Skeletal Muscle Lesions

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					Skeletal Muscle Lesions
Skeletal muscles are tightly integrated with the central and peripheral
nervous system. The principal element of this association is called the
motor unit, which consists of a motor cell of the brain or spinal cord, the
corresponding peripheral axon, distal neuromuscular junction and finally
the skeletal muscle fibers that are innervated.
Depending on the nerve fiber doing the innervation, the associated
skeletal muscle fibers develop into one or two major subpopulations: Type
I (slow twitch) and Type II (fast twitch) fibers.
Normal skeletal muscle
Normal skeletal muscle
Diseases that affect skeletal muscle can involve any portion of the motor
unit, namely: primary disorders of the motor neuron or axon,
abnormalities of the neuromuscular junction, and disorders affecting
directly skeletal muscle (myopathies).
Muscle atrophy is a non-specific response to several muscle and systemic
disorders. It is characterized by abnormal small myofibers.
The etiology of the atrophic changes can be identified depending on what
type of fibers are affected, their distribution in the muscular mass and the
morphology of individual fibers.
Type I (light) and Type II (dark) fibers in a normal
     muscle. Adenosine triphosphate stain
Type I and Type II fibers in atrophic muscle.
Type II fiber atrophy is relatively common and is associated with inactivity
 or disuse, such as prolonged bed rest or immobilization to heal a bone
 Exogenous glucocorticoids, Cushing’s syndrome, pressure exerted by
 tumors on neighboring muscles and malnutrition are also causes of
 muscle atrophy.
 Finally, atrophic fibers may be found in different myopathies.
 Neurogenic atrophy is caused by axonal degeneration resulting in the
 primary destruction of the axon followed by secondary degeneration of
 the myelin sheath.
 Reinnervation of atrophic muscle fibers within an injured motor unit
 occurs when axons of intact neighboring motor units extend sprouts to
 reach the neuromuscular junctions of the previously degenerated muscle
Deprived of normal innervation, skeletal fibers will undergo progressive
If a single neuron is affected, atrophy will take place only in skeletal fibers
 innervated by that particular neuron.
Neurogenic (denervation) atrophy
                    Muscular dystrophy
Muscular dystrophies an heterogeneous group of inherited disorders often
presented in childhood, characterized by progressive degeneration of
muscle fibers leading to muscle wasting and weakness.
Histologically, muscle fibers are eventually replaced by fatty tissue, which
differentiate dystrophies from all the other myopathies.
 X Linked Muscular Dystrophy (Duchenne (DMD) and Becker Muscular
Dystrophy (BMD) are the most common types of muscular dystrophy and
they are X linked. DMD is the most severe and the most common form.
DMD becomes clinically evident by age 5 with progressive weakness
ending in wheelchair dependence by age 12. Despite the same gene
abnormalities, BMD is less severe.
Histologically, both dystrophies show a mixture of atrophic and
hypertrophic fibers.
Muscle biopsy specimens from individuals with DMD show no evidence of
dystrophin by immunohistochemical stains or Western blot analysis.
Individuals with BMD show diminished amount of an abnormal molecular
weight dystrophin which is a partially active protein.
Boys with DMD are normal at birth. Walking however, is often delayed.
Weakness begins in the pelvic girdle and then extends to the shoulder
girdle. Enlargement of the calf muscles associated with weakness is called
psuedohypertrophy which is an important clinical finding.
Approximately two thirds of cases are inherited, while the remainder
represents new mutations.
In affected families, females are carriers. They are clinically asymptomatic but
often show an elevated serum creatine kinase. They are also at risk to develop
dilated cardiomyopathy
 At the beginning the increased muscle bulk is due to hypertrophic changes but
when the muscles become atrophic by the increase in fat and connective
Pathologic changes are also seen in the heart and patients may develop
arrythimias or heart failure. Mental retardation is another associated finding.
Death may result from respiratory insufficiency, pulmonary infection, or heart
Patients develop symptoms at later childhood and adolescence with a much
slower progression – and many of them have a nearly normal life span.
Duchenne’s type muscular distrophy.
               Myotonic dystrophy.

