common causes of myocarditis Skin – more erythema migrans lesions Joints – most common site of involvement – Lyme arthritis seems to frequently affect the knee Stage 3 – most common late manifestation is arthritis of one or a few large joints which can be intermittent ▪ Meningoencephalitis is usually a rare complication Lyme disease – additional clinical details Although Lyme disease can be treated at all stages, a significant proportion of patients can have post-treatment Lyme disease syndrome ▪ Chronic pain, neurocognitive disturbances, fatigue that lasts months/years ▪ Antibiotics don’t seem to help this, and are not worth the side effects Diagnosis is complex ▪ Difficult to culture the organism, and often none are found in joint/blood samples ▪ Two-tiered serologic testing – ELISA followed by an immunoblot test… since it tests antibodies, though, doesn’t discriminate between past and current infection Endocarditis microbes – general virulence factors Common streptococcal species that cause endocarditis have extracellular dextrans that facilitate adhesion to thrombotic vegetations or to damaged valvular endothelium ▪ Dextrans allow binding to platelet-fibrin complexes ▪ FimA, produced by streptococci allows adherence to the endocardium or valve Fibronectin is normally “hidden” by the endothelium/endocardium (part of ECM) ▪ Exposure of fibronectin allows particular microbes to adhere ▪ E. Faecalis, S. aureus, and the viridans group of streptocci bind well to fibronectin ▪ Medical devices can also become coated by fibronectin as well Many of these microbes can build mucopolysaccharide biofilms that aids colonization Endocarditis microbes – general virulence factors S. aureus – you’ve already talked about this bug ▪ In infective endocarditis, production of tissue factor helps to build clots, which aids invasion of S. aureus onto cardiac structures/vegetations HACEK? ▪ Haemophilus species, Aggregatibacter (formerly Actinobacillus) species, Cardiobacterium species, Eikenella corrodens, and Kingella kingae ▪ These are all gram-negative bugs that usually live in the oral cavity ▪ They are fastidious, are slow to grow, and require carbon dioxide ▪ Why do they cause endocarditis? No particular virulence factors seem to be identified outside of the fact that they happily colonized dental structures and frequent gain access to the bloodstream during dental work or flossing BMS 200 – Cardiology 9 Pericarditis, Myocarditis, Endocarditis Orthostatic and vasovagal syndromes Outcomes Briefly describe the pathogenesis, major clinical features, and prognosis of the following clinical classifications of pericarditis: acute pericarditis, subacute pericarditis, constrictive pericarditis Briefly describe the pathogenesis, major clinical features, and prognosis of infectious and non- infectious forms of myocarditis Briefly describe the pathogenesis, major clinical features, and prognosis of acute and subacute bacterial endocarditis Describe the biology, life cycle, major virulence factors, diagnosis, and clinical manifestations of infection for the following: Borrelia burgdorferi, trypanosoma cruzi, ehrlichia chaffeensis Outcomes Briefly describe the biology, major virulence factors, diagnosis, and clinical manifestations of coxsackie virus and echovirus Briefly describe the cardiac complications of COVID19 coronavirus Briefly describe the biology, major virulence factors, diagnosis, and clinical manifestations of HACEK group of bacteria Staph epidermidis and viridans streptococci Describe the pathophysiology of postural-tachycardia syndrome (POTS) and relate it to clinical features POTS – Postural Orthostatic Tachycardia Syndrome What is it? The name describes it well – when people go from lying down to standing, they experience a > 30 beat/min increase in HR That increase in heart rate cannot be accompanied by a decrease in blood pressure… ▪ Otherwise that would be known as orthostatic hypotension ▪ It is normal for BP to drop when standing – if there is a less than 20/10 mm Hg drop, then that’s considered normal This is part of a set of syndromes known as dysautonomias ▪ Include POTS, orthostatic hypotension, vasovagal syncope as the more common syndromes POTS – key clinical features Symptomatic orthostatic intolerance without hypotension ▪ Accompanied by increase in HR > 120 beats/min or > 30 beats/min over supine HR What is meant by orthostatic intolerance? ▪ In response to standing, troublesome symptoms occur, which can include: Light-headedness, weakness, blurred vision Nausea, tremulousness (shakiness), and palpitations Although pre-syncopal symptoms are the defining feature, syncope does not tend to happen POTS – a tricky subject Even though it requires tilt-table testing to diagnose, there are no clear single pathophysiologic mechanisms or diagnostic criteria beyond the ones mentioned in the last slide Most experts agree that there’s “more than one POTS” ▪ There are a multitude of different causes of this syndrome and each patient has a somewhat unique variant on a number of different pathophysiologic themes ▪ So, if there’s more than one POTS, some sort of standardized recognition needs to happen before you can standardize diagnosis https://www.mayoclinic.org/tests-procedures/tilt-t test/about/pac-20395124#dialogId36740715 The baroreceptor reflex – a review POTS – why does it happen? Let’s unpack that last slide Neuropathic causes of POTS ▪ Neuropathy where? ▪ For reasons that aren’t understood, patients with POTS have “pooling” of blood in the lower vascular beds Include the pelvic, splanchnic, and lower limb vessels ▪ Interestingly, this pooling might not be due to venous vasodilation, but instead due to inappropriate arteriolar vasodilation Studies in patients with POTS seem to indicate that less NE is released in the lower limbs in response to orthostatic or pharmacologic challenges Strangely enough, NE release was the same between controls and POTS patients in the upper extremities Other studies also find an exaggerated response to exogenously administered catecholamines… why might this be? The baroreceptor reflex – a review Still unpacking… Hypovolemic POTS ▪ It’s easy to understand why reduced blood volume leads to tachycardia – see baroreceptor reflex again ▪ Some POTS patients seem to have reduced blood volume – 13 -22% lower plasma volume than health controls Why hypovolemia? ▪ Not sure - but the following experimental findings are observed: Elevated renin compared to aldosterone (a low aldosterone:renin ratio) Elevated levels of angiotensin II… What does this evidence suggest? Hypovolemic POTS Other findings in patients with “hypovolemia- predominant” POTS ▪ Patients who are deconditioned tend to reduce their blood volume. This is seen