Pathology of the Musculoskeletal Muscles Elaborate

PATHOLOGY OF
MUSCULOSKELETAL
SYSTEM
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I. DISEASES OF THE
BONES AND JOINTS

Healing of fracture by callus formation
depends upon some clinical
considerations whether the fracture is:
traumatic (in previously normal
bone)
pathological (in previously diseased
bone)
1.TRAUMATIC DISEASES.
FRACTURE HEALING

 complete or incomplete like green-stick
fracture
 simple (closed) - overlying tissue is
intact
 comminuted (splintering of bone or
displacing )
 compound (communicating to skin
surface).

Primary union of fractures
occurs in a few special situations
when the ends of fracture are
approximated as is done by
application of compression clamps.
In these cases, bony union takes
place with formation of medullary
callus without periosteal callus
formation. The patient can be made
ambulatory early but there is more
extensive bone necrosis and slow
healing.

Secondary union is the more
common process of fracture healing.
3 headings:
1) Procallus formation
2) Osseous callus formation
3) Remodelling

Procallus formation
1. Haematoma forms due to bleeding
from torn blood vessels, filling the
area surrounding the fracture.
2. Local inflammatory response
occurs at the site of injury with
exudation of fibrin, polymorphs and
macrophages. The macrophages
clear away the fibrin, red blood cells,
inflammatory exudate and debris.
Fragments of necrosed bone are
scavenged by macrophages and
osteoclasts.

3. Ingrowth of granulation tissue
begins with neovascularisation and
proliferation of mesenchymal cells
from periosteum and endosteum. A
soft tissue callus is thus formed
which joins the ends of fractured
bone without much strength.

4. Callus composed of woven
bone and cartilage
Starts within the first few days. The
cells of inner layer of the periosteum
have osteogenic potential and lay down
collagen as well as osteoid matrix in the
granulation tissue.
The osteoid undergoes calcification
and is called woven bone callus. A much
wider zone over the cortex on either
side of fractured ends is covered by the
woven bone callus and united to bridge
the gap between the ends, giving
spindle shaped or fusiform appearance
to the union.

In poorly immobilised fractures
(e.g. fracture ribs), the subperiosteal
osteoblasts may form cartilage at the
fracture site.
At times, callus is composed of
woven bone as well as cartilage,
temporarily immobilising the bone
ends. This stage is called provisional
callus or procallus formation and is
arbitrarily divided into external,
intermediate and internal procallus.

II. OSSEOUS CALLUS FORMATION
The procallus acts as scaffolding on
which osseous callus composed of
lamellar bone is formed. The woven
bone is cleared away by incoming and
the calcified cartilage disintegrates.
In their place, newly-formed blood
vessels and osteoblasts invade, laying
down osteoid which is calcified and
lamellar bone is formed by developing
Haversian system concentrically around
the blood vessels.

III. REMODELLING
During the formation of lamellar bone,
osteoblastic laying and osteoclastic
removal are taking place remodelling the
united bone ends, which after sometime,
is indistinguishable from normal bone.
The external callus is cleared away,
compact bone (cortex) is formed in place
of intermediate callus and the bone
marrow cavity develops in internal
callus.

COMPLICATIONS
1. Fibrous union may result instead of
osseous union if the immobilisation of
fractured bone is not done.
Occasionally, a false joint may develop
at the fracture site (pseudoarthrosis).
2. Non-union may result if some soft
tissue is interposed between the
fractured ends.
3. Delayed union may occur from
causes of delayed wound healing in
general such as infection, inadequate
blood supply, poor nutrition, movement
and old age.

Fracture healing A, Haematoma formation and local inflammatory
response at the fracture site. B, Ingrowth of granulation tissue with
formation of soft tissue callus. C, Formation of procallus composed of
woven bone and cartilage with its characteristic fusiform appearance
and having 3 arbitrary components—external, intermediate and internal
callus. D, Formation of osseous callus composed of lamellar bone
following clearance of woven bone and cartilage. E, Remodelled bone
ends; the external callus cleared away. Intermediate callus converted
into lamellar bone and internal callus developing bone marrow cavity.

Response of bone to fracture. Osteoblasts arise
from pluripotent progenitor cells in the periosteum and
granulation tissue. They produce woven bone, resulting
in a bony callus that stabilizes the fracture site.

Contrast the morphology of the original lamellar bone to that
of woven bone. Woven bone contains many more osteocytes.
The necrotic lamellar bone and the reactive woven bone will be
removed by osteoclasts and replaced by new, mature lamellar
bone. This process is called remodeling and takes place over
months to years. Uploaded by: http://mbbshelp.com

Healed
fracture. Femur
recovered by
archaeologists
from a burial
about 200 years
ago. There has
been a fracture,
which has
healed with a
great deal of
callus formation.

2.INFLAMMATORY
DISEASES

RHEUMATOID ARTHRITIS
Reumatoid arthritis is a chronic
systemic inflammatory disorder that may
affect many tissues and organs – skin,
blood vessels, heart, lungs and muscles –
but principally attacks the joints,
producing a nonsuppurative proliferative
synovitis that often progresses to
destruction of the articular cartilage and
ankylosis of the joints.

ETIOPATHOGENESIS
Present concept on etiology
and pathogenesis proposes that RA
occurs in an immunogenetically
predisposed individual to the effect
of microbial agents acting as
trigger antigen.
The role of superantigens
which are produced by several
microorganisms with capacity to
bind to HLADR molecules (MHC-II
region) has also emerged.

