Boards and Beyond: Musculoskeletal A Companion Book to the Boards and Beyond Website Jason Ryan, MD, MPH Version Date: 1-7-2018
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Table of Contents Knee Shoulder and Elbow Brachial Plexus Wrist Hand Lumbosacral Plexus Lumbar Radiculopathy Hip Skeletal Muscle Cardiac Muscle Smooth Muscle Bone
1 6 10 14 18 22 27 30 33 32 40 45
Bone Disorders Osteoporosis Osteoporosis Drugs Bone Tumors Osteoarthritis Gout Gout Drugs CPPD Seronegative Spondyloarthritis Spondyloarthritis Muscle Disorders Neuromuscular Disorders
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51 56 59 62 68 72 76 79 81 86 90
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Knee •
Fourbones
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Four ligaments
•
Knee •
Jason Ryan, MD, MPH
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Anterior cruciate
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Posterior cruciate
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Medial collateral
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Lateral collateral
Two menisci •
Medial
•
Lateral
Anterior Cruciate Ligament
Cruciate Ligaments •
Femur, Femur, tibi a, fibula, patella
ACL
Cruciate = cross shaped shaped Twoligaments( ACL/PCL) Form X
Posterior Cruciate Ligament
•
Lateral femoral condyle anteriortibia anterior tibia
•
Resists anterior movement of tibia
Collateral Ligaments
PCL •
Medial femoral condyle posterior tibia
•
Lateral and medial bands
•
Resists posterior movement of tibia
•
Resistvalgus Resist valgus and varus deformity
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Medial Collateral Ligament
Collateral Ligaments •
•
MCL
Valgus •
Knock kneed
•
Lower leg abducted
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•
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Varus •
Bow legged
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Lower leg adducted
Lateral Collateral Ligament •
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Lateral condyle of femur
•
Head of fibula Resists varus (bow leg) stress
•
•
•
•
•
Two crescent-shaped pads (medial and lateral) Fibrous tissue and cartilage Between tibia and femoral condyles
ACL Injury
Knee Injuries •
Medial condyle of tibia Resist valgus (knock knee) stress
Menisci
LCL •
Medial epicondyle of femur
Anterior Cruciate Ligament
Often involve tears of ligaments or menisci Swelling Instability
•
Most commonly injured knee ligament
•
Often a noncontactathletic noncontact athletic injury
Sensation that knee will “give out” •
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•
Running/jumping
•
Sudden change of direction (cutting/pivot) (cutting/pivot)
Classically senses as a “pop” in knee
ACL Injury
PCL Injury
Anterior Cruciate Ligament
Posterior Cruciate Ligament
•
•
•
Patientsupine
•
Anterior drawe drawer r sign •
Bend knee 90° angle
•
Tibia drawn forward
•
Forward movement greater than normal in ACL ACL tear
•
Lachmantest •
Same as drawer sign but 30° angle
MCL Injury
•
Damaged by valgus stress •
Contact
•
Non-contact (twisting)
•
•
•
Abnormal passi passive veabduction •
Force from lateral side (valgus)
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Lower leg away from midline (abduction)
•
Medial space widens
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Force directed posteriorly at knee
•
Classic cause: “dashboard injury” – knee into dashboard
Posterior drawer sign •
Patient supine
•
Knee bent at at 90° angle
•
Tibia moves backwards more than normal
Unhappy Triad
Medial Collateral Ligament •
Often from trauma
Triad of injury common in contact sports Lateral force applied to knee when foot planted Originaltriaddescription: •
•
Anterior cruciate ligament (ACL) (ACL) tear
•
Medial collateral ligament (MCL) tear/sprain
•
Medial meniscal tear
Modern studies: lateral meniscus more common
Shelborune KD, Nitz PA.Am J Sports Med The O'Donoghue triad revisited. Combined knee injuries involving anterior cruciate and medial collateral liga ment tears.1991 tears.1991 19(5): 474-7
LCL Injury
Meniscal Tear
Lateral Collateral Ligament •
•
•
Rarely injured in isolation
•
Often trauma to medial knee Abnormal passi passive veadduction •
Force from medial side (varus)
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Lower leg toward midline (adduction)
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Lateral space widens
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•
•
•
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Often occurs when foot is planted Sudden change in direction twisting of knee Often occurs in sports (soccer, basketball) Pain and swelling following injury Pain worse with twisting or pivoting
McMurray Test •
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Knee
Patientsupine
•
Flexed (bent) knee held byexaminer’s hand Foot held by examiner’s other hand Extend knee while rotating foot Pain or “pop” = positive McMurray test
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Internal rotation tibia tests lateral meniscus
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External rotation tests medial meniscus
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Connects bones
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Synovial membrane
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Synovial fluid
Foot toward midline Foot away midline
Bursitis •
Synovial joint
Prepatellar Bursitis
Bursa = synovial-lined sac Cushion between bones and tendons/muscles tendons/muscles Four bursa near knee
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Inflammation of prepatellar bursa
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Often caused by repeated kneeling
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Other causes: infection, gout
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“Housemaid’s knee”
Pain with activity Swelling anterior to patella Warmth
Baker’s Cyst
Baker’s Cyst
Popliteal Cyst
Popliteal Cyst
•
Popliteal fluid collection
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Gastrocnemius-semimembranosus bursa
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•
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Bursa between two muscle tendons
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Found in back of the knee
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•
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Often communicates with synovial space Often related to chronic joint disease •
Degenerative
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Inflammatory
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Joint injury
Oftensmall, asymptomatic asymptomatic
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•
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Detected by imaging imaging for unrelated joint symptoms
May cause posterior knee pain Pain with prolonged standing Symptoms/swelling Symptoms/swellingworse withactivity Rupture may cause acute pain (mimics DVT) Common in patients with rheumatoid arthitis
Osgood-Schlatter Disease
Patellar Fracture
Tibial tuberosity avulsion •
Occurs in children
•
•
Pain/swelling at tibial tubercle from overuse
•
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Insertion point of patellar tendon
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Secondary ossification center of tibia
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Usuallybenign, self-limited condition
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Results from trauma to knee Swollen, painful knee Cannotextend Cannot extend knee against gravity •
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Indicates loss of knee extension
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Classic cause: patellar fracture
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Quadriceps tendon tear tear
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Injury to patellar tendon
Diagnosis:X-ray
Shoulder •
Shoulder and Elbow
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Ball and socket joint •
“Glenohumeral joint”
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Glenoid = fossa of scapula bone
Three bones •
Clavicle, scapula, humerus humerus
Jason Ryan, MD, MPH
Rotator Cuff •
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Rotatorcuff
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Four muscles surrounding joint
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Supraspinatus, infr aspinatus, subscapularis, teres minor
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Draws humerus head head into glenoid glenoid during abduction
conjoint tendon
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Above spine of scapula
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Initialabduction(0-15°)
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Innervation: suprascapular nerve
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Most common rotator cuff injury
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Tendonitis: common cause of shoulder pain •
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Supraspinatus
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Pain with abduction
Tears: inability to abduct
Supraspinatus
Main abductor: deltoid (15-100°) (15-100°) Also infraspinatus muscle
Empty/Full Can Tests
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Common cause or rotator cuff injury
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Identifysupraspinatusinjury
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Impingement
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Empty Can Test
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Compression of tendon
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Arms out (90° abduct; 30°in front)
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Between humeral head head and acromion process of scapula
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Thumbs down
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Impingement in the subacromial space
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Examiner pushes arms down
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Positive if pain
Leads to tendinopathy (inflammation) or tear Occurs is swimmers and throwers •
“Swimmer’s shoulder”
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“Thrower’s shoulder”
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Full Can Test •
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Thumbs up
Infraspinatus •
Infraspinatus
Below spine of scapula scapula
•
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Assists in e xternal rotation/abduction rotation/abduction of shoulder Innervation: suprascapular nerve Commonly injured injured in overhead throwers (pitchers (pitchers)) •
•
Teres Minor
Most common rotator cuff cuff injuries:supra/infraspinatus
Difficult to assess in isolation
Subscapularis
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Assists in external rotation/adduction rotation/adduction of shoulder
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Internal rotation of shoulder/arm
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Innervation:axillarynerve
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Innervation:Upper/lowersubscapularnerves
Shoulder Movement •
Deltoid: Deltoid : primary shoulder abductor up to 90° •
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Shoulder Dislocation •
Innervated by axillary nerve
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Othermuscles •
Supraspinatus: initiates abduction; first 15°
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Trapezius/serratus anterior: abduction beyond 90°
Trauma anterior dislocation of humeral head
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Vulnerable arm: abducted, externally rotated, extended
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Blocking a basketball shot
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Tackle while throwing a football
Commonlyinjures axillary nerve •
Runs below humeral head
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Wraps around neck
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Sensory loss of deltoid
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Weak abduction (shoulder usually too painful painful to move)
Humerus Fracture •
Common in elderly (falls)
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Often occur in the proximal humerus
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Blood supply: branches of axillary artery
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Fractures may disrupt blood supply supply
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Avascular necrosis of head
Elbow •
•
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Brachial plexus
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Axillary nerve
Humerus (upper arm)
•
Radius/ulna (lower arm) arm)
Prone to overuse injuries •
Golfers, tennis players
loss of arm abduction (deltoid)
Epicondylitis
Lateral epicondyle •
Bone origin of wrist extensors extensors
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Medial epicondyle
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Epicondylitis
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Pain in medial or lateral elbow
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Worsewithrepetitive movements
Bone origin of wrist flexors
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Pain at epicondyle from overuse
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Form of “chronic tendinosis”
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Few inflammatory cells
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Disorganized tissue/vessels
Epicondylitis •
•
Proximalhumerusnerves
Epicondylitis •
Three bones
Epicondylitis
Lateral epicondylitis (tennis elbow)
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Medialepicondylitis (golfer’s elbow)