in: Subjects exposed to microgravity for extended periods of time experienced decreased blood volume and POTS-like responses to standing Decreases in blood volume can also be seen with prolonged bed rest ▪ It is thought that deconditioning may “unmask” inadequate aldosterone secretion in those predisposed to POTS Hyper-adrenergic POTS Some POTS patients secrete much more norepinephrine than patients without the disorder ▪ Experimental data suggests that in healthy controls, there is a doubling of plasma norepinephrine concentrations on standing ▪ In patients with POTS in the same study, there can be a tripling-to-quadrupling of NE release ▪ Epinephrine concentrations seem to be similar Why is there an oversecretion of NE in some? ▪ One study suggests missense mutations in catecholamine transporters 🡪 accumulation of NE in the ECF where it is released ▪ In these patients, standing actually leads to an increase in blood pressure in some Hyper-adrenergic POTS Other theories re: hyper-adrenergic POTS ▪ Activating detected auto-antibodies to beta-1 and beta-2 adrenoreceptors have been Can you think of another disorder that involves activating antibodies? How would inappropriate activation of beta-1 receptors manifest? How about beta-2? POTS – which therapies make sense for which cause? Therapies for POTS (which model?) Midodrine – alpha-1 agonist: _________________ Avoidance of SNRIs: _________________ High sodium diet: _____________ Stockings & abdominal compression: ___________ “Drink more water”: ________________ Desmopressin (AVP agonist) ______________ Lower extremity maneuvers: _________________ Beta-blockers: ______________ Exercise: ___________________  Peripheral Neuropathies (PN) BMS200 Date: November 4th, 2024 Dr. Lakshman, PhD Learning Outcomes Describe the pathophysiologic mechanisms underlying diabetic neuropathy, including hyperglycemia-induced metabolic changes, high insulin, microvascular damage, and oxidative stress. Describe the etiology, risk factors, and pathophysiology of vitamin B12 deficiency neuropathy, including impaired absorption, parasite infections, dietary deficiencies, and pernicious anemia. Describe the pathophysiologic mechanism of chemotherapy-induced peripheral neuropathy Describe the association between hypothyroidism and peripheral neuropathy, including the underlying hormonal imbalances and metabolic abnormalities. Describe the role of microbial infections in the pathophysiology of Pre-Assessment YouTube Video: Peripheral Neuropathy and its Impact on Mental Health Peripheral Nervous System The Peripheral Nervous System (PNS) encompasses all neural structures located external to the spinal cord and the brainstem. - Cranial Nerves III-XII (I and II are special extensions of the brain) - Dorsal and ventral spinal roots - Spinal nerves and their continuation - Ganglia Type of fibers: - Somatic motor fibers - Somatic sensory - Visceral sensory Peripheral Nervous System The epineurium (EP) is in direct continuity with the dura mater (DM). The endoneurium (EN) remains unchanged from the peripheral nerve and spinal root to the junction with the spinal cord. At the subarachnoid angle (SA), the greater portion of the perineurium (P) passes outward between the dura mater and the arachnoid (A), but a few layers appear to continue over the nerve root as part of the root sheath (RS). At the subarachnoid angle, the arachnoid is reflected over the roots and becomes continuous with the outer layers of the  Peripheral Nervous System The endoneurium refers to the delicate connective tissue sheath that encases individual nerve fibers. This tissue also contains longitudinally aligned, interconnected blood vessels that provide nourishment to the nerve fibers and are susceptible to various diseases. Spinal nerves travel through constricted foramina, both intervertebral and cranial, and a subset also transverse narrow passages in the limbs, such as the median nerve within the carpal tunnel between the carpal ligament and the tendon sheaths of the flexor forearm muscles, or the ulnar nerve in the Peripheral Nervous System Axon microtubular apparatus: The axons house a sophisticated internal microtubular structure that serves to uphold the integrity of their membranes and facilitate the transport of substances, including neurotransmitters, across considerable distances between the nerve cell body and the remote extremities of the nerve fiber. Peripheral Nervous System Types of nerve fiber damage: - Axonal degeneration - Segmental demyelination *PNS fibers are able to regenerate and remyelinate to recover function Peripheral Nervous System Axonal Degeneration: - Distal axonal degeneration – Confined to the distal portions of longer, larger nerve fibers, while neuron cell bodies and proximal axons remain unaffected. - Neuronopathy - Axonal degeneration can occur due to the demise of a neuronal cell body, as seen in conditions like autoimmune dorsal root ganglionitis. Peripheral Nervous System Axonal Degeneration: - Wallerian degeneration - Axonal degeneration takes place in a nerve beyond a point where it's been severed or compressed. If the injury occurs too close to the nerve's origin, it may allow for nerve regeneration. In Wallerian degeneration, there is deterioration of the axis cylinder and myelin that occurs beyond the location of axonal interruption (indicated by an arrow), as well as central chromatolysis.  Peripheral Nervous System Segmental Demyelination - The myelin sheath deteriorates, but the underlying axon remains functional. - Primary demyelination – direct injury to the Schwan cell or myelin sheath - Secondary demyelination – underlying axonal abnormalities Peripheral Nervous System Segmental Demyelination - Remyelinated sections display reduced internode lengths. - Hypertrophic neuropathy – repeated episodes of segmental peripheral nerve demyelination and remyelination – accumulation of supernumerary Schwan cells that encircle the axons (onion bulbs).  