MORPHOLOGIC FEATURES
ARTICULAR LESIONS
RA involves first the small
joints of hands and feet and then
symmetrically affects the joints of
wrists, elbows, ankles and knees.
The proximal interphalangeal
and metacarpophalangeal joints
are affected most severely.
Frequently cervical spine is
involved but lumbar spine is
spared.

HISTOLOGICALLY
The characteristic feature is diffuse proliferative
synovitis with formation of pannus. Initially the
synovium becomes grossly edematous, thickned and
hyperplastic, transforming its smooth contour to one
covered by delicate and bulbousfronds. Numerous
folds of large villi of synovium.
The characteristic histologic features include:
1. Infiltration of synovial stroma by a dence
perivascular inflammatory infiltrate composed of
lymphoid follicles, plasma cells, and macrophages
filling the synovial stroma;
2. Increased vascularity owing to vasodilation and
angiogenesis, with superficial hemosiderin deposits
3. Aggregation of organizing fibrin covering portions of
the synovium and floating in the joint space as rice
bodies; Uploaded by: http://mbbshelp.com

4. Accumulation of neutrophils in the synovial
fluid and along the surface of synovium but
usually not deep in the synovial stroma;
5. Osteoclastic activity in underlying bone,
allowing the synovium to penetrate into the
boneforming juxta-articular erosions,
subchondrial cysts and osteoporosis
(increased of porosity of the bones resulting
from a reduction in bone mass); muscle
frequently accompanies the arthritis.

6. Pannus formation – the pannus is a
fibrocellular mass of synovium and synovial
stroma consisting of inflammatory cells,
granulomatous tissue, and fibroblasts, which
causes erosion of the underlying cartilage. In
time, after the cartilage has been destroyed,
the pannus bridges the apposing bones forming
a fibrous ankylosis (loss of joint function).
Inflammation in the tendons, ligaments and
occasionally the adjacent skeletal muscle
frequently accompanies the arthritis.

EXTRA – ARTICULAR LESIONS
Nonspecific inflammatory changes are seen
in the blood vessels (acute vasculitis), lungs,
pleura, pericardium, myocardium, lymph
nodes, peripheral nerves and eyes.
Rheumatoid nodules are particularly found
in the subcutaneous tissue over pressure
points such as the elbows, occiput and
sacrum. The centre of these nodules consists
of an area of fibrinoid necrosis and cellular
debris, surrounded by several layers of
palisading large epithelioid cells, and
peripherally there are numerous lymphocytes,
plasma cells and macrophages. Similar
nodules may be found in the lung
parenchyma, pleura, heart valves,
myocardium and other internal organs.

FORMS OF RA
1. Juvenile RA found in adolescent patients under
16 years of age is characterised by acute onset of
fever and predominant involvement of knees and
ankles. Pathologic changes are similar but RF is
rarely present.
2. Felty’s syndrome consists of polyarticular RA
associated with splenomegaly and hypersplenism
and consequent haematologic derangements.
3. Ankylosing spondylitis or rheumatoid
spondylitis is rheumatoid involvement of the
spine, particularly sacroiliac joints, in young male
patients. The condition has a strong HLA-B27
association and may have associated
inflammatory diseases such as inflammatory
bowel disease, anterior uveitis and Reiter’s
syndrome.

In this case, there is marked destruction of
the epiphyseal bone. The joint spaces are
narrowed, because of the destruction of the
articular cartilage.

This specimen illustrates the inflamed synovium
characteristic of acute rheumatoid arthritis. The
prominent, hyperemic synovial membrane on which
strands of fibrin are evident.

This image emphasizes the inflammatory nature of
rheumatoid arthritis. In this section of reactive synovium,
lymphocytes, plasma cells, and macrophages expand the
synovium. The vascularity is increased. The synovial
membrane is also hyperplastic. The inflammatory infiltrate
may organize into distinct lymphoid nodules.

RANK-L, released from the surface of lymphocytes by
metalloproteinases, stimulates osteoclastogenesis. The
osteoclasts are important players in the destruction of the
subchondral bone in rheumatoid arthritis. Inflammatory
mediators released from the pannus stimulate osteoclast
activity, which results in erosion and destruction of the
subchondral bone. As well, the pannus isolates the articular
cartilage from the synovial fluid, resulting in degeneration of

Rheumatoid nodules consist of a central zone of fibrinoid necrosis
surrounded by a prominent rim of epithelioid histiocytes and
numerous lymphocytes and plasma cells. Rheumatoid nodules
occur in approximately 20% to 25% of patients with definitive or
classic rheumatoid arthritis. Nodules generally are associated with
severe articular and systemic disease and with high titers of
rheumatoid factor.

Pannus

SUPPURATIVE ARTHRITIS
Infectious or suppurative arthritis is invariably an
acute inflammatory involvement of the joint.
Bacteria usually reach the joint space from:
 the blood stream but other routes of infection
 by direct contamination of an open wound
 lymphatic spread.
Immunocompromised and debilitated patients
are increasingly susceptible to suppurative arthritis.
The common causative organisms are gonococci,
meningococci, pneumococci, staphylococci,
streptococci, H. influenzae and gram-negative bacilli.