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Tenderness: lateral epicondyle and proximal proximal wrist extensors
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Tenderness: medial epicondyle epicondyle
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Elbow pain with resisted wrist extension
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Pain with resisted wrist flexion
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Nursemaid’s Elbow •
Radial head subluxation •
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Subluxation = partial dislocation
Caused by “axial traction” on pronated forearm •
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Supracondylar Facture
Arm pulled when extended at at elbow
Annular ligamentslips ligament slips over head of radius •
Trapped in radiohumeral joint
Supracondylar Facture •
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Brachialartery may be injured Median nerve travels with brachial artery Injury to both: most common neurovascular neurovascular injury Radial or ulnar nerves may also be injured •
Ulnar nerve travels under medial epicondyle
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Radial nerve wraps around around humerus laterally
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•
Most common pediatric elbowfracture
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Often from fall on outstretched arm
Brachial Plexus •
Network of nerves
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Motor and sensory innervation of arm
•
Damage to plexus elements nerve syndromes
Brachial Plexus Jason Ryan, MD, MPH
Brachial Plexus Lesions
Spinal Nerve Roots
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Cervical (8) Thoracic (12) Lumbar (5) Sacral (5) •
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Axillary Nerve •
Loss of sensation over deltoid
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Proximal humerus fracture •
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Abduction 15° to 90°
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Elderly patient with fall
Dislocated shoulder •
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Axillary
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Radial
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Median
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Ulnar
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Musculocutaneous
Trunks •
Upper: C5-C6
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Lower: C8-T1
Long thoracic nerve
Radial Nerve
Deltoid muscle •
Nerves
•
Anterior displacement of humerus
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Extensor to arm, wrist, fingers Triceps (extends (extends at the elbow) Extensor muscles in forearm •
Extends wrist and fingers
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Supinates the forearm
Sensory to back of hand/forearm hand/forearm
Radial Nerve Lesions
Wrist Flexion and Extension Major Flexors Median and Ulnar Nerves Nerves Flexor carpi radialis Flexor carpi ulnaris
Major Extensors Radial Nerve Extensor carpi radialis longus Extensor carpi radialis brevis Extensor carpi ulnaris
Wrist drop
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Sensory loss back of hand/forearm
Weakness wrist/finger extensors
Radial Nerve
Causes
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Runs adjacent to humerus
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Humeral fracture (midshaft) (midshaft)
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In spiral/radial groove
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Crutches (compression)
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Vulnerable to compression against bone
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Sleeping with arms out over over chair
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“Saturday night palsy” night palsy”
Radial Nerve Lesions •
Triceps weakness (axillary injury)
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Radial Nerve Lesions •
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Radial Nerve Lesions
Axilla level damage
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Radial groove damage
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Triceps weakness
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Weakness wrist/finger extensors
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Weakness wrist/finger extensors
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Sensory loss back of hand/forearm
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Most sensory nerves (arm/forearm) unaffected
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Triceps spared
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Superficial branch of radial nerve damaged
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Sensory loss dorsal surface surface
C5-C6 Trunk
Musculocutaneous Nerve •
Lateral cord of brachial plexus •
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Erb’s Palsy/Upper Plexus Injury •
C5, C6, and C7
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Innervatesbiceps Innervates bicepsand and other muscles Sensationto lateralforearm
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Nerve lesion (rare) •
Weakness of elbow flexion
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Sensory loss lateral forearm
Caused by excessive angle at neck/shoulder Stretches/tears nerve roots nervedamage Classiccause: birth trauma •
“Shoulder dystocia:” shoulder impedes delivery
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Stretching of angle between neck/shoulder neck/shoulder
C5-C6 Trunk
C5-C6 Trunk
Erb’s Palsy/Upper Plexus Injury
Erb’s Palsy/Upper Plexus Injury
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Axillarynerve
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Deltoid abduction
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Shoulder flat at side
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Musculocutaneous
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Biceps
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Forearm down
Arm straight straight at side side Internally rotated (hand facing out) “Waiter’stip” “Waiter’s tip”
elbow flexion
Suprascapular
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Infraspinatus
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Arm internally rotated
external rotation
C8-T1 Trunk
C8-T1 Trunk
Klumpke Palsy/Lower Plexus Injury
Klumpke Palsy/Lower Plexus Injury
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Caused by excessive abduction of arm
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Catching a tree branch while falling Rarely occurs from birth trauma
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Ulnar and median nerves Affects intrinsic hand muscles Flexors at wrist arm spared •
Also supplied by ulna and and median nerves
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Innervated by different roots
Metacarpophalangeal joints hyperextended Interphalangealjointsflexed Result:clawed Result: clawed hand
Thoracic Outlet Syndrome •
Compression of nerves/vessels leaving thorax
•
Occurs above first rib and behind clavicle •
Thoracic Outlet Syndrome •
“Thoracic outlet”
Scalene triangle •
Anterior scalene
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Middle scalene
•
Above first rib
Thoracic Outlet Syndrome
Thoracic Outlet Syndrome
Causes
Clinical Features
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Cervicalrib
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Brachial plexus: Klumpke palsy
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Anomalous extra rib from 7 th cervical vertebrae
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Lower plexus injury
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Predisposes to outlet syndrome
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Symptoms worse with elevation of arms/hands arms/hands
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Often occurs after hyperextension-flexion (whiplash)
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Venous compression: Arm swelling Arterialcompression(rare) •
Long Thoracic Nerve •
Innervatesserratus Innervates serratus anterior muscle •
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Pulls scapula against against rib cage
Lesion (trauma): winging of scapula •
Patient presses outstretched outstretched arm against wall
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Scapula protrudes from back
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Hand ischemia (pain, pallor, pallor, cool temperature) temperature)
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Lower systolic blood pressure
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Weak distal pulses
Wrist Bones •
Carpus = wrist
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Eight carpal (wrist) bones •
Wrist Jason Ryan, MD, MPH
Scaphoid •
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•
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Palpable in anatomic snuff box Classicallyfrom FOOSH injury
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D: Pisiform
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E: Trapezium
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F: Trapezoid
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G: Capitate
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H: Hamate
Blood supply: Radial artery
Falling On an Out-Stretched Hand
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Palmar and dorsal branches
Radial artery supplies distal bone Proximal portion relies onretrograde on retrogradeflow
Complications Complications offractures •
Avascular necrosis
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Nonunion
Lunate Dislocation
Complications
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C: Triquetrum
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Scaphoid Fracture •
B: Lunate
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Scaphoid Blood Supply
Most commonly fractured carpal bone
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A: Scaphoid
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Avascular necrosis •
Loss of blood supply
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Especially waist fractures
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Nonunion •
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Failure of bone to heal
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Caused by trauma/fall Lunate attached to radius Other bones forced backwards Lunate displaced toward palm Wrist painful/swollen
Lunate Dislocation
Carpal Tunnel
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Lunate may compress carpal tunnel
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Transversecarpalligament(flexor retinaculum)
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Median nervedysfunction nerve dysfunction
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Carpal bones (inferiorly) (inferiorly)
Carpal Tunnel Syndrome •
Entrapment of median nerve in carpal tunnel
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Symptomsofmedian of median nerve dysfunction
Median Nerve Lesions •
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Motor loss to thumb side: •
Thumb movement (thenar muscles)
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Flexion/extension of lateral fingers (lumbricals)
Sensory loss thumb side: •
Carpal Tunnel Syndrome
Carpal Tunnel Syndrome •
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Risk Factors
Begins with sensory symptoms
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Untreated can lead to motor symptoms Classic hallmark: pain or paresthesia •
Described as numbness and and tingling
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Distribution of median nerve
Thenar eminence, lateral 3 ½ fingers
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Repetitive use of hands/wrists (controversial) Obesity Pregnancy(edema) Otherdisorders •
Diabetes
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Rheumatoid arthritis
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Hypothyroidism
Acromegaly •
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Dialysis-related Amyloidosis
Growth hormone excess in adults
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Often caused by pituitary adenoma Enlarged jaw and course facial features Enlargedhands Enlarged hands and feet •
Classic sign: Increasing glove/shoe size
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Rings that no longer fit
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Up to 1/3 have carpal carpal tunnel syndrome
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Amyloid deposits form from β2 microglobulin Complication Complication of renal failure Dialysis does not effectively remove β2 microglobulin microglobulin Bones,joints,tendons Shoulderpain Carpal tunnel syndrome
Carpal Tunnel Syndrome
Guyon’s Canal
Physical Exam
Ulnar Canal
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Tinel’s sign •
Patient extends wrist
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Percussion (light tapping) over over thumb side of wrist
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Tingling in distribution of median nerve = positive
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Abovetransversecarpal ligament Roof formed by palmar fascia Passage of ulnar nerve and artery into wrist
Phalenmaneuver •
Patient asked to flex wrist and hold for 60 seconds
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Tingling in distribution of median nerve = positive
Guyon’s Canal Syndrome
Ulnar Nerve Lesions •
Lossof abduction/adduction abduction/adduction(interossei)
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Overuse of the wrist
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Motor loss to little finger side (little/ring fingers)