Peripheral Neuropathy Peripheral neuritis, also referred to as peripheral neuropathy, is a prevalent neurological condition arising from peripheral nerve damage. It can stem from nerve-related diseases or result from systemic illnesses. Most of the neuropathies are axonal – 80-90% - clinically helpful to find the etiology Demyelinating neuropathy – limited number of etiology, most likely hereditary or immunologically mediated. Large diameter sensory fibers – proprioception and vibratory sensation  Peripheral Neuropathy Main Causes: - Metabolic: Diabetes mellitus, Thyroid disease - Nutritional deficiencies: Vitamin B12 deficiency - Systemic: HIV infection, Lyme disease, Hepatitis B and C, Shingles, Leprosy - Toxic: Alcoholism, Chemotherapy-induced Despite a thorough history and physical examination, the origin remains a mystery in approximately 50% of cases. Peripheral Neuropathy Peripheral Neuropathy Clinical features - Muscle weakness and atrophy, sensory loss, paresthesia, pain and autonomic disfunction - Type of fibers affected: Large-diameter sensory fibers – affects position and vibration sense; Small diameter fibers – deters pain and temperature sensation - Development of symptoms: Acute (day to weeks), subacute (weeks to months), chronic (month to years) In approaching a patient with a neuropathy, the clinician has three main goals: - Identify the location Peripheral Neuropathy Topography and Clinical Patterns Polyneuropathy – generalized process, weakness is relatively symmetrical from the beginning and progresses bilaterally; loss of reflexes in affected parts but mainly at the ankles; sensory issues and decreased sensation are most notable in the extremities' distal regions. Radiculopathy or polyradiculopathy – Neurological signs exhibit asymmetry, displaying a sporadic distribution, such as proximal involvement in one limb and distal in another. This is accompanied by weakness, areas of sensory loss, and frequently, pain within the sensory distribution of the affected nerve root. Peripheral Neuropathy Topography and Clinical Patterns: Multiple mononeuropathies (mononeuropathy multiplex) – accumulation of multiple mononeuropathies. Difficult to differentiate from polyneuropathy. Plexopathy (involvement of multiple nerves in a plexus) – brachial or lumbosacral. While only a single limb is impacted, the motor, sensory, and reflex deficits do not align with a pattern associated with multiple adjacent nerve roots or nerves. Understanding the innervation of the affected muscles at the plexus level typically helps in resolving this situation. Neuronopathy (motor or sensory) – ganglion cells are predominantly Peripheral Neuropathy Symptoms vary depending on: Motor Nerve Impairment Typically linked with muscular weakness Can encompass distressing muscle spasms, twitching Muscular wasting Diminished reflex responses  Peripheral Neuropathy Symptoms vary depending on: Sensory Nerve Impairment: Impairment of larger sensory fibers (surrounded by myelin) results in: - Reduced ability to feel touch, most notably in the hands and feet - Decreased overall sensation - Loss of reflex responses - Impairment of the sense of limb position Impairment of smaller fibers (lacking a myelin sheath) leads to: - Compromised perception of pain and temperature sensations, particularly in cases of injury from cuts, infected wounds, or angina Peripheral Neuropathy Symptoms vary depending on: Autonomic Nerve Impairment: The parasympathetic and sympathetic nerves of the peripheral nervous system (PNS) have control over various organs in the body. Autonomic nerve damage can result in a wide range of symptoms: - Impaired ability to sweat normally, resulting in heat intolerance. - Loss of control over bowel and bladder functions.  Diabetic neuropathy Diabetes mellitus (DM) is linked to several forms of polyneuropathy, including distal symmetric sensory or sensorimotor polyneuropathy, autonomic neuropathy, diabetic neuropathic cachexia, polyradiculoneuropathies, cranial neuropathies, and other mononeuropathies. Risk factors contributing to the development of neuropathy encompass prolonged, inadequately managed DM, along with the coexistence of retinopathy and nephropathy.  Diabetic neuropathy Pathophysiology: Persistent high blood sugar levels are believed to boost the activity of the polyol pathway, leading to the accumulation of fructose and sorbitol within nerves, ultimately causing nerve damage. In conditions of elevated blood glucose levels exceeding 7 mmol/L, there is an augmented flow of glucose through the polyol pathway, which constitutes over 30% of glucose metabolism. The critical step that regulates the pace of the polyol pathway involves the conversion of glucose into sorbitol, a reaction facilitated by the enzyme aldose reductase (AR) and involving the consumption of reduced nicotinamide adenosine dinucleotide phosphate (NADPH).  Diabetic neuropathy Pathophysiology: Immunological mechanisms are also implicated in the onset of diabetic neuropathy. Damage results from the presence of antineural autoantibodies found in the blood of certain diabetic patients. Additionally, the presence of antiphospholipid antibodies may further exacerbate nerve damage, often in conjunction with vascular irregularities. Endoneural vascular insufficiency arises from reduced nitric oxide levels or impaired endothelial function, as well as compromised sodium/potassium- adenosine triphosphatase (Na+/K+-ATPase) activity and elevated homocysteinemia. Over time, vessel occlusion may ensue, resulting in compromised vascular permeability and hindered endoneural blood flow.  Diabetic neuropathy Pathophysiology: Diabetic neuropathy Clinical features: - Typically presents with a "stocking-and-glove" pattern of distribution, resulting in sensory loss, abnormal sensations (dysesthesias), and often painful paresthesias, predominantly affecting the lower limbs. - Frequent symptoms include tingling, pricking, or numbness; sensations of burning or freezing pain; sharp, stabbing, or electric-like pain; heightened sensitivity to touch; muscle weakness; and a decline in balance and coordination.  Vitamin B12 deficiency neuropathy Pernicious anemia stands as the most prevalent cause of cobalamin deficiency. It is an autoimmune condition marked by the production of antibodies targeting parietal cells and intrinsic factor, resulting in a deficiency of intrinsic factor. Simultaneously, the presence of antiparietal cell antibodies triggers the onset of atrophic gastritis, accompanied by the absence of gastric acid secretion, referred to as achlorhydria. Additional triggers include dietary restrictions (common among vegetarians), gastrectomy, gastric bypass surgery, inflammatory bowel disease, pancreatic insufficiency, bacterial overgrowth, and potentially the use of histamine-2 blockers and proton pump inhibitors. Vitamin B12 deficiency causes neurological symptoms such as peripheral neuropathy and cognitive disturbances, and in severe cases, demyelination of nerve fibers.  