Clinically, the patients present with manifestations
of any local infection such as redness, swelling, pain
and joint effusion. Constitutional symptoms such as
fever, neutrophilic leukocytosis and raised ESR are
generally associated.
The hematogenous infections joint involvement is
more often monoarticular rather than polyarticular.
The large joints of lower extremities such as the knee,
hip and ankle, shoulder and sternoclavicular joints are
particularly favoured sites.
The process begins with hyperemia, synovial
swelling and infiltration by polymorphonuclear and
mononuclear leukocytes along with development of
effusion in the joint space. There may be formation of
inflammatory granulation tissue and onset of fibrous
adhesions between the opposing articular surfaces
resulting in permanent ankylosis

3.METABOLIC
DISEASES

HYPERPARATHYROIDISM
Hyperparathyroidism of primary or secondary
type results in oversecretion of parathyroid
hormone which causes increased osteoclastic
resorption of the bone (initiate the release of
mediators that stimulate osteoclasts activity).
Severe and prolonged hyperparathyroidism
results in osteitis fibrosa cystica. The lesion is
generally induced as a manifestation of primary
hyperparathyroidism (usually an adenoma of the
parathyroid gland), and less frequently, as a result
of secondary hyperparathyroidism such as in
chronic renal failure (renalosteodystrophy).
Secondary hyperparathyroidism is commonly
caused by prolonged states of hypocalcemia
resulting in compensatory hypersecretion of
parathyroid hormone.

The clinical manifestations:
susceptibility to fracture, skeletal
deformities, joint pains and dysfunctions
as a result of deranged weight bearing.
The bony changes may disappear
after cure of primary
hyperparathyroidism such as removal of
functioning adenoma.
The chief biochemical abnormality of
excessive parathyroid hormone is
hypercalcaemia, hypophosphataemia and
hypercalciuria.

The bone lesions of primary
hyperparathyroidism affect the long
bones more severely and may range
from minor degree of generalised
bone rarefaction to prominent areas of
bone destruction with cyst formation
or brown tumours.

Grossly, there are focal areas of erosion
of cortical bone and loss of lamina dura
at the roots of teeth.
Histologically, the following sequential
changes appear over a period of time:
Earliest change is demineralisation and
increased bone resorption beginning at
the subperiosteal and endosteal surface
of the cortex and then spreading to the
trabecular bone. There is replacement of
bone and bone marrow by fibrosis
coupled with increased number of
bizarreosteoclasts at the surfaces of
moth-eaten trabeculae and cortex
(osteitis fibrosa).

As a result of increased resorption,
microfractures and microhaemorrhages
occur in the marrow cavity leading to
development of cysts (osteitis fibrosa
cystica).
Haemosiderin-laden macrophages and
multinucleate giant cells appear at the
areas of haemorrhages producing an
appearance termed as ‘brown tumour’ or
‘reparative giant cell granuloma of
hyperparathyroidism’

Osteitis fibrosa
cystica

OSTEOARTHROSIS
Osteoarthritis (OA), also called
osteoarthrosis or degenerative joint
disease (DJD), is the most common
form of chronic disorder of synovial
joints.
It is characterised by progressive
degenerative changes in the articular
cartilages over the years, particularly
in weight-bearing joints.

TYPES AND PATHOGENESIS
OA occurs in 2 clinical forms—primary and
secondary.
Primary OA occurs in the elderly, more
commonly in women than in men. Little is
known about the etiology and pathogenesis of
primary OA. The condition may be regarded as
a reward of longevity. Probably, wear and tear
with repeated minor trauma, heredity, obesity,
aging per se, all contribute to focal
degenerative changes in the articular cartilage
of the joints. Genetic factors favouring
susceptibility to develop OA have been
observed; genetic mutations in proteins which
regulate the cartilage growth have been
identified e.g. FRZB gene.

Secondary OA may appear at
any age and is the result of any
previous wear and tear phenomena
involving the joint such as previous
injury, fracture, inflammation, loose
bodies and congenital dislocation of
the hip. The molecular mechanism of
damage to cartilage in OA appears to
be the breakdown of collagen type
II, probably by IL-1, TNF and nitric
oxide.

The weight-bearing joints such as hips, knee
and vertebrae are most commonly involved but
interphalangeal joints of fingers may also be
affected. The pathologic changes occur in the
articular cartilages, adjacent bones and
synovium:
1. Articular cartilages. The regressive
changes are most marked in the weight-bearing
regions of articular cartilages. There is loss of
cartilaginous matrix (proteoglycans) resulting in
progressive loss of normal metachromasia. This
is followed by focal loss of chondrocytes, and at
other places, proliferation of chondrocytes
forming clusters. Further progression of the
process causes loosening, flaking and fissuring of
the articular cartilage resulting in breaking off of
pieces of cartilage exposing subchondral bone.

2. Bone. The denuded subchondral
bone appears like polished ivory. There
is death of superficial osteocytes and
increased osteoclastic activity causing
rarefaction, microcyst formation and
occasionally microfractures of the
subjacent bone. These changes result in
remodelling of bone and changes in the
shape of joint surface leading to
flattening and mushroom-like
appearance of the articular end of the
bone.

The margins of the joints respond
to cartilage damage by osteophyte or
spur formation. These are
cartilaginous outgrowths at the joint
margins which later get ossified.
Osteophytes give the appearance of
lipping of the affected joint.
Loosened and fragmented
osteophytes may form free ‘joint
mice’ or loose bodies.

3. Synovium. Initially, there are
no pathologic changes in the
synovium but in advanced cases
there is low-grade chronic synovitis
and villous hypertrophy. There may
be some amount of synovial effusion
associated with chronic synovitis.

The manifestations of OA are most
conspicuous in large joints such as hips,
knee and back. However, the pattern of
joint involvement may be related to the
type of physical activity such as ballet-
dancers’ toes, karate fingers etc.
Minor degree of OA may remain
asymptomatic. In symptomatic cases,
clinical manifestations are joint stiffness,
diminished mobility, discomfort and pain.
The symptoms are more prominent on
waking up from bed in the morning.