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Many cases reported inbicyclists in bicyclists
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Hypothenar muscles, muscles, medial two lumbricals
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Sensory loss little finger side
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Direct pressure from handlebars
Pediatric Fracture
Greenstick Fracture
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Often from trauma
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Oftenincomplete
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Torus Fracture Pediatric Fracture •
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“Buckle fracture” Axial forcetrauma force trauma •
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Force into bone
Occurs in distal metaphysis Diaphysis = shaft
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Epiphysis = rounded end end
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Metaphysis = widening
Metaphysis: most porous bone
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Bent bone from fracture Fracturedoes Fracture does not extend through width of bone Often occur in distal radius from trauma Bending force (from side) applied to bone Often FOOSH injury (fall on an outstretched hand)
Terminology •
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Hand
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Jason Ryan, MD, MPH
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Ulnar and Median Nerves •
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Structures toward ulnar bone (little finger) Structures toward radius (thumb)
Thenar Muscles •
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“Volar” = palm of hand “Dorsal” = back of hand Thumb = lateral Little finger = medial medial
Intrinsic •
Mediannerve •
Index = 2nd digit Middle (long) = 3rd digit Ring = 4th digit Pinky (small) = 5th digit
Hand Muscles
Ulnar nerve •
Thumb = 1st digit
Thenar (thumb)
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Hypothenar (little finger)
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Interosseous muscles (abduction/adduction) (abduction/adduction)
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Lumbrical muscles (four fingers)
Hypothenar Muscles
Threemuscles
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Threemuscles
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Abductor pollicis brevis
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Opponens digi ti minimi
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Flexor pollicis brevis
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Flexor digiti minimi brevis
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Opponens pollicis
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Abductor digiti minimi
Associated with thumb
•
Form thenar eminence of palm Innervated bymedian by median nerve Atrophy in median lesions
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Associated with little finger Formhypothenareminence Innervated byulnar by ulnar nerve Atrophy in ulnar lesions
Interosseous Muscles •
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Lumbricals
Abduct and adduct fingers(not fingers (not thumb) •
Dorsal = abduction
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Palmar = adduction
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Originate: tendons of flexor digitorum profundus •
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Innervated byulnar by ulnar nerve
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Medial two lumbricals: ulnar nerve •
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Flexors
Loss of lumbricals: claw fingers Metacarpophalangeal Metacarpophalangeal joints extended (cannot flex)
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Interphalangeal joints flex (cannot extend)
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Underside of forearm
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Flexor digitorum profundus profundus •
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•
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Major Flexors Median and Ulnar Nerves Flexor carpi radialis Flexor carpi ulnaris
Back of the forearm Straighten digits Extensor digitorum ((radial radialnerve) nerve) Strongly extends MCP joints PIP/DIPextension: Lumbricals •
Lateral two digits: Median nerve
•
Medial two digits: Ulnar nerve
Ulnar nerve
Wrist Flexion and Extension
Extensors
•
Median nerve
Medial two digits (little finger) •
Extrinsic Hand Muscles
Median/ulnar Median/ulnar portions
Flex digits make fist Lateral two digits (thumb) •
•
•
Near thumb
Extrinsic Hand Muscles
Lumbricals •
Near little finger
Lateraltwo lumbricals: lumbricals: median nerve •
•
Forearm (extrinsic) muscle that flexes fingers
Flexmetacarpopha Flexmetacarpophalangeal langeal joints Extend interphalangeal interphalangeal joints
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Major Extensors Radial Nerve Extensor carpi radialis longus Extensor carpi radialis brevis Extensor carpi ulnaris
Wrist Deviation •
Seen in lesions involving flexor muscles
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To ulnar (little finger) side with median lesions
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Median Nerve Lesions •
To radial (thumb) side with ulnar lesions •
Motor loss to thumb side: •
Thumb movement (thenar muscles)
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Flexion/extension of lateral fingers (lumbricals)
Sensory loss thumb side: •
Median Nerve Lesions •
•
Median Nerve Lesions
Thumb: •
•
Flexion/abduction/opposition Flexion/abduction/opp osition absent (thenar muscles)
“Pope’s blessing” •
Lateraldigits:
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Also called Hand of Benediction Ask patient to make fist
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Loss of lumbricals
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Thumb, lateral fingers cannot flex
•
“Clawed” lateral digits
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MCP extended
Median Nerve Lesions •
Thenar eminence, lateral 3 ½ fingers
Median Nerve Lesions
“Ape hand” •
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At rest
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Thumb adducted
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Cannot oppose/abduct thumb
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Thenar atrophy
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Wristlesions •
Laceration
•
Carpal tunnel syndrome
Flexor muscles intact No wrist deviation deviation
Recurrent Branch
Median Nerve Lesions •
Median Nerve
Elbowlesions •
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Supracondylar fracture of humerus humerus
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Loss of most flexors/pronators in forearm
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Forearm supinated
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Flexion weak
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Ulnar deviation
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Pull of the flexor carpi ulnaris
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Ulnar Nerve Lesions Lossof abduction/adduction abduction/adduction(interossei)
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Motor loss to little finger side (little/ring fingers)
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Hypothenar muscles, muscles, medial two lumbricals
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Sensory loss little finger side
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Ulnar Nerve Lesions •
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Lacerations
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Guyon Canal Syndrome
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•
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Elbowlesions •
Fracture at medial epicondyle
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Loss of flexor carpi ulnaris
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Radial deviation of wrist with flexion
Fibrous band on palm side of hand
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Covers carpal bones
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Forms carpal tunnel
Injured in superficial laceration Immobilizes thumb Sensation normal
Hand position at rest (fingers straight/not straight/not flexed) Caused by paralysis of medial lumbricals Extensionof metacarpophalangeal metacarpophalangealjoints Flexion at interphalangeal joints
Ulnar Paradox
Wristlesions •
•
Ulnar Claw
•
•
Motor innervation to thenar muscles No sensory innervation Superficial nerve near flexor retinaculum
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•
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Proximal (elbow) lesions: ulnar claw may not be seen Flexion at interphalangeal joints not present Proximal lesions: loss of flexor digitorum profundus Ulnar digits paralyzed without clawing Proximal lesions appears less severe (“paradox”)
Lumbar Plexus
Lumbosacral Plexus
•
Network of nerves T12 to L4
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Lumbar region of spine
•
Supplies skin and muscles of lower limb
Jason Ryan, MD, MPH
Sacral Plexus •
•
•
Iliohypogastric
Network of nerves L4-S4
•
Sacral region of spine Supplies skin/muscles of pelvis and lower limb
•
•
Iliohypogastric •
•
Laparotomy, laparoscopic surgery
•
Hernia surgery, hysterectomy
•
Transverse incisions
•
Sutures may trap nerves
•
May also involve Ilioinguinal nerve Burning pain or paresthesia paresthesia (tingling)
•
Radiates from incision to suprapubic area
•
Sometimes labia/scrotum, or thigh
•
Below umbilicus
•
Above pubic bone
•
L1-L2
•
Motor:Cremasteric Motor: Cremasteric muscle
•
Sensory (genital branch):
•
Symptoms occur after surgery: •
Motor: internal oblique and transversus abdominis abdominis Sensory:Suprapubic(hypogastric)region
Genitofemoral Genitofemoral Nerve
Commonly injured in inabdominal/pelvic abdominal/pelvic surgery •
T12-L1
•
22
Muscle covering testis and spermatic cord
•
Males: skin of anterior scrotum
•
Females: skin over mons pubis and labia majora
Sensory (femoral branch): skin upper anterior thigh
Genitofemoral Genitofemoral Nerve •
Injured in abdominal surgery •
•
•
•
Lateral Femoral Cutaneous
Often damaged by retractor blades
Absent cremasteric cremasteric reflex reflex(males) (males) •
Stroke inner thigh
•
Scrotum rises ipsilateral side
Pure sensory nerve from L2-L3
•
Courses under inguinal ligament into thigh
•
Compressed by tight clothing, obesity, pregnancy
↓ sensation anterior thigh ↓ sensation labia/scrotum
Obturator Nerve
Lateral Femoral Cutaneous •
•
L2-L4
Meralgia paresthetica •
Outer thigh nerve syndrome
•
Burning pain
•
Paresthesia (numbness/tingling)
•
Hypoesthesia (diminished sensation)
•
•
•
•
Obturator Nerve •
•
•
•
•
Obturare = Latin “to close” Closes (adducts) thigh Motor:Thigh Motor: Thigh adductors •
Adductor Longus
•
Adductor Brevis
•
Adductor Magnus
•
Gracilis
•
Obturator Externus
Sensory:Medial Sensory: Medial thigh
Femoral Nerve
Courses through posterior pelvis
•
Injured in pelvic surgery Trocar into pelvis Weak adduction
•
•
•
Numbness medial thigh
23
L2-L4 Motor and sensory Motor: anterior thigh muscles Hip flexors and knee extensors
Femoral Nerve
Femoral Nerve
Hip Flexors
Knee Extensors
•
•
•
Pectineus
•
Iliacus (part (part of iliopsoas) Sartorius
Femoral Nerve Anteriorcutaneousbranches •
Saphenous nerve
•
Saphenous vein stripping
•
CABG
•
May damage saphenous nerve
•
Numbness lower leg leg
•
•
Vastus medialis
•
Vastus intermedius (deep to rectus)
•
Femoral nerve at groin
Along with obturator and femoral femoral cutaneous block
•
Lateral to medial
•
Nerve-artery-vein-lymph (NAVL)
Sciatic Nerve
Injury
•
•
•
Femoral Nerve •
Vastus lateralis
Anesthesia to leg for surgical procedures
Skin on medial leg and foot
•
Rectus femoris
•
•
Skin of anteromedial thigh
•
•
Femoral Nerve Block
Sensory •
Quadriceps femoris
Rarely injured by pelvic fracture or surgery
•
Weakness:flexion Weakness: flexion of thigh, extension at knee Absent patellar reflex Numbness, tingling, burning pain in thigh/knee
•
•
•
24
L4-S3 Largest nerve in the body ( 2cm wide!) Motor/Sensory Branches:common Branches: commonperonealand peroneal and tibial
Common Peroneal Nerve
Common Peroneal Nerve
Common Fibular Nerve
Motor Functions
•
•
•
Motor/sensory to lower leg Fibula: Latin word for clasp Peroneus: Greek work for clasp
•
Short head of biceps femoris
•
Branch: Superficial fibular nerve
•
•
•
Muscles of lateral lower leg
•
Fibularis longus and and brevis
•
Evert the foot
Branch: Deep fibular nerve •
•
Common Peroneal Nerve
Hamstring muscle (flexes knee)
Muscles of anterior lower leg Tibialis ant, extensor digitorum longus, extensor hallucis longus
•
Dorsiflexion of foot , extension of toes
•
Also some intrinsic muscles of foot
Common Peroneal Nerve
Sensory Functions •
Lower leg
•
Wraps around fibula below knee
•
Dorsum of foot
•
Injuredby:
•
•
•
•
Leg casts
•
Fibular neck fracture
Symptoms: •
Foot drop (weak dorsiflexion)
•
Foot feels limp (patient may trip)
•
Sensory loss dorsum foot, lateral shin
Posterior Leg Muscles
Course: down the leg, posterior to tibia
•
Motor to posterior leg muscles At foot travels under medial malleolus •
Prolonged lying (bed rest, surgery)
•
Tibial Nerve
Tibial Nerve •
•
Through tarsal tunnel
Sensory to heel/sole
25
Many deep and superficial muscles •
Popliteus
•
Flexor hallucis Longus
•
Flexor digitorum Longus
•
Tibialis posterior
•
Plantaris
•
Soleus
•
Gastrocnemius
Tibial Nerve
Tibial Nerve Damage
Posterior Leg Muscles •
Manyactions:
•
Plantar flexion
•
Often following fracture/dislocation fracture/dislocation
•
Toe flexion
•
Symptoms mostly sensory sensory
•
Inversion
•
Pain, burning, numbness on sole of foot
•
Pudendal Nerve •
•
•
Pudendal = Latin “to be ashamed”
•
•
•
•