Myotonia is a sustained involuntary contraction of a group of muscles which
is the cardinal neuromuscular symptom of myotonic dystrophy.
Patients complain of stiffness and have difficulty releasing their grip after a
This is an autosomal dominant disorder associated with a CTG trinucleotide
repeat expansion on chromosome 19, affecting the mRNA which results in
defective synthesis of an intracellular protein kinase.
The disease often presents in late childhood with gait abnormalities due to
weakness of foot dorsiflexors. Later on the patient develops weakness of the
intrinsic muscles of the hands and wrist extensors and atrophy of facial
muscles with ptosis.
  They can be divided in two groups: congenital and toxic (acquired).
  Congenital myopathies. They include inherited mutations of ion channels
  (channelopathies), inborn errors of metabolism (glycogen and lipid
  diseases) and mitochondrial abnormalities.
1) Ion channel myopathies are a group of familial disorders characterized by
  myotonia, relapsing episodes of hypotonic paralysis and abnormal serum
  potassium levels. Thus, hyperkalemic periodic paralysis results from
  mutations in the gene for the sodium channel which regulates sodium
  entry during contraction.
2) Myopathies due to inborn errors of metabolism include disorders of
  glycogen synthesis and degradation or deficiencies of the mitochondrial
  dehydrogenase enzyme systems resulting in significant accumulation of
  lipids within myocytes (lipid myopathies).
                           Toxic myopathies

   These disorders are caused by intrinsic exposures (thyrosine) and extrinsic
   exposures (alcohol, therapeutic drugs).
1) Thyrotoxic myopathy may present as an acute or chronic proximal muscle
   weakness and may precede signs of thyroid dysfunction. Histologically there is
   myofiber necrosis, regeneration, and interstitial lymphocytosis.
2) Ethanol myopathy can occur with binge drinking followed by an acute toxic
   rhabdomyolysis with myoglobinuria that may end up in renal failure. Clinically,
   the patient present with an acute onset of pain involving a single or multiple
   muscles. Histologically there is myocyte swelling, necrosis, myophagocytosis
   and regenerative changes.
3) Chloroquin may produce a proximal myopathy and eventually myocyte
                    Myasthenia gravis

Myasthenia gravis is an autoimmune disorder of the neuromuscular
junction characterized by muscle weakness. It can present at any age and
is seen more often in women.
Thymic hyperplasia is found in 65% and a thymoma in 15% of patients.
Patients show circulating antibodies to the skeletal muscle acetylcholine
receptors (AchRs) associated with a decreased number of these receptors.
The disease can be transmitted to animals with serum from affected
patients confirming the role of AchR’s as the etiologic factor of this
 The presence of AchR’s autoantibodies cause the degradation of the
receptors or blocking the binding of acetylcholine to their receptor.
There is no evidence of muscle destruction.
The connection between the autoimmunity to AchRs and the thymic
abnormalities is not known. However, patients get better after a thymectomy.
The first symptoms to appear are weakness of extraocular muscles, like double
vision or ptosis. The generalized muscle weakness may change after several
days, within hours, or even minutes.
Repeated muscular stimulation causes diminishing muscle strength.
Patients show marked improvement after receiving anticholinestenase agents,
which is useful in the diagnosis of this condition.
Sensory and autonomic functions are not affected.
Respiratory failure used to cause great mortality in the past. Today, 95% of the
patients survive more than 5 years because of improved treatments using
anticholinestenase drugs, plasmapheresis, prednisone, and/or thymic
Joint Diseases
Cartilage is a semi-rigid form of supporting tissue. Proteoglycans make up
the ground substance and account for the solid, yet flexible consistency of
Within the ground substance are embedded different amounts of collagen
and elastic fibers which originate the three main types of cartilage: hyaline
cartilage, fibrocartilage, and elastic cartilage.
Hyaline cartilage is the most common type and is the main component of
most articular surfaces.
Joints may be classified in synovial and non-synovial.
Normal joint
Intervertebral joints
Histology of the synovial membrane
             Rheumatoid arthritis
This condition is a chronic, systemic inflammatory disease affecting many
tissues but primarily attacking joints. It causes in the latter a
nonsuppurative proliferative synovitis that ends up destroying the
articular cartilage and underlying bone. Permanent disability is the end
Other tissues may also be affected like the skin, heart, blood vessels and
lungs and in these instances RA may resemble SLE or scleroderma.
 RA is very common and is three to five times more frequent in women
than men. No age is immune.
RA typically presents as a symmetric arthritis involving the small joints of
the hands and feet, ankles, knees, wrists, elbows, and shoulders.
Typically the proximal interphalangeal and metacarpophalangeal joints are
affected but the distal ones are spared.