Degenerative changes in the
interphalangeal joints lead to hard bony
and painless enlargements in the form of
nodules at the base of terminal phalanx
called Heberden’s nodes. These nodes
are more common in females and
heredity seems to play a role.
In the spine, osteophytes of OA may
cause compression of cervical and
lumbar nerve root with pain, muscle
spasms and neurologic abnormalities.

The knee joint
has been opened
anteriorly under the
patella. For
orientation, the hip is
to the right and the
foot to the left. There
has been extensive
destruction of the
articular cartilage of
the lower end of the
femur. The synovium
is not hyperplastic,
nor is it inflamed.
There is no evidence
of pannus.

A common
finding in
degenerative joint
disease is the
formation of
osteophytes at the
margin of affected
joints. In this
image, there are
three osteophytes
projecting from the
intervertebral
joints.

Osteoarthritis
of the hip is
common. In this
typical image,
there is marked
irregularity and
erosion of the
articular surface.
Very little
articular cartilage
remains.

GOUT
Gout is a disorder of purine metabolism
manifested by the following features, occurring
singly or in combination:
1. Increased serum uric acid concentration
(hyperuricaemia).
2. Recurrent attacks of characteristic type of acute
arthritis in which crystals of monosodium urate
monohydrate may be demonstrable in the
leucocytes present in the synovial fluid.
3. Aggregated deposits of monosodium urate
monohydrate (tophi) in and around the joints of the
extremities.

The disease usually begins in 3rd decade of
life and affects men more often than women.
A family history of gout is present in a
fairly large proportion of cases indicating role
of inheritance in hyperuricaemia.
Clinically, the natural history of gout
comprises 4 stages:
asymptomatic hyperuricaemia
acute gouty arthritis
asymptomatic intervals of intercritical periods
 chronic tophaceous stage.
In addition, gout nephropathy and urate
nephrolithiasis may occur.

TYPES
Hyperuricaemia and gout may be
classified into 2 types: metabolic and
renal, each of which may be primary or
secondary.
Primary refers to cases in which the
underlying biochemical defect causing
hyperuricaemia is not known, while
secondary denotes cases with known
causes of hyperuricaemia.

The pathologic manifestations of gout
include:
1. Acute gouty arthritis. This stage
is characterised by acute synovitis
triggered by precipitation of sufficient
amount of needle-shaped crystals of
monosodium urate from serum or
synovial fluid. There is joint effusion
containing numerous polymorphs,
macrophages and microcrystals of
urates.

The mechanism of acute inflammation
appears to include phagocytosis of
crystals by leucocytes, activation of the
kallikrein system, activation of the
complement system and urate-mediated
disruption of lysosomes within the
leucocytes leading to release of lysosomal
products in the joint effusion.
Acute gouty arthritis is predominantly
a disease of lower extremities, affecting
most commonly great toe. Other joints
affected, in order of decreasing
frequency, are: the instep, ankles, heels,
knees, wrists, fingers and elbows.

2. Chronic tophaceous
arthritis. Recurrent attacks of
acute gouty arthritis lead to
progressive evolution into chronic
arthritis. The deposits of urate
encrust the articular cartilage.
There is synovial proliferation,
pannus formation and progressive
destruction of articular cartilage and
subchondral bone. Deposits of
urates in the form of tophi may be
found in the periarticular tissues.

3. Tophi in soft tissue. A tophus
(meaning ‘a porous stone’) is a
mass of urates measuring a few
millimeters toa few centimeters in
diameter. Tophi may be located in
the periarticular tissues as well as
subcutaneously such as on the
hands and feet. Tophi are
surrounded by inflammatory
reaction consisting of macrophages,
lymphocytes, fibroblasts and
foreign body giant cells.

4. Renal lesions. Chronic gouty arthritis
frequently involves the kidneys. Three
types of renal lesions are described in
the kidneys:
1) Acute urate nephropathy is attributed
to the intratubular deposition of
monosodium urate crystals resulting in
acute obstructive uropathy.
2) Chronic urate nephropathy refers to
the deposition of urate crystals in the
renal interstitial tissue.
3) Uric acid nephrolithiasis is related to
hyperuricaemia resulting in
hyperuricaciduria.

This is an example of chronic gout with gouty tophi. There
are numerous asymmetrical, periarticular swellings. These
represent inflammatory reaction to sodium urate crystals. The
lesion on the fifth digit of the left hand has ulcerated, revealing
the white crystals. Tophi appear only after repeated attacks of
gout in patients whose hyperuricemia has not been treated.

Histologically, tophi consist of crystals that are
surrounded by macrophages, lymphocytes, and often
foreign body giant cells. In routinely processed sections,
the crystals are removed during processing.

Gouty tophi

Knee joint in
gout. The knee joint
has been
opened to show the
heavy deposition of
urate crystals in the

4.DISPLASTIC
DISEASES

Fibrous dysplasia
It is a benign condition, possibly of
developmental origin, characterised by the
presence of localised area of replacement of
bone by fibrous connective tissue with a
characteristic whorled pattern and containing
trabeculae of woven bone.
Radiologically, the typical focus of fibrous
dysplasia has well demarcated ground-glass
appearance.
Three types of fibrous dysplasia are
distinguished — monostotic, polyostotic, and
Albright syndrome. The spectrum of
phenotype of the disease is due to activating
mutation in GNAS1 gene, which encodes for
α-subunits of the stimulatory G-protein, GSα.

Monostotic fibrous dysplasia
Monostotic fibrous dysplasia affects a
solitary bone and is the most common type,
comprising about 70% of all cases.
The condition affects either sex and
most patients are between 20 and 30 years
of age.
The bones most often affected, in
descending order of frequency, are: ribs,
craniofacial bones (especially maxilla),
femur, tibia and humerus. The condition
generally remains asymptomatic and is
discovered incidentally, but infrequently
may produce tumour-like enlargement of
the affected bone.