Loss of plantar flexion (can’t stand on toes)
•
Loss of toe flexion
•
Loss of inversion
•
Floor of pelvis between legs
Nerve supply to genital area Motor: •
Muscles of perineum
•
External urethral sphincter
•
External anal sphincter
•
Levator ani
Sensory: penis/clitoris and skin of perineum
Pudendal Nerve •
At knee from large Baker’s cyst or trauma (rare)
Perineum
S2-S4 •
At heel fromtarsal from tarsal tunnel narrowing
•
Pudendal Nerve Block
Often injured from stretching invaginal in vaginal childbirth
•
Perineal pain worse with sitting Vulvar/scrotal Vulvar/scrotal pai n
Used in vaginal childbirth to reduce pain •
•
Fecal/urinary incontinence
26
Largely replaced by epidural anesthesia anesthesia
Anesthesia to ischial spine of pelvis •
Point of entry for nerve to pelvis
•
Lithotomy position: spine palpable through vagina
Radiculopathy •
•
Lumbar Radiculopathy
•
Compression of nerve root at spine Lumbar radiculopath radiculopathy y = radiculopathy radiculopathy lumbar spine Many causes: •
Herniated disc
•
Spondylolisthesis
•
Spinal stenosis
Jason Ryan, MD, MPH
Intervertebral Discs •
•
•
Herniated Disc
Cushionbetweenvertebrae
•
Outer fibrous ring: annulus fibrosus Soft center: nucleus pulposus
•
•
•
Herniated Disc •
Often occurs posteriorly
•
Two ligaments contain disc in spine •
•
•
Anterior and posterior longitudinal ligaments •
Sits within spinal canal canal
•
Covers posterior surface of vertebrae
•
Weaker containment containment than anterior ligament
Degeneration of annulus fibrosis Bulging/extrusion Bulging/extrusionof nucleuspulposus Unilateralnervecompression
Spondylolisthesis
Posterior longitudinal ligament •
Most common cause of radiculopathy
27
Forward displacement of one vertebra over another •
Spondylo = vertebrae/spine
•
Listhesis = movement
•
Spondylosis = degeneration of the spinal column
Maycause radiculopathy radiculopathy
Spinal Stenosis •
•
•
•
•
Neurogenic Claudication
Narrowing of spinal canal canal
•
Usuallyage-related Intervertebral discs shrink narrowsforamen Facet joint arthritis bone spurs Ligamentum flavum hypertrophies
•
Leads to nerve root compression
•
Standing (straight spine) narrows lumbar canal
•
•
•
•
Largest nerve in the body (2cm wide!)
•
Muscles of posterior thigh
•
Hamstring portion of adductor adductor magnus
•
•
•
Branches: muscles of leg/foot No direct sensory functions Branches: skin of lateral leg, heel, and foot
•
Sciatica •
•
•
•
Often used to describepain describe pain of lumbar radiculopathy Low back pain radiating along path of sciatic nerve Low back buttocks
Hamstrings Three posterior thigh muscles
•
Semimembranosus (medial)
•
Semitendinosus
•
Biceps Femoris (lateral)
Adductor magnus •
Medial thigh muscle
•
Two portions
•
Hamstring portion similar to hamstrings
Knee flexion, hip extension, hip rotation
Sciatic Neuropathy
Clinical syndrome with many causes
•
•
Improves with stooped/flexed posture
•
Sensory: Sensory: •
Often persists with rest when standing
•
Motor
Branchesinto commonperoneal/tibial Motor:
•
•
•
Sciatic Nerve
Sciatic Nerve •
Leg pain with walking in spinal stenosis Can mimic vascular claudicatio n Featuresof neurogenicclaudication claudication
•
back of thigh
Commonly caused by herniated disk •
Compresses nerve at root (radiculopathy)
•
Inflammation, pain and numbness numbness in affected leg
•
•
28
Hip fracture or dislocation •
Sciatic nerve behind hip joint
•
Posterior dislocations: most common type
Hip replacement surgery (coma/bed rest) Prolonged compression compression (coma/bed If severe may cause: •
Hamstring muscle weakness weakness
•
Loss of dorsiflexion /foot drop (common peroneal nerve)
•
Sensory loss in lower leg/foot
Radiculopathy Syndromes •
Radiculopathy Syndromes
Nerve root L5: L5: most common
•
S1 nerve root: 2nd most common
•
Herniated disc at L4/L5 vertebrae
•
•
Back pain down lateral leg
•
Pain down back of leg
•
Weak foot dorsiflexion, dorsiflexion, toe extension
•
Weakness plantar flexion
•
Difficult walking on heels
•
•
Common Peroneal Nerve
•
•
Radiculopathy Syndromes •
Higher nerve roots
•
Supply femoral nerve
•
thigh/knee symptoms
•
Pain to anterior thigh and knee
•
Weakness: hip flexion, knee extension
•
Reduced knee (patellar) (patellar) reflex
Difficulty standing on on toes Ankle reflex lost Tibial nerve
Straight Leg Raise Test
L2/L3/L4 nerve roots •
L5/S1 disc
•
•
•
29
Bedsidemaneuverfor lumbarradiculopathy radiculopathy Examiner raises extended leg on symptomatic symptomatic side Stretches sciatic nerve and nerve roots Lasègue's sign: worsening pain
Hip Joint •
•
•
Hip
Head of femur Acetabulum of pelvis Movements •
Abduction
•
Adduction
•
Flexion
•
Extension
•
Internal/external rotation
Jason Ryan, MD, MPH
Major Flexors •
•
•
•
Major Extensors
Iliopsoas •
Psoas major and and iliacus
•
Combine at inferior ends
•
Gluteus maximus
•
Hamstrings
Tensorfasciaelatae Sartorius Pectinius
Major Abductors
•
Hip extenders/knee flexors
•
Semimembranosus
•
Semitendinosus
•
Biceps femoris
Major Adductors
•
Gluteusmedius
•
•
Gluteusminimus
•
•
•
30
Adductor magnus Adductor longus Adductor brevis Others(pectineus, gracillis)
External Rotation
Internal Rotation
Knee away midline/Foot toward midline
Knee toward midline/Foot midline/Foot away midline
•
Gluteusmaximus
•
No primary/major internal rotator muscles
•
Several “externalrotators” “externalrotators”
•
Many muscles contribute
•
Obturator internus
•
Gluteus medius/minimus
•
Gemellus superior/inferior
•
Tensor fasciae latae
•
Quadratus femoris
•
Adductor longus/brevis
Superior Gluteal Nerve •
•
•
•
•
Posterior head of adductor adductor magnus
•
Pectineus
Superior Gluteal Nerve
From sacral plexus (L4-S1)
•
Pure motor nerve nerve Gluteus minimus/medius (abductors)
Injured by intramuscular injection to buttocks •
•
Tensor fasciae latae (flexor)
•
Trendelenburg Sign/Gait
Upper/outer quadrant used to avoidinjury
Weakness on hip abduction difficultywalking Classicfinding: Trendelenburg sign •
Pelvis tilts with walking
•
Weight bearing leg cannot maintain balance
Inferior Gluteal Nerve
•
Classically seen with weak hip abduction
•
•
Also seen in some other hip disorders
•
•
Motor to gluteus maximus Rarely injured by pelvic masses Weakness of hip e xtension •
31
Standing from sitting position
Avascular Necrosis
Avascular Necrosis
Osteonecrosis
Osteonecrosis
•
•
•
•
•
•
Compromise of bone blood vessels Necrosis of bone tissue Common at femoral head Groin pain: most common complaint Also thigh, buttock pain
•
Often caused by trauma
•
Medialcircumflexfemoralartery
•
•
Difficulty with weight bearing or hip movement
Femoral neck fracture
•
From profunda femoris artery
•
Blood supply to neck of femur
Damage: avascular necrosis
Avascular Necrosis
SCFE
Osteonecrosis
Slipped Capital Femoral Epiphysis
•
Many non-traumatic causes •
Steroid therapy
•
Systemic lupus erythematosus erythematosus
•
Heavy alcohol consumption
•
Sickle cell anemia
•
Gaucher disease disease (lysosomal storage disease)
•
•
•
•
•
Legg-Calvé-Perthes Disease •
•
•
•
Idiopathic avascular necrosis Hip disorder in children (4-8 years) Abnormal blood flowto flow to femoral head Presents as hip pain and limping
32
Fracturethroughgrowthplate Slippage of overlying end of femur Most common hip disorder in adolescence (12-14yrs) Causes groin pain on affected side Can lead to avascular necrosis
Types of Muscle •
Skeletal Muscle
•
Cardiac and Skeletal •
“Striated” muscle
•
Striations seen under microscope
Smooth
Jason Ryan, MD, MPH
Skeletal Muscle
Skeletal Muscle •
•
•
•
Vocabulary
Bundles of muscle fibers (cells) •
Narrow and long
•
Contain myofibrils (contractile structures)
•
•
•
Attaches to skeletal bones Attachment closest to spine: origin Attachment furthest from spine: insertion
•
•
•
•
Sarcomeres •
•
•
Contractilestructureswithin structures within myofibrils
•
•
•
Forms thin filaments •
Polymers of protein actin
Myosin •
Forms thick filaments
•
Composed of protein myosin
•
Head and tail domains
Sarcolemma = plasma membrane Myofibrils = contractile structures within cells T-tubule = invaginations of plasma membrane Sarcoplasmic reticulum •
Intracellular Intracellular structure
•
Similar to endoplasmic endoplasmic reticulum
•
Important for calcium storage
Terminal cisternae = SR near T-tubule Triad = T-tubule with cisternae on either side
Sarcomeres
Contain actin and myosin filaments Actin •
Fiber = muscle cell
33
Z disks •
Ends of sarcomeres sarcomeres
•
Mechanical stability
•
Contain filaments vimentin and desmin
Titin •
Cytoskeletal protein
•
Tethers myosin to Z disks
Sarcomere •
I Band: Light band near Z disks •
•
•
•
Sarcomere •
Mostly actin
•
A Band: Between I bands •
Actin and myosin overlap
•
No change with contraction
•
H Band: Center of sarcomere •
Myosin only (no actin)
•
Shrinks in size with contraction
•
•
•
•
•
•
•
•
Troponin
•
Tropomyosin
Thick filaments •
Myosin
•
Myosin head binds actin
contraction
Muscle Contraction
Complex of three subunits subunits
•
Troponin C: binds calcium Troponin T: binds tropomyosin Troponin I: inhibits myosin binding to actin actin
•
•
•
Cardiac troponin used to diagnose MI
Muscle Contraction •
Mostly actin
•
M line: Central proteins for alignment/stability
Troponin •
Thin filaments
Myosin binds to actin Moves along actin filament
•
“Power stroke”
Conformational change in tropomyosin
•
Skeletal muscle contraction: “Thin filament regulated” filament regulated”
Thin Filament
Hydrolyzes to ADP and Pi Assumes “cocked” position (ready for contraction) Tropomyosinblockremoved myosinbinding •
•
Contraction
Myosin binds ATP at rest
•
Initiated with calcium
“binding groove” for myosin Tropomyosinblocks “bindinggroove” Calcium binds troponin Ca-Troponin removal of tropomyosin block
Thick Filament
Ca2+
Myosin binds new ATP
Binds Troponin C
Myosin binds ATP
Tropomyosin moves out of binding groove
Myosin head cocked (ATP ADP)
Myosin Power Stroke
34
Action Potential
EC Coupling
Skeletal Muscle
Excitation-Contraction Excitation-Contraction Coupling
•
•
Action potential = change in membrane voltage Required for skeletal muscle contraction
•
•
Contraction (via Ca2+) linked to action potential Contraction occurs when cell depolarizes Neuron Depolarization
Synaptic Acetylcholine Release Muscle cell Depolarization Contraction
Action Potential
EC Coupling
Skeletal Muscle
Excitation-Contraction Excitation-Contraction Coupling Sarcolemma Depolarizes
T-tubules Depolarizes Dihydropyridine Dihydropyrid ine Receptor Ryanodine Receptor
Calcium Release from SR
Contraction
Dihydropyridine Receptors •
•
•
•
•
Ryanodine Receptors
Proteins that span gap between T-tubule and SR
•
5 subunits - one subunit binds dihydropyridine drugs L-type Ca2+ channels (capable of conducting Ca2+) Conformatio nal change withdepolarization
Bind ryanodine (poison found in plants) •
•
•
•
Opensryanodine Opens ryanodine receptor on terminal cisternae
35
No role in physiologic physiologic function of receptor receptor
Large protein embedded in SR Releases calcium Opened by DHPRs
initiates contraction
SERCA
Malignant Hyperthermia
Sarco/endoplasmic Sarco/endoplasmic reticulum Ca2+-ATPase •
•
Transfers Ca2+ from cytosol back into SR ATPase uses ATP hydrolysis
•
Rare, dangerous reaction to anesthetics
•
Muscle damage: damage: ↑CK, K+
•
•
•
Fever, muscle rigidity after surgery Cause:abnormal Cause: abnormal ryanodine receptors •
•
Dantrolene •
•
•
•
Muscle relaxant
•
Antagonistto ryanodinereceptors Blocks release of calcium from SR Reduces calcium in cytoplasm for contraction
Consumption of ATP for SR reuptake of calcium
•
ATP consumption
Slow and Fast Twitch Fast-twitch fibers Time to peak tension = fast
•
Also called white (pale color)
•
Primarily metabolize glucose and glycogen
•
More glycogen storage
•
Increased activity of glycolysis enzymes enzymes
•
Few mitochondria = less oxidative phosphorylation
•
Eyes muscles = many fast twitch fibers
•
Most muscles a mixture of fast/slow fibers
heat tissue damage
Treatwithdantrolene with dantrolene
Slow-twitch fibers •
Time to peak tension = slow
•
Also called red fibers (deep red color)
•
Color from amount of myoglobin (binds O2)
•
Extra myoglobin resists fatigue
•
More mitochondria = more oxidative phosphorylation
•
More fatty acid metabolism
•
Moderate glycolysis activity
Postural muscles (spine) = more slow twitch •
•
Excessive calcium release release
•
Slow and Fast Twitch
•
•
Halothane, succinylcholine
36
Sustained tone
Cardiac Muscle •
Cardiac Muscle
Many similarities with skeletal muscle •
Striated
•
Sarcomeres for contraction contraction
•
Actin and myosin
•
Troponin and tropomyosin tropomyosin
•
T-tubules abut sarcoplasmic reticulum
Jason Ryan, MD, MPH
Cardiac Muscle
Cardiac Muscle •
•
•
Involuntary Depolarized by pacemaker cells (SA node) Gap junctions •
•
Differentactionpotential
•
Phase 2: Calcium influx via L-type calcium channels
Depolarization spreads from cell to cell
Cardiac L-type Ca+ Channels
Cardiac L-type Ca+ Ca+ Channels
•
Also dihydropyridine receptors
•
•
Low affinity for dihydropyridine Ca+ blockers
•
•
•
Amlodipine, nifedipine
•
Higher affinity for non-dihydropyridine non-dihydropyridine Ca+ blockers •
Diltiazem, verapamil
37
Ca influx important (unlike skeletal muscle) Triggers SR calcium release via ryanodine receptor “Calcium-triggered calcium release”
Contractility •
•
•
Contractility
All cardiac muscle cells contract Cannot recruit extra fibers to ↑ contractility More calcium into cell •
•
more contraction
More Ca+ entry via L-type Ca channels
•
More Ca-triggered calcium release from SR
•
“Increased calcium transient”
•
•
•
•
•
•
•
Diltiazem, verapamil
•
Block L-type calcium calcium channels in cardiac myocytes
•
Decrease contractility (negative inotropes)
•
Also slow conduction and lower heart rate
Increases contractility Works through G proteins on cardiac myocytes Alter intracellular cAMP levels viaadenyl via adenyl cyclase cAMP increase protein kinase A (PKA)
β1 Receptors Linked Gs proteins ↑cAMP ↑Calcium ↑Contractility
PKA phosphorylates Ca channels more Ca into cell
SERCA
Lusitropy •
•
Cardiac Muscle Cells
