MUSCULOSKELETAL SYSTEM & RHEUMATOLOGY

Ø  EMBRYOLOGY: general embryology of the musculoskeletal system

Ø  ANATOMY:

Ø  PHYSIOLOGY:

Ø  PATHOLOGY OF BONE:

·      Non-neoplastic:   Compartment syndrome; limping (abnormality of gait) = LIMP -->  L-leg-Length discrepancy, L-LCP (legg-calves-perthes) syndrome, I-injury (trauma is the #1 cause of a limp), I-infection, I-immune disorder, M-malignancy, P-palsy, P-patellofemoral pain syndrome, P-paget’s disease, S-SCFE (slipped capital femoral epiphyses, S-SCA pain syndrome;

·      Neoplastic: 

o   Benign bone tumors:  EGO --> E-enchondroma, G-giant cell tumor (metaphysis), O-osteoid osteoma, O-osteochondroma (diaphyses).

o   Malignant bone tumors:  ECO --> E-ewing’s sarcoma (diaphyseal), C-chondrosarcoma (diaphyseal), O-osteosarcoma (metaphyseal) including Rothmund Thompson syndrome, retinoblastoma, and Coat’s diease

·      RHEUMATOLOGIC DISORDERS:  F-free O-our S-saint CLAVER = FOSCLAVER --> F-fibromyalgia, O-osteoarthritis, S-seronegative S-spondyloarthropathies (RAPE), S-sarcoidosis, C-connective tissue disorder (MDS), L-low back pain, A-acute monoarticular arthritis (TRIC), A-amyloidosis, V-vasculitis, E-everything else, R-rheumatoid arthritis

ANATOMY:

Diagram of the human skeleton

By LadyofHats Mariana Ruiz Villarreal - Own work. Image renamed from File:Human skeleton front.svg, Public Domain, https://commons.wikimedia.org/w/index.php?curid=6936349

By OpenStax - https://cnx.org/contents/FPtK1zmh@8.25:fEI3C8Ot@10/Preface, CC BY 4.0, https://commons.wikimedia.org/w/index.php?curid=30015057

·       STRUCTURE OF A SKELETAL MUSCLE: 

o   Endomysium:   Connective tissue (mainly reticular fibers) that ensheaths a muscle fiber (myofibril).  It also contains capillaries, nerves and lymphatics.

o   Perimysium:  Connective tissue which groups individual muscle fibers ( anywhere between 10 to 100 or more) into bundles or fascicles

o   Epimysium:  Connective tissue which ensheaths the entire muscle. It is continuous with fascia, tendons (where it becomes thicker and collagenous), and other connective tissue wrappings of muscle.

Muscle structure

Public Domain, https://commons.wikimedia.org/w/index.php?curid=1197565

o   SARCOMERE (give skeletal and cardiac muscles their striated appearance):  The basic unit of a muscle's cross-striated myofibril consisting of 3 different filament →

1.     Thick filament:  Composed of myosin protein which is connected from the M-line to the Z-disc by Titin

2.     Thin filaments:  Composed of actin monomers bound to Nebulin.

3.     Nebulin and Titin:  Provide stability and structure to the sarcomere.

Ø  A sarcomere is defined as the segment between two neighbouring Z-lines (from the German "Zwischenscheibe").

Ø  Surrounding the Z-line is the region of the I-band (for isotropic).

Ø  Following the I-band is the A-band (for anisotropic).

Ø  Within the A-band is a paler region called the H-band (from the German "Heller", bright).

Ø  Finally, inside the H-band is a thin M-line (from the German "Mittel", middle of the sarcomere).

I-band, A-band, H-band are named for their properties under a polarization microscope.

Image of sarcomere

By User:Sameerb - en:WP; Author User:Sameerb in English WP, Copyrighted free use, https://commons.wikimedia.org/w/index.php?curid=764619

PHYSIOLOGY:  

·      Neuromuscular Junction: 

An action potential arrives at the presynaptic terminal (1) à Open voltage-dependent calcium channels and Ca2+ ions flow from the ECF into the motor neuron's cytosol.  Ca2+ triggers synaptic vesicles (3) to fuse to the motor neuron's cell membrane and release acetylcholine (ACh) into the synaptic cleft.
ACh diffuses across the synaptic cleft and binds to the nicotinic acetylcholine receptors (4) on the sarcolemma (2).
ACh receptors open, allowing Na+ and K+ flow in and out of the muscle's cytosol, respectively. This produces a local depolarization of the motor end plate known as an end-plate potential (EPP).
This action potential spreads through the muscle fiber's network of T-tubules, and activates L-type voltage-dependent calcium channels (dihydropyridine receptors).  The resultant release of Ca++ stimulates additional calcium release from the adjacent sarcoplasmic reticulum (5), thus initiating muscle contraction.
The action of acetylcholine is terminated when the enzyme acetylcholinesterase degrades the neurotransmitter and the unhydrolysed neurotransmitter diffuses away.

Detailed view of a neuromuscular junction:
1 Presynaptic terminal
2 Sarcolemma
3 Synaptic vesicle
4 Nicotinic acetylcholine receptor
5 Mitochondrion

CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=305017

Crossbridge cycling

By OpenStax - https://cnx.org/contents/FPtK1zmh@8.25:fEI3C8Ot@10/Preface, CC BY 4.0, https://commons.wikimedia.org/w/index.php?curid=30015038

·       Muscle contraction: 

o   The calcium (from above) binds to the troponin C on the actin-containing thin filaments of the myofibrils. The troponin then allosterically modulates the tropomyosin. Normally the tropomyosin sterically obstructs binding sites for myosin on the thin filament.

o   Myosin (which has ADP and inorganic phosphate bound to its nucleotide binding pocket and is in a ready state) binds to the newly uncovered binding sites on the thin filament (binding to the thin filament is very tightly coupled to the release of inorganic phosphate). The release of ADP and inorganic phosphate are tightly coupled to the power stroke. This will pull the Z-bands towards each other, thus shortening the sarcomere and the I-band.

o   ATP binds myosin, allowing it to release actin (a lack of ATP makes this step impossible, resulting in the rigor state characteristic of rigor mortis). The myosin then hydrolyzes the ATP and uses the energy to move into the "cocked back" conformation. Steps 9 and 10 repeat as long as ATP is available and calcium is present on thin filament.

o   While the above steps are occurring, calcium is actively pumped back into the sarcoplasmic reticulum. When calcium is no longer present on the thin filament, the tropomyosin changes conformation back to its previous state so as to block the binding sites again. The myosin ceases binding to the thin filament, and the contractions cease.

Ø  PATHOLOGY OF MUSCULOSKELETAL SYSTEM & RHEUMATOLOGY:

·      Non-neoplastic:   Compartment syndrome; limping (abnormality of gait) = LIMP →  L-leg-Length discrepancy, L-LCP (legg-calves-perthes) syndrome, I-injury (trauma is the #1 cause of a limp), I-infection, I-immune disorder, M-malignancy, P-palsy, P-patellofemoral pain syndrome, P-paget’s disease, S-SCFE (slipped capital femoral epiphyses, S-SCA pain syndrome;

·      Neoplastic: 

o   Benign bone tumors:  EGO → E-enchondroma, G-giant cell tumor (metaphysis), O-osteoid osteoma, O-osteochondroma (diaphyses).

o   Malignant bone tumors:  ECO → E-ewing’s sarcoma (diaphyseal), C-chondrosarcoma (diaphyseal), O-osteosarcoma (metaphyseal) including Rothmund Thompson syndrome, retinoblastoma, and Coat’s diease

·      Rhematologic disorder:  F-free O-our S-saint CLAVER = FOSCLAVER → F-fibromyalgia, O-osteoarthritis, S-seronegative S-spondyloarthropathies (RAPE), S-sarcoidosis, C-connective tissue disorder (MDS), L-low back pain, A-acute monoarticular arthritis (TRIC), A-amyloidosis, V-vasculitis, E-everything else, R-rheumatoid arthritis

·      COMPARTMENT SYNDROME:  An acute medical problem in which increased pressure within a confined space (fascial compartment) in the body impairs blood supply → nerve damage and muscle death.

PATHOPHYSIOLOGY:  Any condition that results in an increase in compartment contents (edema) or reduction in a compartment’s volume (casts) could lead to compartment syndrome.  Common causes:  Tibial or forearm fractures, ischemic-reperfusion following injury, hemorrhage, vascular puncture, IV drug injection, casts, prolonged limb compression, crush injuries and burns.  As the intracompartmental pressure is elevated, the tissue microvasculature become compressed → ischemia.  Chronic compartment syndrome:  When compartment syndrome is caused by repetitive heavy use of the muscles, as in a runner.  This is usually not an emergency, but the loss of circulation can cause temporary or permanent damage to nearby nerves and muscle.
PRESENTATION:  The 6 "P's" of acute compartment syndrome → P-pain (often reported early as deep, constant,  poorly localized, and out of proportion with the injury, and is aggravated by passive stretching), P-pallor, P-paresthesias, P-poikilothermia (cold compartment), P-pulseless & P-paralysis (late finding). 
P  _______________, _______________, _______________, _______________, _______________
P  _______________, _______________, _______________, _______________, ________________
P  _______________, _______________, _______________, _______________, _______________
P  _______________, _______________, _______________, _______________, _______________
P  _______________, _______________, _______________, _______________, _______________
P  _______________, _______________, _______________, _______________, _______________
DIAGNOSTIC EVALUATION:  Measure the pressure within the muscle compartments.  The normal mean interstitial tissue pressure is < 10 mmH.  If > 20 mmHg → ↓ arterial blood flow;  if  ≥ 30 mmHg muscle and nerve may become necrotic.
TREATMENT:  Acute compartment syndrome:  Medical emergency requiring immediate fasciotomy to allow the pressure to return to normal.  Chronic compartment syndrome:  Can be treated conservatively (rest, anti-inflammatories, and stretching) or surgically (fasciotomy) in cases where symptoms persist.   If left untreated, acute compartment syndrome can lead to more severe necrosis of tissue leading to rhabdomyolysis and kidney failure.

Fasciotomy forearm

By TPompert - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=44546978

·      LIMP:  When a patient present with asymmetric abnormality of the gait, the differential diagnosis is LIMP → L-leg-Length discrepancy, L-LCP (legg-calves-perthes) syndrome, I-injury (trauma is the #1 cause of a limp), I-infection, I-immune disorder, M-malignancy, P-palsy, P-patellofemoral pain syndrome, S-SCFE (slipped capital femoral epiphyses, S-SCA pain syndrome.

L  _______________, _______________, _______________, _______________, ________________
I  _______________, _______________, _______________, _______________, _______________
M  _______________, _______________, _______________, _______________, _______________
P  _______________, _______________, _______________, _______________, _______________
S  _______________, _______________, _______________, _______________, _______________
TYPICAL PRESENTATION ON PHYSICAL EXAM:  REST → R-ROM (range of motion) ↓, E-erythema, S-swelling, T-tenderness. 

R  _______________, _______________, _______________, _______________, ________________
E  _______________, _______________, _______________, _______________, _______________
S  _______________, _______________, _______________, _______________, _______________
T  _______________, _______________, _______________, _______________, _______________

LCP (Legg-Calvé-Perthes) SYNDROME:  The diopathic avascular osteonecrosis of the capital femoral epiphysis of the femoral head.
Ø  EPIDEMIOLOGY:  Prevalence:  1/1200 children.  Caucasians are affected more frequently.  M > F 4-5X.  It most commonly strike persons aged 3-12 years, with a median of 6 years of age.

Ø  PATHOPHYSIOLOGY:  The direct cause is a reduction in blood flow to the joint. It is thought that the artery of the ligamentum teres femoris closes too early, not allowing time for the medial circumflex femoral artery to take over.

Ø  PRESENTATION:  The first signs are complaints of soreness from the child, which are often dismissed as growing pains. Pain (usually in the hip and exacerbated by hip/leg movement, though can also be ‘referred’ to the knee);  ROM ↓ (limited abduction and internal rotation); Painful gait;  Atrophy of thigh muscles from disuse.  In some cases, some activity (standing, walking, running, kneeling, or stooping)  can cause severe irritation or inflammation of the damaged area.  Typically the disease is only seen in one hip, bilateral perthes is seen in about 8-10% of diagnosed cases.

Ø  DIAGNOSTIC EVALUATION:  Diagnosis is made predominantly by X-ray study, together with physical examination.  A bone scan may be useful in helping determine the extent of the avascular changes. A hip aspiration may be performed if there is suspicion of a septic arthritis.

TREATMENT:  Treatment has traditionally centered on removing pressure from the joint until the disease has run its course. Modern treatment focuses on removing pressure from the joint in concert with physiotherapy. Removing pressure from joints:  Options include bed rest and traction (to separate the femur from the pelvis and reduce wear  often for several months or even years), braces and plaster casts, use of crutches or a cane, and the avoidance of running-based sports.  Physiotherapy:   Involves a daily series of exercises focusing on improving and maintaining a full range of motion of the femur within the hip socket.  Swimming is highly recommended - it allows exercise of the hip muscles with the full range of motion, while reducing the stress to a minimum. Younger children have a better prognosis than older children. Analgesic medication may be given as necessary.

X ray of Legg–Calvé–Perthes disease of the left hip

By J. Lengerke - Praxis Dr. Lengerke, Public Domain, https://commons.wikimedia.org/w/index.php?curid=18068382

·      INFECTION (OSTEOMYELITIS): Infection of bone or bone marrow, usually caused by pyogenic bacteria or mycobacteria..

ETIOLOGY: Staphylococcus aureus is the organism most commonly isolated from all forms of osteomyelitis.  Systemic mycotic infections (2 most common are Blastomyces dermatitidis and Coccidioides immitis) may also cause osteomyelitis.

o PATHOPHYSIOLOGY: Hematogenously seeded (20% of cases) osteomyelitis is seen most frequently in children, and nearly 90% of cases are caused by Staphylococcus aureus. Direct spread (80% of cases) caused by injury exposing the bone to local infection is the most common form of the disease in adults, and Staphylococcus aureus is again the most common organism seen, but anaerobes and Gram negative organisms, including Pseudomonas aeruginosa, E. coli, and Serratia marcescens, are also common, and mixed infections are the rule rather than the exception. Acute osteomyelitis almost invariably occurs in children. When adults are affected, it may be because of compromised host resistance due to debilitation, IVDU, infectious root-canalled teeth, other disease or drugs (e.g. immunosuppressive therapy)

o PRESENTATION: H & P (fever and REST → R-ROM ↓, E-erythema of overlying tissue, S-swelling, T-tenderness). In children, the long bones are usually affected. In adults, the vertebrae and the pelvis are most commonly affected. o DIAGNOSTIC EVALUATION: CBC (↑ WBC), ESR/CRP ↑, blood cultures. Obtain intitial X-ray (may show periosteal elevation 10-14 days later → if this is not diagnostic, the next step is to obtain a bone scan except in the evaluation of the spine or foot then an MRI (show ↑ signal in bone marrow consistent with bone marrow edema and signs of soft tissue infection) is preferred. Bone aspiration with Gram stain and culture (defninitive diagnosis).

o TREATMENT: Osteomyelitis often requires prolonged IV antibiotic therapy (4-6 weeks). A PICC line or central venous catheter is often placed for this purpose. Osteomyelitis also may require surgical debridement. Severe cases may require amputation. Initial first line antibiotic choice is determined by the patient's history and regional differences in common infective organisms. Options for empiric antibiotic: S. aureus (Nafcillin, oxacillin, cephalosporin, vancomycin); Gram negative coverage (3rd generation cephalosporin and gentamicin or ciprofloxacin).

o COMPLICATION: Chronic osteomyelitis, sepsis, soft tissue infection, septic arthritis, squamous cell carcinoma of the skin (Marjolin’s ulcer).

Osteomyelitis of the 1st toe

By James Heilman, MD - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=49086925

Osteomyelitis in both feet as seen on bone scan

By James Heilman, MD - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=49086909

·      IMMUNOLOGIC DISEASES: SEE RHEUMATOLOGY  SECTION BELOW

·      MALIGNANCY: 

DEFINITION: 1) Osteoid:  A protein mixture composed of primarily Type I collagen secreted by osteoblasts. When it mineralizes, it becomes bone. When there is insufficient mineral or osteoblast dysfunction, the osteoid does not mineralize properly, and it accumulates. This process is called osteomalacia (in adult) or rickets (in children). 2) Osteoma (plural: "osteomata"):  A new piece of bone usually growing on another piece of bone. It is a benign tumor.  When the bone tumor grows on other bone it is known as "homoplastic osteoma"; when it grows on other tissue it is called "heteroplastic osteoma".

o BENIGN BONE TUMORS: EGO → E-enchondroma, G-giant cell tumor (metaphysis), O-osteoid osteoma, O-osteochondroma (diaphyses).

o E _______________, _______________, _______________, _______________, _______________

o G _______________, _______________, _______________, _______________, _______________

o O _______________, _______________, _______________, _______________, _______________

ENCHONDROMA:  A cartilage cyst found in the bone marrow.  A type of benign bone tumor that originates from cartilage and most often affects the cartilage that lines the inside of the bones. 
Ø  EPIDEMIOLOGY:  Most common between 10-20 y/o. M = F. 

Ø  PATHOPHYSIOLOGY:  Enchondroma is believed to occur either as an overgrowth of the cartilage that lines the ends of the bones, or as a persistent growth of original, embryonic cartilage.  An enchondroma may occur as an individual tumor or several tumors. The conditions that involve multiple lesions include:  Ollier's disease (enchondromatosis):  When multiple sites in the body develop the tumors.  Maffucci's syndrome:  A combination of multiple tumors and angiomas.

Ø  PRESENTATION:  Often asymptomatic.  Enchondroma is most common in the hand (it is the most common hand tumor), but may also affect the femur,humerus, and the tibia.  Most common symptoms include:  Hand pain (if the tumor is very large, or if the affected bone has weakened àfracture), Enlargement of the affected finger; Slow bone growth in the affected area.

Ø  DIAGNOSTIC EVALUATION:  H&P.  X-ray (the typical modality).  Radionuclide bone scan (to rule out any infection or fractures).  MRI (to rule out any associated abnormalities of the spinal cord and nerves).  CT (more detailed than general x-rays) .

Ø  TREATMENT:  Specific treatment determined based on the patient’s age, overall health, medical history extent of the disease, tolerance for specific medications/procedures or preference of the patient.  Options:  1) Observation:  If there is no sign of bone weakening or growth of the tumor). Follow-up with repeat x-rays may be required as some types of enchondromas can develop into malignant, or cancerous, bone tumors later.  2) Surgery (e.g. bone grafting):  When bone weakening is present or fractures occur.

X-ray showing an enchondroma in the femur.

By Hellerhoff - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=10322627

MRI T1 showing an enchondroma in the femur

By Hellerhoff - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=10322702

Micrograph of an enchrondroma

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=12440713

GIANT CELL TUMOR OF BONE (aka giant cell myeloma or osteoclastoma): A uncommon benign tumor characterized by the presence of multinucleated giant cells (osteoclast-like cells). A number of tumors have giant cells, but are not true benign giant cell tumors. These include, aneurysmal bone cyst, chondroblastoma, simple bone cyst, osteoid osteoma, osteoblastoma, osteosarcoma, giant cell reparative granuloma, and brown tumor of hyperparathyroidism
Ø  EPIDEMIOLOGY:  Accounts for 4-5% of primary bone tumors and 18.2% of benign bone tumors. Giant cell tumors are mostly benign, however 5-10% of patients may have a malignant tumor.

Ø  PRESENTATION: Usually present with pain, limited range of motion (caused by tumor's proximity to the joint space), swelling (if the tumor has been growing for a long time). Some patients may be asymptomatic until they develop a pathologic fracture.  Metastasis to the lungs may occur

Ø  DIAGNOSTIC EVALUATION:  Bone X-ray:  Have a metaepiphyseal location and grow to the articular surface of the involved bone, and show a charecteristic 'soap bubble' appearance. They are distinguishable from other bony tumors in that GCTs usually have a non-sclerotic and sharply defined border.  Chest x-ray or CT:  May be needed because giant cell tumors are known to metastasize.  MRI:  To assess intramedullary and soft tissue extension.

Ø  TREATMENT:  Surgery:  The treatment of choice if the tumor is determined to be resectable. Radiation therapy:  For tumors that are not amenable to surgery.  In patient with a pathological fracture:  Immobilize the affected limb and wait for the fracture to heal before performing surgery.  PROGNOSIS:  In most patients, the tumors are slow to develop, but may recur locally in as many as 50% of cases.

Distribution of giant-cell tumors of bone

By Frank Gaillard - [1], CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=17938232

X-ray of a giant-cell bone tumor in the head of the fourth metacarpal of the left hand

By James Heilman, MD - Own work, Public Domain, https://commons.wikimedia.org/w/index.php?curid=4398979

Giant cell tumour of bone show the characteristic giant cells with nuclei that have a similar appearance to the surrounding (mononuclear) cells.

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=14831566

OSTEOID OSTEOMA:  A benign tumor arises from osteoblasts and originally thought to be a smaller version of an osteoblastoma.
Ø  PRESENTATION:  Severe pain typically at night, commonly associated with relief by aspirin or other NSAIDs.

