Musculoskeletal Pathology

Skeletal Muscle
1. Muscles of posture, movement & respiration
2. Response of Muscle to Injury
  1. Degeneration/ Necrosis
    1. Tends to be segmental
      1. (Necrosis of entire myofibre is uncommon => crush injury or widespread ischaemia resulting from pressure on a large artery)
    2. Lots of causes
    3. Common triggering factor is increase in Ca2+ w/in the cell
      1. Allows muscle contraction
        Ca-dependent enzymes & lysosomal enzymes increase => myofibre destruction
    4. Muscle cell contents may leak into blood if the cell membrane is damaged
      1. Creatine kinase (CK) is an enzyme which leaks following injury & is commonly used to measure the extent of muscle damage
  2. Regeneration
    1. Requirements:
      1. Intact basal lamina (Sarcolemmal tube)
        Blood supply => macrophages to clear up debris
        Viable satellite cells (act as progenitor cells for new sarcoplasm production)
      2. If not met, fibrosis will occur
    2. Skeletal muscle myofibres have substantial regenerative ability
  3. Atrophy
    1. Entire muscle or individual myofibres within are reduced in diameter
    2. Causes:
      1. Disuse (Ex. fracture, failure to use limb, recumbancy)
        Cachexia, old age, malnutrition
        Denervation (nerve provides trophic factors: any interference or damage => muscle atrophy)
        Endocrine disease
        Ex. Equine "roarers" - Laryngeal hemiplegia (Damage to left recurrent laryngeal nerve)
        Can be rapid - over 50% of muscle mass lost in a few weeks
  4. Hypertrophy
    1. Entire muscle or individual myofibre diameter increases in size
    2. Causes:
      1. Increased work load
        Compensatory
        Ex. COPD heaves lines
        Physiological
  5. Innumerable factors can induce these changes (Trauma, toxins, infectious agents, nutritional deficiencies, Ischaemia, Hereditary disease)
    1. => Specific Dx is NOT POSSSIBLE based on morphological or histological features alone
3. Muscle Diseases
  1. Inflammation: Myositis
    1. Infectious
      1. Bacteria
        Gain entry via direct penetration, haematogenously or extension (Ex. from an infected joint)
        Disease or manifestation
        Abscesses
        Arcanobacterium pyogenes (Bovine, Pigs)
        Streptococcus equi (Equine)
        Corynebacterium pseudotuberculosis (Sheep, Goats, Equine)
        Black leg
        Clostridium chauvoei ( Bovine, Sheep)
        Activation of latent spores
        Gas gangrene
        Clostridium septicum & C. novyi (Sheep, Bovine, Equine), C. perfringens & C. sordelli (Pigs)
        Penetrating wounds
        Wooden tongue
        Actinobacillus lignieresii (Bovine)
      2. Viruses (Rare)
      3. Parasites
        Nematodes
        Trichinella, Ancylostoma & Ascarid larvae
        Cestodes
        Taenia solium (cysticercosis in swine & humans). T.ovis (cystercercosis in sheep)
        Protozoa
        Toxoplasma gondii, Neospora caninum, Sarcocystis
    2. Immune mediated
      1. Canine Masticatory Muscle Myositis (MMM)
        Autoantibodies SELECTIVELY attack muscle of mastication (Type IIM fibres)
        Manifests in the masseter & temporalis muscles (Bilateral)
        Acute stage: Eosinophillic myositis
        Chronic stage: Atrophic myositis
      2. Extraocular myositis
        Autoantibodies selectively target only the muscles around the eye in the Dog
      3. Canine Polymyositis
        Can affect masticatory muscles but Dogs DO NOT have antibodies to type IIM fibres
        Generalized inflammatory myopathy
        Muscle necrosis, regeneration & fibrosis
        Muscle enzymes may be increased
        Fever, pain, weakness, resp. distress
        T Lymphocytes, plasma cells, granulocytes
        Single biopsy may not be enough to make the Dx (it tends to be multifocal & disseminated)
        DDx = Toxoplasma gondii, MMM
    3. Other
      1. Paraneoplastic, drug-induced, idiopathic
  2. Congenital
    1. Defects in muscular form
      1. Congenital diaphramatic defects
        Myofibrillar hypoplasia (Pigs - splayleg)
        Can spontaneously resolve, cause unknown, responsible for significant deaths
        Hyperplasia of muscle fibres (Calves, lambs)
        Double muscling due to increased number of myofibres in affected muscle (thighs, rump, loin) -> Predisposes to dystocia
    2. Muscular Dystrophies
      1. Inherited group (X-linked) of degenerative muscular diseases causing progressive muscle weakness & wasting
      2. Usually due to a genetic fault leading to a muscular protein deficiency
        Ex. Duchenne MD in humans due to dystrophin deficiency
        Dystrophin gene mutations reported in the Golden retriever, Rottweiler, Irish terrier, etc.