Sympathetic Nervous System •
Non-dihydropyridine Non-dihydropyridinecalcium channelblockers
Sarco/endoplasmic reticulum Ca2+-ATPase
Lusitropy=myocardial =myocardialrelaxation
•
Oppositeof contractility contractility Accompanies Accompaniesincreases incontractility
•
•
Fastercontraction fasterrelaxation
38
Mediates lusitropy Transfers Ca2+ from cytosol back into SR ATPase uses ATP hydrolysis
SERCA
Lusitropy •
Sarco/endoplasmic reticulum Ca2+-ATPase
Key regulatory protein:Phospholamban protein:Phospholamban •
Inhibitor: sarcoplasmic reticulum Ca2+-ATPase (SERCA)
•
Phosphorylated vi a beta adrenergic adrenergic stimulation (PKA)
•
Stops inhibiting SERCA
•
Result: SERCA takes up calcium
•
•
•
relaxation
39
Sympatheticstimulation phosphorylates phosphorylates PLB Inactivates PLB (relieves inhibitory effect) Allows SERCA to uptake more calcium
Types of Muscle •
Smooth Muscle
•
Cardiac and Skeletal •
“Striated” muscle
•
Striations seen under microscope
Smooth
Jason Ryan, MD, MPH
Smooth Muscle Cells •
Components of organs •
•
•
Smooth Muscle Cells •
Intestines, airways, blood vessels vessels
•
Propels organ contents (intestines) Changes resistance to flow (blood vessels)
•
Contains actin and myosin
•
Function differently than in striated muscle
•
•
•
•
•
Do not require membrane depolarization depolarization to contract Slow, sustained contraction •
•
Myosin Light Chain •
Do not depend on action potentials
Contrast with cardiac cells: rapid, quick contraction
Calcium contraction contraction (as in striated muscle)
MLC Phosphorylation
Actin = thin filaments
•
Myosin = thick filaments Myosin = heavy and light chains Myosin light chains = modified to control contraction
•
•
Regulates contraction/tone Only phosphorylated MLC interacts with actin Myosin light chain kinase •
Smoothmuscle: “Thick filament regulated”
•
•
40
Phosphorylates myosin
Myosinlightchain phosphatase phosphatase De-phosphorylates myosin
Calcium-Calmodulin
CONTRACTED
•
Myosin Light Chain
P
Myosin Light Chain Phosphatase
•
Myosin Light Chain Kinase
•
•
Calmodulin (CAM) •
Smooth muscle cell protein protein
•
Ubiquitous (lots inside cells)
Bindscalcium Calcium-CAM activates MLCK Calcium
contraction
Myosin Light Chain
Relaxed
L-type Calcium Channels
CONTRACTED
•
Myosin Light Chain
P
•
•
INACTIVE Myosin Light Chain Phosphatase
Myosin Light Chain Kinase
Allow calcium into smooth muscle cells Binddihydropyridines Binddihydropyridines “Dihydropyridine receptors”
Myosin Light Chain Kinase
Ca+ CAM Myosin Light Chain
Relaxed
Dihydropyridine Drugs
Smooth Muscle Tone
Amlodipine, Felodipine, Nicardipine
Regulation
•
L-type calcium channel blockers
•
Vascular smooth muscle relaxation •
•
•
Less Ca relaxation •
Used to lower blood pressure in hypertension
•
41
Two major regulators of contraction/tone: •
Calcium in cell cell
•
Myosin light chain phosphorylation
Both modified by to alter tone •
Autonomic nervous system system
•
Local factor (i.e. vasodilator)
Work through 2nd messengers and G proteins
Second Messengers •
Second Messengers
Three major 2nd messengers:cAMP, messengers: cAMP, cGMP, IP3 •
Cyclic AMP
•
Cyclic GMP
•
Inositol trisphosphate
•
Calcium
•
Myosin light chain phosphorylation
•
P
cAMP
•
cAMP MLC kinase inhibition
•
cGMP MLC phosphatase phosphatase activation
Myosin Light Chain Kinase
+
Norepinephrine/epinephrine
•
Vasopressin
•
Adenosine
•
Prostaglandins
INACTIVE
•
Myosin Light Chain Kinase
•
Ca+ CAM
•
+
Myosin Light Chain
Relaxed
relaxation
•
•
Myosin Light Chain Phosphatase
Relaxation cGMP
contraction
relaxation
2nd Messengers
CONTRACTED Myosin Light Chain
IP3 Calcium release from SR
IP3, cAMP IP3 cAMP
cAMP
Contraction IP3 Ca
Smooth Muscle Tone
Nitric Oxide
Regulation Local Signal/Neurotransmitter
•
Also called EDRF •
Nitric Oxide G-Proteins
•
•
nd
2 Messenger
•
Calcium MLC Phosphorylation
Tone
42
Endothelial derived relaxing factor factor
Synthesized by endothelial endothelial cellsfrom cells fromL-arginine L-arginine Basalproduction Many stimuli for increased production •
Blood flow/shear stress
•
Acetylcholine
•
Bradykinin
•
Substance-P
Nitric Oxide •
•
•
•
Nitric Oxide
NO diffuses into smooth muscle cells
NO
Activates guanylyl cyclase GTP cGMP cGMP + MLC Phosphatase relaxation Acetylcholine Acetylcholine Bradykinin Others
NO
Endothelial Cell Guanylyl Cyclase GTP
Smooth Muscle Cell cGMP
Nitric Oxide Drugs •
•
G Proteins
Nitroglycerine •
Vasodilator
•
Angina, heart failure
•
Converted to NO in smooth m uscle cells
•
•
•
Transmit signals to smooth muscle cells Work through smooth muscle 2nd messengers
Nitroprusside •
Vasodilator for hypertensive emergency
•
Nitric oxide donor
Nitroglycerine
Nitroprusside
G Proteins
Gs and Gi Systems
Smooth Muscle Effects •
Activatedbyneurotransmitters(i.e. epinephrine)
Gs proteins relaxation •
Increase cAMP
•
Inhibit MLCK
•
Gi proteins contraction
•
Gq proteins contraction
•
•
Vascular Smooth Muscle
Decrease cAMP Increase IP3
Stimulation (Gs) Relaxation Inhibition (Gi) Contraction
43
G-Protein Systems
Gq Systems Vascular Smooth Muscle
Gq Contraction
44
Types of Bones •
•
Long bones •
Support weight, allow movement
•
Legs, arms
Flat bones •
Bone
•
•
•
Jason Ryan, MD, MPH
Protect organs (skull)
Short bones (wrists, ankle) Irregular bones (vertebrae) Sesamoidbones •
Embedded in tendons tendons
•
Patella
Bone
Bone
Macroscopic Macroscopic Structure
Macroscopic Macroscopic Structure
•
•
Periosteum
•
Trabecular bone
Membrane
•
•
Covers outer surface of bones
•
“Spongy bone”
•
Blood vessels
•
Soft, flexible
•
Sensory nerves
•
Found at ends of long bones
•
Trabeculated
•
Lots of surface area
Cortical bone •
“Compact bone” “Compact bone”
•
Hard, exterior bone
•
Medullary cavity •
Long Bones •
•
•
Covered by cartilage cartilage •
Widening Shaft •
45
Synthesize bone matrix
Osteoclasts •
Diaphysis •
Osteoblasts •
Metaphysis •
Contains marrow
Bone Cells
Epiphysis •
•
“Cancellous bone”
•
Specialized macrophages
•
Derived from circulating monocytes
•
Secrete acid (H+) and proteases
•
Dissolve bone matrix
Osteocyte •
Osteoblasts buried in bone matrix matrix become osteocytes
•
Control local calcium and and phosphate levels
Bone Matrix •
•
•
•
•
Bone Matrix
Extracellular component of bone
•
Synthesizedby osteoblasts Type I collagen Hydroxyapatite: Ca10(PO4)6(OH)2 Bone: 99% of body calcium; 85% phosphorus
•
Bone Turnover •
•
•
•
•
•
Non-mineralized bone matrix
•
Mostly proteins
•
Laid down by osteoblasts
Followedby mineralization mineralizationwith calcium/phosphate calcium/phosphate
Bone Turnover
Balance between formation/breakdown Modulated by signals from osteoblasts
•
Somestimulate osteoclasts Some limit osteoclasts Combination determines formation/breakdown
•
ignals
Osteoblast
First synthesized as osteoid
Osteoclast
RANK •
Receptor activating nuclear factor kβ
•
Receptor expressed on surface of osteoclasts
•
Ligand binds to receptor synthesis of NF-kB
•
Osteoclast stimulation
RANK-L •
Receptor activating nuclear factor kβ ligand
•
Binds RANK
•
Expressed b y osteoblasts osteoblasts
Osteoblast
Osteoclast R
RANK-L
Bone Turnover •
•
Bone Formation
Osteoprotegerin (OPG) •
Decoy receptor for RANK-L RANK-L
•
Binds RANK-L
•
Prevents RANK-L from binding RANK RANK
•
Made by osteoblasts osteoblasts
More RANK-L/MCSF More osteoclast activity More OPG Less osteoclast activity
MCSF
Osteoblast
M-CSF •
Macrophage colony stimulating stimulating factor
•
Secreted by osteoblasts
•
Stimulates osteoclasts
RANK
Osteoclast
R RANK-L
RANK
OPG
46
Bone Formation
Endochondral Ossification
•
Endochondral ossification
•
•
Membranous ossification
•
•
•
•
•
•
•
Osteoblasts lay down matrix (“ossification”)
•
Between metaphysis and epiphysis epiphysis
•
“Primary center of ossification”
•
Physis = growth plate
At ends (epiphysis) •
Osteoblasts also lay down matrix
•
“Secondary center of ossification” of ossification”
•
Forms epiphyseal (growth) plate
•
•
•
Woven and Lamellar Disorganized collagen fibers
•
Weaker Layered bone
•
Organized
•
Stronger
Growth toward diaphysis
•
Growth plate “closes” at puberty
•
Forms epiphyseal line
•
•
•
Woven bone later remodeled to lamellar bone •
•
•
Also called primary or immature
•
Containshyaline cartilage cartilage Chondrocytesgrowtowardepiphysis Osteoblasts lay down matrix
Membranous Ossification
First type of bone formed: woven bone •
•
Found at ends of long bones
•
Eventuallyanlagen(cartilage)trapped
•
Osteoblastsdeliveredfromblood
Epiphyseal Plate
At center (diaphysis)
•
•
Long bones develop from hyaline cartilage Secreted by chondroblasts and chondrocytes Cartilage “mold” of bone forms (anlagen (anlagen)) Growth chondrocytes die
Growth Plate
Endochondral Ossification •
Occursduring embryogenesis
•
Woven bone seen in adults after injury
47
Matrix formed directly Not from cartilage Osteblasts lay down woven bone Later remodeled to lamellar bone Formation of most flat bones •
Calvaria (skull)
•
Facial bones
Achondroplasia •
Most common cause of dwarfism
•
Genetic disorder •
Fibroblast growth factor receptor-3 receptor-3 (FGFR3) gene mutation
•
Most (80%) cases due to spontaneous mutation
•
Autosomal dominant
•
Survivors = heterozygous
•
Homozygous = stillborn
Achondroplasia •
Defective endochondral ossification ossification •
Gain-of-function mutation
•
Growth factor activated (turned on) on)
•
Inhibits chondrocyte proliferation
•
Arms, legs short
•
Torso, head largely normal
Mucopolysaccharidoses
Osteoblasts
Lysosomal storage diseases
Activity Markers
•
•
•
•
•
Hunter’s and Hurler’s syndromes Inability to metabolize heparan and dermatan sulfate Chondrocytes degrade mucopolysacchari des Accumulation chondrocytedeath
•
Osteocalcin
•
Type I procollagen procollagen
•
Short stature, malformed bones common
Alkaline Phosphatase Enzyme found in bone and liver (different forms)
•
•
Also a placental form
•
•
Placental alkaline phosphatase (PALP)
•
Seen in some germ cell tumors
•
•
Major protein present in bone tissue
•
Bound to osteoblasts and free
•
Createsalkaline Creates alkaline environmentfor environment for calcium deposition
Major non-collagen protein in bone matrix
•
Three pro-alpha chains
•
Secreted fr om osteoblasts osteoblasts
•
Forms tropocollagen and collagen
Acidosis
•
•
Alkaline phosphatase phosphatase
•
Stimulates osteoclasts May cause hypercalcemia from bone breakdown May reduce bone mineral density Complication of some RTAs
H+
48
Parathyroid Hormone •
Multiple effects on bone
•
Stimulatesbone resorption and formation
•
Parathyroid Hormone •
Dominant effect varies with dosage/timing •
Parathyroid Hormone •
•
•
↓ in response to continuous PTH
Trabecular bone •
↑ in response to intermittent, intermittent, low dose PTH
•
Teriparatide strengthens spine (lots of trabecular bone)
•
Parathyroid Hormone •
•
•
•
Secreted by osteoblasts
•
RANK-L •
•
Expressed on surface of osteoblasts
•
Both produced by osteoblasts activateosteoclasts
Osteoblast R RANK-L
Bone resorption
•
Important physiologically
Low dose once daily bolus administration •
Increased bone mass (bone formation)
•
Teriparatide used to treat osteoporosis
Osteoblasts •
Contain PTH receptors receptors
•
Can ↑ bone mass in response to PTH
Osteoclasts •
No PTH receptors
•
Activated indirectly by osteoblasts
Estrogens
M-CSF •
↑ serum calcium
•
Parathyroid Hormone
Cortical bone •
Continuous administration of PTH
Numerous effects on bone Close growth plate at puberty Increase bone density Loss of estrogen at menopause osteoporosis
MCSF
Osteoclast Estradiol (17β -estradiol)
RANK
49
Estrogens •
Induce apoptosis of osteoclasts
•
Stimulate OPG synthesis by osteoblasts
•
Decrease M-CSF and RANK production
•
More OPG Less osteoclast activity
MCSF
Osteoblast Osteoclast
R RANK-L
RANK
OPG
50
Bone Disorders •
•
Bone Disorders
•
•
Osteoporosis(thinbones) Osteopetrosis(thickbones) Rickets/Osteomalacia Rickets/Osteomalacia(nutritionalbone disorders)
Paget’s disease (↑ bone turnover)
Jason Ryan, MD, MPH
Osteopetrosis •
•
•
Osteopetrosis
Defective osteoclast activity
•
Osteoblasticactivity>>osteoclasticactivity Increased bonedensity
•
Osteopetrosis Bones prone to fracture
•
•
Excess bone loss of bone marrow
•
•
Pancytopenia
•
Enlarged liver and spleen spleen (extramedullary hematopoiesis)
•
•
Excess bone in skull cranial nerve compression •
Vision loss
•
Deafness
•
Facial paralysis
•
Most severe form
•
Presents in infancy
•
Mutations in carbonic anhydrase anhydrase type II gene
•
Also may have renal tubular acidosis
•
Children may have seizures, intellectual disability
Autosomal dominant form •
Albers-Schönberg disease
•
Presents in adolescence adolescence
•
Milder form of disease
•
May be asymptomatic – identified by x-ray
Osteopetrosis
•
•
Autosomal recessive (infantile) form
Hydrocephalus
51
Potentiallycurablewithbone with bone marrow transplant Used for infantileform Osteoclasts derived from monocytes/macrophages
Rickets and Osteomalacia •
Nutritional bone disorders
•
Low calcium or vitamin D intake
Rickets and Osteomalacia •
•
Growth Plates •
•
•
•
•
•
Found at ends of long bones in children
•
Containshyalinecartilage Chondrocytesgrowtowardepiphysis Osteoblasts lay down matrix toward diaphysis
Collapse with pressure
Laid down by osteoblasts
•
Later mineralized with calcium and phosphate
Sites of osteoid and new bone growth: •
Children: Growth plates plates
•
Children and adults: Bone turnover
Growth plate thickens •
Chondrocytes expand (disorganized growth)
•
Osteoblasts lay down osteoid only
Bone thickening from fromosteoid osteoid accumulation Distorted bone growth
•
Rachitic rosary
•
•
•
•
•
Craniotabes (soft (soft skull) Occipital/parietal bones
Mostly proteins
•
•
Bowed legs (genu varum) Swellingat costochondraljunctions
•
Non-mineralized bone matrix
•
Osteomalacia
Epiphyseal widening
•
•
•
Rickets
Rickets •
Poormineralizationof osteoid
•
52
Children and adults Occurs in areas of bone turnover Bone pain/tenderness pain/tenderness Most often spine, pelvis, and legs Fractures
Rickets and Osteomalacia
Osteomalacia •
•
Causes
Two classic x-ray findings:
•
Vitamin D deficiency
•
Pseudofractures