Ø  DIAGNOSTIC EVALUATION: Bone X-ray:  Characteristically less than 1.5cm diamete.  Most frequently occur in vertebrae and long bones and less commonly in the mandible or other graniofacial bones.

CT scan showing an osteoid osteoma of the fibula with a clearly visible nidus.

By Hellerhoff - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=14523885

Micrograph of an osteoid osteoma showing the characteristic anastomosing bony trabeculae and osteoblastic rimming.

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=14858328

OSTEOBLASTOMA:  An uncommon primary neoplasm of the bone with clinical and histologic manifestations similar to those of osteoid osteoma; therefore, some consider the two tumors to be variants of the same disease, with osteoblastoma representing a giant osteoid osteoma.
Ø  EPIDEMIOLOGY:  Account for only 0.5-2% of all primary bone tumors and only 3% of benign bone tumors.  M > F 2-3X.  Predominantly affects younger persons (~ 80% occur in patients < 30 y/o), with mean age at presentation of 20 y/o.

Ø  PRESENTATION:  ~ 40% of all osteoblastomas are located in the spine (usually involve the posterior elements).  The lower extremities’ long bones are another common site of involvement (often diaphyseal).  Usual symptoms:  Pain (less intense, not worse at night, and not relieved readily with salicylates in contrast with osteoid osteoma),  Localized swelling and tenderness (if the lesion is superficial).   Spinal lesions can cause painful scoliosis, mechanically interfere with the spinal cord or nerve roots (causing neurologic deficits). Conventional osteoblastoma is a benign lesion with little associated morbidity. However, metastases and even death have been reported with the controversial aggressive variant, which can behave in a fashion similar to that of osteosarcoma. This variant is also more likely to recur after surgery than is conventional osteoblastoma. 

Ø  DIAGNOSTIC EVALUATION:  H&P.  Bone X-ray of the site of the patient's pain. CT:  To define the margins of the lesion for potential surgery. MRI:  Detect nonspecific reactive marrow and soft tissue edema/tumor extension.  Bone biopsy (necessary for confirmation): Histologically osteoblastomas are similar to osteoid osteomas, producing both osteoid and primitive woven bone amidst fibrovascular connective tissue.

Ø  TREATMENT:  Radiation or chemotherapy:  Controversial in the treatment of osteoblastoma. Cases of postirradiation sarcoma have been reported after use of these modalities.  Surgical therapy: The recommended treatment consist of removal of gross and microscopic tumor and a margin of normal tissue. This is usually curative.

High magnification micrograph of an osteoblastoma.

By No machine-readable author provided. Nephron assumed (based on copyright claims). - No machine-readable source provided. Own work assumed (based on copyright claims)., CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=12449254

OSTEOCHONDROMA (aka bone spur or osteocartilaginous exostosis):   A benign tumor that consists of cartilage and bone.  It is the most frequently observed neoplasm of the skeleton.
Ø  EPIDEMIOLOGY:  Accounts for 20-50% of benign bone tumors and 10-15% of all bone tumors. Occur most frequently in the first two decades of life.  M>F 1.5X.

Ø  PATHOPHYSIOLOGY:  Caused by either a congenital defect or trauma of the perichondrium which results in the herniation of a fragment of the epiphyseal growth plate through the periosteal bone cuff. The lesions occur only in bones that develop from cartilage (endochondral ossification). Osteochondromas are also the result of radiation therapy in children. Hereditary multiple osteochondromatosis is an autosomal dominant condition that can lead to both sessile and pedunculated lesions with an increase risk of malignant transformation to chondrosarcoma; 25-30% compared to approximately 1% for a solitary osteochondromas. The risk of malignant degeneration increases as the number and size of the osteochondromas increases.  In general, a sessile lesion is more likely to degenerate into sarcoma than an exostosis.

Ø  PRESENTATION:   Mass (often occur at joints, most commonly in long bones, especially the distal femur and proximal tibia à 40% of the tumors occurring around the knee) as a cartilage capped subperiosteal bone projection), Pain (due to mechanical irritation), Fracture can occur through the stalk of the lesion which also causes pain.     

Ø  DIAGNOSTIC EVALUATION:  Bone X-ray:  Sessile lesions cover a wide area and as a result cause metaphyseal widening or a "trumpet shaped deformity" on x-ray. Lesions with stalks are often found more distally and are common over the posterior femoral. metaphysis. CT:  Help determine if the marrow and cortices of the lesion are continuous with the bone. MRI.  Biopsy:  On gross examination, an osteochondroma is an irregular bony mass with a bluish gray cap of cartilage. Histologically, an osteochondroma has endochondral ossification on the basal surface of hyaline cartilage so it resembles a normal growth plate with rows of chondrocytes. The cartilage is more disorganized than normal, has binucleate chondrocytes in lacunae, and is covered with a thin layer of periosteum. 

Ø  TREATMENT:  Asymptomatic osteochondromas:  No treatment necessary. Surgical excision:  If the lesion is causing pain or neurologic symptoms due to compression. As long as the entire cartilage cap is removed there should be no recurrence.

Lateral radiograph of the knee demonstrating ossification in the peritendinous tissues in a patient with osteochondroma.

By Michael R Carmont, Sian Davies, Daniel Gey van Pittius and Robin Rees - Accelerated para-articular osteochondroma formation within the knee: a case report, Cases Journal. doi:10.1186/1757-1626-1-6, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=4280855

Surgical extraction of osteochondromas is sometimes beneficial. Shown is an osteochondroma surgically extracted from a ten-year-old patient. The bone is the cylindrical stalk at the bottom, about 1/2 inch long, the two diagonal growths are cartilage. This morphology is typical of a tibial bone spur.

By Paigeblue08 - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=22953355

o MALIGNANT BONE TUMORS: ECO → E-ewing’s sarcoma (diaphyseal), C-chondrosarcoma (diaphyseal), O-osteosarcoma (metaphyseal)

o E _______________, _______________, _______________, _______________, _______________

o C _______________, _______________, _______________, _______________, _______________

o O _______________, _______________, _______________, _______________, _______________

EWING’S SARCOMA:  A primitive neuroectodermal tumor.
Ø  EPIDEMIOLOGY:  Most frequently in male teenagers.  Incidence: 4.6/1,000,000 in adolescents aged 15-19 years.  Due to the prevalence of diagnosis during teenage years, there may possibly be a link between the onset of puberty and the early stages of this disease.

Ø  PATHOPHYSIOLOGY:  Associated with t(11,22) mutation, which fuses the EWS gene of chromosome 22 to the FLI1 gene of chromosome 11

Ø  PRESENTATION:  Pain and swelling at the site. The diaphyses of the femur are the most common sites, followed by the tibia, humerus, pelvis, and ribs.  30% are overtly metastatic at presentation (most commonly occur in the chest/lung and bone).  Cachexia.

Ø  DIAGNOSTIC EVALUATION:  H&P.  Bone X-ray:  Classic description of lamellated or "onion skin" type periosteal reaction (secondary to a permeative lytic lesion with periosteal reaction). The wide zone of transition (e.g. permeative) is the most useful plain film characteristic in differention of benign versus aggressive or malignant lytic lesions.  CT/MRI:  Define the extraosseous (soft tissue) extent of the tumor, and reveal distant metastasis.  Both CT and MRI can be used to follow response to radiation and/or chemotherapy.      

Ø  TREATMENT:  Because of the high rate of occult & overt metastatic disease, multidrug chemotherapy as well as local disease control with surgery and/or radiation is indicated in all patients. Treatment often consists of neo-adjuvant chemotherapy generally followed by wide or radical excision, and may also include radiotherapy. Most patients will undergo chemotherapy for 6-12 months and radiation therapy for 5-8 weeks. 

Ø  PROGNOSIS:  Localized disease: 65-70% survival when treated with chemotherapy. Metastatic disease:  Long term survival ranges 10%-30%.   

Ø  SUMMARY OF EWING’S SARCOMA:  EWING → E-ESR ↑, E-eleven-tWenty tWo translocation- t(11,22), W-wings and ONINION SKINS, I-increase risk of metastasis (30%), N-neuroectodermal origin (small round cell), G-guy teens.

Ø  E  _______________, ______________, ______________, ______________, _______________

Ø  W  ______________, _______________, _______________, ______________, ______________

Ø  I  _______________, _______________, ______________, ______________, ______________

Ø  N  ______________, _______________, _______________, ______________, ______________

Ø  G  ______________, _______________, _______________, ______________, ______________

Distribution of Ewing's sarcoma: Most frequent locations are the large long bones and the pelvis.

By Frank Gaillard - [1], CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=17938132

X-ray of a child with Ewing's sarcoma of the tibia

By Michael Richardson, M.D. on Oct 25th, 2004; Upload by Christaras A - EN:Wikipedia. IMG EwingSarcomaTibia.jpg, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=1192595

Magnetic resonance imaging slice showing Ewing's sarcoma of the left hip

By Unknown photographer/artist - National Cancer Institute, AV Number: AV-0000-4364, Public Domain, https://commons.wikimedia.org/w/index.php?curid=5581877

Micrograph of a metastatic Ewing's sarcoma with the characteristic cytoplasmic clearing on H&E staining, which was showing to be PAS positive.

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=14949113

MRI of a left-pelvis chondrosarcoma in a 26-year-old male

By An MRI Machine - Magnetic Resonance Image, CC0, https://commons.wikimedia.org/w/index.php?curid=14710757

Histopathologic image of chondrosarcoma of the chest wall. Surgical resection of recurrent mass.

By No machine-readable author provided. KGH assumed (based on copyright claims). - No machine-readable source provided. Own work assumed (based on copyright claims)., CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=552857

CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=552862

OSTEOSARCOMA:  A malignant connective (soft) tissue tumor whose neoplastic cells present osteoblastic differentiation and form tumoral bone.
Ø  EPIDEMIOLOGY:  The most common malignant bone cancer (made up 35% of primary bone malignancies). Incidence:  Bimodal with the first peak occurs in people 15-30 y/o and the second peak occurs in the elderly (usually associated with an underlying bone pathology such as Paget's disease, medullary infarct, or prior irradiation).

Ø  PATHOPHYSIOLOGY:  A low selenium or Vitamin D3 level or a high level of inflammation, as measured by interleukin-6, interleukin-8, or Nf-kB, Tumor Necrosis Factor Alpha may have a significant role as tumor suppressors and tumor initiators, respectively. Recent studies show that an increased level of c-Fos can lead to osteosarcoma.

Ø  PRESENTATION:  Intractable pain (may be worse at night), swelling (if the tumour is large), pathological fracture, fever, and weight loss. There is a preference for the metaphyseal region of long bones (most often it affects the distal femur or the proximal tibia, or humerus), with 50% of cases occur around the knee. 

Ø  DIAGNOSTIC EVALUATION:    H&P.  Bone X-ray:  Irregular "fir-tree" or "sun-burst" appearance due to the tumor spicules of calcified bone radiating in right angles. These right angles form what is known as Codman's triangle.  Other modalities: PET scan, bone scan, MRI.  Bone biopsy:  The characteric feature of osteosarcoma is presence of osteoid within the tumour. Tumor cells are very anaplastic (pleomorphic, giant cells with numerous atypical mitoses). These cells produce osteoid (amorphous, eosinophilic/pink) with or without central calcification (hematoxylinophilic/blue, granular). Tumor cells are included in the osteoid matrix. Depending on the features of the tumour cells present (whether they resemble bone cells, cartilage cells or fibroblast cells), the tumour can be subclassified.

Ø  TREATMENT:  Current standard treatment is to use neoadjuvant chemotherapy followed by surgical resection, then adjuvant therapy. The percentage of tumor cell necrosis (cell death) seen in the tumor after surgery gives an idea of the prognosis and also lets the oncologist know if the chemotherapy regime should be altered after surgery.  Standard options for chem0therapy is a combination of high dose methotrexate with leucovorin rescue, intra-arterial cisplatin caffeine, adriamycin, ifosfamide with mesna, BCD, etoposide, muramyl tri-peptite (MTP).

Ø  PROGNOSIS:  Osteosarcoma has one of the lowest survival rates for pediatric cancer despite chemotherapy's success.  The mortality rate is 25% with 5-year survival ranges from 60%-85.  The prognosis for patients with metastatic osteosarcoma improves with longer times to metastases, (more than 12 months-24 months), a smaller number of metastases (and their resectability). It is better to have fewer metastases than longer time to metastases.   

Ø  SUMMARY OF OSTEOSARCOMA:  SARCOMA → S-surgical resection is the treatment of choice, S-sunburst pattern on XR, A-associated with  R-RECQL4 mutation, R-Rb mutation, R-rothmund thompson syndrome, and Li-Fraumeni syndrome,  C-codman’s triangle is seen on XR, O-osteoid matrix seen on biopsy, M-most common bone tumor.

Ø  S  _______________, ______________, ______________, ______________, _______________

Ø  A  ______________, _______________, _______________, ______________, ______________

Ø  R  _______________, _______________, ______________, ______________, ______________

Ø  C  ______________, _______________, _______________, ______________, ______________

Ø  O  ______________, _______________, _______________, ______________, ______________

Ø  M  ______________, _______________, _______________, ______________, ______________

Ø  A  ______________, _______________, _______________, ______________, ______________

Predilections of osteosarcoma

By Human_skeleton_front.svg_-_no_labels.svg: Mikael Häggström - Human_skeleton_front.svg_-_no_labels.svg, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=5805909

X-ray of osteosarcoma of the distal femur in a dog

By Joel Mills - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=1773331

Osteosarcoma (center and right of image) adjacent to non-malignant bone (left-bottom of image): The top-right of the image has poorly differentiated tumor. Osteoid with a high density of malignant cells is seen between the non-malignant bone and poorly differentiated tumor.   By definition, osteosarcomas form osteoid (the organic extracellular component of bone), which is pink, bland/homogenous on H&E staining. 

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=12277142

Osteoid formation in an osteosarcoma

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=12277162

Ø  RTS (rothmund thompson syndrome):  A hereditary benign skin condition with several reported cases associated with osteosarcoma. 

v  PATHOPHYSIOLOGY:  Mutations in the DNA Helicase RECQL4 has been implicated in the syndrome.

v  PRESENTATION:  Muscle atrophy and soft tissue contractures, Abnormal skin pigmentation, Telangiectasia, Juvenile cataracts, Saddle nose, Congenital bone defects and short stature, Hair growth problems, Hypogonadism, Hypodontia, Anemia, Osteosarcoma

v  SUMMARY OF RTS:  ROTHMUNDS → R-RECQL4 mutation, O-osteosarcoma, O-ocular cataract, T-telangiectasia, H-hypogonadism, H-hypodontia, H-hair growth problems, MU-muscle atrophy & soft tissue contracture, N-neoplasm (SqCC of skin), S-saddle nose, S-short stature.

v  R  _______________, _____________, ______________, _____________, ______________

v  O  ______________, ______________, ______________, ______________, _____________

v  T  ______________, ______________, ______________, ______________, _____________

v  H  _____________, ______________, _______________, ______________, _____________

v  MU  _____________, ______________, _______________, ______________, _____________

v  N  _____________, ______________, _______________, ______________, _____________

v  D  _______________, _____________, ______________, _____________, ______________

v  S  ______________, ______________, ______________, ______________, _____________

Panel showing some clinical features of the RTS syndrome. A) Chronic phase of cheek poikiloderma (4-year-old girl). B) Poikiloderma with alopecia (21-year-old boy). C) Poikiloderma. D) Poikiloderma sparing the trunk (courtesy of Professor M. Paradisi, Rome). E) Photo distributed poikiloderma and valgism of the knees. F) Thumb aplasia (patient B). G) Bone defect seen by X-Rays: cystic-like destructive lesion of the humerus (distal epiphysis) without apparent solution of continuity of the cortical bone (patient E).

By Lidia Larizza, Gaia Roversi, Ludovica Volpi - Lidia Larizza, Gaia Roversi, Ludovica Volpi (2010) Rothmund-Thomson syndrome. Orphanet Journal of Rare Diseases 2010, 5:2doi:10.1186/1750-1172-5-2, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=12310891

Ø  RETINOBLASTOMA:  A cancer of the retina.

v  EPIDEMIOLOGY:  Mostly in children < 5 y/o and accounts for ~ 3% of the cancers occurring in children < 15 years. Incidence:  4/million children.

v  PATHOPHYSIOLOGY:  Development of this tumor is initiated by mutations that inactivate both copies of the RB1 gene, which codes for the retinoblastoma protein. Knudson's two-hit hypothesis was originally devised to explain the incidence of tumours in retinoblastoma patients. In this model, usually in a healthy individual, two spontaneous mutation events must occur in the same gene (i.e. RB), in the same cell, for cancer to develop. If, however, one defective copy is inherited, only one further mutational event is required to 'knock out' normal RB function. It is this feature that results in the early age of tumour development and the persistent recurrence of further tumours that are not produced through metastasis, this being a common feature of all the cancer syndromes.

v  PRESENTATION:  It begins with unilateral or bilateral leukocoria.  Then loss of vision occurs (as the retina is the light-sensitive part necessary for vision).  Retinoblastoma is usually confined to the eye but can spread to the brain via the optic nerve.  Affected children in developing countries present with advanced features and usually die of metastatic spread.

v  TREATMENT:  Unilateral cases:  Chemotherapy is the treatment of choice.  Locally advanced disease:  External beam radiation may be needed.   Bilateral disease:  Many children with bilateral retinoblastoma can be treated with a preservation attempt; however, in some, enucleation may be the only option. Tumor chemoreduction with carboplatin and other drugs may reduce the tumor volume making them amenable to local therapies.  Local therapies include:  Laser therapy (destroy the blood vessels surrounding a tumor), Cryotherapy (shrink the tumor), Thermotherapy, Radiotherapy (used as a last resort because of its many drawbacks including secondary cancerous growths, destruction of healthy cells, bone deformation due to the destruction of the growth plates mainly in the area of the temple).  In its initial stages, retinoblastoma is very similar to Coats’ disease, a non-cancerous retina disease. Coats' Disease should be ruled out before enucleation is done. A mis-diagnosis of Retinoblastoma accounts for the greatest number of Coats' disease eyes being enucleated. 

v  RETINOBLASTOMA SUMMARY:  RB → R-Rb gene mutation (2 hits) → R-retinal tumor, B-bilateral disease in some cases, B-brain metastasis via optic nerve.

v  R  _______________, _____________, ______________, _____________, ______________

v  B  ______________, ______________, ______________, ______________, _____________

Leukocoria in a child with retinoblastoma

By J Morley-Smith (talk) - Own work (Original text: I created this work entirely by myself.), Public Domain, https://commons.wikimedia.org/w/index.php?curid=6463697

Retinoblastoma retina scan before and after chemotherapy

By Morleyj - Own work, Public Domain, https://commons.wikimedia.org/w/index.php?curid=4983783

MRI pattern of retinoblastoma with optic nerve involvement (sagittal enhanced T1-weighted sequence)

By Aerts et al. - Aerts, I, Lumbroso-Le Rouic, L, Marion Gauthier-Villars, M, Brisse, H, Doz, F, Desjardins, L. Retinoblastoma. Orphanet Journal of Rare Diseases. 1, 31. 2006. PMID 16934146. (http://www.ojrd.com/content/1/1/31), CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=2492688

Flexner-Wintersteiner rosettes in Retinoblatoma

By The Armed Forces Institute of Pathology (AFIP) - PEIR Digital Library (Pathology image database). Image# 413737. https://commons.wikimedia.org/w/index.php?curid=4339878

v  COATS’ DISEASE (aka exudative retinitis or retinal telangiectasis):  A rare eye disorder, causing full or partial blindness.  

§  EPIDEMIOLOGY:  Occurs predominantly in young male in the first decade of life.

§  PATHOPHYSIOLOGY:  The disease is characterized by abnormal development of blood vessels behind the retina. Blood leaks from the abnormal vessels into the back of the eye, leaving behind cholesterol deposits and damaging the retina.

§  PRESENTATION:  Coats’ disease is usually unilateral, progresses slowly, and results in a gradual loss of vision.  Symptoms:  Leukoria (an early sign of the disease causes by light reflecting off cholesterol), blurred vision, deterioration of sight (most likely to begin in the upper part of the vision field as this corresponds with the bottom of the eye where blood usually pools), Photopsia (flashes of light), floaters, persistent color patterns (result of both retinal detachment and foreign fluids mechanically interacting with the photoreceptors).  At advanced stages, retinal detachment is likely to occur. Glaucoma, atrophy, and cataracts can also develop secondary to Coats’ disease.   Coats’ disease itself is not painful. Pain may develop as a result of retinal detachment or if fluid is not able to properly drain from the eye, causing the internal pressure to swell. 

§  TREATMENT: Early stages:  Laser surgery or cryotherapy can be used to destroy the abnormal blood vessels. However, if the leaking blood vessels are clustered around the optic nerve, this treatment is not recommended as accidental damage to the nerve itself can result in permanent blindness. Coats’ disease may stop progressing all on its own, either temporarily or permanently. Cases have been documented in which the condition even reverses itself. However, once total retinal detachment occurs, sight loss is permanent in most cases.  If pain or further complications arise:  Enucleation is an option.