POLYOSTOTIC FIBROUS DYSPLASIA
Polyostotic form of fibrous dysplasia
affecting several bones constitutes about 25%
of all cases.
Both sexes are affected equally but the
lesions appear at a relatively earlier age than
the monostotic form.
Most frequently affected bones are:
craniofacial, ribs, vertebrae and long bones of
the limbs. Approximately a quarter of cases
with polyostotic form have more than half of the
skeleton involved by disease.
The lesions may affect one side of the body
or may be distributed segmentally in a limb.
Spontaneous fractures and skeletal deformities
occur in childhood polyostotic form of the
disease. Uploaded by: http://mbbshelp.com

ALBRIGHT SYNDROME
Also called McCune-Albright
syndrome, this is a form of polyostotic
fibrous dysplasia associated with
endocrine dysfunctions and accounts for
less than 5% of all cases.
Unlike monostotic and polyostotic
varieties, Albright syndrome is more
common in females. The syndrome is
characterised by polyostotic bone
lesions, skin pigmentation (cafe-au-lait
macular spots) and sexual precocity, and
infrequently other endocrinopathies.

All forms of fibrous dysplasia have an
identical pathologic appearance.
Grossly, the lesions appear as
sharply-demarcated, localised defects
measuring 2-5 cm in diameter, present
within the cancellous bone, having thin
and smooth overlying cortex. The
epiphyseal cartilages are generally spared
in the monostotic form but involved in the
polyostotic form of disease.
Cut section of the lesion shows
replacement of normal cancellous bone of
the marrow cavity by gritty, grey-pink,
rubbery soft tissue which may have areas
of haemorrhages, myxoid change and
cyst formation.

HISTOLOGICALLY
The lesions of fibrous dysplasia have
characteristic benign-looking fibroblastic
tissue arranged in a loose, whorled
pattern in which there are irregular and
curved trabeculae of woven (non-
lamellar) bone in the form fish-hook
appearance or Chinese letter shapes.
Characteristically, there are no
osteoblasts rimming then trabeculae of
the bone, suggesting a maturation defect
in the bone. Rarely, malignant change
may occur in fibrous dysplasia, most often
an osteogenic sarcoma.

Fibrous dysplasia

Fibrous
dysplasia

CHONDROMATOSIS OF
JOINTS
Synovial chonromatosis is an uncommon
condition of unknown cause characterized by
the occurrence of multiple foci of cartilaginous
metaplasia in the synovial membrane.
The cartilage appears as nodules that may
undergo ossification and may become
detached into the joint cavity as “loose
bodies”. The knee is commonly affected, with
of pain, swelling, limitation of movement, and
intermittent locking. Osteoarthrosis may
result.

II.DIASEASES OF THE
SKELETAL MUSCLES

Depending on the etiology of the disease
of muscle are divided into the following
groups:
neurogenic (e.g., muscle atrophy after
crossing the nerve);
hereditary-muscular dystrophy (myopathy);
metabolic-endocrine myopathies (such as in
hyperthyroidism);
toxic-myopathy caused by salts of heavy
metals, alcohol, etc.;
Autoimmune - myasthenia gravis,
polymyositis, dermatomyositis;
infectious-viral and bacterial meningitis
myositis
traumatic-Lysis syndrome long muscle
strength;
tumor muscle diseases.

MUSCULAR DYSTROPHIES
Muscular dystrophies are a group of
genetically-inherited primary muscle diseases,
having in common, progressive
andunremitting muscular weakness.
Six major forms of muscular dystrophies
are described: Duchenne’s, Becker’s,
myotonic, facio-scapulohumeral, limb-girdle
and oculopharyngeal type.
Each type of muscular dystrophy is a
distinct entity having differences in inheritance
pattern, age at onset, clinical features, other
organ system involvements and clinical
course. However, in general, muscular
dystrophies manifest in childhood or in early
adulthood. Family history of neuromuscular
disease is elicited in many cases.

CONTRASTING FEATURES OF
MUSCULAR DYSTROPHIES
Type Inheri
tance
Age
at
Onset
Clinical
Features
Other
Systems
Course
1.
Duchenne’
s type
X-
linked
recessi
ve
By age
5
Symmetric
weakness;
initially
pelvifemoral;
later weakness of
girdle muscles;
pseudo-
hypertrophy of
calf muscles
Cardiomeg
aly;
reduced
intelligence
Progress
ive;
death by
age 20
due to
respirato
ry failure
2. Becker’s
type
X-
linked
recessi
ve
By
2nd
decad
e
Slow progressive
weakness of
girdle muscle
(minor variant of
Duchenne’s type)
Cardiomeg
aly
Benign

3.
Myotonic
type
Autosom
al
dominant
Any
decade
Slow
progressive
weakness and
myotonia of
eyelids, face,
neck, distal limb
muscles
Cardiac
conduction
defects; mental
impairment;
cataracts;
frontal baldness;
gonadal atrophy
Benign
4.
Faciosc
apulo-
humera
l type
Autoso
mal
dominan
t
2nd-
4th
decad
e
Slowly
progressive
weakness of
facial,
scapular and
humeral
muscles
Hypertension Benign
5.
Limb-
girdle
type
Autoso
mal
recessiv
e
Early
child-
hood
to
adult
Slowly
progressive
weakness of
shoulder and
hip girdle
muscles
Cardiomyopath
y
Variabl
e
progre
ssion

6. Oculo-
pharynge
al type
Autoso
mal
domin
ant
5th-6th
decade
Slowly progressive
weakness of
extraocular eyelid,
face and pharyngeal
muscles
— Rarelypro
gressive

Common to all forms of muscular dystrophies
are muscle fibre necrosis, regenerative activity,
replacement by interstitial fibrosis and adipose
tissue.
1)variation in fiber size (diameter) due to
presence of both small and giant fibers, some-times
with fiber splitting;
2)increased numbers internalized nuclei (beyond
the normal range of 3% to 5%);
3)degeneration, necrosis and phagocytosis of
muscle fibers;
4)regeneration of muscle fibers;
5)proliferation of endomysial connective tissue.