Vitamin B12 deficiency neuropathy B12 is also crucial for the conversion of methylmalonyl-CoA to succinyl CoA, a prerequisite for myelin synthesis and stability. In B12 deficiency, methylmalonyl-CoA leads to the formation of abnormal fatty acids, contributing to abnormal myelination or demyelination. The utilization of nitrous oxide, whether as an anesthetic agent or recreationally, can lead to the onset of acute cobalamin deficiency neuropathy and subacute combined degeneration. In a study conducted by Kalita et al. involving 66 patients with B12 deficiency neurological syndrome, nerve conduction studies revealed abnormalities in 54.5% of patients, with 22.2% displaying axonal involvement, 11.1% showing demyelinating changes, and the remainder exhibiting mixed features. Nerve biopsy indicated early-stage Vitamin B12 deficiency neuropathy (A) Acute axonal degeneration and formation of myelin ovoids evident on longitudinal sections (arrow). The myelin was preserved in these nerve fibers. (B) Focal depletion of large, myelinated fibers with prominent remyelination was seen in cases with short duration of illness (2 months). (C). Increasing fibrosis of endoneurium accompanied by fiber depletion. Vitamin B12 deficiency neuropathy Patients often first report numbness in their hands, which typically precedes the development of paresthesia in the lower extremities. A distinct pattern of sensory loss primarily affecting large fibers, impacting proprioception and vibration, while sparing small-fiber modalities, becomes evident. The presence of an unsteady gait, coupled with diffuse hyperreflexia and the absence of Achilles reflexes, should raise suspicions of cobalamin deficiency.  Chemotherapy-induced Peripheral Neuropathy Chemotherapy-induced peripheral neuropathy (CIPN) represents a frequently encountered adverse effect associated with various antineoplastic agents, its severity often contingent on the administered dose. CIPN has the potential to necessitate undesirable reductions in treatment dosage or even treatment discontinuation, significantly compromising the quality of life for cancer survivors. Clinically, CIPN manifests as impairments in sensory, motor, and autonomic functions, exhibiting a pattern similar to a glove and stocking distribution, primarily affecting longer axons. The pathophysiological mechanism through which chemotherapy adversely impacts neural structures, leading to chemotherapy-induced peripheral neuropathy (CIPN), is complex and encompasses a variety of factors. These  Chemotherapy-induced Peripheral Neuropathy Cisplatin, carboplatin, and bortezomib are recognized for inducing a dose- dependent sensory polyneuropathy that typically emerges several weeks after the completion of treatment, affecting at least half of the patients. The extent of histopathological changes in the peripheral nervous system is directly related to the concentration of platinum within these tissues, with the highest levels observed in the dorsal root ganglia. Paclitaxel and the more potent docetaxel, both known for inhibiting neurotubule depolymerization, are primarily used in the treatment of ovarian cancer and can produce a sensory polyneuropathy like that caused by cisplatin. Pathological studies have revealed neuronopathy and distal axonopathy, predominantly impacting large fibers. Vincristine and thalidomide may also lead to similar neuropathies, with  Hypothyroidism and Peripheral Neuropathy Thyroid hormones play a pivotal role in regulating numerous functions and processes within the nervous system. While proximal myopathy is a more common association with hypothyroidism, some patients may experience neuropathic symptoms, with Carpal Tunnel Syndrome (CTS) being the most typical manifestation. In rare cases, individuals may develop a generalized sensory polyneuropathy characterized by painful paresthesia and numbness affecting both the legs and hands. One potential mechanism for the deterioration of nerve conduction parameters may be linked to weight gain, as indicated by significantly higher BMI in individuals with hypothyroidism. In hypothyroidism, there is an accumulation of mucopolysaccharides, chondroitin sulfate, and hyaluronic acid in the interstitial  Hypothyroidism and Peripheral Neuropathy Peripheral neuropathy in hypothyroidism can arise from an energy deficit stemming from reduced nutrient oxidation, as thyroid hormones are responsible for stimulating mitochondrial respiratory activity to generate adenosine triphosphate (ATP) during aerobic metabolism. Furthermore, decreased glycogen degradation can result in the accumulation of glycogen deposits around the nerves. The metabolic changes induced by hypothyroidism can initially impair nerve functions and subsequently lead to structural alterations. In healthy individuals, thyroid hormones also enhance ATPase activity, consequently increasing Na-K pump activity. However, in hypothyroidism, the shortage of ATP and reduced ATPase and Na-K pump activity disrupts pump- dependent axonal transport, contributing to peripheral neuropathy. The reduction in thyroid hormones can additionally trigger primary axonal degeneration, characterized by axon shrinkage, disintegration of neurofilaments  Shingles and PN - Peripheral neuropathy from herpes varicella-zoster (HVZ) infection can result from the reactivation of latent virus or a primary infection. - Two-thirds of adult infections are characterized by dermal zoster, leading to severe pain and paresthesia in a dermatomal region. Within a week or two, a vesicular rash develops in the same distribution as the pain. - Weakness in muscles innervated by roots corresponding to the affected dermatome occurs in 5–30% of patients. Shingles and PN During the primary infection, VZV establishes latent infection in perineuronal satellite cells of the dorsal nerve root ganglia. Viral genes continue to be transcribed during latency, and viral DNA can be detected years after the initial infection. Shingles occurs when virus replication happens in ganglion cells, travels down sensory nerves, and infects the corresponding skin area, leading to a localized, painful vesicular eruption. The risk of shingles increases with age, and most cases occur in the elderly population. Impaired cell-mediated immunity also raises the risk of VZV reactivation. Lyme disease and PN Neuropathy occurs in 10 to 15 percent of patients with Lyme disease and takes several forms. Cranial nerve involvement is common, with facial palsy being the most frequent manifestation. Other cranial nerves and spinal roots can also be affected, primarily in the cervical or lumbar region. Concurrent aseptic meningoradiculitis (characterized by a mild to moderate presence of mononuclear cells in cerebrospinal fluid) is characteristic of Lyme disease. Lyme disease can manifest with a triad of cranial nerve palsies, radiculitis, and aseptic meningitis during its disseminated phase, which typically occurs 1 to 3 weeks after a tick bite or the appearance of the typical rash. Pathological studies of peripheral nerves in Lyme disease are limited, but Hepatitis B and C and PN Peripheral neuropathy is the most common neurologic complication of hepatitis C virus (HCV) infection. The pathophysiology