Computed Tomography image of a patient with Coats' disease, showing total exudative retinal detachment in the right eye.

By Fernandes BF et al. - Fernandes BF, Odashiro AN, Maloney S, Zajdenweber ME, Lopes AG, Burnier MN Jr. Clinical-histopathological correlation in a case of Coats' disease. Diagn Pathol. 1, 24. 2006. PMID 16942617. DOI:10.1186/1746-1596-1-24, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=3187532

Clinical photography of patient with Coats' disease, showing conjunctival hyperemia, mild corneal edema, posterior synechiae and cataract.

By Fernandes BF et al. - Fernandes BF, Odashiro AN, Maloney S, Zajdenweber ME, Lopes AG, Burnier MN Jr. Clinical-histopathological correlation in a case of Coats' disease. Diagn Pathol. 1, 24. 2006. PMID 16942617. DOI:10.1186/1746-1596-1-24, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=3187529

Add Text Here...

Coats' disease, showing total retinal detachment with subretinal exudate containing cholesterol crystals and a fibrous nodule in the posterior pole.

By The Armed Forces Institute of Pathology (AFIP) - PEIR Digital Library (Pathology image database). Image# 406682. https://commons.wikimedia.org/w/index.php?curid=4336214

Coats' disease, showing total exudative retinal detachment, and subretinal exudate containing cholesterol crystals

By Fernandes BF, Odashiro AN, Maloney S, Zajdenweber ME, Lopes AG, Burnier MN Jr. Clinical-histopathological correlation in a case of Coats' disease. Diagn Pathol. 1, 24. 2006. PMID 16942617. DOI:10.1186/1746-1596-1-24, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=3187537

Ø  LI-FRAUMENI SYNDROME:  A rare autosomal dominant hereditary disorder.   Also known as the sarcoma, breast, leukaemia and adrenal gland (SBLA) syndrome.

v  PATHOPHYSIOLOGY:  Caused by mutations in p53, a tumor suppressor gene. p53 is a transcription factor that tetramerizes before binding to DNA to transactivate genes involved in inducing, cell cycle arrest, and apoptosis. Sufferers inherit one defective copy of the p53 gene retaining one normal copy. Knudson's two-hit hypothesis is also used to describe the incidence of tumours these patients.  Patients unusually inherit one mutant copy of the p53 tumor suppressor gene and the second mutation occurs sometime during life in a target cell.

v  PRESENTATION:  Unusual characteristics of Li-Fraumeni Syndrome:  1) Several kinds of cancer are involved 2) Cancer often strikes at a young age and 3) Cancer often strikes several times throughout the life of an affected person.  Classic tumors seen:   SO LAMB --> S-soft tissue sarcoma, O-osteosarcoma, B-breast cancer,  A-adrenocortical carcinoma, A-astrocytoma, L-leukemia, M-meningioma.  Other malignancies: Gastric cancer, Pharyngeal cancer, Choroid plexus carcinoma, Pancreatic Cancer, Melanoma, Germ cell tumors, Wilm's tumor, Colorectal Cancer, Phyllodes tumor, Ovarian Cancer, Thyroid Cancer, Endometrial cancer, Prostate cancer, and Cervical cancer.

§  S  _______________, _____________, ______________, _____________, ______________

§  O  ______________, ______________, ______________, ______________, _____________

§  B  ______________, ______________, ______________, ______________, _____________

§  A  _____________, ______________, _______________, ______________, _____________

§  L  _____________, ______________, _______________, ______________, _____________

§  M  ______________, ______________, _______________, ______________, ____________

v  DIAGNOSTIC EVALUATION:  Li-Fraumeni Syndrome is diagnosed if the following 3 criteria are met:  1) Patient has been diagnosed with a sarcoma at a young age (< 45), 2) A first-degree relative has been diagnosed with any cancer at a young age (< 45), and 3) Another first-degree or a second-degree relative has been diagnosed with any cancer at a young age (< 45) or with a sarcoma at any age. Genetic counseling and genetic testing are used to confirm that somebody has this gene mutation. Once such a person is identified, early and regular screenings for cancer are recommended for him or her.

v  TREATMENT:  If caught early the cancers can often be successfully treated. Unfortunately, people with Li-Fraumeni are likely to develop another primary malignancy at a future time.

·      PALSY (CEREBRAL):  Encompassing a group of non-progressive (meaning the brain damage does not worsen), non-contagious diseases that cause physical disability in human development. 

EPIDEMIOLOGY:  Incidence:  2/1000 live births.  M>F 1.33X.  CP is the second-most expensive developmental disability to manage over the course of a person's lifetime (second to mental retardation), with an average lifetime cost per person of USD $921,000 (in 2003 dollars).
PATHOPHYSIOLOGY:  Some causes of CP:   1) Before birth:  Asphyxia, hypoxia of the brain, birth trauma, premature birth, and certain infections in the mother during and before birth such as strep infections, CNS infections, trauma, consecutive hematomas, placenta abruptio and multiple birth.  Between 40% and 50% of all children who develop cerebral palsy were born prematurely 2) After birth:  Toxins, severe jaundice, lead poisoning, physical brain injury, shaken baby syndrome, incidents involving hypoxia to the brain (e.g. near drowning), and encephalitis or meningitis. 
PRESENTATION:  CP symptomatology is very diverse.   Symptoms:  Abnormal muscle tone, posture (i.e. slouching), reflexes, or motor development and coordination. There can be joint and bone deformities and contractures (permanently fixed, tight muscles and joints). The classical symptoms are spasticity, spasms, other involuntary movements (e.g. facial gestures), unsteady gait, problems with balance, arthritis, and/or soft tissue findings consisting largely of decreased muscle mass. Scissor walking (where the knees come in and cross) and toe walking are common among people with CP who are able to walk.   Common comorbidities:  Mental retardation (IQ < 50 in 31%), Seizures (21%), unable to walking (20%), Blindness (11%). 
TYPES: CP is divided into four major classifications based on the different movement impairments, which reflect the area of brain damaged. The four major classifications are:  SAM → S-spastic, A-athetoid/Dyskinetic, A-ataxic,  M-mixed.
S  _______________, _____________, ______________, _____________, ______________
A  ______________, ______________, ______________, ______________, _____________
M  ______________, ______________, ______________, ______________, _____________
SPASTIC:   Most common type (70% to 80% of all cases of CP).  
Ø  PATHOPHYSIOLOGY:  Patients’ neuromuscular condition stemming from damage to the corticospinal tract, motor cortex, or pyramidal tract. These patient are characteristically hypertonic.

Ø  SUBTYPES (classified by topography dependent on the region of the body affected):  Hemiplegia, Bilateral hemiplegia, Diplegia, Quadriplegia.

v  HEMIPLEGIA:  One side being affected. Upper extremities (UE) affected greater than the lower extremities (LE).  Injury to the left side of the brain will cause a right sided deficit.  

v  BILATERAL HEMIPLEGIA:  Bilateral.  UE affected more than LE.

v  DIPLEGIA:  Bilateral.  LE affected more than UE. Most diplegics eventually walk, but typically with a characteristic crouched gait. Other commom features:  toe walking, flexed knees, hip problems (dislocations), myopia, and strabismus (occur 75% of spastic diplegics  due to weakness of the extraocular muscle).  In many cases the IQ of a person with spastic diplegia is normal.

v  QUADRIPLEGIA:  Whole body affected.  All four limbs affected equally. Features:  hemiparetic tremors (unilateral uncontrollable shaking of the limbs that impairs normal movement), fluid buildup (diuretics and steroids are administered to decrease any buildup of fluid in the spine that is caused by leakage from dead cells), frequent UTI, hardened feces (important to monitor because it can cause high blood pressure and autonomic dysreflexia.  Blockage of tubes inserted into the body to drain or enter fluids also needs to be monitored to prevent autonomic dysreflexia in quadriplegia, which can arise from the overreaction of the nervous system and can result in high blood pressure, heart attacks, and strokes.

ATAXIC CP: These patients have hypotonia and tremors.  Features:  Impaired balance (i.e. walking) and motor skills (i.e. writing, typing, or using scissors), and difficulty with visual and/or auditory processing.
Ø   PATHOPHYSIOLOGY:  Damage to the cerebellum.. 

ATHETOID/DYSKINETIC:   Mixed muscle tone (sometimes hypertonia and sometimes hypotonia).  Features:  Trouble holding self in an upright position (for sitting or walking), and involuntary motions.
Ø  PATHOPHYSIOLOGY:  Damage occurs to the extrapyramidal motor system &/or pyramidal tract and to the basal ganglia. 

TREATMENT:  There is no cure for CP, but various forms of therapy can help a person with the disorder to function and live more effectively. In general, the earlier treatment begins the better chance children have of overcoming developmental disabilities or learning new ways to accomplish the tasks that challenge them. Treatment may include one or more of the following:
Ø  Physical/Occupational therapy:  Improved gait and volitional movement, maintain muscle tone, bone structure, prevent dislocation of the joints.  Orthotic devices such as ankle-foot orthoses (AFOs) are often prescribed to minimise gait irregularities.

Ø  Speech therapy:  Often starts before a child begins school and continues throughout the school years.   It helps patient breathe; talk clearly; and bite, chew and swallow food. Non-speaking people with CP are often successful availing themselves of augmentative and alternative communication systems such as Blissymbols. 

Ø  Drugs to control seizures, alleviate pain, or relax muscle spasms (e.g. benzodiazepienes, intrathecal baclofen).

Ø  Surgery: Usually involves one or a combination of:  Loosening tight muscles and releasing fixed joints, most often performed on the hips, knees, hamstrings, and ankles.

Ø  Other: Nutritional counseling, massage therapy.

Cmdr. John King, a physician embarked aboard the amphibious assault ship USS Kearsarge, assesses the reflexes of a Cerebral Palsy patient at the Arima District Health Facility as part of the humanitarian/civic assistance mission Continuing Promise 2008.

By MC2 Jilleanne Buda - https://www.dvidshub.net/image/126489, Public Domain, https://commons.wikimedia.org/w/index.php?curid=39546149

Micrograph showing a fetal (placental) vein thrombosis, in a case of fetal thrombotic vasculopathy. This is associated with cerebral palsy and is suggestive of a hypercoagulable state as the underlying cause.

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=16158471

Researchers are developing an electrical stimulation device specifically designed for children with cerebral palsy, who have foot drop which results in tripping when walking.

By The National Institutes of Health - https://www.flickr.com/photos/nihgov/24233878371/in/album-72157656890787872/, Public Domain, https://commons.wikimedia.org/w/index.php?curid=49182012

·      PATELLOFEMORAL PAIN SYNDROME (aka chondromalacia patellae or Runner's Knee):  A degenerative condition of the cartilage surface of the back of the patella. Patellofemoral pain syndrome is also used by clinicians when they do not have a specific explanation for a patient's knee pain.

PATHOPHYSIOLOGY:  It is common in athletes participating jumping-sports where the knees are under great stress (e.g. soccer players, cyclists, rowers, tennis players, ballet dancers, runners, snowboarders).  The condition may result from acute injury to the patella or from chronic friction between the patella and the groove in the femur through which it passes during motion of the knee. It is theorized that the softened cartilage (chondro-malacia) is the cause of pain.
PRESENTATION:  Discomfort or dull pain around or behind the patella.
TREATMENT:  Depend on the specific source of a person's pain. If pain is due to a tight iliotibial band, treatment will be focused on stretching of that band. If a person suffers from irritation of the infrapatellar branch of the saphenous nerve, treatment might consist of a small injection. If core stability is the issue, treatment might consist of physical therapy focused on the abdomen, pelvis and hips.

Rough distribution of areas affected by PFPS highlighted in red: patella and distal femur.

By BodyParts3D/Anatomography - Anatomography, CC BY-SA 2.1 jp, https://commons.wikimedia.org/w/index.php?curid=35786360

Vastus medialis muscle (red), thought to be the cause of PFPS

By modified by Uwe Gille - Gray430.png, Public Domain, https://commons.wikimedia.org/w/index.php?curid=2827532

·      SCFE (slipped capital femoral epiphysis):  

EPIDEMIOLOGY:  Often present in obese prepubescent (11-13 y/o) black males.
PATHOPHYSIOLOGY:  A fracture through the epiphyseal growth plate causes the capital (head of the femur) to slip on the femoral neck.  Obesity is a risk factor.  SCFE can sometimes be associated with endocrinopathies (i.e. hypothyroidism).
PRESENTATION:  Thigh/knee pain; ↓ ROM. 
DIAGNOSTIC EVALUATION:  X-rays of the pelvis (AP and frog lateral):  The appearance of the head of the femur in relation to the shaft likens that of a "melting ice cream cone". The severity of the disease can be measured using the Southwick angle. 
TREATMENT:  Promt pinning with screw stabilization. Some also advocate pinning the unaffected side prophylactically.  Untreated cases can result in serious growth abnormalities and permanent disability. 

X-ray showing a slipped capital femoral epiphysis, before and after surgical fixation.

By Dr. Jochen Lengerke - Praxis Dr. Jochen Lengerke, Public Domain, https://commons.wikimedia.org/w/index.php?curid=6637014

PAGET’S DISEASE OF THE BONE (aka osteitis deformans):  A chronic disorder that typically results in enlarged and deformed bones.

·      EPIDEMIOLOGY:  Prevalence:  1.5-8% depending on age and country of residence. Patient usually > 40 y/o. M > F.

·      PATHOPHYSIOLOGY:  Paget's disease may be caused by a slow virus infection (i.e., paramyxoviruses such as measles and respiratory syncytial virus). There is also a hereditary factor since the disease may appear in more than one family member.  Pevalence of familial Paget's disease (where more than one family member has the disease) ranges from 10 to 40 percent in different parts of the world.  The excessive breakdown and formation of bone tissue that occurs with Paget's disease can cause bone to weaken, resulting in bone pain, arthritis, deformities, and fractures.

·      PRESENTATION:  Many patients are asymptomatic. Symptoms include:  Bone pain (the most common symptom; Paget's disease occurs most frequently in the spine, skull, pelvis, thighs, and lower legs), Headaches and hearing loss (when Paget's disease affects the skull and the bone that surrounds the inner ear),  Somnolence (due to vascular steal syndrome of the skull),  Paralysis (due to vascular steal syndrome of the vertebrae), Increased head size (from excessive reparative bone formation), Bowing of limb, Curvature of spine, and Chalkstick fractures (from the softening of bone), Arthritis (pagetic bone enlarge, causing joint surfaces to undergo excessive wear and tear),  Cardiovascular disease (in severe cases with more than 15% skeletal involvement, the heart works harder to pump blood to affected bones leading to left ventricular hypertrophy and high-output congestive failure in rare cases), Aortic stenosis (from aortic valve calcification due to turbulent flow caused by increased cardiac output), Kidney stones (more common in patients with Paget's disease), Osteosarcoma (develop in 1% of patient),  Disturbance in chewing (when facial bone is affected), Loss of vision (when nerves to the eye affected),

·      DIAGNOSTIC EVALUATION:  ↑ alkaline phosphatase in the blood in combination with normal calcium, phosphate, and aminotransferase levels in an elderly patient are suggestive of Paget's disease.  Bone scans:  View the osteoblastic lesion.  Bone X-ray: Expanded bone cortex with increased bone density, and thickened trabeculae.  Bone biopsy: Jigsaw, mosaic bone.

·      TREATMENT:  Treatment can control Paget's disease and lessen symptoms but is not a cure. Medications: Bisphosphonates (should not be used by people with severe kidney disease).  Calcitonin (administered by injection as nasal spray form of this drug is not approved for the treatment of Paget's disease).  NSAIDs.   Surgery:  May be recommended for 1) Fractures 2) Severe degenerative arthritis (joint replacement) 3) Bone deformity (cutting and realignment of Pagetic bone to relieve painful weight-bearing joints, and injury to the nervous system).  Diet and Exercise (help maintaining skeletal health and joint mobility, and avoiding weight gain).  Calcium and vitamin D supplement.

Marked thickening of the calvarium. The diploic space is widened and there are ill-defined sclerotic and lucent areas throughout. The cortex is thickened and irregular. The findings probably correspond to the “cotton wool spots” seen on plain films in the later stages of Paget’s disease."

By dr Laughlin Dawes - radpod.org, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=4052399

An ivory vertebra due to probable Paget disease

By James Heilman, MD - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=49065897

Paget's disease of right coxa.

By Jmarchn - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=31374719

Paget's disease of the bone with the characteristic jigsaw puzzle-like/mosaic pattern

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=12440623

RHEUMATOLOGIC DISORDER:  F-free O-our S-saint CLAVER = FOSCLAVER → F-fibromyalgia, O-osteoarthritis, S-seronegative S-spondyloarthropathies (RAPE), S-sarcoidosis, C-connective tissue disorder (MDS), L-low back pain, A-acute monoarticular arthritis (TRIC), A-amyloidosis, V-vasculitis, E-everything else, R-rheumatoid arthritis.

·      F  _______________, ______________, ______________, ______________, _______________

·      O  ______________, _______________, _______________, ______________, ______________

·      S  _______________, _______________, ______________, ______________, ______________

·      C  ______________, _______________, _______________, ______________, ______________

·      L  ______________, _______________, _______________, ______________, ______________

·      A  ______________, _______________, _______________, ______________, ______________

·      V  ______________, _______________, _______________, ______________, ______________

·      E  ______________, _______________, _______________, ______________, ______________

·      R  ______________, _______________, _______________, ______________, ______________

·      FIBROMYALGIA:  A chronic syndrome characterized by diffuse or specific muscle, joint, or bone pain, fatigue, and a wide range of other symptoms in the absence of inflammation.

EPIDEMIOLOGY:  Prevalence:  3% -6% of the general population. F > M X9.   Most diagnosed in individuals between 20-50 y/o. 

PATHOPHYSIOLOGY:  The cause of fibromyalgia is currently unknown.  However, many hypotheses have been presented.  Predisposing factors:  Stress (e.g. PTSD is linked with fibromyalgia), Dopamine abnormality (  Pramipexole, a drug that stimulates dopamine D2/D3 receptors and is used to treat both Parkinson's disease and restless legs syndrome, has also been shown in controlled trials to have a positive effect on fibromyalgia),   Serotonin dysregulation (the antidepressant duloxetine has been shown to  release stating they had done trials which found Cymbalta, 60 mg once or twice daily, significantly reduce the pain of fibromyalgia), Sleep disturbance (EEG studies have shown that people with fibromyalgia lack of slow-wave sleep), Comorbid diseases  (a hypothesis that proposes that fibromyalgia is almost always a comorbid disorder, occurring in combination with, for example, gluten sensitivity and/or irritable bowel.

PRESENTATION:  Pain (chronic, widespread), tenderness to light touch, moderate to severe fatigue, allodynia, paresthesia (often needle-like), muscle ache, chronic sleep disturbances (deep stages of sleep-stages 3 & 4 are often dramatically reduced due to alpha-delta sleep, a condition in which delta sleep is frequently interrupted by bursts alpha waves), cognitive dysfunction (known as "fibrofog" which may be characterized by impaired concentration and short-term memory consolidation, impaired speed of performance, inability to multi-task, and cognitive overload), irritable bowel syndrome, genitourinary symptoms, dermatological disorders, headaches, myoclonic twitches, symptomatic hypoglycemia, temporomandibular joint disorder.  Many people with fibromyalgia find that, at least some of the time, the condition prevents them from performing normal activities such as driving a car or walking up stairs.

SUMMARY OF ASSOCIATED COND: GAD → G-GAD (general anxiety disorder), G-GU & G-GI disturbances, A-ache, A-anxiety, D-depression, D-dizziness.

DIAGNOSTIC EVALUATION:  A diagnosis of exclusion.  The diagnostic criteria include 1) ≥ 3 months of widespread pain 2) Patient must feel pain at 11 or more of 18 designated possible tender or trigger points when pressure equivalent to the amount of pressure required to blanch the thumbnail is applied.

TREATMENT:  There is no universally accepted cure for fibromyalgia.  Medications (most are used to treat specific symptoms of fibromyalgia):  Muscle Relaxants (cyclobenzaprine or tizanidine used to treat the muscle pain).  Tricyclic antidepressants (low doses of sedating antidepressants like amitriptyline and trazodone  have been used to reduce the sleep disturbances and associated symptoms of fibromyalgia).  Anti-seizure drugs (pregabalin has been FDA approved for treatment of fibromyalgia). Dopamine agonists (Mirapex are now being used).   Non-drug treatment:  Physical treatments (exercise improves fitness, sleep and reduces pain and fatigue).  Applying heat to painful areas.  Physical therapy, massage, acupuncture, reassurance about the benign nature of the disease and psychotherapy (e.g. biofeedback, CBT) may be beneficial.

The location of the nine paired tender points that constitute the 1990 American College of Rheumatology criteria for fibromyalgia.