Histopathology of gastrocnemius muscle from
patient who died of Duchenne myopathy. Cross section
of muscle shows extensive replacement of muscle
fibers by adipose cells. Uploaded by: http://mbbshelp.com

MYOSITIS (INFLAMMATION OF
MUSCLE)
A large number of infectious agents affect muscle,
leading to myositis.
Causes of myositis.
I.Infectious diseases:
1.Bacterial: 1)local infection with pyogenic bacteria,
usually secondary to trauma;
2)bacteremic myositis (in infective
endocarditis, typhoid fever, etc.);
3)gas gangrene.
2.Viral (coxsackievirus infection, influenza, HIV
infection, etc.).
3.Parasitic (trichinosis, toxoplasmosis, cysticercosis).
4.Exotoxic – Diphtheria.

II.Immune diseases:
1.Polymyositis-dermatomyositis.
2.Systemic lupus erithematosus.
3.Progressive systemic sclerosis.
4.Sarcoidosis.
5.Myastenia gravis (associated with anti-
striated muscle antibody in serum).
III.Other causes:
1.Radiation.
2.Ischemia.
3.Myositis ossificans (is characterized by bone
formation in the involved muscle).

Classification of myositis.
I.Course: 1)acute, b)chronic.
II.Morphology:
1)serous, 2)purulent, 3)granulomatous.
Morphology.
Grossly – muscle become soft, flabby and
edematous.
Microscopically – hyperemia, edema,
inflammatory infiltration with leukocytes,
lymphocytes, plasma cells etc., foci of
necrosis.

MYASTHENIA GRAVIS
Myasthenia gravis (MG) is a
neuromuscular disorder of autoimmune
origin in which the acetylcholine receptors
(AChR) in the motor end-plates of the
muscles are damaged.
The term ‘myasthenia’ means ‘muscular
weakness’ and ‘gravis’ implies ‘serious’;
thus both together denote the clinical
characteristics of the disease.

MG may be found at any age but adult
women are affected more often than adult men
in the ratio of 3:2.
The condition presents clinically with
muscular weakness and fatiguability, initially in
the ocular musculature but later spreads to
involve the trunk and limbs.
There is about 10% mortality in MG which is
due to severe generalised disease and
involvement of respiratory muscles.
Several other autoimmune diseases have
been found associated with MG such as
autoimmune thyroiditis, rheumatoid arthritis,
SLE, pernicious anaemia and collagenvascular
diseases. Uploaded by: http://mbbshelp.com

Grossly, the muscles appear normal until late
in the course of disease when they become
wasted.
By light microscopy, a few clumps of
lymphocytes may be found around small blood
vessels. Degenerating muscle fibres are
present in half the cases.
Electron microscopy reveals reduction in
synaptic area of the motor axons due to
flattening or simplification of postsynaptic
folds. The number of AChRs is greatly
reduced. By immunocytochemistry combined
with electron microscopy, it is possible to
demonstrate the complex of IgG and
complement at the neuromuscularjunctions.

NEOPLASMS OF MUSCLE
1.Rhabdomyoma – benign tumor, is
distinctly rare.
2.Rhabdomyosarcoma – malignant
tumor; histologically subclassified into the
embrional, alveolar and pleomorphic
variants.
From connective tissue stroma of muscle
may arise: fibroma and desmoid (benign
tumors from fibrous tissue), hemangioma
(benign tumor from blood vessels).

Rhabdomyosarcoma

Rhabdomyosarcoma, Alveolar

Embryonal Rhabdomyosarcoma

TUBERCULOSIS OF
BONES AND JOINTS

TUBERCULOUS OSTEOMYELITIS
The tubercle bacilli, M. tuberculosis,
reach the bone marrow and synovium
most commonly by hematogenous
dissemination from infection elsewhere,
usually the lungs, and infrequently by
direct extension from the pulmonary or
gastrointestinal tuberculosis.
The disease affects adolescents and
young adults more often. Most frequently
involved are the spine and bones of
extremities.

The bone lesions in tuberculosis
have the same general histologic
appearance as in tuberculosis
elsewhere and consist of central
caseous necrosis surrounded by
tuberculous granulation tissue.
The tuberculous lesions appear as a
focus of bone destruction and
replacement of the affected tissue by
caseous material and formation of
multiple discharging sinuses through
the soft tissues and skin. Involvement
of joint spaces and intervertebral disc
are frequent.

Tuberculosis of the spine, Pott’s disease,
often commences in the vertebral body
and may be associated with compression
fractures and destruction of intervertebral
discs, producing permanent damage and
paraplegia.
Extension of caseous material along with
pus from the lumbar vertebrae to the
sheaths of psoas muscle produces psoas
abscess or lumbar cold abscess. The cold
abscess may burst through the skin and
form sinus. Long-standing cases may
develop systemic amyloidosis.

Tuberculosis Pott's
fracture of the
vertebrae
Tuberculous psoas
abscess.