  •Joint tenderness or pain on motion
  •Morning stiffness
  •Nonspecific constitutional symptoms
  •Anorexia, weight loss

• Subcutaneous nodules
• Symmetrical joint swelling
• Deformity
• Contracture
• Subluxation
• Destruction of tendons, ligaments and joint capsules cause
characteristic deformities such as radial deviation of the wrist, ulnar
deviation of fingers, and flexion-hypertension of the fingers (swan-neck
Rheumatoid arthritis is a disease of unpredictable course and severity. Impairment may be quite
moderate, as seen in the first of the two slides, or devastatingly severe, as in the second. The
second hand probably has very little if any function, and the grotesque deformity arises from a
combination of joint and tendon contractures coupled with severe atrophy of the intrinsic muscles of
the hand.
    Rheumatoid arthritis, late
stage,metacarpophalengeal joint.
Rheumatoid arthritis
The distribution of           lesions in
rheumatoid arthritis overlaps that
observed in osteoarthritis. Points that
are helpful in differentiating the two are
the usual symmetrical involvement and
the high frequency of lesions in the
small joints of hands and feet in
rheumatoid disease.
Histologically the affected joints show chronic synovitis characterized by:
1) synovial cell hyperplasia and proliferation
2) dense perivascular inflammatory cell infiltrates including lymphoid
   follicles composed of CD4+T cells, plasma cells and macrophages
3) increased vascularity due to angiogenesis
4) neutrophils and organizing fibrin on the synovial surface and joint
5) increased osteoclast activity leading to synovial penetration and bone
Rheumatoid arthritis
These tissue changes involve the formation of a pannus formed by
proliferating synovial cells, granulation tissue and fibrous connective
The overgrowth of the pannus is so exuberant that the synovial membrane
becomes markedly edematous, and display multiple papillary projections.
Eventually the periarticular soft tissue becomes edematous manifested
clinically by a fusiform swelling of the proximal interphalangeal joints.
Rheumatoid arthritis
With progression of the disease the articular cartilage below the pannus
becomes eroded and in time destroyed.
The sub-articular bone is also attacked and eroded, followed by the
pannus filling the joint space. Finally, fibrosis and calcification may result
in permanent ankylosis.
Radiographic findings consist of joint effusions and juxta-articular
osteopenia with erosions, narrowing of the joint space and loss of articular
Rheumatoid subcutaneous nodules develop in about 25% of patients.
They are found along the extension surface of the forearm.
Rarely, they can be found in the lungs, spleen, heart, and aorta. They
consist of firm, white nodules measuring up to 2cm in diameter.
On section, they show a core of fibrinoid necrosis surrounded by a
palisade of macrophages.
Rheumatoid nodule
Patients with severe erosive disease, rheumatoid nodules, and a high titer
of rheumatoid factor (RF) are at risk of developing vasculitis.
Serosal involvement may present as fibrinous pleuritis or pericarditis.
The lung parenchyma may be damaged by progressive interstitial fibrosis.
Ocular changes similar to the ones seen in Sjogren’s syndrome may also
develop, and may be prominent in some cases.
At this stage, RA should be distinguished from all of the other
autoimmune disorders such as SLE, scleroderma, polymyositis and other
forms of arthritis.
Helpful finding in making the correct diagnosis are:
1) characteristic radiographic findings
2) sterile turbid synovial fluid with decreased viscosity and poor mucin clot
3) inclusions bearing neutrophils
4) RF (in 80% of patients).