By Sav vas - Own work, based on: https://commons.wikimedia.org/wiki/File:Tender_points_fibromyalgia.gif, CC0, https://commons.wikimedia.org/w/index.php?curid=21328615

Widespread Pain Index (WPI) Areas

By Jmarchn - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=47230073

By Mikael Häggström - Image: File:Frau-2.jpg by Ralf Roletschek (User:Marcela), CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=7039490

·      OSTEOARTHRITIS (aka degenerative arthritis, degenerative joint disease):  A condition in which low-grade inflammation results in pain in the joints, caused by abnormal wearing of the articular cartilage

EPIDEMIOLOGY:  OA is the most common form of arthritis.  80% of the population have radiographic evidence of OA by age 65, although only 60% of those will be symptomatic. There is a greater prevalence of the disease between siblings and especially identical twins, indicating a hereditary basis.
PATHOPHYSIOLOGY:  OA is related to but not caused by aging, as there are people well into their nineties who have no clinical or functional signs of the disease. As a person ages, the water content of the cartilage decreases due to a reduced proteoglycan content, thus causing the cartilage to be less resilient. Without the protective effects of the proteoglycans, the collagen fibers of the cartilage can become susceptible to degradation and thus exacerbate the degeneration. Inflammation of the surrounding joint capsule can also occur, though often mild (compared to that which occurs in rheumatoid arthritis). This can happen as breakdown products from the cartilage are released into the synovial space, and the cells lining the joint attempt to remove them. New bone outgrowths, called "spurs" or osteophytes, can form on the margins of the joints, possibly in an attempt to improve the congruence of the articular cartilage surfaces. These bone changes, together with the inflammation, can be both painful and debilitating.
PRESENTATION:  OA commonly affects the hands, feet, spine, and the large weight-bearing joints, such as the hips and knees. Chronic pain (described as sharp ache &/or a burning sensation in the associated muscles and tendons that is worsened with activity), crepitus (when the affected joint is moved or touched), muscle spasm and contractions in the tendons, and the joints may also be filled with fluid. Humid weather increases the pain in many patients. As OA progresses, the affected joints appear larger, are stiff and painful.  Heberden's nodes (on the distal interphalangeal joints) and/or Bouchard's nodes (on the proximal interphalangeal joints), may form, and limit the movement of the fingers significantly. OA at the toes leads to the formation of bunions, rendering them red or swollen.  Due to decreased movement because of the pain, regional muscles may atrophy, and ligaments may become more lax.
DIAGNOSTIC EVALUATION:  Joint x-ray (the primary means to diagnose OA):  Loss of cartilage, subchondral sclerosis, subchondral cysts, narrowing of the joint space between the articulating bones, and osteophytes are seen clearly.  Other techniques MRI, arthrocentesis and arthroscopy can also be employed.  Lab, ESR, and synovial fluid evaluation are normal in OA.
TREATMENT:  Mild OA:  Conservative measure such as weight control (relieve joint stress and may delay progression), appropriate rest and exercise (walking, swimming), application of heat, use of mechanical support devices (braces, a cane, or a walker), dietary supplements (glucosamine & chondroitin may improve symptoms of OA and delay its progression).  Medication: Acetaminophen (often trialed first), NSAID, COX-2 selective inhibitors, Corticosteroids (injected into joint), Narcotics (for severe pain).  Surgery (if conservative treatments are ineffective):  fragment removal, repositioning bones, or fusing bone to increase stability, and joint replacement surgery may be required.

Osteoarthritis most often occurs in the hands (at the ends of the fingers and thumbs), neck, lower back, knees, and hips

By US federal government - http://www.niams.nih.gov/health_info/Osteoarthritis/default.asp, Public Domain, https://commons.wikimedia.org/w/index.php?curid=40173053

Primary osteoarthritis of the left knee. Note the osteophytes, narrowing of the joint space (arrow), and increased subchondral bone density (arrow).

By James Heilman, MD - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=10335934

Formation of hard nobs at the middle finger joints (known as Bouchard's nodes) and at the farther away finger joint (known as Heberden's node) are a common feature of osteoarthritis in the hands.

By Drahreg01 - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=1358952

·      SERONEGATIVE SPONDYLOARTHROPATHY:  A group of related inflammatory joint diseases associated with the MHC class I molecule HLA-B27. This set of conditions may mimic rheumatoid diseases such as rheumatoid arthritis, but serological tests are typically negative for rheumatoid factor (RhF).  TYPES:  RAPE → R-reactive arthritis (Reiter’s syndrome), A-ankylosing spondyloarthropathy, P-psoriatic arthropathy, E-enteropathic arthropathy

R  _______________, ______________, ______________, ______________, _______________
A  ______________, _______________, _______________, ______________, ______________
P  _______________, _______________, ______________, ______________, ______________
E  ______________, _______________, _______________, ______________, ______________

REACTIVE ARTHRITIS (aka Reiter’s syndrome):  An RF-seronegative, HLA-B27-linked spondyloarthropathy (autoimmune damage to the cartilages of joints) often precipitated by genitourinary or gastrointestinal infections. 
Ø  EPIDEMIOLOGY:  Most commonly strikes individuals aged 20-40.  M > F.   White > Black.

Ø  PATHOPHYSIOLOGY:  It is set off by a preceding infection, the most common of which would be a genital infection with Chlamydia trachomatis in the US. Other bacteria known to cause reactive arthritis which are more common worldwide are Neisseria gonorrhoeae, Ureaplasma urealyticum, Salmonella spp., Shigella spp., Yersinia spp., and Campylobacter spp.   It is caused either by an over-excited autoimmune response or by bacterial antigens which have somehow become deposited in the joints.

Ø  PRESENTATION:  Symptoms generally appear within 1-3 weeks but can range from 4-35 days from the onset of the inciting episode of the disease.  The classical presentation is the triad of 1) Urogenital problem: urethritis-dysuria, polyuria, frequency- and prostatitis in men, and cervicitis, salpingitis &/or vulvovaginitis in women) 2) Arthritis:  Usually affects the large joints such as the knees causing pain and swelling with relative sparing of small joints such as the wrist and hand 3) Eye involvement (occur in 50%): Conjunctivitis & uveitis can cause redness of the eyes, eye pain and irritation, and blurred vision. The triad is commonly remembered with the mnemonic "Can't See, Can't Pee, Can't Climb a Tree".  Other symptoms:  Balanitis circinata (painless shallow ulcer on the end of the penis occuring in 20-40 %), Keratoderma blennorhagicum (small hard nodules on the soles of the feet, and less often on the palms of the hand), Oral ulcers, Cardiac manifestation (including aortic regurgitation and pericarditis occur in 10%. 

Ø  TREATMENT:  The main goal of treatment is to identify and eradicate the underlying infectious source with the appropriate antibiotics if still present. Otherwise, treatment is symptomatic for each problems with analgesics, steroids and immunosuppressants

Ø  PROGNOSIS: Approximately 15 to 50 percent of cases have recurrent bouts of arthritis with repeated attacks. However, most people with reactive arthritis can expect to live normal life spans and maintain a near-normal lifestyle with modest adaptations to protect the involved organs.

Reactive arthritis of the knee

CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=45707

Keratoderma blennorrhagicum due to reactive arthritis

By Photo Credit:Content Providers(s): CDC/ Dr. M. F. ReinTranswiki approved by: w:en:User:Dmcdevit - This media comes from the Centers for Disease Control and Prevention's Public Health Image Library (PHIL), with identification number #6950.Note: Not all PHIL images are public domain; be sure to check copyright status and credit authors and content providers.English | Slovenščina | +/−, Public Domain, https://commons.wikimedia.org/w/index.php?curid=2740350

o   ANKYLOSING SPONDYLITIS (AS; aka Bechterew's disease; Bechterew syndrome; Marie Strümpell disease / Marie Struempell disease / Spondyloarthritis):  A chronic, painful, degenerative inflammatory arthritis primarily affecting spine and sacroiliac joints, causing eventual fusion of the spine results in a complete rigidity of the spine, a condition known as bamboo spine.

Ø  PREVALENCE:  Prevalence: 0.25% of the population.  M > F 3:1. The typical patient is 15-30 y/o.

Ø  PATHOPHYSIOLOGY:  About 90% of the patients express the HLA-B27 genotype. TNF-α and IL-1 are also implicated in ankylosing spondylitis. Although specific autoantibodies cannot be detected, its response to immunosuppresive medication has prompted its classification as an autoimmune disease. 

Ø  PRESENTATION:  Chronic pain and stiffness in the lower spine that is increased with inactivity and resolved with exercise, eye pain and photophobia (iridocyclitis occurs in 40% of cases).  Other possible symptoms:  Cardiac conduction block (3rd degree), Cauda equina syndrome, Apthous ulcer, Aortic regurgitation, Amyloidosis, Pulmonary fibrosis, Paresthesia (from spinal nerve damage), Uveitis. In addition, AS can have some manifestations which make anaesthesia more complex.  Changes in the upper airway can lead to difficulties in intubating the airway, spinal and epidural anaesthesia may be difficult due to calicification of ligaments, and a small number have aortic insufficiency. The stiffness of the thoracic ribs results in ventilation being mainly diaphragm-driven, so there may be a decrease in pulmonary function. 

Ø  DIAGNOSTIC EVALUATION:  There is no direct test to diagnose AS.  H&P: Schober's test is a useful clinical measure of flexion of the lumbar spine.   Elevated CRP & ESR:  During acute inflammatory periods.  HLA-B27 is positive in over 95% of people with AS.  Spinal X-ray:   Characteristic spinal changes syndesmophytes, sacroiliitis, fusion of the spine leadint to bamboo spine.  However, the drawback is that signs and symptoms of AS have usually been established as long as 8-10 years prior to X-ray evident changes.   MRI of the sacroiliac joints:  An option for more accurate and much earlierdiagnosis.

Ø  TREATMENT:  No cure is known for AS, although physical therapy and exercise, along with medication, are available to reduce symptoms and pain.  Physiotherapy and physical exercises: Help diminish pain and stiffness.   Medication:   There are three major types of medications used to treat ankylosing spondylitis 1) Analgesics (NSAIDs to reduce inflammation and pain), 2) DMARDs (cyclosporin, methotrexate, sulfasalazine, and corticosteroids):  Reduce the immune system response through immunosuppression, 3) TNFα blockers ( etanercept, infliximab and adalimumab):  Shown to be the best promising treatment, slowing the progress of AS in the majority of clinical cases.   Surgery (an option in severe cases):  Joint replacements (knees and hips), surgical correction (for severe flexion deformitie of the spine). 

Ø  PROGNOSIS:  AS can range from mild to progressively debilitating, and from medically controlled to refractive.  Unattended cases of AS normally lead to knee pain, and may be accompanied by dactylitis or enthesitis, which may result in a misdiagnosis of normal rheumatism. In a long-term undiagnosed period, osteopenia or osteoporosis of AP spine may occur, causing eventual compression fractures and a back "hump" if untreated.

The ankylosis process

By http://en.wikipedia.org/wiki/User:Senseiwa - http://en.wikipedia.org/wiki/Image:Ankylosing_process.jpg, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=5106210

X-ray showing bamboo spine in a person with ankylosing spondylitis.

By Stevenfruitsmaak - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=6303945

T1-weighted MRI with fat suppression after administration of gadolinium contrast showing sacroiliitis in a patient with ankylosing spondylitis

By Lange123 - selbst erstellt, Public Domain, https://commons.wikimedia.org/w/index.php?curid=18418087

PSORTIATIC ARTHRITIS:  A seronegative spondyloarthropathy that occur more commonly in patients with tissue type HLA-B27.
Ø   EPIDEMIOLOGY:  Affects around 5-7% of people suffering from psoriasis. Tends to appear about 10 years after the first signs of psoriasis  with the majority of people affected between the ages of 30 and 50.  M = F.   

Ø  PRESENTATION:  Joint inflammation, tendinitis, dactilytis (sausage-like swelling of the digits).  More than 80% of patients with psoriatic arthritis will have psoriatic nail lesions characterised by POO → P-pitting of the nails, O-onycholysis, O-oil spots. 

Ø  TREATMENT:  Treatments are directed at reducing and controlling inflammation. Medications: NSAIDs (e.g. diclofenac and naproxen) are usually the first line medication, Corticosteroids joint injectionsm, DMARDs (e.g. methotrexate) are second line treatments, Tumor necrosis factor-alpha inhibitors have (e.g. infliximab, etanercept, and adalimumab) are reserved for the most severe cases.

MRI of the fingers in psoriatic arthritis. Shown are T1-weighted (a) pre-contrast and (b) post-contrast coronal images. Enhancement of the synovial membrane at the third and fourth proximal interphalangeal (PIP) and distal interphalangeal (DIP) joints is seen, indicating active synovitis (inflammation of the synovial membrane; large arrows). There is joint space narrowing with bone proliferation at the third PIP joint and erosions are present at the fourth DIP joint (white circle). Extracapsular enhancement (small arrows) is seen medial to the third and fourth PIP joints, indicating probable enthesitis (inflammation of a tendon insertion).

By Fiona McQueen, Marissa Lassere and Mikkel Østergaard. - Magnetic resonance imaging in psoriatic arthritis: a review of the literature. Arthritis Research & Therapy 2006, 8:207. doi:10.1186/ar1934, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=5885823

(a) T1-weighted and (b) short tau inversion recovery (STIR) magnetic resonance images of lumbar and lower thoracic spine in psoriatic arthritis. Signs of active inflammation are seen at several levels (arrows). In particular, anterior spondylitis is seen at level L1/L2 and an inflammatory Andersson lesion at the upper vertebral endplate of L3.

By Fiona McQueen, Marissa Lassere and Mikkel Østergaard. - Magnetic resonance imaging in psoriatic arthritis: a review of the literature. Arthritis Research & Therapy 2006, 8:207. doi:10.1186/ar1934, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=5885869

Severe psoriatic arthritis of both feet and ankles. Note the changes to the nails.

By James Heilman, MD - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=9445021

o   ENTEROPATHIC ARTHRITIS:  acute or subacute arthritis in association with, or as a reaction to, an enteric (usually colonic) inflammatory condition. 
Ø EPIDEMIOLOGY:  Causes and associations:  Reactive arthritis (reactive to enteric infection e.g. Whipple’s disease), and spondyloarthropathies associated with inflammatory bowel disease (Crohn's disease and ulcerative colitis) and Celiac disease.

Ø PRESENTATION: Malabsorption and arthritis

·       SARCOIDOSIS (aka Besnier-Boeck disease):  A systemic immune system disorder characterised by non-caseating granulomas.   

EPIDEMIOLOGY:  In the US the disease affect more people of African descent than Caucasians.  Incidence:  10-30/100,000.   Sarcoidosis most commonly affects young adults between 20 to 29 y/o.  F > M.  Worldwide, it is most prevalent in Northern European countries with the highest annual incidence of 60/100,000 found in Sweden and Iceland.
PATHOPHYSIOLOGY:  No direct cause of sarcoidosis has been identified, although there have been reports of cell wall deficient bacteria that may be possible pathogens. These bacteria are not identified in standard laboratory analysis.
PRESENTATION:  It is often asymptomatic.  Common symptoms:  Fatigue, weight loss, aches and pains, arthralgia, and GRUELING → G-granuloma (non-caseating type), R-rheumatoid arthritis, R-RF positivity, R-renal (nephrotic syndrome), U-uveitis (dry eyes, blurry vision, photophobia), E-erythema nodosum (skin symptoms vary from rashes and small bumps to erythema nodosum or lupus pernio), L-lymphadenopathy, I-interstitial fibrosis (SOB, dry hacking cough), N-neurosarcoidosis,  N-negative TB test, G-GI (portal HTN), G-gammaglobulinemia.  Renal, liver, heart or brain involvement may cause further symptoms. Sarcoidosis has been associated with celiac disease.
v  G  _______________, ______________, ______________, ______________, _______________

v  R ______________, _______________, _______________, ______________, ______________

v  U  _______________, _______________, ______________, ______________, ______________

v  E  _______________, ______________, ______________, ______________, _______________

v  L  ______________, _____________, _____________, _____________, _____________

v  I  _______________, ______________, ______________, ______________, _______________

v  N  ______________, _______________, _______________, ______________, ______________

v  G  _______________, ______________, ______________, ______________, _______________

      LOFGREN SYNDROME:  Triad of erythema nodosum, bilateral hilar lymphadenopathy and arthralgia. This syndrome has a relatively good prognosis. 

HEERFORDT-WALDENSTROM SYNDROME:  Triad of anterior uveitis, parotitis and fever. 

Ø  DIAGNOSTIC EVALUATION:  CBC: Lymphopenia.  CMP: Hypercalcemia (macrophages inside the granulomas convert vitamin D to its active form; fatigue, lack of strength or energy, irritability, metallic taste, temporary memory loss or cognitive problems).  ACE ↑. Alk phos ↑.  CXR (Stage 1 bihilar lymphadenopathy; Stage 2 bihilar lymphadenopathy and reticulonodular infiltrates; Stage 3 bilateral infiltrates; Stage 4 fibrocystic sarcoidosis typically with upward hilar retraction, cystic & bullous changes.  PFTs:  Restrictive disease of the lungs → ↑ FEV1/FVC ratio to 90%.  Kveim skin test:  Subcutaneous injection of sarcoid tissue →papule at injection site with granuloma after 4-6 weeks.  Tissue biopsy:  Non-caseating granuloma.  EKG. Ophthalmologic exam.  LFTs.   

Ø  TREATMENT:  In many cases the disease remits spontaneously.  Lifestyle changes:  Avoidance of sunlight and Vitamin D foods to prevent hypercalcemia.  Severe symptoms are generally treated with steroids (e.g. prednisone), and steroid-sparing agents such as azathioprine and methotrexate are often used.  Corticosteroids is the standard treatment that can slow or reverse the course of the disease in some patient.  As the granulomas are caused by collections of immune system cells, particularly T cells, there has been some early indications of success using immunosuppressants, interleukin-2 inhibitors or anti-tumor necrosis factor-alpha treatment (such as infliximab).

CT scan of the chest showing lymphadenopathy (arrows) in the mediastinum due to sarcoidosis

By Hellerhoff - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=7567689

Hilar adenopathy especially on the person's left (AP CXR)

By James Heilman, MD - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=49068284

Signs and symptoms of sarcoidosis.

By NHLBI authors.Minor editing by Mikael Häggström (compare with original jpg-version below) - National Heart, Lung, and Blood Institute: DCI Home: Lung Diseases: Sarcoidosis: Signs & Symptoms Retrieved on May 9, 2009., Public Domain, https://commons.wikimedia.org/w/index.php?curid=6738077

Sarcoidosis in a lymph node

By No machine-readable author provided. KGH assumed (based on copyright claims). - No machine-readable source provided. Own work assumed (based on copyright claims)., CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=523877

Asteroid body in sarcoidosis

By Ed Uthman, MD - http://www.flickr.com/photos/euthman/1858194397/, CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=3062809

·      CTD (Connective Tissue Disorders):  M.D.’s = MDS → M-MCTD (mixed connective tissue disorder), D-dermatomyositis/polymyositis, S-SLE (systemic lupus erythematosis), S-SSc (systemic sclerosis), S-sjogren’s syndrome.  These are weakly or non-heritable CTD.  The heritable CTDs include:  Marfan’s syndrome, Osteogenesis imperfecta, Ehler-Danlos.

v M  _______________, ______________, ______________, ______________, _______________

v D  ______________, _______________, _______________, ______________, ______________

v S  _______________, _______________, ______________, ______________, ______________

MCTD (aka Sharp syndrome):  A disorder in which features of various connective-tissue diseases such as mDS → D-dermatomyositis/polymyositis, S-SSc, S-Sjögren syndrome can coexist and overlap. The course of the disease is chronic and usually milder than other CTDs. In most cases, MCTD is considered an intermediate stage of a disease that eventually becomes either SLE or Scleroderma.
Ø  PRESENTATION:  Joint pain/swelling, Raynaud phenomenon, muscle inflammation, and scarring of the skin of the hand.   It does not typically cause kidney disease or seizures. Distinguishing laboratory characteristics are a positive, speckled anti-nuclear antibody and an anti-U1-RNP antibody.

DERMATOMYOSITIS:   A connective-tissue disease that is characterized by inflammation of the muscles and the skin. Its cause is unknown, but it may result from either a viral infection or an autoimmune reaction. Up to 50% of the cases may be a paraneoplastic phenomenon, indicating the presence of cancer. 
Ø  PATHOPHYSIOLOGY:  Dermatomyositis is associated with autoantibodies, especially anti-Jo-1 antibody.   The mechanism is conjectured to be complement-mediated damage of microscopic vessels with muscle atrophy and lymphocytic inflammation secondary to tissue ischemia.  

Ø  PRESENTATION:  Skin rash and muscle pain. Characteristic signs:  Heliotrope rash (a purple/red rash affecting the eyelids, cheeks, forehead and nasolabial folds) and Gottron's papules (purple/red raised plaques over the knuckles and extensor regions). There is a form of this disorder that strikes children, known as juvenile dermatomyositis.  "Gottron's papules", pink patches on the knuckles, and priapism, are associated with this disorder.