of the neuropathy associated with HCV is not definitively known; however, proposed mechanisms include cryoglobulin deposition in the vasa nervorum and HCV-mediated vasculitis. Cryoglobulinemia is a common extrahepatic manifestation of chronic hepatitis C infection. When cryoglobulinemia affects nerves or the vascular supply to nerves, it can lead to peripheral neuropathies. Immune-Mediated Mechanisms: Both hepatitis B and C infections can trigger an autoimmune response, leading to the production of antibodies and immune complexes. These immune responses can damage peripheral nerves and cause demyelination or axonal injury. The immune Hepatitis B and C and PN Direct Viral Invasion: Hepatitis B and C viruses may directly infect nerve cells or nerve tissue. Although they primarily affect the liver, these viruses have been detected in other tissues and organs, including peripheral nerves. The direct viral invasion of nerve cells can lead to nerve damage and neuropathies. Toxic Metabolites: The liver plays a crucial role in metabolizing various substances in the body, including drugs and toxins. In patients with chronic hepatitis B or C, liver dysfunction can lead to the accumulation of toxic metabolites. These metabolites can damage nerve cells and peripheral nerves, leading to neuropathies. Vitamin Deficiencies: Chronic liver disease, including hepatitis B  Leprosy and PN Leprosy, which results from the presence of the acid-fast bacteria Mycobacterium leprae, stands as the prevailing source of peripheral neuropathy in Southeast Asia, Africa, and South America. This infectious disease primarily affects the skin and peripheral nerves. The bacterium has a predilection for nerve tissue and can directly damage peripheral nerves, leading to various forms of peripheral neuropathy. Clinical symptoms can vary from tuberculoid leprosy on one end of the spectrum to lepromatous leprosy on the other, with borderline leprosy in the middle. Neuropathies are most frequently observed in individuals with borderline leprosy. Nerve Conduction Study – Sensory are usually absent in the lower limb and Leprosy and PN Peripheral neuropathy in Tuberculoid Leprosy is usually asymmetric and typically confined to the nerves underlying or encircling the skin lesion. This type of neuropathy is linked to a heightened level of cell-mediated immunity, which not only eliminates the bacilli in the tissue but also leads to concurrent nerve damage wherever the bacilli are present. In Lepromatous Leprosy, peripheral neuropathy progresses relatively slowly compared to other forms. It is more extensive, giving rise to bilateral, symmetrical distal polyneuropathy. Peripheral neuropathy in Borderline Leprosy results in some of the most severe deformities, as multiple nerves are affected more rapidly than in Lepromatous Leprosy. This condition may lead to irreversible nerve damage, similar to what is observed in Tuberculoid Leprosy. It is characterized by immunological instability, with an upgrading response  HIV and PN HIV-1 can lead to various peripheral neuropathies, resulting in different clinical manifestations. They may include distal symmetric polyneuropathy, autonomic neuropathy, lumbosacral polyradiculopathy, mononeuropathy, or mononeuropathy multiplex. Distal symmetric polyneuropathy is the most prevalent neuropathy among HIV-positive individuals. Typically, it occurs in the later stages of AIDS and is characterized by axonal degeneration in the distal nerves. The exact cause of axonal degeneration remains unclear, and there is currently no effective treatment available. HIV and PN Some mononeuropathies and lumbosacral polyradiculopathies in AIDS are attributed to cytomegalovirus infection of the peripheral nervous system. Vasculitic neuropathy can present as a mononeuropathy or mononeuropathy multiplex in certain AIDS patients. Some drugs used to treat AIDS can induce toxic neuropathies. These antiretroviral-induced axonal neuropathies may clinically resemble HIV-associated distal symmetric polyneuropathy. Diffuse infiltrative lymphocytosis syndrome in AIDS may Alcoholism and PN Nutritional Deficiencies: Chronic alcohol abuse often results in poor dietary habits and impaired nutrient absorption. This leads to deficiencies in essential vitamins and minerals, including thiamine (vitamin B1), vitamin B6, vitamin B12, and folic acid. These deficiencies can contribute to nerve damage. Thiamine deficiency is strongly associated with neuropathy. Thiamine serves as an important coenzyme in carbohydrate metabolism and neuron development. Its deficiency affects the cellular structure and can cause cell membrane damage and irregular ectopic cells. Toxic Effects of Alcohol: Ethanol, the active component in alcoholic beverages, can exert direct toxic effects on nerve tissues. It disrupts nerve cell function, interferes with nerve signal transmission, and damages nerve cell membranes. Over time, these effects can lead to neuropathy. Impaired Blood Flow: Alcohol abuse can lead to poor circulation and reduced blood flow to the extremities. Inadequate blood supply deprives  Alcoholism and PN Inflammation: Chronic alcohol consumption can lead to systemic inflammation, a known contributor to nerve tissue damage. Inflammatory processes within the body can harm nerve tissues and contribute to neuropathy. Metabolic Changes: Alcoholism can result in metabolic disturbances, including abnormal glucose metabolism and insulin resistance. These metabolic changes may directly contribute to nerve damage and the development of neuropathies. Oxidative Stress: The metabolism of alcohol generates reactive oxygen Alcoholism and PN Post-Assessment - MCQ 1) Which of the following statements accurately describes the pathophysiology of peripheral neuropathy associated with vitamin B12 deficiency? A) Vitamin B12 deficiency neuropathy is primarily caused by dietary deficiencies alone. B) Impaired absorption, parasite infections, and dietary deficiencies are unrelated to the pathophysiology of vitamin B12 deficiency neuropathy. C) Pernicious anemia, resulting from impaired intrinsic factor production, can contribute to vitamin B12 deficiency neuropathy. Post-Assessment - MCQ 1) Which of the following statements accurately describes the pathophysiology of peripheral neuropathy associated with vitamin B12 deficiency? A) Vitamin B12 deficiency neuropathy is primarily caused by dietary deficiencies alone. B) Impaired absorption, parasite infections, and dietary deficiencies are unrelated to the pathophysiology of vitamin B12 deficiency neuropathy. C) Pernicious anemia, resulting from impaired intrinsic factor production, can contribute to vitamin B12 deficiency neuropathy. Post-Assessment - MCQ 2) Which microbial