•
Maternal deficiency during pregnancy
•
Looser Zones
•
Reduced sun exposure exposure
•
Fat malabsorption Cystic fibrosis, pancreatitis, Celiac disease, disease, IBD Liver and renal failure (both activate viatamin D)
Caused by: •
Repaired stress fractures, inadequately inadequately mineralized
•
•
Erosion of bone by arterial pulsations
•
•
Calcium deficiency (rare)
•
Treatment:Vitamin Treatment:Vitamin D and Ca supplementation
•
Rickets and Osteomalacia
Vitamin D
Lab Findings •
•
Only seen with severe dietary deficiency
↓ Calcium ↓ Vitamin D
•
•
•
•
Liver: 25-OH Vitamin D (calcidiol) Kidney: 1,25-OH2 Vitamin D (calcitriol; active form) 25-OH Vitamin D = storage form •
Constantly produced by liver
•
Available for activation by kidney as needed
Serum 25-OH VitD best indicator vitamin D status •
Long half-life
•
Liver production not regulated by PTH
Rickets and Osteomalacia
Paget’s Disease
Lab Findings
Osteitis Deformans
•
↑ Parathyroid hormone (PTH) •
•
↓ Phosphate •
•
Normal response of parathyroid gland
Focaldisorder Focal disorder
•
Common in older patients •
Excretion promoted by PTH
↑ Bone alkaline phosphatase •
•
↑ osteoblast activity
53
Average age at diagnosis: diagnosis: 70
Paget’s Disease
Paget’s Disease
Osteitis Deformans
Osteitis Deformans
•
•
•
•
•
Excessiveboneremodeling Overgrowth of bone at focal sites of bone New bone: abnormally large, deformed Exact cause unknown Believe to be due to abnormalosteoclasts abnormalosteoclasts
•
Evolves through phases/stages
•
Initialphase:osteolytic phase: osteolytic •
•
•
Osteoclasts bre akdown bone bone
•
Bizarre shape, numerous
•
Multi-nucleated
Mixedphase: osteolytic-osteoblastic osteolytic-osteoblastic Finalphase:Osteosclerotic •
Bone formation dominates
•
Hypervascularity of bone occurs
Paget’s Disease
Paget’s Disease
Bone Morphology
Clinical Features
•
Hallmark: mosaic mosaic pattern of lamellar bone
•
•
Cement lines
•
•
May be asymptomatic Often affects long bones, skull, spine Pathologicfractures(mostcommon complication) complication) •
“Chalkstick” fracture
•
Bonepain (microfractures) (microfractures)
•
Bowing of legs
Paget’s Disease
Paget’s Disease
Clinical Features
Clinical Features
•
•
•
•
Enlarged skull (increased hat size) Cranial nerve compression (deafness) Radiculopathy Radiculopathyat spine Erythema may occur over affected bone area •
•
High output heart failure
•
Osteosarcoma
•
•
Due to hypervascularity
54
AV fistula in new bone
Increased r isk in Paget’s Paget’s disease
Paget’s Disease
Osteitis Fibrosa Cystica
Clinical Features •
Increasebone Increase bone alkaline phosphatase
•
•
Treatment:bisphosphonatesand calcitonin
•
•
Osteitis Fibrosa Cystica •
•
Commonly seen in bones bones of fingers
•
Irregular or indented edges to bones
•
•
•
Brown tumors (osteoclastoma) •
Collections of giant osteoclasts in bone
•
Mixed with stromal cells and matrix proteins
•
Clinical features: Bone pain and fractures Parathyroid adenoma •
↑ PTH
•
Hypercalcemia
•
↓ Phosphate
Renal Osteodystrophy Osteodystrophy
Subperiosteal boneresorption •
Classic bone disease of hyperparathyroidism
•
•
•
Appear as black spaces spaces in bone on x ray
•
•
•
Bone Pain/Fractures
55
Bone abnormalities seen in renal failure Hypocalcemia Hyperparathyroidism OsteitisFibrosaCystica Rickets/osteomalacia Osteopenia/osteoporosis Growth retardation Bone pain Fractures
Osteoporosis •
Porousbone
•
Weak bones prone to fracture
•
No clinical symptoms until fracture
Osteoporosis Jason Ryan, MD, MPH
Terminology •
•
•
Osteoporosis
Osteopenia: ↓ bone mass
•
Osteoporosis:markedly ↓ bone mass Osteoporosisassociatedwith ↑ fracture risk •
Osteoporosis •
Trabecular bone > cortical bone •
Trabecular bone: high surface area
•
Osteoblasts/osteoclasts found on surface
High trabecular bone content: •
Spine
•
Head of femur (hip)
•
Wrist (distal radius)
Bone Mass
Common in elderly, white women
•
Peak bone mass occurs in young adulthood •
•
Decreasesslowlythereafter •
56
Many influences: gender, gender, genetics, diet
Each resorption/formation resorption/formation cycle
some bone loss
Bone Loss •
•
•
•
Menopause
Males achieve higher peak bone mass Bone loss less likely to lead to osteoporosis Whites > African Americans
•
Accelerates bone loss in women
•
Caused by estrogen deficiency
Weight-bearing activity ↑ bone mass
•
Increased osteoclast activity
•
Increased levels of RANK-L RANK-L
•
Decreased osteoprotegerin (OPG)
Osteoblast Osteoclast
R RANK-L
RANK
OPG
Osteoporosis
Osteoporosis •
•
•
Secondary Causes
Most osteoporosis:senile/postmenopausal
•
Calcium, PTH, Alkaline phosphatase all normal Less commonly: secondary osteoporosis
Glucocorticoids •
Increase bone resorption resorption
•
Reduce bone formation formation
•
Suppress synthesis of OPG
•
Increase RANK production
Osteoblast Osteoclast
R RANK-L
RANK
OPG
Osteoporosis
Anticonvulsants
Secondary Causes •
•
Alcohol •
Heavy use associated associated with osteoporosis
•
Often leads to falls/hip fracture
•
Moderate use effects effects not clear
•
•
•
•
Smoking •
•
Accelerates bone loss
•
57
Phenobarbital, Phenytoin, Carbamazepi ne Used to treat seizures/epilepsy Risk of osteoporosis with long term therapy Increase activity of P450 enzymes Increases breakdown of vitamin D Less calcium increased PTH bone loss
Thyroid Replacement Replacement
Anticoagulants •
•
•
Unfractionated Heparin •
Decreases bone formation
•
Increases resorption
•
•
•
Only with long term use Low molecular weight heparin: unclear bone effects
thyroidism osteoporosis/fractures Hyper thyroidism Levothyroxine (T4) used inhypothyroidism Too high dose iatrogenic hyperthyroidism •
•
•
•
If mild may produce no symptoms
Key test: TSH If TSH is low (“suppressed”) need to lower dose Many elderly, post-menopausal women take T4
Unfractionated Heparin
Osteoporosis
Osteoporosis
Secondary Causes
Diagnosis
•
•
•
•
Hyperparathyroidism
•
Hyperthyroidism Multiple myeloma •
Myeloma cells Increase osteoclast activity
•
Results in “lytic” bone lesions of MM
•
•
Malabsorption syndromes •
Celiac disease, Crohn’s, Ulcerative Colitis
•
Poor absorption calcium and vitamin D
DXA •
•
•
•
•
Fall from standing height or less
•
Not from major trauma (i.e. MVA)
•
Spine, hip, wrist, humerus, rib, orpelvis
•
Also a spontaneous vertebral “compression” fracture
T score of -2.5 or lower
Fractures
Dual-energy X-ray absorptiometry absorptiometry •
Fragility fracture
Two X-rays of different energy levels aimed at bones
•
T score: score: patient BMD vs. healthy 30-year-old BMD Normal: -1.0 or higher (least fractures) Osteopenia: -1.0 to -2.5
•
Osteoporosis: -2.5 or lower (most fractures) Recommendedfor screening in women >65
58
Hip •
Weight-bearing joint
•
Easily injured from fall
Spine •
Lower thoracic/lumbar spine
•
“Compression” fractures
•
Often occur slowly over time
•
Minor trauma of daily activates
•
Loss of height
•
Kyphosis (forward curved spine)
•
Back pain
Osteoporosis Therapy •
•
Osteoporosis Drugs
•
•
•
Allpatients: lifestylemodification Weight-bearing exercise Avoidance of heavy alcohol use Smoking cessation Calcium and vitamin D supplementation
Jason Ryan, MD, MPH
Bisphosphonates
Bisphosphonates
Alendronate,Pamidronate,Ibandronate, Zoledronate •
•
•
First line therapy
•
Analogs ofpyrophosphate of pyrophosphate Used to make nucleotides •
•
•
Two phosphonate (PO3) groups attached to carbon Vary by side chains (R1 and R2) Oral and IV drugs drugs
Pyrimidines/purines
•
Purin es: ATP, GTP
•
Pyrimidines: Uridine, Cytidine, Thymidine
Purine Synthesis
Ribose5-phosphate
5-Phosphoribosyl-1-pyrophosphate (PRPP)
Bisphosphonates
Bisphosphonates •
•
•
•
•
Adverse Effects
Phosphonategroupsbind calcium
•
Accumulate Accumulate in bone Taken up by osteoclasts Inhibit osteoclasts
Oraldrugs (Alendronate,Risedronate) Risedronate) •
Various mechanisms depending on drug/side chain
59
Upper GI upset
•
Reflux, esophagitis, esophageal ulcers
•
Local effects of bisphosphonates on mucosa
•
Often taken weekly
•
Take with water on empty stomach
•
Remain upright for 30 minutes
Bisphosphonates
Bisphosphonates
Adverse Effects
Adverse Effects
•
IVdrugs (Pamidronate, (Pamidronate,Ibandronate,Zoledronate) •
Flu-like symptoms
•
24 to 72 hours after infusion
•
Low-gr ade fever, myalgi as
•
Treated with ibuprofen and acetaminophen acetaminophen
•
Long dosing intervals: 3-months to annually
•
•
•
•
Atypical Femur Fractures •
•
Intracapsular (femoral neck or head)
•
Trochanteric
•
Associated with trauma
•
•
•
•
Atypical fractures •
Below lesser trochanter
•
Diaphyseal (femoral diaphysis)
•
No or minimal trauma
•
Recombinant human parathyroid hormone (PTH)
•
Continuous administration of PTH
•
•
Bone resorption
•
Important physiologically
•
•
Low dose once daily bolus administration •
Increased bone mass
•
Increased osteoblast osteoblast bone formation
•
Contrast with most therapies: inhibit osteoclasts
Avascular necrosis of jaw Pain, swelling of mandible May lead to exposed bone, local infection May cause pathologic fracture of jaw Often occurs in setting of dental disease
Adverse Events
↑ serum calcium
•
Associated with IV and oral drugs
Teriparatide
Teriparatide •
Osteonecrosis of the jaw Rare, serious complications
Jaw Osteonecrosis
Most hip fractures: fractures: •
Atypicalfemur fractures
Teriparatide:Subcutaneousdaily injection
60
Brief rise in serum calcium •
Drug has quick on/off on/off effect over hours
•
Rarely leads to very high levels levels or symptoms
Theoretical risk of osteosarcoma •
Very few cases reported
•
High doses for long duration
cancer in rats
Raloxifene
Calcitonin
SERM(Selective Estrogen Receptor Modulator) •
•
•
•
•
•
Estrogen actions on bone Anti-estrogenin breast/uterus Also used for prevention of breast cancer May cause hot flashes
•
•
•
•
Associated with DVT/PE Minimal effects on uterus •
•
Not associated with bleeding, hyperplasia/cancer
Denosumab •
•
MonoclonalRANK-Lantibody Blocks osteoblast activation of osteoclasts
Osteoblast R RANK-L
Osteoclast RANK
61
Hormone produced by thyroid Synthesized by parafollicular cells (C-cells) Binds to osteoclasts osteoclasts Inhibits bone resorption Salmoncalcitonin used in humans
Bone Metastasis
Bone Tumors
•
Bone metastasis >> primary bone tumors ( rare)
•
Common in diaphysis
•
Osteoclastic lesions
•
Jason Ryan, MD, MPH
•
Bone breakdown by metastasis
•
Multiple Myeloma: classic classic osteolytic disease
Osteoblastic lesions •
Deposition of new bone
•
Prostate CA: classic osteoblastic lesion
BruceBlaus/Wikipedia
Primary Bone Tumors •
•
•
Primary Bone Tumors
Often occur in children/young adults
•
Often involve long bones especially at knees Most are more common in males
•
•
Can be an incidental finding May cause bone pain May cause pathologic pathologic fractures •
Osteoid Osteoma •
•
•
•
•
•
Small tumors (<2cm) of young men (teens/20s) Occur in “appendicularskeleton” “appendicularskeleton”
•
•
Not in “axial” skeleton
Most cases at knee •
•
Often from minor trauma
•
Proximal femur and humerus: humerus: Most frequent frequent sites
Osteoid Osteoma
Benign tumor of bone
•
Fracture in bone weakened weakened by underlying abnormality
•
Tibia/fibula
•
Presents as bone pain at night Responsive to aspirin
62
Surface of cortex/diaphysis Tumor of osteoblasts Osteoid core •
Non-mineralized bone matrix
•
Mostly proteins
Rim of bone woven bone
Osteoid Osteoma
Osteoblastoma
•
Central osteoid core = radiolucent (clear)
•
Larger (>2cm) tumor
•
Surrounded by “reactive” bone
•
Often involvesspine involvesspine
•
Pain not responsive to aspirin
Gardner’s Syndrome •
•
•
•
•
Osteosarcoma
Variant of FAP •
Familial Adenomatous Polyposis
•
APC gene mutation
•
•
•
Colonic polyp disorder Multiple extra-colonic manifestations Osteomas (benign bone growths) •
Often occur in patients with Gardner’s
•
Usually in skull or mandible
•
Often painless, palpable
•
Malignant bone tumor of osteoblasts Most common primary bone tumor More common in males Bimodal age distribution •
75% young adults (<20years) (<20years)
•
25% older adults with bone disease disease (i.e. Paget’s)
May proceed development of colon symptoms
Osteosarcoma
Osteosarcoma
•
Malignant cells of varying shape (pleomorphic cells)
•
•
Irregular osteoid formation (pink)
•
•
•
63
Painful, enlarging mass on bone May present as pathologic fracture Usually occurs in metaphysis of long bones 50% cases occur at knee •
Distal femur
•
Proximal tibia
Osteosarcoma
Classic X-ray Findings •
•
Associated Conditions
Codman triangle •
Tumor breaks through cortex
•
Lifts periosteum
•
•
•
Sunburst/Sunray sign •
•
Tiny bone fibers in periosteum
Osteosarcoma
•
Treated with surgical resection or amputation •
“En bloc” resection
•
Removal of entire tumor in one piece
•
Together with a layer of healthy tissue
•
Limb salvage when possible
•
•
•
Presumed all patients have metastasis metastasis
•
Prior treatment with surgery alone poor survival
•
Chemo may be given before before surgery to shrink tumor
•
“Neoadjuvant” therapy
Ewing Sarcoma •
Most commonly femur
•
Also tibia, fibula, humerus humerus
•
Seen in bones of pelvis
•
Aggressivewithearly metastasis
•
Treatment: surgery/chemo/radiation •
5-year survival: 70% in localized disease
•
33% metastases at diagnosis
Familial cancer syndromes
•
Germline mutations
•
Familial retinoblastoma (Rb gene mutation) mutation)
•
Li Fraumeni syndrome (p53 tumor suppressor gene)
Malignantbonetumor Undifferentiatedprimitiveneuroectoderm primitive neuroectoderm cells Youngest age of presentation of all bone tumors 80% cases < 20 years old
•
Boys > Girls
•
Whites >> African Americans
Ewing Sarcoma
Occurs in diaphysis of long bones •
•
•
Always Always treated with chemotherapy chemotherapy •
Often years after radiation therapy therapy for childhood cancer
Paget’s disease Inheritedgenetic conditions
Ewing Sarcoma
Treatment •
Prior radiation
•
•
•
•
•
64
Painful, growing mass over bone Often warm, swollen swollen May see fever, leukocyt osis May be confused with osteomyelitis Blood cultures and tumor aspiration: sterile
Onion Skin
Ewing Sarcoma
•
Classic X-ray finding
•