Ø  DIAGNOSTIC EVALUATION:  X-ray: Dystrophic calcifications in the muscles.  Muscle biopsy (confirm the diagnosis):  Muscle fascicles with small, shrunken polygonal muscle fibers on the periphery of a fascicle surrounding central muscle fibers of normal, uniform size. Aggregates of mature lymphocytes with small, dark nuclei and scant cytoplasm are seen surrounding vessels. There are two classic microscopic findings of dermatomyositis. They are:  A mixed B- and T-cell perivascular inflammatory infiltrate; Perifascicular muscle fiber atrophy.  Other inflammatory cells are distinctly uncommon. Immunohistochemistry:  Demonstrate that both B- and T-cells are present in approximately equal numbers.

Ø  TREATMENT:  Prednisolone, Intravenous immunoglobulin, Azathioprine, Cyclophosphamide

Gottron's papules. Discrete erythematous papules overlying the metacarpal and interphalangeal joints in a person with juvenile dermatomyositis.

By Elizabeth M. Dugan, Adam M. Huber, Frederick W. Miller, Lisa G. Rider - http://dermatology.cdlib.org/1502/reviews/photoessay/2.jpg, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=9748012

Heliotrope with swelling around the eyes.

By Elizabeth M. Dugan, Adam M. Huber, Frederick W. Miller, Lisa G. Rider - http://dermatology.cdlib.org/1502/reviews/photoessay/16.jpg, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=9749952

Calcification from dermatomyositis.

By James Heilman, MD - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=49086915

Micrograph of dermatomyositis. Muscle biopsy.

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=12532096

POLYMYOSITIS: 
Ø  EPIDEMIOLOGY:  Generally occur during adulthood.  F > M.

Ø  PATHOPHYSIOLOGY:  The cause is unknown, but seems to be related to autoimmune factors, genetics, and perhaps viruses. In rare cases, the cause is known to be infectious, associated with the pathogens that cause Lyme disease, toxoplasmosis, and others. 

Ø  PRESENTATION:  Bilateral progressive proximal muscle weakness, often noted in the upper legs due to early fatigue while walking. Sometimes the weakness presents itself by the person being unable to rise from a seated position without help, or inability to raise their arms above their head. The skin involvement of dermatomyositis is absent in polymyositis.

Ø  DIAGNOSTIC EVALUATION:  H&P.  Creatine kinase ↑.  EMG alteration.  Muscle biopsy:  Lymphocytic inflammation (mainly cytotoxic T8 lymphocytes).

Ø  TREATMENT:  Treatment generally involves glucocorticoids (prednisone), TNF alpha (infliximab).

Micrograph of polymyositis. Muscle biopsy.

By Jensflorian - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=11773843

SLE:  A chronic autoimmune disease that can be fatal.
Ø  EPIDEMIOLOGY:  Prevalence:  1/4000 people in the US have lupus.  F > M X9.  SLE occurs with much greater severity among African-American women.  It is most common in women of childbearing age. There are several types of lupus; generally when the word 'lupus' alone is used, it refers to the systemic lupus erythematosus or SLE. Other types include:  Drug-induced lupus erythematosus (induced by HIP → H-hydralazine, I-INH, P-procainamide), Lupus nephritis, Discoid lupus erythematosus (a skin disorder which causes a red, raised rash on the face, scalp or rest of the body, which occasionally (1-5%) develops into SLE), Subacute cutaneous lupus erythematosus (causes non-scarring skin lesions on patches of skin exposed to sunlight), Neonatal lupus (affecting babies born to women with SLE, Sjögren's syndrome or sometimes no autoimmune disorder. It is theorized that maternal antibodies attack the fetus, causing skin rash, liver problems, low blood counts (which gradually fade) and heart block leading to bradycardia.

Ø  PATHOPHYSIOLOGY:  A type III hypersensitivity response characterized by the body's production of antibodies against the nuclear components of its own cells. There are three mechanisms by which lupus is thought to develop: genetic predisposition, environmental triggers and drug reaction (drug-induced lupus).  One manifestation of lupus is abnormalities in apoptosis and tangible body macrophages (large phagocytic cells in the germinal centers of secondary lymph nodes, which express CD68 and normally engulf B cells which have undergone apoptosis after somatic hypermutation).  In SLE, apoptosis is increased in monocytes and keratinocytes, and there is increased expression of Fas by B cells and T cells.  In some patients with SLE, significantly fewer TBMs can be found, and these cells rarely contain material from apoptotic B cells. Thus, uningested apoptotic nuclei can be found outside of TBMs. This material may present a threat to the tolerization of B cells and T cells. 

Ø  PRESENTATION:  SLE is one of several diseases known as "the great imitators" because its symptoms vary so widely it often mimics or is mistaken for other illnesses, and it follows and exacerbating and remitting course. SLE can affect any part of the body, but most often harms the heart, joints, skin, lungs, blood vessels, liver, kidneys and nervous system.  Common initial and chronic complaints are fever, malaise, joint pains, myalgias and fatigue. Other possible symptoms:  SOAP BRAIN MD → S-serositis (pericarditis, myocarditis, and Libman-Sacks endocarditis), O-oral ulcers, A-arthritis (occur is 90% of patien; typically the small joints of the hand and wrist), P-photosensitivity, P-pulmonary manifestation (lung and pleura inflammation can cause pleuritis, pleural effusion, lupus pneumonitis, chronic diffuse interstitial lung disease, pulmonary hypertension, pulmonary emboli, pulmonary hemorrhage), B-blood changes (anemia and iron deficiency, thrombocytopenia, leucopenia, antiphospholipid antibody syndrome → prolonged PTT, positive test for antiphospholipid antibodies and anticardiolipin antibody, which can cause a false positive test for syphilis), R-renal involvement (hallmark of SLE is membranous glomerulonephritis with "wire loop" abnormalities due to immune complex deposition along the glomerular basement membrane), A-ANA (10), I-immunological changes, N-neurological signs (seizures, frank psychosis), M-malar Rash, D-discoid rash. Other rarer manifestations lupus gastroenteritis, lupus pancreatitis, lupus cystitis, autoimmune inner ear disease, parasympathetic dysfunction, retinal vasculitis, and systemic vasculitis.

v  S  _______________, ______________, ______________, ______________, _______________

v  O  ______________, _______________, _______________, ______________, ______________

v  A  _______________, _______________, ______________, ______________, ______________

v  P  _______________, ______________, ______________, ______________, _______________

v  B  ______________, _______________, _______________, ______________, ______________

v  R _______________, _______________, ______________, ______________, ______________

v  A  _______________, ______________, ______________, ______________, _______________

v  I  ______________, _______________, _______________, ______________, ______________

v  N  _______________, _______________, ______________, ______________, ______________

v  M  _______________, ______________, ______________, ______________, _______________

v  D  ______________, _______________, _______________, ______________, ______________

Common symptoms of SLE.

By Mikael Häggström.When using this image in external works, it may be cited as:Häggström, Mikael (2014). "Medical gallery of Mikael Häggström 2014". WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 2002-4436. Public Domain.orBy Mikael Häggström, used with permission. - All used images are in public domain., Public Domain, https://commons.wikimedia.org/w/index.php?curid=8805434

Ø  DIAGNOSTIC EVALUATION:  Serologic studies:  The ANA is the most sensitive screening test while Anti-Sm (Anti Smith) is the most specific. The ds-DNA (double-stranded DNA) antibody is also fairly specific and often fluctuates with disease activity. The ds-DNA titer is therefore sometimes useful to diagnose or monitor acute flares or response to treatment.   Hypocomplementemia occur during acute attack due to either consumption of C3 and C4 by immune complex-induced inflammation.  Antiphospholipid and anticardiolipin antibodies are also positive, and can predispose for thrombosis. Other tests:  Electrolytes and renal function, liver enzymes and a complete blood count.

Ø  TREATMENT:  There is no known cure, treatment is restricted to dealing with the symptoms.   Drug therapy:   NSIADs (used as initial treatment). Opiates: used for more severe pain.  Steroids (used for acute exacerbation).  DMARDs (used preventively to reduce incidence of flares in progressive or refractory cases).  DMARDs commonly in use are anti-malarials (e.g. hydroxychloroquine) and immunosuppressants (e.g. methotrexate, azathioprine, cyclophosphamide). Hydroxychloroquine  is FDA approved for constitutional, cutaneous, and articular manifestations, while Cyclophosphamide (trade names Cytoxan and Neosar) is used for severe glomerulonephritis or other organ-damaging complications.  In 2005, mycophenolic acid CellCept became accepted for treatment of lupus nephritis.  Lifestyle changes:  Avoiding sunlight (preventing problems due to photosensitivity), weight loss (alleviate some of the effects of the disease, especially where joint involvement is significant).  The warning signs of an impending flare include increased fatigue, pain, rash, fever, abdominal discomfort, headache and dizziness. Early recognition of warning signs and good communication with a doctor can help individuals with lupus remain active, experience less pain and reduce medical visits.  Prevention of complications during pregnancy  While most infants born to mothers with lupus are healthy, pregnant mothers with SLE should remain under a doctor's care until delivery. Neonatal lupus is rare, but identification of mothers at highest risk for complications allows for prompt treatment before or after birth. In addition, SLE can flare during pregnancy and proper treatment can maintain the health of the mother for longer. Women pregnant and known to have the antibodies for anti-Ro (SSA) or anti-La (SSB) should have echocardiograms during the 16th and 30th weeks of pregnancy to monitor the health of the heart and surrounding vasculature.

Young woman with the typical "butterfly rash" found in lupus

By Doktorinternet - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=36008045

Vacuolar interface dermatitis, as may be seen in SLE

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=17076051

Direct immunofluorescence using an anti-IgG antibody. The skin is from a person with SLE and shows IgG deposits at two different places: The first is a bandlike deposit along the epidermal basement membrane ("lupus band test" is positive); the second is within the nuclei of the epidermal cells (antinuclear antibodies are present).E

By Emmanuelm at en.wikipedia, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=13377673

SYSTEMIC SCLEROSIS (aka scleroderma):   A chronic disease characterized by excessive deposits of collagen in the skin or other organs.
Ø  EPIDEMIOLOGY:  Prevalence: 300,000 people in the United States. Incidence:  2-20 per million per year in the United States.   F > M X4.

Ø  PATHOPHYSIOLOGY:  There is no clear obvious cause for scleroderma and systemic sclerosis. The overproduction of collagen is thought to result from an autoimmune dysfunction, in which the immune system would start to attack the kinetochore of the chromosomes, which lead to genetic malfunction of nearby genes. T cells accumulate in the skin and secrete cytokines and other proteins that stimulate collagen deposition. TGFβ appears to be overproduced, which stimulate excessive collagen deposit by fibroblasts. An intracellular pathway (consisting of SMAD2/SMAD3, SMAD4 and the inhibitor SMAD7) is responsible for the secondary messenger system that induces transcription of the proteins and enzymes responsible for collagen deposition. Sp1 is a transcription factor most closely studied in this context. Damage to endothelium is an early abnormality in the development of scleroderma, and this too seems to be due to collagen accumulation by fibroblasts. There are three major forms of scleroderma: diffuse, limited (CREST syndrome) and morphea/linear. Diffuse and limited scleroderma are both a systemic disease, whereas the linear/morphea form is localized to the skin. 

1.     Diffuse scleroderma (progressive systemic sclerosis):  Most severe form - it has a rapid onset, involves more widespread skin hardening, will generally cause much internal organ damage (specifically the lungs and gastrointestinal tract), and is generally more life threatening.  The presence of anti-Scl70 (anti-topoisomerase 1) is specific for this condition.

2.     Limited scleroderma/CREST syndrome:  Slow onset and progression, skin hardening is usually confined to the hands and face, internal organ involvement is less severe, and a much better prognosis is expected.  In typical cases of limited scleroderma, Raynaud's phenomenon may precede scleroderma by several years. Raynaud's phenomenon is due to vasoconstriction of the small arteries of exposed peripheries - particularly the hands and feet - in the cold. It is classically characterised by a triphasic colour change - first white, then blue and finally red on rewarming.   The presence of anti-centromeres antibodies is specific for this condition.

3.     Morphea/linear scleroderma:  Involves isolated patches of hardened skin - there generally is no internal organ involvement. The localized type of the disease, while disabling, tends not to be fatal.

Ø  PRESENTATION:  Skin symptoms:  Hardening of the skin and associated scarring. Typically, the skin appears reddish or scaly. Blood vessels may also be more visible. Where large areas are affected, fat and muscle wastage will weaken limbs and affect appearance.  Patients with larger amounts of cutaneous involvement are more likely to have involvement of the internal tissues and organs.  CREST syndrome involves C-calcinosis, R-raynaud’s phenomenon, E-esophageal dysmotility, S-sclerodactyly, T-telangiectasia.  The more severe diffuse scleroderma can cause musculoskeletal, pulmonary, gastrointestinal, renal and other complications.  Musculoskeletal:  From initial non-specific joint pains to arthritis, and muscle weakness.  Lungs:  Some impairment on pulmonary function testing is almost universally seen in patients with diffuse scleroderma. Some patients can develop pulmonary hypertension, which can lead to cor pulmonale, and pulmonary fibrosis.  GI tract:  Reflux esophagitis (may lead to peptic stricturing, esophageal dysmotility (may lead to dysphagia and chest pain), small intestine bacterial overgrowth and malabsorption (bile salts, fats, carbohydrates, proteins, and vitamins), colonic pseudo-obstruction or ischemic colitis.  Patients with severe gastrointestinal involvement can become profoundly malnourished.  Scleroderma may also be associated with gastric antral vascular ectasia (GAVE), also known as watermelon stomach. This is a condition where atypical blood vessels proliferate usually in a radially symmetric pattern around the pylorus of the stomach. GAVE can be a cause of upper gastrointestinal bleeding or iron deficiency anemia in patients with scleroderma. Renal:   The most important clinical complication of scleroderma involving the kidney is scleroderma renal crisis. Symptoms of scleroderma renal crisis are malignant hypertension, hyperreninemia, azotemia, and microangiopathic hemolytic anemia.  Approximately 10% of all scleroderma patients develop renal crisis at some point in the course of their disease.  Treatments for scleroderma renal crisis include ACE inhibitors, which are also used for prophylaxis, and renal transplantation.

Acrosclerotic piece-meal necrosis of the thumb in a patient with systemic sclerosis.

By Frank Breuckmann, Thilo Gambichler, Peter Altmeyer and Alexander Kreuter - UVA/UVA1 phototherapy and PUVA photochemotherapy in connective tissue diseases and related disorders: a research based review, BMC Dermatology 2004, 4:11. doi:10.1186/1471-5945-4-11, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=4345803

Endoscopic image of peptic stricture, or narrowing of the esophagus near the junction with the stomach due to chronic gastroesophageal reflux. This is the most common cause of dysphagia, or difficulty swallowing, in scleroderma..

By Samir धर्म - From en.wikipedia.org, Public Domain, https://commons.wikimedia.org/w/index.php?curid=1931423

Ø  DIAGNOSTIC EVALUATION:  Diagnosis is by clinical suspicion, presence of autoantibodies (specifically anti-centromere and anti-scl70/anti-topoisomerase antibodies) and occasionally by biopsy. Of the antibodies, 90% have a detectable anti-nuclear antibody. Anti-centromere antibody is more common in the limited form (80-90%) than in the systemic form (10%), and anti-scl70 is more common in the diffuse form (30-40%) and in African-American patients (who are more susceptible to the systemic form).

Thrombotic microangiopathy, the histomorphologic finding seen in scleroderma renal crisis. Kidney biopsy. PAS stain..

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=17293564

Ø  TREATMENT:  There is no cure for every patient with scleroderma, though there is treatment for some of the symptoms. Acute exacerbation:  Treated with systemic glucocorticoids.  NSAIDs:  Used to ease symptoms. PPI:  Help with esophageal dysmotility.  Prostacylins (a vasodilator):  Used for pulmonary hypertension and digital ulceration.  Immunosuppressant drugs, such as mycophenolate mofetil (Cellcept), cyclophosphamide or methotrexate are sometimes used to slow the progress.  Hematopoietic stem cell transplantation is being studied in patients with severe systemic sclerosis; improvement in life expectancy and severity of skin changes has been noted.

SJOGREN’S SYNDROME:  An autoimmune disorder in which immune cells attack and destroy the exocrine glands that produce tears and saliva. The hallmark symptoms of the disorder are dry mouth and dry eyes (part of what are known as sicca symptoms).
Ø  EPIDEMIOLOGY:  Prevalence: 1-4 million people in the US. Most people are > 40 y/o at the time of diagnosis. F > M 9X. 

Ø  PRESENTATION:  The hallmark symptoms is the triad of xerostomia X 3 months, xeropthalmia X 3 months, and an Autoimmune or Connective tissue disorder (the most common associated condition is rheumatoid arthritis). The above symptoms lead to blurred vision, constant eye discomfort, recurrent mouth infections, swollen parotid glands, hoarseness, and difficulty in swallowing and eating, and debilitating fatigue and joint pain. In addition, Sjögren's syndrome may cause skin, nose, and vaginal dryness, and may affect other organs of the body, including the kidneys (autoimmune tubulointerstitial nephritis), blood vessels, lungs, liver, pancreas, and brain.  Sicca syndrome:  The combination of xerostommia and xeropthalmia without an associated autoimmune/connective tissue disorder.

Ø  DIAGNOSTIC EVALUATION:  Serologic test:  Rheumatoid factor (because SS frequently occurs secondary to rheumatoid arthritis).  ANA patterns: SSA (anti-Ro) and SSB (anti-La).  SSA is more sensitive but SSB is more specific.  Schirmer test:  A test to measures the production of tears in which strip of filter paper is held inside the lower eyelid for five minutes, and its wetness is then measured with a ruler.  Slit-lamp exam:  To look for dryness on the surface of the eye. Salivary gland function can be tested by collecting saliva and determining the amount produced. Lip biopsy:  Reveal lymphocytes clustered around salivary glands, and damage to these glands due to inflammation (sialoadenitis).  Radiological procedure:  A contrast is injected into Stensen's Duct (i.e., parotid duct). Widespread puddling of the injected contrast scattered throughout the gland indicates Sjögren's syndrome. 

Ø  TREATMENT:  Generally symptomatic and supportive. Artificial tears may ease the symptoms of dry eyes. Cyclosporin (Restasis):  Treat chronic dry eye by suppressing the inflammation that disrupts tear secretion. Cevimeline and pilocarpine:  Stimulate salivary flow. NSIADs:  Treat musculoskeletal symptoms. Corticosteroids, immunosuppressive drugs, and DMARDs:  For individuals with severe complications. 

Lymphoid infiltration in the minor salivary gland associated with Sjögren syndrome. Lip biopsy. H & E stain.

By No machine-readable author provided. KGH assumed (based on copyright claims). - No machine-readable source provided. Own work assumed (based on copyright claims)., CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=513949

Speckled Immunofluorescence staining pattern of antinuclear antibodies on HEp-20-10 cells

By Simon Caulton - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=20591742

·      LOW BACK PAIN:  A common musculoskeletal disorder which affects the lumbar segment of the spine. It can be either acute, subacute or chronic in its clinical presentation.

o   EPIDEMIOLOGY:  Back pain affects most adults at some stage in their life and accounts for more sick leave and disability than any other single medical condition.  It is the #2 reason for visiting a doctor after URI.

o   PATHOPHYSIOLOGY:  An acute lower back injury may be caused by a traumatic event (e.g. car accident, fall).  It occurs suddenly and its victims will usually be able to pinpoint exactly when it happened. In acute cases, the structures damaged will more than likely be soft tissue like muscles, ligaments and tendons. With a serious accident or due to osteoporosis or other causes of weakened vertebral bones, vertebral fractures in the lumbar spine may also occur. Chronic lower back pain usually has a more insidious onset, occurring over a long period of time. Physical causes may include osteoarthritis, rheumatoid arthritis, degeneration of the discs between the vertebrae, or a spinal disc herniation, a vertebral fracture (such as from osteoporosis), or rarely, a tumor (including cancer) or infection. The cause may also be psychological or emotional or due to other non-anatomical factors.  Possible causes of low back pain: 

1.     Mechanical (97% of cases):  Non-specific muscular or ligamentous strains or sprains (70% of causes),  Degenerative Discs, Spinal disc herniation, Spinal stenosis (causes pseudoclaudication), Spondylolisthesis, fractures, Metabolic (Osteoporotic fractures, Osteomalacia, Ochronosis, Chondrocalcinosis)

2.     Non-mechanical causes:  Inflammatory (Seronegative spondylarthritides, Rheumatoid arthritis), Infection (epidural abscess or osteomyelitis), Neoplastic (Bone tumors, Intradural Spinal tumors), Paget's disease

3.     Visceral referred pain: Pelvic/abdominal disease, Prostate Cancer, Pyelonephritis

4.     Psychosomatic:  Depression, Tension myositis syndrome

The structures surrounding and supporting the vertebrae can be sources of low back pain.

By Anuskafm, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=3676929

The five lumbar vertebrae define the lower back region.