infection is primarily associated with peripheral neuropathy due to direct nerve damage? A) Shingles (Herpes zoster) B) Lyme disease (Borreliosis) C) Hepatitis B virus (HBV) D) Leprosy (Hansen's disease) E) HIV (Human Immunodeficiency Virus) Post-Assessment - MCQ 2) Which microbial infection is primarily associated with peripheral neuropathy due to direct nerve damage? A) Shingles (Herpes zoster) B) Lyme disease (Borreliosis) C) Hepatitis B virus (HBV) D) Leprosy (Hansen's disease) E) HIV (Human Immunodeficiency Virus) Post-Assessment - MCQ 3) Which of the following mechanisms best explains the association between alcoholism and the pathophysiology of peripheral neuropathies? A) Elevated levels of vitamin B12 and folate B) Enhanced neuronal regeneration and repair C) Impaired metabolism of thiamine and other essential nutrients D) Increased production of nerve growth factors Post-Assessment - MCQ 3) Which of the following mechanisms best explains the association between alcoholism and the pathophysiology of peripheral neuropathies? A) Elevated levels of vitamin B12 and folate B) Enhanced neuronal regeneration and repair C) Impaired metabolism of thiamine and other essential nutrients D) Increased production of nerve growth factors Sleep 2 BMS 200  Clock Genes? What is a clock gene? ○An intracellular “time-keeping” system present in most (all?) cells that generate rhythms in biological behaviour ○Regulate circadian rhythms, which are the body's natural 24-hour cycles governing physiological and behavioral processes like sleep-wake cycles, hormone release, body temperature, and metabolism. ○These genes interact through a complex network of feedback loops to generate and maintain rhythmic activity in cells. ○These rhythms are usually approximately 24 hours, but usually need input from light-dark cycles to stay entrained (synchronized) ○These genes are transcribed and produce proteins on an approximately 24 hour cycle ○The following are well-known clock genes: Clock, Bmal1, the “period” genes (Per1, Per2, Per3), Cry1, and Cry2 ○The protein products of these genes increase and then decrease over a 24-hour period – the period is likely synchronized via melatonin fluctuations Clock genes in circadian rhythms Are clock genes responsible for the intrinsic rhythms of the SCN (hypothalamic nucleus that receives input from the retina)? ○ Surprisingly, no – the homeostatic regulation of sleep is not dependent on clock genes or their products in the SCN Are clock genes responsible for intrinsic rhythms in most of the rest of the body (leukocytes, skeletal muscle, brain)? ○ Yes – and these genes seem to be modified by: Sleep (and sleep deprivation) Hormones (melatonin and others) Clock genes in circadian rhythms How “clinically relevant” are these genes and their daily fluctuations? ○Regulate up to 25% of the human genome ○Many of the genes are “metabolic” in nature Cell growth/division Energy metabolism, anabolic and catabolic processes Body temperature Perhaps various neurological functions – the hippocampus in particular in association with memory formation “Immunologic functions” Clock Gene Overview - FYI Clock gene synchronization Clock genes can be entrained by a variety of stimuli: ○ Light-dark cycles ○ Eating ○ Exercise Stimuli that can entrain clock genes are called “zeitgebers” Proper “synchronization” of clock genes seems to promote normal physiological processes and be somewhat protective against cardiometabolic disease ○ People with disrupted sleep cycles are at an increased risk of a variety of cardiometabolic disorders, as well as a modestly increased risk of certain types of cancer (epidemiologic evidence) ○ Many animal studies show that feeding during “active” (i.e. daylight phases) results in improved insulin sensitivity and reduced adiposity, even in the face of identical caloric intake FYI – state of the evidence re: clock genes Melatonin Melatonin is amphipathic – carried by albumin, diffuses readily across cell membranes A single daily light pulse of suitable intensity and duration in constant darkness can phase shift and synchronize the melatonin rhythm to 24 hours ○ Higher-frequency (i.e. blue light) is more effective in suppressing melatonin secretion Individuals living in dim light are more sensitive to light, and secrete more melatonin with a smaller “light stimulus” ○ Blind individuals without light perception show free-running or abnormally synchronized melatonin and circadian rhythms Melatonin can act as a paracrine signal within the retina, Paracrine signaling is a form of cell-to-cell communication in which a cell releases signaling molecules (like hormones or cytokines) that act on nearby cells rather than traveling through the bloodstream to distant targets ○ enhances retinal function in low-intensity light Melatonin Increases expression of antioxidant enzymes ○ superoxide dismutase and glutathione peroxidase Blocks Bax proapoptotic activity and reduces caspase 3 Anti-inflammatory and analgesic properties ○Inhibits cyclooxygenase (COX) enzyme expression reducing excessive prostaglandin and leukotriene production ○May have analgesic properties as well via MT1 and MT2 receptors – reducing pain transmission in dorsal horn neurons Melatonin – additional information Melatonin is a very potent antioxidant, and it seems to be localized in the mitochondria of a wide variety of tissues ○ Independent of the receptor effects – the hormone itself has antioxidant activity ○ Unsure of the clinical significance of physiological concentrations of melatonin as an antioxidant – gram per gram, though, it is a better antioxidant than glutathione ○ Some evidence that melatonin: Is protective against breast and prostate cancer Reduces both systolic and diastolic blood pressure Has been seen (in rodents) to be neuroprotective in ischemic stroke model “Proper” fluctuations in melatonin throughout the day likely improves overall insulin sensitivity and decreases visceral fat mass and hyperglycemia Cardiometabolic consequences of disrupted sleep - summary Increased visceral fat mass Decreased insulin sensitivity and higher incidence of obesity Increased incidence of the metabolic syndrome Dyslipidemia ○Lower HDL, elevated triglycerides FYI – state of the evidence re: sleep disruption in humans FYI – state of the evidence re: sleep disruption in humans  Complications of Obstructive Sleep Apnea (OSA) - Overview Associated with premature death ○ Respiratory events lead to increased sympathetic overactivity 🡪 nocturnal and daytime hypertension ○ Large intrathoracic negative pressure swings (trying to inspire against an occluded airway) 🡪 alter preload and afterload 🡪 cardiac remodeling and reduced function Increased risk of congestive heart failure as