      3. Innervation is normal
        Muscle biopsy -> confirm lack of dystrophin with IHC
  3. Toxic, Nutritional & Exertional Myopathies
    1. Toxic
      1. Plants
        Gossypol, Cassia (coffee senna)
      2. Drugs
        Monensin
        Coccidiostat
        Toxic to: Horses, Sheep, Cattle, Dogs, Birds
        Skeletal & myocardial necrosis
        Rapid onset recumbancy & potentially death
        Usually due to mixing errors in feed
        Ionophore
        Disturbs transport of Na & K across membrane
        Increases Ca2+ => Hypercontraction & Degeneration
      3. Chemicals
        Ex. Fe injections can cause local myonecrosis
      4. Mycotoxins
    2. Endocrine
      1. Hyperadrenocorticism & Hypothyroidism => Muscle atrophy
    3. Nutritional
      1. White Muscle Disease
        Economic importance in young Cattle, Sheep & Pigs (also foals)
        Se &/or Vit. E deficiency
        Grossly:
        Lesions are bilaterally symmetrical (hard working muscles)
        Pigs: lesions in heart & liver
        Pathogenesis:
        Oxygen free radicals (OFR) can damage cell membranes
        Vit. E involved in binding OFR & Glutathione peroxidase (includes Se) => Neutralizes effects of OFR
        If Vit. E & Se deficient: Balance shifts to membrane damage => Ca2+ entry & mitochondrial damage => cell swells & dies
    4. Exertional
      1. Caused by intensive & exhaustive activity of major muscle masses
      2. Classically occurs in the Horse after unaccustomed exercise
      3. Equine exertional rhabdomyolysis
        Dissolution of striped (skeletal) muscle
        Membrane damage & leakage of myoglobin
        Myoglobinura = rhabdomyolysis
      4. Azoturia
        Exercise following prolonged period of rest
        Unable to move, sweating, tremors
        Myoglobin leaks from muscle cells -> leaks into urine -> urine is dark red/brown (myoglobinuria) -> damages renal tubules
      5. Tying-up (similar to Azoturia, but milder)
      6. Linked to polysaccharide storage myopathy (many breeds)
        Ex. Equine polysaccharide storage myopathy (EPSM)
      7. Capture myopathy, Porcine stress syndrome
  4. Neuromuscular Junction
    1. Myasthenia gravis (MG)
      1. 1) Acquired
        Autoimmune disease: Abs directed against acetyl choline receptors
        Associated w/ thymomas, megaoesophagus & hypothyroidism (Dogs)
      2. 2) Congenital
        Inherited deficiency in acetyl choline receptors (Rare)
        No Abs against acetyl choline receptors in serum
      3. Both forms manifest as weakness which worsens on exercise
    2. Botulism
      1. Due to ingestion of Clostridium botulinum toxin which inhibits acetyl choline release
      2. Dx: Demonstrate toxin in faeces, ingested material, serum
  5. Neoplasia
    1. Rare in domestic animals
    2. Primary benign: Rhabdomyoma
      1. Primary malignant: Rhabdomyosarcoma
    3. Metastases can also occur to skeletal muscle (e.g. carcinoma, haemangiosarcoma)
4. Anatomy
  1. Types of Myofibres
Bones function, structure & organization
1. Bone is a hard, highly specialized connective tissue, comprising interconnected cells embedded in a clacified, collagenous matrix
2. A living, dynamic, responsive tissue, growing & remodeling throughout life
3. Functions:
  1. Supports movement
    1. Protects body
      1. Storage:
        Mineral bank
        Haematopoietic stem cells
        Fat
4. Structure:
  1. Composed of cells & matrix
  2. Cells:
    1. Osteoblasts
      1. Mesenchymal cells of bone marrow stromal origin
        Form the bone matrix (Osteoid)
    2. Osteoclasts
      1. Multinucleated cells derived from haematopoietic stem cells
        Responsible for bone resorption
    3. Osteocytes
      1. Osteoblasts that have become surrounded by mineralized bone matrix
        Occupy cavities called lacunae
  3. Matrix:
    1. Composed of type I collagen & mineral
    2. Mineral - accounts for 65% of bone (includes: Ca, P, Mg, Mn, Zn, Cu & Na)
    3. Ground substance (water, proteoglycans, lipids)
    4. Strength
5. Bone Organization
  1. Not all bones are organized in the same way
    1. Organization dictated by the pattern of collagen deposition
  2. 1) Immature (Woven) Bone
    1. Collagen is arranged in a "random weave"
      1. This is only normal in the fetus
        In adults: Randomly woven bone => sign of pathological condition (e.g. fracture, inflammation, neoplasia)
  3. 2) Mature (Lamellar ) Bone
    1. The collagen is arranged in orderly layers which are much stronger than woven bone
    2. Two main types:
      1. Compact or cortical bone
        forms the diaphyses of long bones & the shell of all other bones (contains Osteons)
      2. Cancellous (spongy or trabecular) bone
        occurs in vertebrae, flat bones & epiphysyes of long bones (Contains NO Osteons)
6. Periosteum
  1. A sheath of connective tissue covering the bone (except at the articular surfaces)
    1. The inner layer merges w/ the outer layer of bone & contains osteoblasts & stem cells
      1. The blood supply to the mature bone enters via the periosteum
        Damage to the periosteum triggers a hyperplastic rxn of the inner layer
7. Bone Development
  1. 2 Main Types:
    1. Intramembranous ossification
      1. Flat bones mainly (e.g. skull)
      2. Mesenchymal cells differentiate into osteoblasts
        There is NO cartilage precursor template
    2. Endochondral ossification
      1. Long bones mainly
      2. Cartilage model of the bone to be formed is vascularised & replaced by bone
8. Physis (Growth plate)
  1. Esentially the remnant of the cartilage model located at the junction of Diaphysis & Epiphysis
  2. Imp. site: Many congenital or nutritional bone diseases in the growing animal manifest here
  3. In neonates & growing animals: Growth plate is "open", i.e. chrondrocyte proliferation balances cell maturation & death
    1. The growth plate "closes" & ossifies @ maturity
9. Bone Resorption
  1. Mediated by PTH & Calcitonin
  2. Parathyroid Hormone (PTH)
    1. Produced by chief cells in the parathyroid glands
      1. Increases serum Ca2+ levels (released in response to decreased serum Ca2+)
    2. STIMULATES Osteoclasts
  3. Calcitonin
    1. Produced by C -cells in the thyroid glands
      1. Decreases serum Ca2+ levels ( released in response to Increased serum Ca2+)
    2. INHIBITS Osteoclasts
  4. Low serum Ca2+ -> Induces PTH secretion -> Osteoclasts increase in # -> Attach to bone & resorb mineralized matrix => Serum Ca2+ INCREASES
10. Bone Dynamics
  1. Bone growth & maintenance of normal structure are directly related to mechanical forces which generate bioelectrical potentials (piezoelectricity)