Layering near periosteum
•
Splitting/thickening Splitting/thickening of cortex
•
Giant Cell Tumor
Ewing Sarcoma •
•
•
•
Sheets of small, round cells
Osteoclastoma
85% of cases associated with genetic translocation translocation
•
Chromosomes Chromosomes 11 and 22 Fusion of EWSR1 gene (22) to FLI1 gene (11) Detected with FISH 11
•
•
•
•
11 22
Multi-nucleated giant osteoclasts Bone resorption by tumor Usually benign but locally aggressive aggressive Occurs in epiphysis Most commonly in femur/tibia (at knee)
22
FLI1
Fusion gene EWSR1
Giant Cell Tumor
Osteochondroma
Osteoclastoma •
•
•
Stromal tumor cells expresshigh express high levels RANK-L
•
Drives osteoclasts activity in tumor Leads to giant osteoclastic cells
•
•
•
Osteoblast R RANK-L
Osteoclast RANK
65
Benigncartilage-forming Benigncartilage-formingtumor tumor Occur in late adolescence/early adolescence/early adulthood More common in males Slow growing mass attached to stalk •
Cartilage-capped bone spur
•
“Exostosis:” new bone on surface of bone
•
Can cause pain
•
Often detected incidentally
Osteochondroma •
•
•
•
•
Fibrous Dysplasia
Arise fromgrowth from growth plate
•
Lateral projection Found at metaphysis Stop growing with GP closure Treated with simple excision
•
•
•
•
Benigntumor Woven bone surrounded by fibroblasts Occurs in early adolescence Grows until growth plate closes Often asymptomatic
•
Rarely lead to chondrosarcoma
•
May cause pain, fractures
•
Cartilage cap malignant
•
Occurs in medulla/diaphysis
Fibrous Dysplasia •
Fibrous Dysplasia
“Chinesecharacter” “Chinese character” trabeculae of woven bone
•
X-ray: Lytic lesion in diaphysis
Simple Bone Cyst
Simple Bone Cyst
Unicameral Bone Cyst
Unicameral Bone Cyst
•
•
•
•
•
•
•
•
Fluid-filled spaces with fibrous lining Usually occur < 20 years old Most common locations: proximal humerus and femur Commonly an incidental finding May lead to pathologic fracture Treatment:ObservationwithserialX-rays Rarely require surgery Oftenspontaneouslyimprove
66
•
Found in metaphysis
•
Abuttinggrowthplate
Chondroma •
•
Chondrosarcoma
Benigncartilagetumor •
In medullary cavity: endochondromas endochondromas
•
Surface of bone: juxtacortical chondromas
•
•
•
Occur in small bones of hands and feet
•
•
Bone Pain/Fractures
•
•
•
Bonevariant:Eosinophilic variant: Eosinophilic granuloma Occurs as bone mass in children Most commonly involved bone: skull Biopsy:Langerhans cells/eosinophils •
Langerhans cells: Dendritic cells
•
Myeloid origin
•
Similar to histiocytes (tissue macrophages)
•
Express CD1a, S100, S100, CD207
Also occurs in medulla Occurcentrally Pelvis,shoulder, ribs Distalextremitiesrarelyinvolved
Long Bone Tumors
Langerhans Cell Histiocytosis •
Malignant cartilage tumor
67
Arthritis •
•
•
Osteoarthritis Jason Ryan, MD, MPH
Fingers, hips, knees
•
•
Articularcartilage
•
•
Synovium •
•
Rheumatoid arthritis
•
Septic arthritis
•
Gouty arthritis
•
Psoriatic arthritis
•
Reactive arthritis
Hyalinecartilagebreakdown cartilage breakdown Abnormal chondrocytes •
Only cell type in cartilage
•
Normally quiescent
Secretes synovial fluid
•
Proliferate in OA
Hyaluronic acid
•
Inadequate repair
Type II collagen
•
Secrete proteases
•
Secrete cytokines
•
Eventually die exposed bone
Osteoarthritis
Osteoarthritis •
Osteoarthritis
•
Pathophysiology
•
•
•
Osteoarthritis
Synovial Joints
•
Joint inflammation Joint pain, warmth, stiffness Many types
Classic X-ray Findings
Low WBC in synovial fluid “Non inflammatory inflammatory arthritis”
•
•
•
•
68
Joint space narrowing narrowing Subchondral sclerosis Osteophytes (bone spurs) Subchondral cyst
Osteophytes
Subchondral Sclerosis •
•
Bone Spurs
Thickening of the subchondral bone ↑ collagen with abnormal mineralization mineralization
•
Thickening of the subchondral bone at joint margins
•
Often insertion points of tendons or ligaments
Osteoarthritis
Subchondral Cysts
Knee Involvement
•
Fluid filled sack
•
Often involves both knees
•
Bone cracks synovialfluid accumulation accumulation
•
More weight bearing medial knee •
Osteoarthritis
Nodal osteoarthritis
Hand Involvement •
•
•
•
Imaging may show asymmetric asymmetric narrowing on medial medial side
Distal interphalangeal (DIP) joints
•
Proximalinterphalangeal(PIP)joints Not MCP 1st Carpometacarpal (CMC) joint
•
•
•
•
•
•
69
Heberden’s (DIP) and Bouchard’s (PIP) nodes Occur in patients with interphalangeal interphalangeal (hand) OA Over years, joints become less painful Inflammatorysignssubside Swellings (nodes) remain Common at index and middle fingers Believed to be caused by osteophytes
Osteoarthritis
Osteoarthritis
Spine Involvement
Symptoms
•
•
•
Facetjoints
•
Lower cervical spine spine Lower lumbar spine
Joint pain •
Especially after use of joint
•
At end of day for weight-bearing weight-bearing joint
•
Improves with rest
•
Stiffness
•
Restricted motion
Osteoarthritis
Osteoarthritis
Risk Factors
Treatment
•
Advanced age •
•
•
•
•
80% patients over 55 years old
•
Femalegender Obesity •
Modifiable risk factor factor
•
Especially the knee
•
Hands
•
Hip
•
•
•
•
•
•
Acetaminophen
•
NSAIDs
Intraarticular glucocorticoid injection
•
Surgery
•
•
Short term pain relief Total knee and hip replacement
Knee, hip
Rheumatoid Arthritis •
•
•
Joint injuries •
Exercise Weightloss Pain control
Septic Arthritis
Autoimmune condition
•
Women aged 40-50 High synovial WBC Morning stiffness
•
•
•
Pain improves with use Many systemic complications •
Uveitis
•
Serositis
•
Baker’s cyst
70
Acute onset Swelling and pain usually of single joint Acute monoarthritis = medical emergency Must exclude septic arthritis and gout
Septic Arthritis •
•
•
•
Fevers, chills, sweats
•
Synovial fluid purulent with 50k to 150k WBC Positive gram stain and culture S. aureus or S. pneumoniae •
•
Hemochromatosis •
•
•
Often from hematogenous seeding of joint
•
Neisseria gonorrhoeae •
Sexually transmitted infection
71
Iron overload disorder Arthritis:commonin hemochromatosis hemochromatosis May present as arthritis Most commonly involves MCP joints Often presents with pain, minimal swelling
•
Younger patient
•
High serum ferritin
Gout •
•
•
•
•
Gout
•
Monosodiumuric Monosodiumuric acid deposition in joints Crystalsphagocytosed by macrophages/neutrophils macrophages/neutrophils Triggerinflammatoryresponse Recurrent attacks of acute arthritis Severe joint pain Redness,swelling, warmth
Jason Ryan, MD, MPH
Uric Acid/Urate
Gout
Chronic Tophaceous Gout
•
Hyperuricemia Hyperuricemia + cool temperatures + genes
•
•
Most common: base of great toe (podagra)
•
•
•
1st metatarsophalangeal joint
•
Also often occurs in knee
•
•
Urate Nephropathy •
•
•
Tophi: uric acid collections in connective tissue Ears, tendons, bursa Usually not painful or tender Usually follows gouty arthritis Seen withlongstandinghyperuricemia
Gout
Uric acid crystals in urine
•
Uric acid kidney stones Chronic renal failure •
72
Primary gout •
Not due to other disease disease or medication
•
Most cases due to over-production uric acid
•
Cause unknown
Secondarygout •
Due to other disease or medication
•
Many causes
Uric Acid Excretion
Uric Acid Production
•
Mostly viakidneys/urine via kidneys/urine
•
Any reduction in GFR ↓ uric acid excretion
•
•
Renal failure
•
Volume depletion
•
Diuretics (also ↓ uric acid secretion secretion in urine)
Uric Acid/Urate
Commonly cause gout attacks Purine Nucleotides
Adenosine
Uric Acid Production
Guanosine
Purine Sources •
•
•
•
Guanosine
Red meat Seafood Trauma/surgery (tissue breakdown) All classic causes of gout attack
Xanthine Oxidase
Purines
Hypoxanthine Hypoxanthine
Uric Acid
Adenosine
Myeloproliferative Disorders •
•
•
•
•
Lesch-Nyhan Syndrome
Chronic myeloid leukemia Essential thrombocytosis Polycythemia vera Associated with high cell turnover
•
Enzyme defect in purine salvage pathway
•
X-linked absence of HGPRT •
•
Hyperuricemia gout
•
•
Hypotonia,chorea
•
Selfmutilatingbehavior
•
Classicpresentation •
73
Hypoxanthine-Guanine Hypoxanthine-Guanine phosphoribosyltransferase
Excess uric acid production (“juvenilegout”) (“juvenilegout”) Neurologicimpairment(mechanismunclear)
Male child with motor symptoms, self-mutilation, gout gout
Purine Purine Salvage Pathway
PRPP
Alcohol
AMP/GMP
HGPRT
•
Classic trigger for gout
•
Metabolism consumes ATP uric acid
•
Urate transporter- 1 (URAT1) •
Inosine monophosphate (IMP)
Hypoxanthine
Renal uric acid transporter
•
Facilitates uric acid excretion in urine
•
Lactic acid produced in alcohol metabolism metabolism
•
Increased reabsorption of uric acid
Xanthine Oxidase
Uric Acid
Lactic Acid
Von Gierke’s Disease
Gout Attacks •
•
•
Glycogen Storage Disease Type I
More common in males
•
More common among obese patients Classic case:
•
•
Obese male
•
Seizures
•
Steak dinner with heavy alcohol consumption
•
Lactic acidosis (Cori cycle)
Gout
•
•
Urate transporter-1 (URAT1) •
Lactate competes competes with uric acid for URAT1
•
Leads to hyperuricemia hyperuricemia
Polarized Light Microscopy
Diagnosis
•
Presents in infancy: 2-6 months of age Severehypoglycemiabetweenmeals
•
•
•
Glucose-6-phosphatase deficiency
Arthrocentesis Arthrocentesis
•
Sampling of synovial fluid WBC 20k to 50k Polarized light microscopy
Whitelight •
Unpolarized
•
Waves vibrate in random directions
•
Polarizedlight
•
Isotropic
•
Birefringent
•
•
74
Waves vibrate only in one direction Reflects the same in all all orientations
•
Reflects polarized light in two ways
•
Reflection based on orientation orientation
Gout Crystals •
•
•
“Negatively birefringent” •
Two reflections of polarized
•
Change in index of refraction is negative
Yellow when parallel to axis of the polarization Blue when perpendicular topolarizationaxis
75
Gout Treatment •
•
Gout Drugs
Acute attacks •
NSAIDs
•
Glucocorticoids
•
Colchicine
Preventative •
Xanthine oxidase inhibitors (allopurinol, febuxostat)
•
Pegloticase
•
Probenecid
Jason Ryan, MD, MPH
Colchicine
Colchicine
•
Microtubule inhibitor
•
Binding to intracellular protein tubulin •
•
•
•
Microtubules: polymers of alpha and beta beta tubulin
Preventspolymerizationinto microtubules microtubules •
Inhibits WBC migration and phagocytosis
Adverse effects: GI •
Diarrhea
•
Nausea, vomiting
•
Abdominal pain
Three main niche uses: •
Gout
•
Pericarditis
•
Familial Mediterranean Fever
Xanthine Oxidase Inhibitors
Xanthine Oxidase Inhibitors
Allopurinol, Febuxostat
Allopurinol, Febuxostat
•
•
Inhibitors of xanthine oxidase
•
Both abruptlychange abruptly change serum uric acid levels
•
Allopurinol: competitive inhibitor
•
May precipitate a gout attack
•
Febuxostat: non-competitive inhibitor
•
Initiated together with NSAIDs/Colchicine
Also used to prevent tumor lysis syndrome Allopurinol Febuxostat X
Xanthine Oxidase
Hypoxanthine
Uric Acid
76
Xanthine Oxidase Inhibitors
Xanthine Oxidase Inhibitors
Allopurinol, Febuxostat
Allopurinol, Febuxostat
•
Allopurinol •
GI upset: nausea, vomiting, diarrhea
•
Hepatic toxicity
•
Skin rash (hypersentivity)
•
•
•
Interact with azathioprine and 6-MP
•
Both metabolized by xanthine oxidase
•
•
Rarely bone marrow suppression
•
Febuxostat
Allopurinol
Caution with XO inhibitors May boost effects effects Mayincrease toxicity
nd
•
2 line agent
•
Patients intolerant of allopurinol
Xanthine Oxidase
Pegloticase
Pegloticase •
•
Intravenous drug •
Given at infusion center every every two weeks
•
Used for severe, refractory gout
•
•
•
Converts uric acid to allantoin More water soluble soluble Excreted by kidneys
Recombinant porcine uricase (uric acid oxidase) •
•
Enzyme that degrades uric acid acid
Attached to polyethylene glycol (PEG) •
Prolongs half-life
•
Limits immune r eaction to drug drug
Pegloticase
Uric Acid
Rasburicase •
•
•
Also converts uric acid to allantoin Not attached to polyethylene glycol •
Allantoin
Tumor Lysis Syndrome
Also a r ecombinant uricase uricase
•
•
Thiouric acid (inactive)
6-MP
Azathioprine
Febuxostat
•
Occurs in treatment of some malignancies
•
Rapid cell lysis ↑ serum levels of cell contents •
Potassium, phosphate
Rapid on/off action
•
Hyperkalemia
More immunogenic
•
Hyperphosphatemia
Used only in tumor lysis syndrome
77
arrhythmias
hypocalcemia
•
Hyperuricemia from breakdown of purines
•
Uric acid nephropathy acute renal failure
Probenecid •
“Uricosuric drug”
•
Promotes uric acid excretion in urine
•
•
•
•
•
Blocks proximal tubule reabsorption of uric acid Also blocks secretion of penicillinin penicillin in urine •
•
Aspirin
Boosts PNC levels •
Originally develops to enhance enhance PCN effects
High dosages (>2.6grams/day) •
Inhibit secretion and reabsorption
•
Net effect: same as probenecid (uricosuric)
•
Promote uric acid excretion
•
Lower serum uric acid levels
Low dosages •
Sulfa drug May cause uric acid kidney stones
•
•
78
Inhibit secretion only Less uric acid excretion Aspirin not used for pain control control in gout
CPPD Calcium Pyrophosphate Deposition Disease •
•
•
Calcium pyrophosphatedeposition pyrophosphate deposition Affects joints and connective tissue Cause unknown
CPPD Jason Ryan, MD, MPH Uric Acid
CPPD
Asymptomatic CPPD
Calcium Pyrophosphate Deposition Disease •
Occurs in older patients •
•
•
•
Average age: 72-years-old
•
Men = women Clinicalfeatures •
•
•
•
Acute arthritis (similar to gout)
•
Chronic joint disease (similar to OA)
Crystal deposits discovered on imaging Chondrocalcinosis: Chondrocalcinosis: calcification of hyaline cartilage
Pseudogout
Acute attacks of arthritis Resemble attacks of gout: pseudogout Knee involved in 50% of cases •
Most joints with CPPD have no symptoms
Asymptomatic (discovered (discovered on imaging)
•
Pseudogout •
Pyrophosphate
Pain, redness, warmth, swelling
79
•
Provoked by trauma, surgery, medical illness
•
Many flares reported afterparathyroidectomy afterparathyroidectomy
Pseudogout
Chronic Joint Disease
Polarized Light Microscopy •
•
•
Rhomboid crystals
•
Positively birefringent Blue when parallel to light (yellow for gout)
•
•
•
•
Pseudo-osteoarthritis Progressivejoint degeneration Occurs in ~50% of patients with CPPD joints Progressivecartilage deterioration Bony enlargement, tenderness similar to OA