well as supraventricular and ventricular dysrhythmias ○ Hypoxia 🡪 vasoconstriction and increased right ventricular afterload Formerly thought to be important, however more recent data indicates that most important cause of increased pulmonary vascular afterload is congestion due to reduced left ventricular function Complications of Obstructive Sleep Apnea (OSA) - Overview Associated with premature death ○ Increased thrombosis and systemic free radical production likely also contribute to mortality Atherosclerosis 🡪 Ischemic heart disease and stroke Hypercoagulability? ○ Prevalence of atrial fibrillation and atrial flutter also higher in OSA Also contributes to stroke risk ○ Interestingly, treatment of OSA also improves insulin resistance Improved sleep quality? Sleep Deprivation and Reproductive Health: Testosterone Sleep deprivation decreases testosterone production ○Testosterone concentration peaks during sleep Testosterone declines with age (males 45-74) ○Poor sleep quality is associated with lower testosterone concentrations 🡪 increased in impact on testosterone levels compared to younger males Sleep Deprivation and Female Reproductive System High levels of melatonin found within ovarian follicular fluid ○Protects oocyte from oxidative stress during ovulation ○Low levels in follicle correlate with increase ROS and infertility ○FYI: IVF outcomes are improved with melatonin supplementation – increase oocyte quality and maturation Sleep: Hormonal and Immune Impacts TSH levels increase during sleep ○TSH is reduced during chronic sleep deprivation Cortisol, epinephrine and norepinephrine decrease during sleep GH, prolactin increase during sleep Increased melatonin levels in children help to suppress GnRH secretion from the pituitary ○Decline of melatonin production during adolescence is linked to onset of puberty Sleep: Hormonal and Immune Impacts Impact of sleep on the immune system Enhanced production of IL2 and IFN-gamma by T cells during nocturnal sleep and reduction in IL-10 ○ Nocturnal sleep is associated with shift towards Th1 adaptive immune response; peaks around 3am ○ Enhanced antiviral and intracellular bacterial response? NK cell count and their activity peak in late morning hours ○ Blocked if experiencing sleep disturbances IL-6 and TNF (pro-inflam cytokines) increase during the night ○ IL-6 associated with sleep, while TNF is regulated by other circadian (non-sleep) factors Sleep includes increased GH and prolactin release 🡪 increase T cell proliferation and promote Th1 cytokine activity Sleep: Hormonal and Immune Impacts Summary – Immune: ○Impaired sleep may increase the predisposition to infection ○Impaired sleep may decrease the effectiveness of vaccination (seen in influenza A vaccinations) ○Perhaps greater Th1 (vs. Th2) activity during sleep Sleep and Carcinogenesis Sleep plays a critical role in various physiological processes, and its disruption has been associated with an increased risk of carcinogenesis This is concerning for those with Sleep disorders Shift Workers Sleep and Carcinogenesis Shift work: Circadian genes impact expression of genes associated with cell division and DNA repair ○ Increased cancer risk in shift workers in epidemiologic studies (breast, prostate, colon, endometrial and non-Hodgkin’s lymphoma) ○ Circadian disruption is deemed “probable carcinogen” Disorders of sleep: ○ Increased risk of prostate cancer, but not breast cancer – associated with problem falling or staying asleep Circadian Rhythms: Gut Microbiome Gut microbiome consists of trillions of microorganisms residing in the gastrointestinal tract, plays a significant role in various physiological processes, even the regulation of circadian rhythms in the host. ○Microbes do not appear to express clock genes Gut microbiome may be able to regulate the circadian rhythms of the host In mice fed a high-fat diet, microbiome-dependent changes in clock genes (Per2, ARNTL) were seen within the liver May be mediated by butyrate production Circadian Rhythms: Gut Microbiome FYI Internal Molecular Clock: ○ (1) Central pacemakers ○ (2) Suprachiasmatic Nucleus (SCN) ○ (3) Auxiliary oscillators Primary clock genes: ○ CLOCK, ARNTL, PER, CRY Secondary clock genes: ○ NR1D1, RORA, DBP, PRARGC1A Influence other genes responsible for energy metabolism and other functions Seizures A seizure is a sudden, uncontrolled electrical disturbance in the brain that can cause a range of symptoms, including changes in behavior, movements, feelings, and levels of consciousness. Seizures can vary significantly in their manifestation, duration, and severity, depending on the areas of the brain involved. Seizures Classifications ○Focal seizures – originate from one brain region Often due to structural problems Intact or impaired awareness Motor or nonmotor at onset ○Generalized seizures – arise from and spread rapidly throughout both cerebral hemispheres Often due to cellular, biochemical or structural problems ○ Motor onset – tonic-clonic or another motor complication at onset of seizure ○Nonmotor – absence seizure, sensory, autonomic or emotional symptoms Focal Seizures – Intact Awareness EEG during non-seizure periods of time is typically normal or exhibiting brief epileptiform spikes or sharp waves Arise from: medial temporal lobe or inferior frontal lobe Presentations and progressions vary: ○ Seizure may start in one region i.e. motor cortex responsible for fingers and spread to include entire hand, patient may experience paresis after the seizures (hours; rarely days) May experience sensory changes or emotional experiences (i.e. déjà vu, fear, detachment) Focal Seizures – Impaired Awareness Impaired awareness ○Not necessarily loss of consciousness, but inability to respond appropriately to environmental changes (i.e., conversation) and possible having poor recollection after seizure is done ○May experience an aura ○May be experience automatism; involuntary, automatic behaviours Can be simple like chewing or complex ○Full recovery of consciousness may take seconds, hours or longer Generalized Seizures 1 Typical Absence Seizures ○Sudden, brief lapse of consciousness without loss of postural control (seconds in duration) ○Typical onset during childhood ○May occur 100 times per day – appear as “daydreaming” Atypical Absence Seizures ○Lapse of consciousness is longer and more gradual in onset ○May include focal and motor symptoms ○Usually due to diffuse or multifocal structural abnormalities, which result in additional neurological complications Generalized Seizures 2 Generalized, Tonic-Clonic Seizure ○Occur in many different clinical setting because can result from metabolic problems One of the more common types of seizures ○Tonic Phase: Tonic contraction of muscles throughout