By . - http://training.seer.cancer.gov/module_anatomy/unit3_5_skeleton_divisions.html, Public Domain, https://commons.wikimedia.org/w/index.php?curid=1394201

o   PRESENTATION:  LBP, neurological sign (numbness, weakness, urinary &/or fecal incontinence).  Typically, the symptoms of low back pain do show significant improvement within two to three months from its onset. In a significant number of individuals, low back pain tends to be recurrent in nature with a waxing and waning quality to it. In a small proportion of sufferers this condition can become chronic.

o   DIAGNOSTIC EVALUATION:  H&P.  ROM. Gait. Straight leg raise.  MRI scan or x-ray.

o   TREATMENT:  Dictated by the clinical diagnosis of the underlying cause of the pain.  Conservative treatment (can successfully treat 80-90% of LBP cases):  Advice to stay active.  Analgesics (e.g. NSAIDs or acetaminophen. Muscle relaxants. Massage therapy.  Ice and/or heat application (or moist heat) Physical therapy and/or a regular exercise program that includes stretching, strengthening and low impact cardio conditioning will be part of the treatment and rehabilitation program.  Surgery (Indicated when conservative treatment is not effective or when the patient develops progressive and functionally limiting neurologic symptoms such as leg weakness, bladder or bowel incontinence):  Severe lumbar disc herniation, spinal abscess or cauda equina syndrome. Other possible indications for surgery include:  Severe Degenerative disc disease, Spinal stenosis, Spondylolisthesis, Scoliosis, Compression fracture, Spinal instability, Spinal trauma, Spinal malignancy(cancer), Spinal hematoma.  The most common types of low back surgery include microdiscectomy, discectomy, laminectomy, foraminotomy, or spinal fusion. Another less invasive surgical technique consists of an implantation of a spinal cord stimulator and typically is used for symptoms of chronic radiculopathy (sciatica). Lumbar artificial disc replacement is a newer surgical technique for treatment of degenerative disc disease, as are a variety of surgical procedures aimed at preserving motion in the psine.

Straight leg test that is sometimes used to help diagnose a herniated lumbar disc. With the patient lying down on his or her back on an examination table or exam floor, the examiner lifts the patient's leg while the knee is straight. If the patient experiences sciatic pain when the straight leg is at an angle of between 30 and 70 degrees, then the test is positive and a herniated disc a possible cause of the pain.[3] A negative test suggests a likely different cause for back pain. 

By Davidjr74 - http://www.herniateddiscrecovery.info/diagnosing-a-herniated-disc/lumbar-disc-herniation/, CC0, https://commons.wikimedia.org/w/index.php?curid=15289227

A herniated disc as seen on MRI, one possible cause of low back pain. 

By Mjorter at Dutch Wikipedia - Transferred from nl.wikipedia to Commons., Public Domain, https://commons.wikimedia.org/w/index.php?curid=1851539

·      ACUTE MONOARTICULAR ARTHRITIS:  Differental diagnosis TRIC → T-trauma, R-rheumatologic diseases, I-infection, C-crystalline diseases.

T  _______________, ______________, ______________, ______________, _______________
R  ______________, _______________, _______________, ______________, ______________
I  _______________, _______________, ______________, ______________, ______________
C  ______________, _______________, _______________, ______________, ______________

o INFECTION: Gonococci. SEE Osteomyelitis.

o CRYSTALLINE DISEASE: Gout and Pseudogout

Ø  GOUT (also called metabolic arthritis):   A form of arthritis that created by a buildup of uric acid.

v  EPIDEMIOLOGY:  Affects mostly men between 40-50 y/o.  Racial preference:  Gout is high among the peoples of the Pacific Islands, and the Māori of New Zealand.  In the US African American > Caucasians 2X.  Seasonal link:  significantly higher incidence of acute gout attacks in the spring. Typically, persons with gout are obese, predisposed to diabetes and hypertension, and at higher risk of heart disease. 

v  PATHOPHYSIOLOGY:  Purines can be generated by the body via breakdown of cells in normal cellular turnover, or can be ingested in purine-rich foods such as seafood. Purine metabolism gives rise to uric acid, which is normally excreted in the urine. The kidneys are responsible for approximately one-third of uric acid excretion, with the gut responsible for the rest.  The high levels of uric acid in the blood are caused by protein rich foods and alcohol intake. Gout also can develop as co-morbidity of other diseases, including polycythaemia, leukaemia, intake of cytotoxics, obesity, diabetes, hypertension, renal disorders, and hemolytic anemia. Diuretics (particularly thiazide diuretics) have traditionally been blamed for precipitating attacks of gout.  Gout occurs when mono-sodium urate crystals form on the articular cartilage of joints, on tendons, and in the surrounding tissues.

v  PRESENTATION:  Classic picture:  Excruciating, sudden, unexpected, burning pain, swelling, redness, warmness and stiffness in the joint. Low-grade fever may also be present.  Gout usually (75% of first attacks) attacks the big toe (podagra); however, it also can affect other joints such as the ankle, heel, instep, knee, wrist, elbow, fingers, and spine. Patients with longstanding hyperuricemia can have uric acid crystal deposits called tophi in other tissues such as the helix of the ear. Uric acid stones can form as one kind of kidney stone in some cases.

Gout complicated by ruptured tophi (exudate tested positive for uric acid crystals)

By James Heilman, MD - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=14138906

Nodules of the finger and helix of the ear representing gouty tophi

By Herbert L. Fred, MD and Hendrik A. van Dijk - http://cnx.org/content/m14895/latest/, Attribution, https://commons.wikimedia.org/w/index.php?curid=11116034

v  DIAGNOSTIC EVALUATION:  CBC, electrolytes, ESR, and renal function. Hyperuricemia (plasma uric acid > 7.0 mg/dL):  Occur in many cases, but uric acid is within the normal range in up to two-thirds of cases.  If gout is suspected, the serum urate test should be repeated once the attack has subsided.  Joint X-ray:  Characteristic punched-out erosions with overhanging cortical bone are seen in advanced gout.  Joint fluid aspiration (the definitive diagnosis):   Demonstrate intracellular monosodium urate crystals in synovial fluid polymorphonuclear leukocytes.  The urate crystal is identified by strong negative bi-refringence under polarised microscopy and its needle-like morphology.

v  TREATMENT:  Acute attacks:  The first line of treatment should be pain relief. NSAIDs (e.g. indomethacin 50 mg PO), oral or intra-articular glucocorticoids, colchicine (impairs the motility of granulocytes preventing the inflammatory phenomena that initiate an attack; it should be taken within the first 12 hours of the attack and usually relieves the pain within 48 hours).  Another possibility is use of acetazolamide, which inhibits the action of carbonic anhydrase on the proximal convoluted tubules within the kidneys, which effectively inhibits reabsorption of bicarbonate, thus alkalinizing the urine. Preparation H hemorrhoidal ointment can be applied to the swollen skin to reduce the swelling temporarily.  Ice may be applied for 20–30 minutes several times a day.  Keeping the affected area elevated above the level of the heart also may help.  Prevention:  Allopurinol (an inhibitor of xanthine oxidase) is used for overproducers of uric acid.   Probenecid:  Promotes the excretion of uric acid in urine and if often used in conjunction with colchicine. The drug fenofibrate, which is used in treating hyperlipidemia, also exerts a beneficial uricosuric effect.  As arterial hypertension quite often coexists with gout, treating it with losartan, an angiotensin II receptor antagonist, might have an additional beneficial effect on uric acid plasma levels. This way losartan can offset the negative side-effect of thiazides. It is suspected that in many cases gout may be secondary to untreated sleep apnea, when oxygen-starved cells break down and release purines as a by-product. Treatment for apnea can be effective in lessening incidence of acute gout attacks. Ethylenediaminetetraacetic acid, a chelator of lead, has successfully increased uric acid excretion. This should be an advantageous treatment for those people whose gout was caused by lead poisoning. Care should be taken to increase intake of trace essential elements since chelation often remove these elements also. Gout can be triggered by the same agents that cause potassium losses such as fasting, surgery, and potassium losing diuretics. A potassium deficiency can increase urate levels in the blood. So potassium supplements should be advantageous to treat gout. Diet:  Reduce intake of purines (beef, seafood, beer, asparagus), Ingestion of 500 mg of Vitamin C per day has been shown to bring about a 0.5 mg/dl decrease in serum uric acid through increased excretion.  Other approaches: Drink plenty of liquids, especially water, to dilute and assist excretion of urates; Avoid diuretic foods or medicines like aspirin (aspirin should be avoided by those suffering from gout, unless specified by a qualified physician).  For extreme cases of gout, surgery may be necessary to remove large tophi and correct joint deformity. 

Spiked rods of uric acid crystals from a synovial fluid sample photographed under a microscope with polarized light. Formation of uric acid crystals in the joints is associated with gout.

By Bobjgalindo - Own work, GFDL, https://commons.wikimedia.org/w/index.php?curid=5653456

Gout on X-rays of a left foot. The typical location is the big toe joint. Note also the soft tissue swelling at the lateral border of the foot.

By Hellerhoff - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=12077637

Ø  PSEUDOGOUT (aka calcium pyrophosphate deposition disease):  A polyarticular arthritis, although it can initially present as monoarticular.   

v  PATHOPHYSIOLOGY:  Manifestations are due to precipitation of calcium pyrophosphate dihydrate crystals in the connective tissues.  Crystal-induced synovitis is the result of shedding of crystals in the joint space after rupture of a CPPD deposit. Associated conditions:  Hyperparathyroidism, hemochromatosis, hypophosphatemia, hypomagnesemia (pyrophosphate complexes with magnesium prior to its degradation), renal osteodystrophy

v  PRESENTATION:  Acute synovitis (red, tender, and swollen joints), and chondrocalcinosis (radiographic evidence of calcification in hyaline and/or fibrocartilage). CPPD crystals tend to form within articular tissues. Common locations of chondrocalcinosis include the knees, wrists, elbows, and hips.

v DIAGNOSTIC EVALUATION:  H&P.  CBC.  CMP. Joint X-ray:  Signs of chondrocalcinosis (crystal deposition within cartilage).  Joint fluid aspirate:  Rhomboidal crystals seen under the microscope, which exhibit weakly positive birefringence under polarized light

v  TREATMENT: Mostly aimed at preventing further crystal formation and reducing symptoms from crystal deposition. CPPD crystal deposition cannot be reversed. If CPPD results from underlying metabolic abnormalities (hyperparathyroidism, hemochromatosis, hypophosphatasia, or hypomagnesemia), these can be treated directly.  For symptomatic joints, treatment is similar to treatment of gout.  Single joint involved:   Joint aspiration and intra-articular corticosteroid injection, NSAIDs, and colchicine. Multiple joints involved:  Oral systemic treatment is chosen instead because joint injection is often impractical. 

CPPD crystal deposition in an intervertebral disc

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=17159746

Rhombus-shaped calcium pyrophosphate crystal seen in a knee arthrocentesis specimen.

By David Iberri - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=24763637

·      AMYLOIDOSIS: Conditions in which amyloid proteins are abnormally deposited in organs and/or tissues.

PATHOPHYSIOLOGY:  A protein is amyloid if, due to an alteration in its secondary structure, it takes on a particular insoluble form, called the beta-pleated sheet.  Amorphous, eosinophilic, fibrous amyoid protein are deposited extracellularly. 
CLASSIFICATION:  Amyloidoses can be 1) Systemic (affecting many different organ systems) or Organ-specific.
Ø   Systemic amyloidosis is further classified into

1.     Primary/Hereditary amyloidosis:  Hereditary disorders are usually due to point mutations in precursor proteins, and are also usually autosomal dominantly transmitted.  Some examples of precursor proteins are FLAT → F-fibrinogen, L-lysozyme, A-apolipoprotein A1, T-transthyretin (the most commonly implicated protein)

v F  _______________, ______________, ______________, ______________, _______________

v L  ______________, _______________, _______________, ______________, ______________

v A  _______________, _______________, ______________, ______________, ______________

v T  ______________, _______________, _______________, ______________, ______________

2.     Secondary amyloidosis:  These are far more common than the primary amyloidoses. It is due to different diseases causing overabundant or abnormal protein production Some expample of precursor proteins are T-the LAB = TLAB →T-transthyretin (a protein that transport THYroxine and RETINol; it is associated with familial amyloid polyneuropathy, and senile amyloidosis in the heart), L-light chain amyloid (AL amyloidosis; immunoglobulin light chains precursor protein are overproduced in multiple myeloma), A-amyloid associated (AA amyloidosis; a secondary amyloidosis from chronic tissue destruction leading to increase hepatic synthesis of serum amyloid A protein (SAA), an acute-phase protein; it occur with a wide variety of diseases associated with chronic inflammation, such as Rheumatoid arthritis, Familial Mediterranean fever or chronic infection), B-beta2-microglobulin-MHC I (dialysis related amyloidosis; the beta-2-microglobulin precursor protein is removed with dialysis, and thus accumulates in patients with ESRD on dialysis).

v T  _______________, ______________, ______________, ______________, _______________

v L  ______________, _______________, _______________, ______________, ______________

v A  _______________, _______________, ______________, ______________, ______________

v B  ______________, _______________, _______________, ______________, ______________

Ø  Organ-specific amyloidosis  is further classified into:

1.     Neurological amyloid:  Alzheimer's disease (Aβ 39-43). Parkinson's disease (alpha-synuclein). Huntington's disease (huntingtin). Transmissible spongiform encephalopathies (PrP): These diseases include;  Creutzfeldt-Jakob disease (PrP in cerebrum) Kuru (diffuse PrP deposits in brain) Fatal Familial Insomnia (PrP in thalamus) Bovine spongiform encephalopathy (PrP in cerebrum of cows)

2.     Cardiovascular amyloid:  Cardiac amyloidosis, 

3.     Pancreatic amyloid:  Amylin deposition can occur in the pancreas in some cases of type 2 diabetes mellitus

o   PRESENTATION:  Constitutional symptoms: Fatigue and weight loss (15-20 lbs).  Specific symptoms (depend on organ of amyloid deposition):  Cardiac (orthostatic hypotension and bradycardia from restricted cardiomyopathy, conduction abnormalities), GI (macroglossia, motility disorder, malabsorption), Hematologic (easy bruising and periorbital ecchymoses from acquired factors deficiency), Hepatic (intrahepatic cholestasis, hepatomegaly), Neurologic (polyneuropathy, autonomic dysfunction, carpal tunnel syndrome), Renal (nephrotic syndrome, RTA), Rheumatologic (symmetric arthritis, deposit in skin as raised waxy papule).

Skin features of amyloidosis cutis dyschromica. Hyperpigmented and hypopigmented macules on (A) lower legs, (B) back and waist, (C) waist. (D) Individual blisters on upper arm

By Wenlin Yang, Yangyang Lin, Jian Yang, Wensheng Lin - https://www.scienceopen.com/document_file/52597476-7704-4d33-8e1a-f000a58ebdb0/PubMedCentral/52597476-7704-4d33-8e1a-f000a58ebdb0.pdf, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=36909294

Classic facial features of AL amyloidosis with purpura around the eyes

By Professor P N Hawkins - http://www.wikilite.com/wiki/index.php/AL_Amyloidosis, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=38177055

o DIAGNOSTIC EVALUATION: EKG (AV block, low-voltage QRS). Echo (thicken ventricular wall, sparkling of myocardium). UA (proteinuria). Immunoelectrophoresis (monoclonal spike in primary amyloidosis and multiple myeloma). Lab: Alk phos ↑ due to cholestasis; albumin ↓ due to malabsorption and nephrotic syndrome); PT ↑ due to acquired factor X deficiency. Biopsy with Congo red staining (required for diagnosis): Done on affected organ or often in the case of systemic amyloid, from the rectum or anterior abdominal adipose tissue. Amyloid deposits produce a distinctive 'apple green birefringence' when viewed under polarized light where. In addition, all amyloid deposits contain serum amyloid P component (SAP), a circulating protein of the pentraxin family.

o TREATMENT: Suportive for most cases. Diuretics (for CHF and edema); dialysis (for ESRD). Treat underlying cause (e.g. multiple myeloma is treated with prednisone and melphalan).

Amyloidosis, blood vessels

By Ed Uthman, MD - http://www.flickr.com/photos/euthman/377490432/, CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=1629771

Amyloidosis, dystrophic calcification

By Ed Uthman, MD - http://www.flickr.com/photos/euthman/377490313/, CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=1629784

Amyloidosis, lymph node, polarizer apple-green birefringence

By Ed Uthman, MD - http://www.flickr.com/photos/euthman/377559955/, CC BY-SA 2.0, https://commons.wikimedia.org/w/index.php?curid=1629705

Amyloid deposition (red fluffy material) in the heart (cardiac amyloidosis). Congo red stain.

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=8674729

·      VASCULITIS:  A group of diseases featuring inflammation of the wall of blood vessels including veins (phlebitis), arteries (arteritis) and capillaries due to leukocyte migration and resultant damage. They generally affect several organ systems and can cause severe disability.

TYPES:  P-peter H-hates T-touching B-boobs and K-kissing W-wet C-cunt = PHTBKWC → P-PAN (polyarteritis nodosa), H-HSP (henoch-scholein purpura), H-hypersensitivity vasculitis (leukocytoclastic vasculitis), T-temporal arteritis, B-buerger’s disease, B-behcet’s, K-kawasaki’s disease, W-wegener’s granulomatosis, C-churg-strauss arteritis
P  _______________, ______________, ______________, ______________, _______________
H  ______________, _______________, _______________, ______________, ______________
T  _______________, _______________, ______________, ______________, ______________
B  ______________, _______________, _______________, ______________, ______________
K  _______________, ______________, ______________, ______________, _______________
W  ______________, _______________, _______________, ______________, ______________
C  _______________, _______________, ______________, ______________, ______________

o PRESENTATION: Patients usually present with systemic symptoms with single or multiorgan dysfunction. Common (and nonspecific) complaints include fatigue, weakness, fever, arthralgias, abdominal pain, hypertension, renal insufficiency, and neurologic dysfunction. The following symptoms should raise a strong suspicion of a vasculitis: Mononeuritis multiplex (aka asymmetric polyneuropathy; highly suggestive of vasculitis, since diabetes is the only other cause of this), Palpable purpura (if purpura is in isolation is most likely due to cutaneous leukocytoclastic vasculitis; if in combination with systemic organ involvement, it is most likely to be Henoch-Schonlein purpura or microscopic polyarteritis), and pulmonary-renal syndrome (combination of hemoptysis and renal involvement is most likely WG or GP.

Petechia and purpura on the lower limb due to medication-induced vasculitis.

By James Heilman, MD - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=11857197

o DIAGNOSTIC EVALUATION: H&P: Recent medications, any risk of hepatitis infection, or any recent diagnosis with a connective tissue disorder such as SLE. Lab tests: CBC, CMP, muscle enzyme, LFT, ESR, hepatitis seroloties, urinalysis, CXR, EKG, ANA (can detect an underlying connective tissue disorder, especially SLE), Complement (low level can suggest mixed cryoglobulinemia, hepatitis C infection, and SLE), ANCA ( suggest Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome, or drug-induced vasculitis). Electromyography (if neuromuscular symptoms are present). Arteriography (helpful in vasculitis affecting the large and medium vessels; angiograms of mesenteric or renal arteries in polyarteritis nodosa may show aneurysms, occlusions, and vascular wall abnormalities). Tissue biopsy (gold standard).

Severe vasculitis of the major vessels, displayed on FDG-PET/CT

By Hg6996 - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=18889860

Micrograph showing a vasculitis (Eosinophilic granulomatosis with polyangiitis). H&E stain.

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=15244869

o TREATMENT: Targeted to the underlying cause. However, most vasculitis in general are treated with steroids (e.g. methylprednisolone) because the underlying cause of the vasculitis is due to hyperactive immunological damage. Immunosuppressants such as cyclophosphamide and azathioprine may also be given.

PAN (polyarteritis nodosa; aka Kussmaul disease or Kussmaul-Meier disease):  A vasculitis of medium-sized arteries, which become swollen and damaged from attack by rogue immune cells.
Ø  EPIDEMIOLOGY:  Affects adults more frequently than children, and is more common in people with hepatitis B infection.

Ø  PATHOPHYSIOLOGY:  Immune cells attack the affected arteries caused by antibodies against HBV, via a type III hypersensitivity reaction. It damages the tissues supplied by the affected arteries because they don't receive enough oxygen and nourishment without a proper blood supply.

Ø  PRESENTATION:  Generalised symptoms:  Fever, fatigue, weakness, loss of appetite, and weight loss. Specific symptoms (result from damage to affected organs):  Musculoskeletal (muscle and joint aches).  Dermatologic (rashes, swelling, ulcers, and lumps).  Nervous system (numbness, pain, burning, weakness to strokes or seizures). Kidney (#1 cause of death; renal lesion and HTN).  Cardiac (heart attack, heart failure, and pericarditis).  GI (N/V, Abdominal pain, intestinal necrosis/perforation). 