TUBERCULOUS ARTHRITIS
Tuberculous infection of the joints results most
commonly from hematogenous dissemination of
the organisms from pulmonary or other focus of
infection. Another route of infection is direct spread
from tuberculous osteomyelitis close to the joint.
The disease may occur in adults but is found
more commonly in children.
Tuberculous involvement of the joints is
usually monoarticular type but tends to be more
destructive than the suppurative arthritis. Most
commonly involved sites are the spine, hip joint
and knees, and less often other joints are affected.
Tuberculosis of the spine is termed Pott’s disease
or tuberculous spondylitis.

Grossly, the affected articular surface
shows deposition of grey-yellow exudates and
occasionally tubercles are present. The joint
space may contain tiny grey-white loose
bodies and excessive amount of fluid.
Histologically, the synovium is studded with
solitary or confluent caseating tubercles. The
underlying articular cartilage and bone may be
involved by extension of tuberculous
granulation tissue and case necrosis.

VASCULITIDES

Systemic damage of blood vessels
CLASSIFICATION
According to the type of inflammation: a
destructive, destructive - productive,
productive
In the depths of defeat: endo vasculitis,
mesovasculitis, endo - meso vasculitis,
panvasculitis, perivasculitis.
In topography: aortitis, arteriitis, arteriolitis,
capillaritis, phlebitis, lymphangitis

CLASSIFICATION OF VASCULITIS:
1.Large vessel vasculitis (Giant cell
arteritis, Takayasu arteritis).
2.Medium-sized vessel vasculitis
(Polyarteritis nodosa, Kawasaki disease).
3.Small vessel vasculitis (Wegener
granulomatosis, microscopic polyangiitis,
Henoch - Schonlein purpura, cutaneous
leukocytoclastic angiitis).

TAKAYASU ARTERITIS
Takayasu arteritis is a granulomatous
vasculitis of medium and larger arteries.
Clinically is characterized principally by ocular
disturbances and marked weakening of the pulses
in the upper extremities (pulseless disease),
related to fibrous thickening of the aortic arch
with narrowing or virtual obliteration of the
origins or more distal portions of the great
vessels arising in the arch.
Although Takayasu arteritis classically
involves the aortic arch, in one third of cases, it
also affects the remainder of the aorta and its
branches and often the pulmonary arteries.

The gross morphologic changes
comprise, in most cases, irregular thickening
of the aortic or branch vessel wall with intimal
wrinking. When the aortic arch is involved,
the orifices of the major arteries to the upper
portion of the body may be markedly
narrowed or even obliterated by intimal
thickening, accounting for the designation
pulseless disease.
The coronary and renal arteries may be
similarly affected. Sometime the lesions
extend for some distance into the aortic
branches and in half of cases involve the
pulmonary arteries.

Histologically, the early changes consist of an
adventitial mononuclear infiltrate with perivascular
cuffing of the vasa vasorum. Later, there may be
intence mononuclear inflammation in the media, in
some cases accompanied by granulomatous
changes, replete with giant cells and patchy
necrosis of the media. As the disease runs its
course or after treatment with steroids, the
inflammatory reaction is predominantly marked by
collagenous fibrosis involving all layers of the
vessel wall but particularly the intima,
accompanied by lymphocytic infiltration. When the
root of the aorta is affected, it may undergo
dilation, producing aortic valve insufficiency.
Narrowing of the coronary ostia may lead to
myocardial infarction.

Takayasu's
arteritis
The aortic
wall is thickened,
and there are
thick yellow
plaques on the
intima. The walls
of the innominate
and both
common carotid
arteries are
thickened and
their lumina are
narrowed. The
left subclavian
artery is almost
completely
occluded.

 Takayasu arteritis

Histologic appearance in active Takayasu aortitis,
illustrating destruction and fibrosis of the arterial
media associated with mononuclear infiltrates and
inflammatory giant cells Uploaded by: http://mbbshelp.com

POLYARTERITIS NODOSA
Polyarteritis nodosa is a systemic vasculitis
manifested by transmural necrotizing inflammation of
small or medium-sized muscular arteries, typically
involving renal and visceral vessels and sparing the
pulmonary circulation.
The distributions of lesions, in descending order of
frequency is kidneys, heart, liver and gastrointestinal
tract, followed by pancreas, testes, skeletal muscle,
nervous system and skin. Individual lesions are sharply
segmental, may involve only a portion of the vessel
circumference, and have a predilection of branching
points and bifurcations.

Segmental erosion with weakning of the
arterial wall owing to the inflammatory process
may cause aneurismal dilation or localized
rupture that is perceived clinically as a
palpable nodule and can be demonstrated by
arteriography.
Impairment of perfusion causing
ulcerations, infarcts, ischemic atrophy, or
hemorrhages in the area supplied by these
vessels may provide the firs clue to the
existence of the underlying disorder.
Sometimes, however, the lesions are
exclusively microscopic and produce no gross
changes.

Histologically the vasculitis during the acute
phase is characterized by transmural
inflammation of the arterial wall with a heavy
infiltrate of neutrophils, eosinophils, and
mononuclear cells, frequently accompanied by
fibrinoid necrosis of the inner half of the vessel
wall.
Typically the inflammatory reaction permeates
the adventitia. The lumen may become
thrombosed. In some lesions, only a portion of
the circumference is affected, leaving segments of
normal arterial wall juxtaposed to areas of
vascular inflammation. At a later stage, the acute
inflammatory infiltrate begins to disappear and is
replaced by fibrous thickening of the vessel wall
accompanied by a mononuclear infiltrate.Uploaded by: http://mbbshelp.com

The fibroblastic proliferation may extend
into adventitia, contributing to the
firm nodularity that sometimes marks
the lesions. At a still later stage, all that
remains is marked fibrotic thickening of
the affected vessel, devoid of significant
inflammatory infiltration.
Particularly characteristic of
polyarteritis nodosa is that all stages of
activity may coexist in different vessels
or even within the same vessel. Thus,
whatever the inflammatory insult, it is
apparently recurrent and strangely
haphazard.