CPPD
CPPD
Treatment
Associated Conditions
•
•
•
Acute pseudogout attack •
Intraarticular glucocorticoid injection injection
•
NSAIDs
•
Colchicine
•
•
•
Prophylaxisfor pseudogout:Colchicine Chronic joint disease: same treatment as OA
Hemochromatosis •
Hereditary iron overload disorder
•
Arthritis: common in hemochromatosis
•
Calcium pyrophosphate may also deposit
•
Seen in 2/3 of patients
•
Iron deposition in synovial tissue
80
Joint trauma Hyperparathyroidism Hemochromatosis
Seronegative Spondyloarthritis
Seronegative Spondyloarthritis
•
Spondylo = spine
•
Arthritis = joint inflammation inflammation
•
Family of disorders with common features
Jason Ryan, MD, MPH
•
•
Ankylosing spondylitis
•
Psoriatic arthritis
•
Inflammatory bowel diseases diseases
•
Reactive arthritis
Terminology
Seronegative Spondyloarthritis •
•
Autoimmune Autoimmune disorders Mediated byT-cells by T-cells Unknown trigger
•
•
•
Monoarthritis = 1 joint Oligoarthritis Oligoarthritis = 2-4 joints Polyarthritis = >5 joints
Seronegative Spondyloarthritis
Seronegative Spondyloarthritis
Common Features
Common Features
•
•
Asymmetric Asymmetric oligoarthritis oligoarthritis •
Acute attacks of joint joint pain and swelling
•
Often lower extremities
•
•
Contrast with RA •
Symmetric
•
Polyarthritis
•
Often hands
Axial spine inflammation
•
Dactylitis (sausage digits)
•
Enthesitis •
81
Commonly sacroiliac (SI) joints
Inflammation of ligament/tendon attachment to bone
HLA B27 •
•
•
•
•
Ankylosing Spondylitis
Human Leukocyte Antigens Antigens
•
Antigens that make up MHC class I and II molecules Genes on chromosome 6 determine “HLA type” MHC Class I Genes: HLA-A, HLA-B, HLA-C HLA B27: Common in spondyloarthritis disorders •
90% of ankylosing spondylitis cases
•
50% of psoriatic arthritis cases
•
Most people with B27 never never develop AS
•
•
•
Ankylosing Spondylitis •
Younger age (<40 years)
•
Slow, insidious onset
•
Improves with exercise
•
Does NOT improve with rest
•
Pain at night (better with awakening/movement)
Enthesitis •
•
•
•
•
Ankylosis = new bone formation in spine stiffness More common in males Usually 20-30 years old
Ankylosing Spondylitis
“Inflammatory” back pain (~75% of patients) •
Classicformof seronegativespondyloarthritis
•
Classically involves the sacroiliac (SI) joint
•
Sacroiliitis
Dactylitis
Inflammation Inflammation of tendon insertions to bone Classically insertion of Achilles tendon to calcaneus Or plantar fascia to calcaneus Causes heel pain Commonpresentingfeature
82
•
Swelling of fingers and toes
•
Caused by tendon and soft tissue inflammation
Ankylosing Spondylitis
Ankylosing Spondylitis
Other Features
Other Features
•
Uveitis
•
•
Aortitis
•
•
Restrictivelungdisease ↓ chest wall and spine mobility
Often leads to aortic regurgitation
Ankylosing Spondylitis
Ankylosing Spondylitis
Lab Testing
Classic Case
•
Elevated acute phase reactants
•
•
Most patients: ↑ESR and ↑CRP
•
•
•
•
•
•
25 year old male male Inflammator y back pain Heel pain Swollen finger and toes Elevated ESR and CRP HLA B27positive B27positive Treatment:Anti-inflammatorydrugs •
NSAIDs
•
Anti-TNF antibodies (infliximab)
Psoriasis
Psoriatic Arthritis
Nail Findings
•
Arthritisassociatedwithpsoriasis
•
•
Occurs in less than 1/3 of psoriasis patients
•
•
•
•
83
Nailpitting Onycholysis (separation of nail from nailbed) Hyperkeratosis 46% of uncomplicated uncomplicated psoriasis cases 90% of psoriatic arthritis cases
Psoriatic Arthritis
Psoriatic Arthritis
Common Features
Common Features
•
Asymmetric polyarthritis •
•
•
•
•
Morning stiffness
•
Improves with use
•
Distal interphalangeal (DIP) arthritis
•
Classic finding: “pencil in cup” deformity DIP joint
Distal interphalangeal (DIP) arthritis Sacroiliitis Dactylitis •
•
Mimics RA
Sausage digits occur in half half of patients
Heel pain (enthesitis) (enthesitis)
Inflammatory Bowel Disease
Reactive Arthritis
Crohn’s disease and Ulcerative colitis •
Frequentlycomplicatedby arthritis
•
•
Type 1 pattern
•
•
•
<5 joints
•
Usually large joints: knees, knees, hips, shoulders
•
Symptoms often with flare of GI disease
•
•
•
Type 2 •
>5 joints
•
Small joints of the hands
•
Independent of GI disease
•
Can see spondylitis and sacroiliitis
•
Rarely enthesitis and dactylitis
•
Arthritisfollowinginfection following infection Formof spondyloarthritis spondyloarthritis(autoimmune) Occursdays Occurs days to weeks after an infection One or multiple joints affected Sometimes occurs with dactylitis and enthesitis Symptoms usually resolve in 6-12 months
Reactive Arthritis
Reactive Arthritis
Triggering Infections
Clinical Features
•
•
GIbacteria:
•
Asymmetric Asymmetric oligoarthritis oligoarthritis
•
Salmonella
•
Usually 1-4 weeks after infection
•
Shigella
•
Most commonly affects lower extremities (knees)
•
Yersinia
•
Campylobacter
•
Clostridium difficile
•
•
•
Urogenital: Chlamydia trachomatis
84
Enthesitis (heel pain) Dactylitis Inflammatory low back pain
Reactive Arthritis Clinical Features •
•
•
•
Conjunctivitis Urethritis (dysuria) Oral ulcers ReiterSyndrome •
Older term
•
Arthritis, urethritis, conjunctivitis following infection
85
Polymyalgia Rheumatica •
•
•
•
•
Muscle Disorders
•
Inflammatory disorder Unknown cause Occurs in older patients (age > 50) Muscle pain/stiffness Diagnosed clinically: no pathognomonic pathognomonic test Commonly occurs with temporal arteritis
Jason Ryan, MD, MPH
Polymyalgia Rheumatica
Polymyalgia Rheumatica
Clinical Features
Clinical Features
•
•
•
Bilateralproximalmusclestiffness muscle stiffness
•
Neck or torso
•
Strength testing normal
•
Shoulders/proximal arms
•
Normal CK level
•
Hips/proximal thighs
Worse in morning Often difficulty dressing
Polymyalgia Rheumatica •
•
•
Muscle pain (myalgias) especially in shoulder
•
Sometimes malaise , fever,fatigue
Fibromyalgia
Diagnosis and Treatment •
Does not cause muscle weakness
•
Characteristic clinical features ↑ CRP, ↑ESR Responds well toglucocorticoids to glucocorticoids
•
•
•
•
•
•
•
•
86
Chronic pain disorder Widespread musculoskeletal pain Common in women 20 to 55 years old Depression/anxiety Depression/anxiety in 30 to 50% of patients Unknown cause Diagnosedclinically Musclebiopsy:normal Normal lab tests
Fibromyalgia
Fibromyalgia
•
Point tenderness on exam
•
Exercise
•
Usually in specific anatomic locations
•
Tricyclic antidepressants (amitriptyline)
•
SSRIs
Inflammatory Inflammatory Myopathies
Inflammatory Inflammatory Myopathies •
•
•
•
•
Diagnosis and Treatment
Autoimmune Autoimmune muscle disorders Polymyositis Dermatomyositis Usually involve skeletal muscle (weakness)
•
Diagnosis:muscle Diagnosis:muscle biopsy
•
Treatment: immunosuppression
Can involve heart
•
Usually corticosteroids (prednisone) initially
•
Long term treatment treatment with steroid sparing drugs
•
Often azathioprine or methotrexate
Inflammatory Inflammatory Myopathies
Inflammatory Inflammatory Myopathies
Clinical Features
Lab Testing
•
•
•
•
Myalgias
•
Slow onset symmetric muscle weakness Hallmark: proximal muscle weakness at first
•
•
Elevatedcreatinine Elevated creatininekinase(CK) ESR can be elevated (sometimes normal) Anti-nuclearantibodies(ANA)
•
Muscles closest to midline
•
Not specific for myopathies
•
Difficulty rising from a chair chair
•
Positive in 80-90% of patients
•
Difficulty climbing stairs
•
Difficulty combing hair hair
•
Fine hand movements intact
•
Distal weakness occurs later in disease
•
87
Anti-Jo1 antibodies antibodies •
Histidyl t-RNA synthetase
•
Most common myositis myositis antibody
Other antibodies (anti-Mi2, anti-SRP)
Polymyositis •
Slow onset proximal muscle weakness
•
No skin involvement involvement
•
Skeletal Muscle •
Perimysium
•
Endomysium
•
Diagnosis:musclebiopsy
•
Polymyositis Endomysial inflammation
•
•
Predominant cell type: CD8+ T-cells
•
•
Muscle biopsy: perimysial inflammation Major cell type: CD4+ T-cells
Slow onset proximal muscle weakness Skin changes Diagnosis:musclebiopsy
Dermatomyositis
Dermatomyositis •
Connective tissue surrounding surrounding each muscle fiber (myocyte)
Dermatomyositis
•
•
Connective tissue surrounding fascicles (bundles of fibers)
Classic Skin Findings •
Heliotrope rash
•
Grotton papules
•
•
•
88
Purple discoloration of upper eyelid Symmetric red, scaly papules papules on hand/finger hand/finger joints
Both pathognomonic for dermatomyositis
Dermatomyositis
Malignancy
Other Skin Findings •
•
•
Malar rash (similar to SLE) “Shawl and Vsigns” Vsigns” •
Red-brown discoloration of skin
•
Occurs in sun exposed area area
•
Upper back (like a shawl)
•
Neck/upper chest sparing skin below chin (V sign)
•
•
•
•
•
Mechanic’s hands •
Associated with inflammatory myopathy Mechanism unclear Stronger evidence for DM versus PM Associated malignancies mostly adenocarcinomas
Cracks/fissures on palms with increased increased pigmentation
89
Cervix
•
Lung
•
Ovaries
•
Pancreas
•
Bladder
•
Stomach
NMJ Disorders •
Myasthenia gravis
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Lambert-Eaton Lambert-Eaton MyasthenicSyndrome
Neuromuscular Disorders Jason Ryan, MD, MPH
Neuromuscular Junction •
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Depolarization
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Release of acetylcholine (ACh) vesicles
calcium influx
Post-synapse: motor end plate
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Acetylcholine
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Muscle depolarization
nicotinic receptors contraction
ACh broken down by acetylcholine acetylcholine esterase (AChE)
Myasthenia Gravis
Myasthenia Gravis •
Pre-synapse: nerve terminal
Clinical Features
Autoimmune Autoimmune disease
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AntibodiesblocknicotinicACh receptors Compete with Ach for receptor biding Muscle weakness Diagnosis: Acetylcholine Acetylcholine receptorantibodies
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Muscle fatigability •
Repeated nerve stimulation
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Muscles weaken with use
↓ ACh release
Myasthenia Gravis
Myasthenia Gravis
Clinical Features
Treatment
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Diplopia and ptosis
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Neostigmine,Pyridostigmine, Edrophonium
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Extraocular muscle weakness
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50% patients present with eye complaints
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↓ ACh metabolism
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↑ ACh levels in synapse
Speech, chewing and swallowing problems •
15% patients present with “bulbar symptoms”
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Acetylcholine esterase inhibitors
Immunosuppressants
Myasthenia Gravis
Myasthenia Gravis
Exacerbations
Exacerbations
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Occur for two reasons
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#1: Insufficient dose AChE inhibitor #2: Cholinergic crisis •
Too much medication
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Muscle refractory to ACh
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Tensilontest:Administoredrophonium Administoredrophonium •
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Short acting AChE inhibitor
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Muscle function improves: ↑ dose AChE inhibitor
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Muscle function fails to improve:↓ dose
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Tensilon test may lead to complications Caused by diffusely increased ACh levels Activationofparasympathetic of parasympathetic activity Salivation Abdominalcramping(bowel stimulation) stimulation) Asthma (bronchoconstriction) Bradycardia
Myasthenia Gravis
LEMS
Disease Associations Associations
Lambert-Eaton Lambert-Eaton Myasthenic Syndrome
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Most MG patients have abnormal thymus •
Hyperplasia ~85%
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Thymoma ~15%
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MG often resolves with thymectomy
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Key test: Imaging of mediastinum (CT or MRI)
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Also a disorder of NMJ (more rare) Paraneoplastic Paraneoplastic syndrome (small cell lung cancer) Antibodies against pre-synaptic Ca channels Prevent ACh release Diagnosis:VGCCantibodies •
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Antibodies to voltage-gated calcium channel (VGCC)
LEMS
LEMS
Lambert-Eaton Lambert-Eaton Myasthenic Syndrome
Lambert-Eaton Myasthenic Syndrome
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Slow onset symmetric proximal muscle weakness •
Also seen in myositis
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Normal CK levels
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No muscle pain/myalgia
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Difficulty walking or rising from chair
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Difficulty combing hair
LEMS
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Muscle use
improved symptoms
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Contrast with myasthenia gravis
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More depolarization
more ACh release
Tensilon test: mild ↑ in muscle function •
↑ ACh more contraction
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Much less effective than than in MG (reverses symptoms)
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Treat (or locate) underlying malignancy
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Guanidine: inhibits K+ channels ↑ ACh release
Classicallydry Classically dry mouth from ↓ salivation Erectiledysfunction, constipation constipation
NMJ Syndromes
Lambert-Eaton Lambert-Eaton Myasthenic Syndrome •
Autonomic dysfunction common
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