Ø  DIAGNOSTIC EVALUATION:  H&P. CBC (elevated white blood count). ESR/CRP (elevated). p-ANCA (not associated with "classic" polyarteritis nodosa, but is present in a form of the disease affecting smaller blood vessels, known as microscopic polyangiitis or leukocytoclastic angiitis). Tissue biopsy (reveals inflammation).  Criteria for diagnosis of polyarteritis nodosa (meet ≥ 3 of the 10 following signs):    1. Weight loss:  ≥ 4 kg.    2. Livedo reticularis:  Mottled purplish skin discoloration over the extremities or torso.    3. Testicular pain or tenderness:  occasionally, a site biopsied for diagnosis).    4. Muscle pain, weakness, or leg tenderness.    5. Nerve disease (mono or polyneuropathy).    6. Diastolic blood pressure > 90mmHg.    7. Elevated kidney blood tests:  BUN > 40 mg/dl or creatinine > 1.5 mg/dl.    8. Hepatitis B virus tests positive 9. Arteriogram:  Showing aneurysm or constricted by the blood vessel inflammation.   10. Biopsy of tissue:  Show arteritis. 

Polyarteritis nodosa: Macroscopic specimen of the heart with abundant adipose tissue and nodular thickened coronary vessels

By A. Kussmaul († 1902), R. Maier († 1888); uploader: Eberhard J. Wormer - A. Kussmaul, R. Maier: Über eine bisher nicht beschriebene eigenthümliche Arterienerkrankung (Periarteriitis nodosa), die mit Morbus Brightii und rapid fortschreitender allgemeiner Muskellähmung einhergeht. Dtsch Arch Klin Med 1 (1866) 484, Public Domain, https://commons.wikimedia.org/w/index.php?curid=7556259

Microscopic findings in polyarteritis nodosa: nodular thickened and branched arteries from small bowel mucosa (Fig. 1), flexor digitorum superficialis artery with early diffuse nuclear proliferation (X155; Fig. 2), nodular thickened and aneurysmal expanded artery: (a) tunica intima, (b) tunica media, (c) tunica adventitia, (d) newly formed connective tissue and fat (Fig. 3; X155)

By A. Kussmaul († 1902), R. Maier († 1888); uploader: Eberhard J. Wormer - A. Kussmaul, R. Maier: Über eine bisher nicht beschriebene eigenthümliche Arterienerkrankung (Periarteriitis nodosa), die mit Morbus Brightii und rapid fortschreitender allgemeiner Muskellähmung einhergeht. Dtsch Arch Klin Med 1 (1866) 484, Public Domain, https://commons.wikimedia.org/w/index.php?curid=7556266

Ø  TREATMENT:  Immunosuppressant: Including prednisone and cyclophosphamide. Therapy results in remissions or cures in 90% of cases. Untreated, the disease is fatal in most cases. The most serious associated conditions generally involve the kidneys and gastrointestinal tract. Complications: Stroke Kidney failure Heart attack Intestinal necrosis and perforation. 

Ø  SUMMARY OF PAN: PAN → P-P-ANCA (antibodies to neutrophil MPO) positive, P-purpura, P-pericarditis, A-abdominal pain, A-arthralgia, A-arthritis, A-aneurysmal nodule, N-neurodysfunction.

Ø  P  _______________, ______________, ______________, ______________, _______________

Ø  A______________, _______________, _______________, ______________, ______________

Ø  N  _______________, _______________, ______________, ______________, ______________

o   HSP (henoch-schonlein purpura):  A systemic vasculitis characterized by deposition of immune complexes containing the antibody IgA, especially in the skin and kidney.

Ø  EPIDEMIOLOGY:  The most common vasculitis in childhood. Incidence: 20/100,000 children per year.  Half of affected patients are < 6 y/o, and 90% under ten. Boys > girls 2X.

Ø  PATHOPHYSIOLOGY:  HSP usually follows an URT infection.  HSP has been associated with 1) Infections:  Group A β-haemolytic streptococci, hepatitis B, HSV, parvovirus B19, Coxsackievirus, adenovirus, Helicobacter pylori, measles, mumps, rubella, mycoplasma… 2) Drugs (ideosyncratic reaction):   Vancomycin, ranitidine, streptokinase, cefuroxime, diclofenac, enalapril, captopril..  Most of its features are due to the deposition of abnormal IgA in the wall of blood vessels, leading to vasculitis. It is uncertain whether the main cause is overproduction (in the digestive tract or the bone marrow) or decreased removal of abnormal IgA from the circulation.

Ø  PRESENTATION:  The "classic triad" of HSP 1) Purpura (occur in all cases):  Typically appear on the legs and buttocks, but may also be seen on the arms, face and trunk;  2) Arthritis (occur in 80%): Tend to involve the ankles, knees, and elbows but arthritis in the hands and feet is possible; the arthritis is non-erosive and hence causes no permanent deformity; 3) Abdominal pain (occur in 62%):  Colicky in character.   Other symptoms:  Gastrointestinal hemorrhage occurs in 33% of case, and sometimes but not necessarily due to intussusception.  Renal involvement (occur in 40%):  Hematuria (occur in almost all), Proteinuria (occur in about 50%), CKD (occur only in 1%, and more likely in adults).  Hypertension may occur.  Problems in other organs (CNS and lungs) occur much less commonly than the skin, bowel and kidneys. The disease tends to last about 4 weeks, and then resolves spontaneously. HSP → H-hematuria, H-hematochezia, S-stomach pain,  S-stool bloody, P-palpable P-purpura, P-painful joint

v H  _______________, ______________, ______________, ______________, _______________

v S ______________, _______________, _______________, ______________, ______________

v P  _______________, _______________, ______________, ______________, ______________

Typical purpura on lower legs and buttocks

By Madhero88 - http://www.dermnet.com/Henoch-Schonlein-Purpura/picture/14796, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=9699485

More severe case of HSP on child's foot, leg, and arm

By The original uploader was Okwikikim at English Wikipedia - Transferred from en.wikipedia to Commons., Public Domain, https://commons.wikimedia.org/w/index.php?curid=4233585

Immunostaining showing IgA in the glomerulus of a patient with Henoch-Schönlein nephritis

By Lazarus Karamadoukis, Linmarie Ludeman and Anthony J Williams - Henoch-Schönlein purpura with intracerebral haemorrhage in an adult patient: a case report, Journal of Medical Case Reports. doi:10.1186/1752-1947-2-200, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=4281112

Microphotograph of a histological section of human skin prepared for direct immunofluorescence using an anti-IgA antibody, the skin is a biopsy of a patient with Henoch-Schönlein purpura. IgA deposits are found in the walls of small superficial capillaries (yellow arrows). The pale wavy green area on top is the epidermis, the bottom fibrous area is the dermis.

By Emmanuelm at en.wikipedia, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=4233591

Ø  TREATMENT:  Most patients do not receive therapy because of high spontaneous recovery rate.   Medication: Corticosteroids:  May enhance rate of recovery from arthritis or abdominal pain but does not prevent recurrence; in those with crescentic nephritis (> 50% of glomeruli), a pulse IV methylprednisolone 250-1000 mg/day for three days followed by oral prednisone (1 mg/kg/day for three months) is used. Plasmapheresis (exchange of plasma) may be curative but data is inconclusive. IVIG:  Has been tried in patients with heavy proteinuria and decrease in glomerular filtration rate.  Renal transplant:  Can be considered in those with ESRD, although recurrence is common, as evidenced by mesangial hypercellularity and IgA deposition in the graft. It is recommended that transplantation be delayed for 12-24 months after the disappearance of purpura.

Ø  PROGNOSIS:  Overall prognosis is good in most patients, with one study showing recovery occurring in 94% and 89% of children and adults, respectively.  In children, the condition recurs in about a third of all cases, but recurrence is more common in older children and adults.  HSP accounts for about 3% of end-stage renal disease in children.

o   HYPERSENSITIVITY VASCULITIS (aka hypersensitivity angiitis or leukocytoclastic vasculitis):   

Ø  PATHOPHYSIOLOGY:  Usually due to a hypersensitivity reaction to a known drug, auto-antigens or infectious agents.  Immune complexes lodge in the vessel wall, attracting polymorphonuclear leukocytes who in turn release tissue-degrading substances leading to an inflammatory process.

Ø  PRESENTATION:  3 P’s → P-palpable, P-painful, P-petechiae or P-purpuric lesions arise in crops.  Common localizations being the forearms and legs. Necrosis of skin tissue can yield lesions with black or brown centres. This disorder may affect the skin only, but sometimes affect nerves, the kidneys, joints and the heart. 

Ø  DIAGNOSTIC EVALUATION:  H&P:  Identify the causing agent (e.g. drug or a microbe).   Chest X-ray.  ESR/CRP. Skin biopsy:   Neutrophil infiltration around vessel of the lesions (leukocytoclastic vasculitis), which is most prominent in postcapillary venules. Tests for hepatitis virus, antinuclear antibodies, rheumatoid factor and cryoglobulins might be indicated. Diagnostic Criteria:  Meeting of at least 3 out of 5 criteria yields a sensitivity of 71% and a specificity of 84%: 1) Age > 16; 2) Use of possible triggering drug in relation to symptoms; 3) Palpable painful purpura (the three P's); 4) Maculopapular rash; 5) Skin biopsy showing neutrophil infiltration around vessel.

Ø  TREATMENT:  Eliminate the cause of the vasculitis (most important).  Antihistamines prove helpful to some patients. If the vasculitis is damaging organ systems such as the kidneys, immunosuppressive agents are indicated.

Leukocytoclastic vasculitis as per skin biopsy. Believed to be due to minocycline.

By James Heilman, MD - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=11606861

Leukocytoclastic vasculitis

By James Heilman, MD - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=11606885

Leukocytoclastic vasculitis due to minocycline

By James Heilman, MD - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=11606895

Leukocytoclastic vasculitis due to minocycline

By James Heilman, MD - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=11606899

o   TAKAYASU ARTERITIS (aka pulseless disease):  An inflammatory disease of unknown etiology that affects the aorta and its branches.

Ø  EPIDEMIOLOGY:  F > M 8X.  Predilection for young Asian women between 15-30 y/o.

Ø  PRESENTATION:  Constitutional symptoms (occur in ~ half of all patients):  Fever, night sweats, weight loss, arthralgia, and fatigue.  The other half of patients with Takayasu's arteritis present with only late vascular changes, without an antecedent systemic illness. Ocular/retinal changes:  "Wreathlike" appearance of blood vessels in the retina, which occur as a response (angioneogenesis) to carotid artery narrowings.  The eye findings described are more frequently in Asian patients, and are rarely seen in patients from North America.  Absence of upper extremities pulses:  Occur because of narrowings of blood vessels to the arms. This phase gradually subsides and is followed by a more chronic stage characterized by inflammatory and obliterative changes in the aorta and its branches. In the late stage, weakness of the arterial walls may give rise to localized aneurysms.  Four types of late-phase Takayasu arteritis are described on the basis of the sites of involvement: Type I - Classic pulseless type that involves the brachiocephalic trunk, carotid arteries, and subclavian arteries Type II - Combination of type I and III Type III - Atypical coarctation type that involves the thoracic and abdominal aortas distal to the arch and its major branches Type IV - Dilated type that involves extensive dilatation of the length of the aorta and its major branches.  There is often an anemia and marked elevation of the ESR.  TAKAYASU ARTERITIS:  FAN MY S-skin O-on W-wednesday = FANMYSOW →F-female A-asian present with F-fever, A-arthritis, N-night sweat, MY-myalgia, S-skin nodules, O-ocular disturbances, and W-weak UE pulse.

v F  _______________, ______________, ______________, ______________, _______________

v A ______________, _______________, _______________, ______________, ______________

v N  _______________, _______________, ______________, ______________, ______________

v M  _______________, ______________, ______________, ______________, _______________

v Y _____________, _______________, _______________, ______________, ______________

v S  _______________, _______________, ______________, ______________, ______________

v O  _______________, ______________, ______________, ______________, _______________

v W ______________, _______________, _______________, ______________, ______________

Ø  DIAGNOSTIC EVALUATION:  H&P.  CBC. ESR/CRP. CXR.  Chest CT. Arteriogram.

Ø  TREATMENT:  Prednisone:  Starting dose of 1 mg/kg/day.   Then tapered over several weeks to a dose that is tolerable for the patient. The great majority of patients with Takayasu’s arteritis respond to prednisone.

Left anterior oblique angiographic image of Takayasu's arteritis showing areas of stenosis in multiple great vessels

By Justin Ly - http://rad.usuhs.edu/medpix/parent.php3?mode=single&recnum=4839&th=-1#thumbnails, Public Domain, https://commons.wikimedia.org/w/index.php?curid=8723731

Axial T1-weighted post-gadolinium MRI in a patient with Takayasu arteritis showing thickened, enhancing aortic wall, consistent with large vessel vasculitis

By Dr Laughlin Dawes - http://www.radpod.org/2007/04/15/takayasu-arteritis/, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=4165069

o   BEHCET’S DISEASE (aka silk road disease):  

Ø  EPIDEMIOLOGY:  Behçet disease is considered more prevalent in the areas surrounding the old silk trading routes in the Middle East and in Central Asia. Thus, it is sometimes known as Silk Road Disease. US prevalence: 15,000-20,000.  Globally, M > F; while in the US, F > M. This disease usually first strikes patients in their 20s and 30s. It then becomes a fluctuating lifelong disorder with a series of remissions and exacerbations which can be from days to months. Complete remission is rare.

Ø  PATHOPHYSIOLOGY:  Behçet disease is caused by an over-active immune system which, without any apparent infections, produces recurrent outbreaks of inflammation in small blood vessels. There may exist a  genetic linkage to HLA-B51 antigen, just like the prevalence of HLA-B27 in ankylosing spondylitis.

Ø  PRESENTATION:  It is diagnosed clinically by specific patterns of symptoms and repeated outbreaks. Other causes for these symptoms have to be ruled out before making the diagnosis.  Diagnostic criteria (symptoms do not have to occur together, but can have happened at any time):  1) Must have aphthous ulcers (any shape, size or number at least 3 times in any 12 months), and 2) Must have 2 out of the following 4 "hallmark" symptoms: PEGS → P-pathergy reaction (papule >2 mm dia. 24-48 hrs or more after needle-prick), E-eye inflammation (iritis, uveitis, retinal vasculitis, cells in the vitreous), G-genital ulcers (including anal ulcers and spots in the genital region and swollen testicles or epididymitis in men), S-skin lesions (papulo-pustules, folliculitis, erythema nodosum, acne in post-adolescents not on corticosteroids). Other possible symptoms:  Arthritis/arthralgia, nervous system symptoms, stomach and/or bowel inflammation, deep vein thrombosis, superficial thrombophlebitis, cardio-vascular problems of inflammatory origin, inflammatory problems in chest and lungs, problems with hearing and/or balance, extreme exhaustion, changes of personality, psychoses.

v P  _______________, ______________, ______________, ______________, _______________

v E ______________, _______________, _______________, ______________, ______________

v G  _______________, _______________, ______________, ______________, ______________

v S  _______________, _______________, ______________, ______________, ______________

Behçet's mouth ulcer

By Ahmet Altiner MD, Rajni Mandal MD - http://dermatology.cdlib.org/1611/articles/18_2009-10-20/2.jpg, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=17863021

A person with hypopyon which can be seen in anterior uveitis in a person with Behçet's disease

By EyeMD (Rakesh Ahuja, M.D.). - Own work., CC BY-SA 2.5, https://commons.wikimedia.org/w/index.php?curid=1229578

Funduscopic photo left eye centered on the optic disc

By self - my left eye; imaged and given to me as part of class demonstration, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=4868894

Magnetic resonance venogram demonstrating occlusion of the left sigmoid and transverse sinuses

By P Thomas, A Keightley, R Kamble, N Gunasekera, M R Johnson - Sigmoid sinus thrombosis presenting with posterior alexia in a patient with Behcet's disease and polycythaemia: a case report. Journal of Medical Case Reports 2008, 2:175 (23 May 2008), CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=4114961

Ø  TREATMENT:  Aimed at easing the symptoms, reducing inflammation, and controlling the immune system. Anti-TNF therapy:  Infliximab (shown promise in treating the uveitis associated with the disease); Etanercept (e useful in patients with mainly skin and mucosal symptoms).  Interferon alfa-2a:  Alternative treatment, particularly for the genital and oral ulcers, as well as ocular lesions. Colchicine:  Useful for treating some genital ulcers, erythema nodosum, and arthritis. Dapsone and rebamipide:  Shown, in small studies, to have beneficial results for mucocutaneous lesions.  

o   BUERGER’S DISEASE (aka thromboangiitis obliterans): An acute inflammation and thrombosis of arteries and veins of the hands and feet.

Ø  EPIDEMIOLOGY:  M > F. The disease is most common among South Asians, who often smoke cigarettes made of raw tobacco (bidis). It is also more common in Israel, Japan and India along the "old silk route".

Ø  PATHOPHYSIOLOGY:  It is strongly associated with use of tobacco products, primarily from smoking, but also from smokeless tobacco.  The underlying mechanisms are still largely unknown, but immunological reactions play a role leading to recurrent acute and chronic inflammation and thrombosis of arteries and veins of the hands and feet.

Ø  PRESENTATION:  Pain and ulcerations/gangrene in the extremities are common complications, often resulting in the need for amputation of the involved extremity.  The commonly followed diagnostic criteria are:  1) < 45 years old 2) History of tobacco use 3) Presence of distal extremity ischemia (indicated by claudication, pain at rest, ischemic ulcers or gangrene) documented by noninvasive vascular testing such as ultrasound 4) Exclusion of autoimmune diseases, hypercoagulable states, and diabetes mellitus by laboratory tests 5) Exclusion of a proximal source of emboli by echocardiography and arteriography 6) Consistent arteriographic findings in the clinically involved and noninvolved limbs.

Ø  TREATMENT:  Cessation of tobacco:  May slow any further progression. Vascular surgery:  Treat limbs with poor perfusion. Vascular growth factor and stem cell injections:  Show promise in clinical studies.  Streptokinase:  Proposed as adjuvant therapy in some cases.

Ø  PROGNOSIS:  Amputation is common and more severe in patients who continue to use tobacco.

Complete occlusion of the right and stenosis of the left femoral artery as seen in a case of thromboangiitis obliterans

By Milorad Dimic MD - Intermedichbo, Nis, Serbia, GFDL, https://commons.wikimedia.org/w/index.php?curid=7579804

CT angiogram showing segmental stenosis of arteries of the lower leg (indicated by arrows). The changes are particularly apparent in the blood vessels in the lower right hand portion of the picture (the femoral artery distribution).

By Milorad Dimic MD - Intermedichbo, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=15501075

 Treatment by 100% hyperbaric oxygen.

By Original uploader was Intermedichbo at sr.wikipedia - Transferred from sr.wikipedia; transfer was stated to be made by User:Intermedichbo., Public Domain, https://commons.wikimedia.org/w/index.php?curid=15543136

o   KAWASAKI DISEASE:  (aka mucocutaneous lymph node disease):  A self-limited vasculitis that affects many organs, including the skin and mucous membranes, lymph nodes, blood vessel walls, and the heart.

Ø  EPIDEMIOLOGY:  Incidence:   Highest in Japan (175 per 100,000).  80% of patients < 5 y/o.

Ø  PATHOPHYSIOLOGY:  The causative agent of Kawasaki disease is still unknown. However, current etiological theories center primarily on immunological causes for the disease. An unknown virus may play a role as an inciting factor. 

Ø  PRESENTATION:  CRASH (4/5 of these criteria) & BURN → C-conjuntivitis (without pus or drainage), R-rash (polymorphous, non-blistering rash on the trunk), A-adenopathy (frequently only one cervical lymph node > 15 mm), A-arthralgia (frequently symmetrical, with swelling), S-strawberry tongue (white coating on the tongue with prominent red papillae, occuring along with bright red, chapped, or cracked lips and erythematous oral mucous membranes), H-hand and feet  (initially erythematous with desquamation of the palms and soles occuring later);  BURN (Kawasaki disease often begins with a high [>102 °F] and persistent [>5 days]  fever that is not very responsive to normal doses of acetaminophen or ibuprofen). If left untreated, it can cause vasculitic changes in the coronary arteries and subsequent coronary artery aneurysms. These aneurysms can lead to myocardial infarction even in young children. Overall, about 10–18% of children with Kawasaki disease develop coronary artery aneurysms, with much higher prevalence among patients who are not treated early in the course of illness. Kawasaki disease is the most common cause of acquired heart disease among children in the United States.

v C  _______________, ______________, ______________, ______________, _______________

v R ______________, _______________, _______________, ______________, ______________

v A  _______________, _______________, ______________, ______________, ______________

v S  _______________, ______________, ______________, ______________, _______________

v H _____________, _______________, _______________, ______________, ______________

v BURN  ______________, ______________, _____________, _____________, _____________

Signs of Kawasaki disease:  (A) Bilateral, non-exudative conjunctival injection with perilimbal sparing. (B) Strawberry tongue and bright red, swollen lips with vertical cracking and bleeding. (C) Erythematous rash involving perineum. (D) Erythema of the palms, which is often accompanied by painful, brawny edema of the dorsa of the hands. (E) Erythema of the soles, and swelling dorsa of the feet. (F) Desquamation of the fingers. (G) Erythema and induration at the site of a previous vaccination with Bacille Calmette-Gurin (BCG). (H) Perianal erythematous desquamation.