body, “ictal cry”, impaired respiration yielding cyanosis, jaw clenching, increased SNS; lasts 10-20 seconds ○Clonic Phase: superimposed periods of muscle relaxation that increase in duration to a maximum of 1 min ○Post-Ictal Phase: unresponsive, muscles are flaccid, excess salivation (possibly partially obstructing airway), bladder or bowel incontinence ○Gradually regain consciousness after minutes to hours ○May complain of headache, fatigue and muscle pain for hours later Generalized Seizures 3 Atonic Seizure ○ Sudden loss of postural muscles 1-2 sec in duration ○ Brief impairment in consciousness, no post-ictal confusion Could be as brief as a head drop or a full body collapse Myoclonic Seizure ○ Sudden and brief muscle contraction of body part or whole body ○ Can be due to metabolic disorders, degenerative CNS disorders or anoxic brain injury Epileptic Spasms ○ Predominantly in infants 🡪 brief flexion or extension of proximal and truncal muscles Etiology and Pathophysiology of Seizures: General General knowledge/ observations: ○Seizure is a shift from normal balance between excitation and inhibition within CNS ○Brain has different seizure thresholds at different maturational stages ○Epileptogenesis – transformation of normal brain tissue into a network that is hyperexcitable Include: penetrating head trauma, stroke, infections, abnormalities in CNS development (congenital) ○Epileptogenic factors – specific changes that promote lowering of seizure threshold ○Precipitating factors – trigger or provoke an episode of seizure (seizures don’t occur 24/7) Include: psychological or physical stress, sleep deprivation, hormonal changes, toxic substances, certain meds, intermittent photic stimulation (video games and strobe lights) Etiology and Pathophysiology of Seizures Almost simultaneous firing of large number of local excitatory neurons 🡪 hypersynchronization of excitatory bursts across large cortical region Individual neuron: ○Paroxysmal depolarization shift – long-lasting depolarization of membrane due to influx of extracellular Ca2+ 🡪 triggers voltage gated Na+ channels to open 🡪 influx Na+ 🡪 repetitive action potentials Spike discharge (EEG) – when these action potentials happen in a relatively synchronized manner in sufficient number of neurons 🡪 summation of field potentials Etiology and Pathophysiology of Seizures Spread of activation to surrounding neurons is facilitated by: 1. increase in extracellular K+ which shifts the Nernst potential for potassium Resting membrane potential becomes more positive 🡪 neurons reach threshold more easily 2. accumulation of Ca2+ in presynaptic terminals promoting neurotransmitter release 3. NMDA receptor activation 🡪 additional Ca2+ influx Etiology and Pathophysiology of Seizures: Neonate/ Infant: ○ Congenital CNS abnormalities, trauma, CNS infection, hypoxic ischemic encephalopathy, drug withdrawal, perinatal injury, inborn errors of metabolism (i.e., pyridoxine deficiency) Early Child: ○ Febrile seizures Childhood: ○ Many well-defined epilepsy syndrome present in this age group, often due to idiopathic or genetic causes Adolescents and Adults: ○ Shift towards acquired due to CNS lesions, head trauma, CNS infection (i.e. neurocystericosis), tumors, illicit drug use or alcohol withdrawal, autoimmune (i.e., antibodies against CNS K+ channels) Etiology and Pathophysiology of Seizures: Etiologies 2 Older Adults: ○Cerebrovascular disease (FYI 50% of new cases of epilepsy in >65yo), trauma, degenerative diseases Chronic seizures often appear months or years after the initial stroke Any age: ○Metabolic disturbances (electrolyte imbalance, hypoglycemia, hyperglycemia), renal failure, hepatic failure, hematological disorders, endocrine disorder, vasculitis as well as variety of medications Sleep Deprivation and Epilepsy Sleep deprivation can provoke seizures ○Cortical excitability increases with time being spent awake ○This is especially true for generalized epilepsy BUT not all seizures or epilepsies Epilepsy can affect sleep quality: ○Increase wake time after sleep onset (strongest feature of epilepsy) ○Reduce REM sleep quality and delay the first REM episode ○Change NREM sleep oscillations ○Overall disruption of normal sleep  Taenia – worm infestations Tapeworm: ○ Cattle or pigs become infected by eating contaminated vegetation ○ Taenia invades muscle and survive for years ○ Humans get infected by eating undercooked or raw infected meat (beef, pork) ○ SX: mild abdominal symptoms (attaches to SI and give rise to proglottids which exit via anus and passed in the stool Cysticercosis and Neurocysticercosis Cysticercosis is infection of the muscle (or other tissue) by the larval cysts of Taenia solium (pork tape worm) ○ Worm was able to penetrate the intestinal wall and disseminate (preference for muscle and brain) Neurocysticercosis is infection of the brain, which is a major cause of adult-onset seizures in low-income countries ○ Most common parasitic disease of CNS ○ Complex immune evasion is believed to be the reason it can survive for so long in the brain without sx ○ Presentation is variable: minimal sx, then suddenly seizures and increased intracranial pressure and possibly death Depends on parasitic load (number of invaders) and location Neurocysticercosis Pathogenesis MMP-9 polymorphism ○Associated with patients who exhibit symptoms (seizures) compared to asymptomatic, yet infected, patients ○Increased BBB permeability (MMP-9 remodels and degrades the BBB) 🡪 thought to allow greater influx of immune cells into CNS and thus result in greater inflammatory response 🡪 degradation of the cysticerci AND subsequently greater seizure activity Trypanosoma brucei and Sleeping Sickness Trypanosoma brucei (T.b. gambiense) ○Unicellular parasite transmitted by the bite of the tse-tse fly, extra-cellular parasite ○Endemic to sub-Saharan Africa (location of the tse-tse fly) Sleeping Sickness 3 years in duration; largely fatal (some problematic treatments exist) ○Early phase: parasite is in the bloodstream and interstitial space of a few organs Chronic, intermittent fevers, headache, pruritus, lymphadenopathy, possibly hepatosplenomegaly ○Late phase: parasite invades the CNS Sleep disturbance and neuropsychiatric disorders Sleeping Sickness Invade the brain: ○ Observed in CSF (diagnostic!), but don’t seem to survive there long, may be penetrating BBB directly (unclear) BUT there is no damage in BBB itself ○ Concentrate in the median eminence and hypothalamic areas Change in sleep architecture ○ No change in total amount of time asleep! Increased daytime sleep and insomnia at night ○ Similar features with narcolepsy: SOREM episodes; sudden transition from wake to sleep Excessive daytime sleepiness Sleep fragmentation