    1. These potentials strengthen bone while inactivity reduces them, leading to bone loss
  2. Neonates: Bone growth predominates & modeling is Imp.
    1. Adults: Formation of bone is balanced by resorption (remodeling)
  3. Bone resorption may exceed formation in pathological stages (Hormonal, trauma, nutritional) or in old age & disuse
Pathology of Bone
1. Fractures
  1. Traumatic
    1. Normal bone broken by excessive force
  2. Pathological
    1. Abnormal bone broken by minimal or no trauma
  3. Fracture Repair
  4. Callus
    1. Bridges the gap, Encircles fracture site, Stabilizes fracture
  5. Factors which delay healing:
    1. Malnutrition
      1. Inadequate blood supply (leads to hypoxia)
        Leads to excess cartilage in Callus
        Healing can still occur since this can turn to bone
        Excess movement
        Leads to excess fibrous tissue in Callus
        This forms a false joint & can't heal properly
        Presence of Necrotic bone (may form a sequestrum)
        Bacterial Infection
2. Metabolic Bone Diseases
  1. Manifestation of Systemic Disease in the skeleton (Endocrine, Nutritional or Toxic Origin)
  2. Hyperparathyroidism (Fibrous Oesteodystrophy)
    1. Bone is resorbed & replaced by Fibrous, "rubbery" connective tissue
      1. Caused by: Persistently elevated PTH
    2. Causes of Increased PTH:
      1. Primary (Rare)
        Increased production of PTH NOT related to Ca2+ or P levels (i.e. autonomous)
        Due to parathyroid neoplasia or bilateral idiopathic parathyroid hyperplasia
        Results in => Hypercalcaemia
      2. Secondary (much more common)
        Renal
        Chronic renal failure (Reduced perfusion)
        => Retention of P ( & inadequate production of Vit. D by kidneys)
        Hyperphosphataemia & Hypocalcaemia (High P depresses Ca2+)
        Low Ca2+ => PTH production => Increased Ca2+ resorption from bone ("Rubber jaw")
        => Fibrous Osteodystrophy
        Nutritional (Poor diet) - "Rubber Jaw"
        Low Ca2+/ High P diets/ Vit. D deficiency
        Increased Osteoclastic resorption of bone & deposition of fibro-osteoid matrix that fails to mineralize
        Flat bones of the skull (Maxillary & Nasal bones) => Swell
        Long bones become soft w/ thin cortices (fracture easily)
        Ex: Horses - Grain/corn/bran
        Swine - Fed grain rations
        Dogs & Cats - Fed meat only diets
        More common in young, fast growing animals (w/ exception of horses)
        PTH secretion triggered by Decreased plasma Ca2+
      3. Paraneoplastic
        Parathyroid hormone- related protein produced by certain neoplasms
  3. Osteoporosis
    1. a LESION, not a distinct disease entity
    2. Reduction in bone quantity, not quality
      1. Bone resorption exceeds formation -> Pathological loss of bone
        The bone that remains is normally mineralized (Just not enough of it)
        => Prone to fractures due to reduced strength
    3. Causes:
      1. Starvation, nutritional deficiency (Ca2+)
        Senility
        Physical inactivity (Disuse)
        Farm animals (Most common cause)
        Calves on indigestible milk replacer
        Cattle on low quality hay in cold climates
    4. Localized or general
    5. Bone atrophy or osteopaenia
  4. Rickets
    1. Disease of the young, fast growing skeleton
    2. Pathogenesis:
      1. Failure of mineralization of Physeal & Epiphyeal cartilage during endochrondral ossification & of newly formed osteoid
    3. Due to diets low in Vit. D (or P - less common)
      1. Vit. D. maintains normal plasma levels of Ca2+ & P (acts on intestines, bones, kidneys)
        Calcitriol enhances GI absorption of Ca & P
        w/o Vit. D, only 10-15% of dietary Ca2+ is absorbed
    4. Growth plates are thickened
      1. As the zone of proliferation does not mineralize & mature => blood vessels & chondroclasts cannot invade so the cartilage is not removed
    5. Metaphyses are flared
      1. Because bone & cartilage cannot be removed (Osteoclasts cannot bind to poorly mineralized bone -> further accentuated by weight bearing)
    6. Enlarged costochondral junctions
  5. Osteomalacia
    1. Similar to Rickets, except disease of adult skeleton
    2. Failure of newly formed osteoid to mineralize
  6. Others
    1. Hormone -related (Hormones which directly affect bone growth & resorption - other than PTH & Calcitonin)
      1. Insulin, Growth hormone (Somatotrophin), Glucocorticoids, Oestrogens, Androgens & Thyroid Hormones
    2. Vitamin -Related Conditions
      1. Vitamin A
        Hypervitaminosis A
        Cats fed liver for prolonged periods
        Vertebrae fuse (Vertebral ankylosis) with each other due to bone proliferation (esp. in neck)
        Pathogenesis not clear
        Can also be teratogenic -> Cleft palate
        Hypovitaminosis A
        Due to dietary deficiency in Dam: Can be teratogenic in Pigs & large Cats
        More commonly, due to dietary deficiency in Neonates (Puppies, Kittens, Calves, Piglets)
        Deficiency => Failure of osteoclastic remodeling => Bone overgrowth & nerve compression (esp. optic nerves)
        Essential for normal bone growth in foetuses & neonates
        Stimulates osteoclasts
      2. Hypervitaminosis D
        Dietary or iatrogenic origin
        Usually chronic
        Hypercalcaemia: Metastatic calcification of soft tissues
      3. Vitamin C (Ascorbic Acid)
        Scurvy in Pigs, NHPs
        Imp. for collagen formation
        Haemorrhage
        Fractures
3. Inflammation
  1. Causes
    1. Bacteria (Most common)
      1. Viral, Fungal, Protozoal (Less common)
      2. Staphy, Strep, A. pyogenes, Gram -ve
  2. Routes of Infection
    1. Direct Inoculation
      1. At time of fracture
    2. Direct Extension
      1. From other infected sites (sinuses, middle ear, joints)
        Arthritis, synovitis, otitis media, rhinitis, sinusitis, meningitis or tooth root abscess