By Dong Soo Kim - Kawasaki disease., CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=9962875

X-ray showing aneurysmal enlargement of the coronary arteries, which is a complication in a Kawasaki syndrome

By Wkmatzek at German Wikipedia(Original text: wkmatzek) - Transferred from de.wikipedia to Commons.(Original text: selbst angefertigt von wkmatzek), Public Domain, https://commons.wikimedia.org/w/index.php?curid=3129211

Ø  DIAGNOSTIC EVALUATION:  H&P. Blood tests:  CBC (may reveal normocytic anemia and thrombocytosis); ESR & CRP:  ↑.  LFT:  May show ↑ AST & ALT and ↓ albumin.   UA:  May show sterile pyuria and proteinuria.  LP:  May show evidence of aseptic meningitis.  EKG:  May show ventricular dysfunction or arrhythmia due to myocarditis. Echocardiogram:  May show subtle coronary artery changes or, later, true aneurysms.   Abdominal US or CT:  May show hydrops of the gallbladder.   Angiography:  Gold standard to detect coronary artery aneurysms. 

Ø  TREATMENT:  Treatment ASAP to prevent damage to the coronary arteries.  Hospitalized.  Medication: IVIG:   Administered in high doses and is most useful within the first 7 days of onset of fever, in terms of preventing coronary artery aneurysm.  Salicylate therapy (particularly aspirin):  Started at high doses until the fever subsides, and then is continued at a low dose when the patient returns home, usually for 2 months. Corticosteroids:  Its addition to IVIG and aspirin did not improve outcome.

Ø  PROGNOSIS:  ~ 2% of patients die from complications of coronary vasculitis. Patients who have had Kawasaki disease should have an echocardiogram initially every few weeks, and then every 1–2 years to screen for progression of cardiac involvement.  It is also not uncommon that a relapse of symptoms may occur soon after initial treatment with IVIG. This usually requires re-hospitalization and retreatment

Signs and symptoms and time course of Kawasaki disease

[By Maen K Househ - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=17543116

Angiography showing ectatic LAD, with largest aneurysm = 6.5 mm in diameter

By mprice18 - http://pediatricimaging.wikispaces.com/file/view/price_lad_angio.jpg/235212558/price_lad_angio.jpg, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=17585867

o   WEGENER’S GRANULOMATOSIS:  A vasculitis that affects the lungs, kidneys and other organs. It is part of a larger group of vasculitic syndromes, all of which feature the presence of an abnormal type of circulating antibody termed ANCAs (antineutrophil cytoplasmic antibodies) and affect small and medium-sized blood vessels. Apart from Wegener's, this category includes Churg-Strauss syndrome and microscopic polyangiitis

Ø  EPIDEMIOLOGY:  Incidence:  10/1 million per year.  90% of the patients are white. Mainly occurs in the middle-aged.

Ø  PATHOPHYSIOLOGY:  C-ANCAs (c = cytoplasmic) are responsible for the inflammation.  It react with proteinase 3, an enzyme prevalent in neutrophil granulocytes. This activate neutrophils, increase their adherence to endothelium, and lead to their degranulation. This causes extensive damage to the vessel wall, particularly of arterioles.  As with many autoimmune disorders, the cause is probably genetic predisposition combined with molecular mimicry caused by a virus or bacterium.

Ø  PRESENTATION:  Initial signs are non-specific nature of the symptoms.

1.     Upper airway, eye and ear disease: Nose (pain, stuffiness, nosebleeds, rhinitis, crusting, saddle-nose deformity due to a perforated septum); Ears (conductive hearing loss due to Eustachian tube dysfunction, sensorineural hearing loss); Eyes (pseudotumours, scleritis, conjunctivitis, uveitis, episcleritis). 

2.     Airways: Trachea (subglottal stenosis); Lungs (pulmonary nodules- "coin lesions", infiltrates-often interpreted as pneumonia, cavitary lesions, pulmonary hemorrhage causing hemoptysis); Bronchial stenosis.

3.     Kidney: RPGN (75%), leading to chronic renal failure

4.     Arthritis: Pain or swelling (60%), often initially diagnosed as rheumatoid arthritis

5.     Skin: nodules on the elbow, purpura, various others (see cutaneous vasculitis)

6.     Nervous system: occasionally sensory neuropathy (10%) and rarely mononeuritis multiplex

Typical saddle nose damage due to granulomatosis with polyangiitis.

By Vw38 - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=47554159

Photo showing the sclerokeratitis associated with GPA

By Jonathan Trobe, M.D. - University of Michigan Kellogg Eye Center - The Eyes Have It, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=16116693

Ø  DIAGNOSTIC EVALUATION:  H&P:  Nasal or oral inflammation.  CXR:  May show nodules, infiltrates or cavities.  UA:  May show microhematuria or RBC casts.  Biopsy: Granulomatous inflammation involving the respiratory tract, and a vasculitis of small- to medium-sized vessels.  IHC:  c-ANCAs determination can aid in the diagnosis.

Micrograph showing features characteristic of granulomatosis with polyangiitis - a vasculitis and granulomas with multi-nucleated giant cells. H&E stain.

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=14968435

Immunofluorescence pattern produced by binding of ANCA to ethanol-fixed neutrophils, from a person with GPA

By Malittle at English Wikipedia - Transferred from en.wikipedia to Commons., Public Domain, https://commons.wikimedia.org/w/index.php?curid=2208830

Ø  TREATMENT:  Mediation: Initial treatment is with Corticosteroids (1 mg/kg/day) and Cyclophosphamide (2 mg/kg/day). Once remission is attained (normally 3 to 6 months), treatment is frequently changed to azathioprine or methotrexate, which are less toxic drugs. Total duration of therapy should be at least 1 year, or longer in high risk patients. Corticosteroids are tapered to a low maintenance dose, 5-10 mg/day. Plasmapheresis:  May be beneficial in severe disease or pulmonary hemorrhage. Tracheotomy:  Required to maintain an airway in patients with severe subglottic stenosis.

Ø  PROGNOSIS:  25 to 40% of patients suffer from flare-ups, but a majority respond well to treatment. Long-term complications are very common (86%): mainly chronic renal failure, hearing loss and deafness.

Ø  ASSOCIATED CONDITION:  MICROANGIOPATHIC POLYANGIITIS:  Another ANCA-associated vasculitis.  In MPA, the ANCA are directed specifically against MPO and proteinase 3.  The presentation is similar to WG with 1) Kidney inflammation (~ 80% of patients) 2) Weight loss (> 70%) 3) Skin lesions (> 60%) 4) Nerve damage (60%), and 5) Fevers (55%).   However, there is no clinical or pathological evidence of necrotizing granulomatous inflammation.

o   CHURG-STRAUSS SYNDROME (aka allergic granulomatosis):  A medium and small vessel autoimmune vasculitis, leading to necrosis. It involves mainly the blood vessels of the lungs (it begins as a severe type of asthma), GI system, and peripheral nerves.

Ø  PATHOPHYSIOLOGY:  Churg-Strauss syndrome was once considered a type of Polyarteritis nodosa (PAN) due to their similar morphologies. It is non-heritable and non-transmissible.

Ø  PRESENTATION:  3 clinical stages:  1) First stage:  Often involves the sinuses and the onset of allergies not previously had or the worsening of pre-existing allergies; 2) Second stage:   Onset of acute asthma. Normally, the person would not have had asthma previously;  3) Third stage (most life-threatening and painful):  Involvement of various organ systems, and may include:  Peripheral nerve (severe nerve pain in their legs, arms and hands), heart (cardiomyopathy) and lungs or kidneys (proteinuria, ↑ BUN/Cr) and liver, and skin/mucosa (purple marks on the skin, apthous ulcer).  People can live for many years in the first two stages before progressing to stage three. 

Ø  DIAGNOSTIC EVALUATION:  p-ANCA ↑.  CBC with diff:  Eosinophilia (>10%).  CXR:  Migratory or transient pulmonary opacities on CXR.  Sinus CT:  Paranasal sinus abnormalities.  Tissue biopsy:  Vessel showing eosinophilic infiltration and granulomatous changes.

Ø  TREATMENT:  Immunosuppressant:   Acute cases can be induced into remission with glucocorticoids (prednisone) and cyclophosphamide.  Remission can be maintained with a less toxic drug, such as azathioprine or methotrexate.

Micrograph showing an eosinophilic vasculitis consistent with Churg–Strauss syndrome. H&E stain.

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=15244866

o   CRYOGLOBULINEMIA:  Presence of high amount of heavy globulins (e.g. IgM) in the bloodstream which thicken on exposure to cold.

Ø  PATHOPHYSIOLOGY:  Cryoglobulins may be present in IgM = IM → I-infection (e.g. occur in 35% of chronic hepatitis C as essential cyroglobuninemic vasculitis), some autoI-immune diseases (e.g. SLE and rheumatoid arthritis),  M-mycoplasma pneumonia, M-mononucleosis, M-multiple myeloma, M-macroglobulinemia (e.g. Waldenstrom macroglobulinemia), M-malignancy (certain leukemias).  Immune complexes of cryoglobulins and complement are deposited in walls of capillaries, venules, or arterioles.

v Ig  _______________, ______________, ______________, ______________, _______________

v M ______________, _______________, _______________, ______________, ______________

Ø  PRESENTATION:  Hyperviscosity:  Typically associated with CG due to hematological malignancies and monoclonal immunoglobulins.  Palpable purpura, arthralgia and myalgia ("Meltzer's triad"):  Generally seen with polyclonal CGs seen in essential-, viral-, or connective tissue disease-associated CG.

Ø  DIAGNOSTIC EVALUATION:  Tissue biopsy:  Vessel inflammation with immune deposits

Ø  TREATMENT:  Treat the underlying disorder.  Alkylating agents.

Cryoglobulinemia

By Madhero88 - http://www.dermnet.com/Cryoglobulinemia/picture/23113, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=9710334

o   RA (rheumatoid arthritis):  A chronic, systemic inflammatory autoimmune disorder that causes the immune system to attack the joints, and extra-articular tissues throughout the body including the skin, blood vessels, heart, lungs, and muscles. 

Ø  EPIDEMIOLOGY:  US incidence:   3/10,000 annually.  Prevalence:  1%.  F > M 5X.  Smokers > non-smokers 4X.   First-degree relatives prevalence rate is 2-3% and disease genetic concordance in monozygotic twins is approximately 15-20%. 

Ø  PATHOPHYSIOLOGY:  RA is strongly associated with the inherited HLA-DR4.  The cause of RA is still unknown to this day, but has long been suspected to be infectious. The offending organism causes an immune response that also recognize native molecule in the body (molecular mimicry).  Once triggered, B lymphocytes produce rheumatoid factors (RF) of the IgG and IgM classes that are deposited in the tissue, this subsequently leads to the activation of the serum complement cascade, the recruitment of the phagocytes,  infiltration by activated T-cells, and synthesis of pro-inflammatory cytokines (e.g. TNF-α, IL-1, IL-6, IL-8 and IL-15, TGF-b, FGF, and PDGF).  Once the inflammatory reaction is established, the synovium thickens, the cartilage and the underlying bone begins to disintegrate and evidence of joint destruction accrues.

Ø  PRESENTATION:  Joint symptoms:  Criteria for the diagnosis of RA MRSA→ M-morning stiffness and pain of >1 hour most mornings for ≥ 6 weeks, R-rheumatoid factor > 95th percentile (IgM anti-IgG Fc), R-rheumatoid nodules (areas of central necrosis surrounded by palisading macrophages and fibroblasts and a cuff of cellular connective tissue and chronic inflammatory cells; usually found over bony prominences [olecranon, calcaneal tuberosity, MCP joint, or other areas that sustain repeated mechanical stress]), R-radiological changes suggestive of joint erosion, S-symmetric arthritis, A-arthritis and soft-tissue swelling of >3 of 14 joints/joint groups (including wrist, MCP and PIP but characteristically sparing the DIP joints, ankles, knees, shoulders, hips, elbows, and cervical spines).  RA pain generally improves with use of the affected joints. Thus, the pain of rheumatoid arthritis is usually worse in the morning compared to the classic pain of osteoarthritis where the pain worsens over the day as the joints are used.  Skeletal deformities (due to erosion and destruction of the joint surface, which impairs their range of movement):  Ulnar deviation of the finger, Boutonniere deformity (hyperflexion at the PIP with hyperextension at the DIP joint), swan neck deformity (hyperextension at the PIP, hyperflexion at the DIP joint), and "Z-Thumb" deformity (fixed flexion and subluxation at the MCP joint, and hyperextension at the IP joint). 

v  M  _______________, ______________, ______________, ______________, _______________

v  R  ______________, _______________, _______________, ______________, ______________

v  S  _______________, _______________, ______________, ______________, ______________

v  A  _______________, ______________, ______________, ______________, _______________

      Extra-articular manifestations:   PopCORN = PCORN → P-pulmonary (Fibrosis may occur spontaneously or as a consequence of therapy [e.g.  methotrexate], Caplan's nodules, pulmonary effusions); C-cardiovascular (pericarditis, endocarditis, LV failure, valvulitis, fibrosis, antiphospholipid-antibody syndrome [characterized by recurrent vascular thrombosis and 2nd  trimester miscarriages], anemia of chronic disease, ↑ MI or/& CHF; over 1/3 of deaths of people with RA are directly attributable to cardiovascular death); C-cutaneous (rheumatoid nodule, microinfarcts around the nailfolds, livedo reticularis [erythematous discoloration of the skin due to the presence of an obliterative cutaneous capillaropathy], pyoderma gangrenosum, Sweet's syndrome, erythema nodosum, lobular panniculitis, atrophy of digital skin, palmar erythema, diffuse thinning (rice paper skin); C-cancer (↑ lymphoma as in most autoimmune conditions); O-ocular (keratoconjunctivitis sicca, scleritis, episcleritis, scleromalacia); O-osteoporosis (classically occurs in RA around inflamed joints caused by inflammatory cytokines); R-renal (amyloidosis); N-neuro (peripheral neuropathy, mononeuritis multiplex [e.g. carpal tunnel syndrome due to compression of the median nerve by wrist swelling], atlanto-axial subluxation [due to erosion of the odontoid process and or/transverse ligaments in the cervical spine's).  

v  P  _______________, ______________, ______________, ______________, _______________

v  C  ______________, _______________, _______________, ______________, ______________

v  O  _______________, _______________, ______________, ______________, ______________

v  R  _______________, ______________, ______________, ______________, _______________

v  N  ______________, _____________, _____________, _____________, _____________

A hand affected by rheumatoid arthritis

By James Heilman, MD - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=11110471

DIAGNOSTIC EVALUATION:  Blood tests:  RF (usually negative during the first year of illness, but eventually will be positive in 80% of patient; it is not specific though); anti-citrullinated protein antibodies-ACPA (considered a better marker for RA as it is also detected in 80% of all RA patients, but is 98% specific); ANA (rule out SLE); ESR/CRP; CBC; LFTs; RFTs; Ferritin (rule out hemochromatosis).   

X-ray of the hand in rheumatoid arthritis.

By Bernd Brägelmann Braegel Mit freundlicher Genehmigung von Dr. Martin Steinhoff - Own work, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=3961869

Signs of destruction and inflammation on ultrasonography and magnetic resonance imaging in the second metacarpophalangeal joint in established RA. Thin arrows indicate an erosive change; thick arrows indicate synovitis. Ultrasonography (left side of image) in the (a) longitudinal and (b) the transverse planes shows both signs of destruction and inflammation. Axial T1-weighted magnetic resonance images were obtained (c) before and (d) after contrast administration, also demonstrating synovitis. Additionally, a coronal T1-weighted magnetic resonance image (e) before contrast administration visualizes the same bone erosion as shown in panels c and d.

By Marcin Szkudlarek, Mette Klarlund, Eva Narvestad, Michel Court-Payen, Charlotte Strandberg, Karl E Jensen, Henrik S Thomsen and Mikkel Østergaard. - Ultrasonography of the metacarpophalangeal and proximal interphalangeal joints in rheumatoid arthritis: a comparison with magnetic resonance imaging, conventional radiography and clinical examination. Arthritis Research & Therapy 2006, 8:R52. doi:10.1186/ar1904, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=5886101

o   JRA (juvenile rheumatoid arthritis):  A subset of arthritis seen in childhood, which may be transient and self-limited or chronic.

Ø  EPIDEMIOLOGY:  US Prevalence: 300,000 children.  Of these children, 50 percent have pauciarticular JIA, 40 percent have polyarticular JIA and 10 percent have systemic JIA. 

Ø  PATHOPHYSIOLOGY:  The cause is currently unknown and.  It arises in a genetically susceptible individual due to environmental factors.

Ø  TREATMENT:  Conservative therapy:  Rest and physical activity (regular exercise is important for maintaining joint mobility and making the joint muscles stronger).  Heat and cold applications.  Pharmacological treatment:  1) Anti-inflammatory agents and analgesics:  Improve pain and stiffness but do not prevent joint damage or slow the disease progression) and 2) Disease-modifying antirheumatic drugs (DMARDs):  Produces durable remissions, delay or halt disease progression,  and prevent bone and joint damage from occurring secondary to the uncontrolled inflammation. This is important as such damage is usually irreversible).  Current strategy employs DMARDs early in the course of the disease as MRI have demonstrated that joint damage occurs much earlier and in more patients than was previously thought when imaged by X-ray.  Also, in the early stage of the disease, the joints are increasingly infiltrated by cells of the immune system that signal to one another and are thought to set up self-perpetuating chronic inflammation. Interrupting this process as early as possible with an effective DMARD (such as methotrexate) appears to improve the outcome from the RA for years afterwards. Anti-inflammatory agents and analgesics:  Glucocorticoids, NSAIDs, acetaminophen, opiates.  DMARDs:  e.g. SHAMROCk → S-sulfasalazine (liver and bone marrow toxicity), H-hydroxychloroquine (ocular toxicity), A-azthioprine (liver and BM toxicity), Au (gold → renal toxicity, allergic skin reaction), M-methotrexate (pneumonitis), M-minocycline (autoimmunity), R-rituximab, O-olencia (abatacept is a T cell activation blocker), C-cyclosporine (renal toxicity).

v  S  _______________, ______________, ______________, ______________, _______________

v  H  ______________, _______________, _______________, ______________, ______________

v  A  _______________, _______________, ______________, ______________, ______________

v  M  _______________, ______________, ______________, ______________, _______________

v  R  ______________, _____________, _____________, _____________, _____________

v  O  _______________, ______________, ______________, ______________, _______________

v  C  ______________, _______________, _______________, ______________, ______________

Appearance of synovial fluid from a joint with inflammatory arthritis.

By James Heilman, MD - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=9445237

Ø  PRESENTATION:  Patient is is ≤ 16 y/o and present with symptoms lasting ≥ 6 weeks.  Non-specific symptoms:  Lethargy, anorexia, limping,  flu-like syptoms that persist. Joint symptoms:  Persistent (> 6 weeks) swelling and pain of the affected joint(s), which commonly include the knee, ankle, wrist and small joints of the hands and feet.  Late effects of arthritis include joint contracture (stiff, bent joint) and joint damage.  Extraauticular symptoms:  Chronic anterior uveitis that may result in blindness.  Reduced overall rate of growth.  There are 3 major types of JIA:  POS → P-polyarticular, O-oligoarticular, and S-sytemic JRA  

1.     POLYARTICULAR (40% of JRA cases):  Affect ≥ 5 joints symmetric small joints (including neck and jaw) in the first 6 months of disease. Systemic features are less prominent.  These patients may develop iridocyclitis.  Girls > boys.

2.     OLIGOARTICULAR (aka pauciarticular; 50% of JRA cases): Affects ≥ 4 larger weight-bearing joints (e.g. knee).  30% develop iridocyclitis.  Subtypes:  A) ANA-type:  More common.  Present with asymmetric involvement of large joint with iridocyclitis; B) RF-type: Most accompanies AS in HLA-B27 positive men.   

3.     SYSTEMIC (aka Still's Disease):  Characterized by arthritis, daily spiking fever, and a salmon pink rash.  Possible internal organ involvement:  HSM, serositis, and pleural/pericardial effusion.

Juvenile rheumatoid arthritis as described by G. F. Still: Chronic Arthritis with Glandular Enlargement. The dotted lines show the lower limit of the liver and spleen. Boy aged 3 years.

By Internet Archive Book Images - https://www.flickr.com/photos/internetarchivebookimages/14781042361/Source book page: https://archive.org/stream/diseasesofchildr00ashb/diseasesofchildr00ashb#page/n491/mode/1up, No restrictions, https://commons.wikimedia.org/w/index.php?curid=43325765

Ø  DIAGNOSTIC EVALUATION:  Serologic studies:  RF, ANA, ESR/CRP ↑.  CBC: leukocytosis, anemia, thrombocytosis.  Regular slit lamp exam:  Screen for chronic anterior uveitis. 

Ø  TREATMENT:  PT/OT.  Medication:  NSAIDs, intra-articular corticosteroid injection, methotrexate, and TNF alpha blockers, which appear to be effective in severe JIA.

Caesar versus Hannibal, Louvre Museum, Paris, France