Polyarteritis nodosa. There is segmental fibrinoid
necrosis and thrombotic occlusion of the lumen of this
small artery. Part of the vessel wall at the upper right
is uninvolved. Uploaded by: http://mbbshelp.com

Polyarteritis nodosa

WEGENER GRANULOMATOSIS
Wegener granulomatosis is a necrotizing
vasculitis characterized by the triad of
1)acute necrotizing granulomas of the
upper respiratory tract, lower respiratory tract
or both;
2)focal necrotizing or granulomatous
vasculitis affecting small to medium-sized
vessels, most prominent in the lungs and
upper airways;
3)renal disease in the form of focal or
necrotizing, often crescentric glomerulitis.

Morphologically the upper
respiratory tract lesions range from
inflammatory sinusitis resulting from the
development of mucosal granulomas to
ulcerative lesions of the nose, palate, or
pharynx, rimmed by necrotizing
granulomas and accompanying vasculitis.
In the lung, dispersed focal necrotizing
granulomas may coalesce to produce
nodules that may undergo cavitation.

Microscopically the granulomas reveal angeographic
pattern of necrosis rimmed by lymphocytes, plasma
cells, macrophages, and variable numbers of giant
cells. In association with such lesions, there is a
necrotizing or granulomatous vasculitis of small and
sometimes larger arteries and veins. These lesions
often contain granulomas, which may be within,
adjacent to, or clearly separated from the vessel
wall.
These areas are generally surrounded by a zone of
fibroblastic proliferation with giant cells and
leukocytic infiltrate and become cavitary creating a
more than superficial resemblance to a tubercule.
Lesions may ultimately undergo progressive fibrosis
and organization.

The renal lesions are of two types. In
milder forms or early in the disease, these is
acute focal proliferation and necrosis in the
glomeruli, with thrombosis of isolated
glomerular capillary loops (focal necrotizing
glomerulonephritis). More advanced glomerular
lesions are characterized by diffuse necrosis,
proliferation, and crescent formation (crescentic
glomerulonephritis). Patients with focal lesions
may have only hematuria and proteinuria
responsive to therapy, whereas those with
diffuse disease can develop rapidly progressive
renal failure.

Vasculitis of a small artery with adjacent granulomatous
inflammation including epithelioid cells and giant cells

THROMBOANGIITIS OBLITERANS
(BUERGER DISEASE)
Thromboangiitis obliterans is a distinctive
disease characterized by segmental,
thrombosing, acute and chronic inflammation
of medium-sized and small arteries, principally
the tibial and radial arteries and sometimes
secondarily extending to veins and nerves of the
extremities.
The condition had occurred almost exclusively
in men who were heavy cigarette smokers. The
relationship to cigarette smoking is one of the
most consistent aspect of this disorder. Several
possibilities have been postulated for this
association, including direct endothelial cell
toxicity induced by or hypersensitivity to some
tobacco products.

Tromboangiitis obliterans is characterized by
sharly segmental acute and chronic vasculitis of
medium-sized and small arteries with secondary
spread to contiguous veins and nerves. Often the
vascular supply to the extremities, upper as well as
lower, is affected.
Microscopically acute and chronic inflammation
permeates the arterial walls, accompanied by
thrombosis of the lumen, which may undergo
organization and recanalization. Characteristically the
thrombus contains small microabscesses marked by a
central focus of neutrophils surrounded by
granulomatous inflammation. Chronic ulcerations of
the toes, feet, or fingers may appear, perhaps
followed in time by frank gangrene.

Thromboangiitis obliterans (Buerger disease). The lumen is
occluded by a thrombus containing abscesses and the vessel wall
is infiltrated with leukocytes.

VASCULITIS ASSOCIATED WITH
OTHER DISORDERS
Vasculitis may sometimes be associated with
an underlying disorder, such as an immunologic
connective tissue disease.
Of the connective tissue disorders,
rheumatic fever, rheumatoid arthritis and
systemic lupus erythematosus commonly
manifest a vasculitis.
In rheumatoid arthritis patients with severe
erosive disease, rheumatoid nodules are at risk
of developing vasculitic syndromes.
Rheumatoid vasculitis is a potentially
catastrophic complication, particularly when it
affects vital organs, usually involves small and
medium-sized arteries.

Frequently, segments of small arteries are
obstructed by an obliterating endarteritis
resulting in peripheral neuropathy, ulcers and
gangrene.
Localized arteritis is most frequently caused
by the direct invasion of infectious agents –
usually bacteria and fungi, particularly
aspergillosis and mucormycosis.
Vascular lesions frequently accompany
bacterial pneumonia or occur adjacent to caseous
tuberculous reactions, in the neighborhood of
abscesses, or in the superficial cerebral vessels in
cases of meningitis.

Much less commonly, they arise from the
hematogenous spread of bacteria, in cases
of septicemia or embolization from infective
endocarditis.
Vascular infections may weaken the
arterial wall and result in the formation of a
mycotic aneurysm.
Clinically, infectious arteritis may be
important on several counts. By including
thrombosis, it adds an element of infarction
to tissues that are already the seat of an
inflammatory reaction and worsen the initial
infection. In bacterial meningitis
inflammation of the superficial vessels of
the brain may predispose to vascular
thromboses, with subsequent infarction of
the brain substance and extension of the
subarachnoid infection into the brain tissue.

Pathology of the Musculoskeletal Muscles Elaborate

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