    3. Haematogenous
      1. Mostly young farm animals
  3. Gross lesions
    1. Suppurative exudate (in bacterial infection), Necrosis, Bone proliferation, Pathological fractures
    2. Dead bone portions may be separated from blood supply => forming bone sequestra
  4. Consequences
    1. Extension to adjacent bone
    2. Haematogenous spread to other bones & soft tissue
      1. Possible consequence of sepsis in young animals
        Salmonella dublin, A. pyogenes, Strep
        Animal often dies of sepsis prior to bone lesions appearing
    3. Pathologic features
      1. Draining fistulas, necrosis & loss of bone, new bone
    4. Sinus tracts to exterior
  5. Metaphyseal Osteopathy
    1. Idiopathic/ unknown cause (Infectious aetiology ?)
    2. Young, fast growing Dogs (Large or giant breeds)
    3. Distal radius & ulna most severely affected: bilaterally symmetrical
    4. Swelling in metaphyses of long bones (Neutrophilic infiltrate)
      1. Fever, lameness, suppurative inflammation & necrosis of metaphyses
    5. Most resolve spontaneously, but can progress to periosteal bone proliferation
      1. May wax & wane
4. Neoplastic Bone Diseases
  1. Bone tissue:
    1. Osteoma
      1. Uncommon
      2. Horses & Cattle
      3. Flat bones (skull & scapula)
      4. Disfigurement: Obstruct nasal passages
      5. Recur if not completely removed
    2. Osteosarcoma (OSA)
      1. Any neoplasm of mesenchymal origin in which the cells produce Osteoid
      2. Dogs & Cats (Otherwise uncommon)
      3. Dogs: OSA(80%) > Chrondrosarcoma (10%) > Fibrosarcoma/haemangiosarcoma (7%) > Lymphoid & myeloid tumors of marrow
      4. Giant breeds of Dog are at massively increased risk
      5. Strong site preference (Dogs):
        Appendicular skeleton 3-4x more frequently involved than axial
        Proximal humerus, distal radius, proximal tibia & distal femur
        "Away from the elbow - towards the knee"
      6. Survival time is slightly better for axial than appendicular OSA (Dogs)
      7. Prognosis is poor due to early metastasis
        Pulmonary metastases
        Bone metastases
  2. Cartilage:
    1. Chondroma
      1. Benign neoplasm of cartilage
      2. Rare
      3. Slow growing, Expansile w/ smooth border
    2. Chrondrosarcoma
      1. Any malignant neoplasm in which mesenchymal cells produce chondroid matrix
      2. Dogs (most common), Sheep
        Flat bones
      3. Slower growth rate, longer clinical course & later to metastasize than OSA
      4. Metastatic rate: 20%
5. Hyperostotic Bone Diseases
  1. Hypertrophic Pulmonary Osteopathy (HPO)
    1. Periosteal proliferation of bone on diaphyses & metaphyses of distal limbs
      1. Progressive & bilateral
        Most cases: Have intrathoracic neoplasm or chronic inflammatory focus
        Has also been associated w/ intra-abdominal lesions - Ex. Botryoid rhabdomyosarcoma in the canine urinary bladder & ovarian tumors in Horses
  2. Craniomandibular Osteopathy
    1. West Highland terriers & Scottish terriers
      1. Puppies: Arises @ 4 -7 months
    2. Bilaterally symmetrical periosteal proliferation of new bone
    3. Irregular thickening of rami of mandibles & skull bones (tympanic bullae)
6. Developmental Bone Diseases
  1. Primary abnormalities of Bone, Cartilage or Mesenchyme
  2. Hereditary or Environmental
  3. Localized or Generalized
    1. Generalized
      1. Proportionate Dwarfism
        Minature breeds: Due to growth factor deficit
      2. Chondrodysplasia
        Abnormal cartilage formation
        Cattle, Dogs, Sheep, Pigs & Cats
        Affects bones which form from a cartilage model (endochondral ossification) - long bones are shorter than normal
        Leads to Disproportionate Dwarfism
        Localized forms occur in some Dogs as a breed associated characteristic (e.g. affecting skulls of Pekingnese & Bulldogs or the limbs of Dachshunds & Basset hounds)
      3. Osteopetrosis (Marble bone disease)
        Hyperactive osteoblasts/ Failure of resorption by osteoclasts => Failure of remodeling of cancellous bone
        Bones become thickened & dense, but brittle
        Associated w/ viral infections (e.g. FeLV, BVD)
    2. Localized
      1. Cervical Vertebral Stenotic Myelopathy (Wobblers)
        Equine disease
        Narrowing of the vertebral canal due to vertebral malalignment or maldevelopment
        Fast growing males ranging from 8 months to 4 yrs
        Hind limb ataxia: Due to cord compression
        Dogs: Great dane, Doberman
        Static: C5-C7 (1-4yrs)
        Dynamic: C3 -C5 (1 yr)
      2. Angular Limb Deformity
        Lateral deviation of distal portion of limb (usually)
        Most common in foals: Congenital or Acquired
        Causes: Malpositioning (in utero), excessive joint laxity, hypothyroidism, trauma, overnutrition, defective endochrondral ossification
7. Miscellaneous Bone Lesions
  1. Ossifying Pachymeningitis
    1. Plaques of bone form in the Dura of the spinal cord (especially in older dogs)
    2. No clinical significance
  2. Heterotopic Bone
    1. Spicules of bone form in the lungs of older dogs
    2. No clinical significance
  3. Ossifying Epulides
    1. Neoplasms of peridontal fibroblast origin
    2. Occur in oral cavity (esp. Boxers)
    3. Benign -> Complete removal -> Good prognosis

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Musculoskeletal Pathology

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