The joint inflammation in RA is immunologically mediated but the initiated
agent or agents are not known.
It is thought that the disease begins by the activation of CD4 helper T cells
by some arthritogenic agent.
Approximately 80% of patients have serum Ig M and less frequently Ig G
that bind to the Fc portion of their own (self) Ig G. These antibodies are
known as RF (rheumatoid factor).
The disease also occurs in the absence of RF, suggesting that these
antibodies are not essential for the tissue injury.
The course of the disease is variable.
In a minority of patients, the disease may become stable and it may even regress,
but in the majority it pursues a chronic remitting relapsing course.
The natural course of the disease is one of progressive joint destruction ending in
disability after 10-15 years.
However, the outcome has been dramatically improved by aggressive treatment of
early RA and the use of agents that antagonize TNF.
RA is an important cause of reactive amyloidosis which develops in 5% to 10% of
these patients, especially in the presence of long-standing severe disease.
Osteoarthritis or degenerative joint disease is the most common joint
It is almost an inevitable part of aging and an important cause of physical
disability in individuals over 65.
The main feature of osteoarthritis is the degeneration of articular cartilage.
Changes in the underlying bone are secondary.
The disease appears insidiously without apparent initial cause (primary
osteoarthritis) and it usually affects a single bone.
When the disease strikes young patients there is usually an underlying
predisposing condition such as previous trauma, developmental deformity,
or underlying systemic disease like diabetes, ochoronosis, or marked
obesity (secondary osteoarthritis).
The estimated annual cost of treating patients with osteoarthritis in the
USA is $33 billion.
The early pathologic changes in osteoarthritis consist of proliferation and
disorganization of chondrocytes on the surface of the articular cartilage of a
synovial joint, associated with an increase in the water content of the matrix
and a decreased contentration of proteoglycans.
These changes are followed by the degradation of the superficial layers of the
 joint cartilage associated with vertical and horizontal fibrillation and cracking
 of the matrix.
At this stage, the articular cartilage shows a soft granular surface.
Eventually fragments of cartilage are shed and the subchondral bone is
Friction smooths the exposed bone which appears like polished ivory
(bone eburnation).
The underlying cancellous bone becomes thickened and sclerotic.
Small fractures dislodged fragments of cartilage and subchondral bone into
the lumen of the joint forming loose bodies (joint mice).
Normal joint
 The essential lesion of degenerative joint disease is caused by repeated microtrauma
to the articular cartilage, resulting in a major loss of cartilage.
1)eburnated surface. 2)subchondral cyst.3)residual
                articular cartilage
Gaps in the cartilagenous surface allow synovial fluid to be pushed into the
subchondral region to form synovial pseudocysts.

Degenerative changes of articular cartilage are the main cause of osteoarthritis.
In order to fulfill its function of spreading weight across the joint surface and
 provide virtually friction-free movement within the joint, the cartilage must be
 elastic and to have a high tensile strength.
The latter undergoes constant matrix degradation and replacement and the
chondrocytes are the ones to control this process.
An imbalance of this function may lead to osteoarthritis.
A second consequence of the erosive destruction of subchondral bone is
reactive proliferation of new bone. This osteoneogenesis does not restore the
normal configuration of subchondral bone. Rather, the new bone tends to grow
out into the joint capsule as bony spurs called osteophytes or bone plants. The
polypoid bony excrescence seen on the right side of this photomicrograph is an

• Joint pain associated with movement
• Limitation of motion
• Stiffness after periods of rest
• "Referred" pain

•Changes in shape of the joint
•Limitation of motion
•Spasm or atrophy of surrounding muscles
•Fine crepitation on joint motion
Osteoarthritis may involve many joints,
both large and small, but patients
complain most often of symptoms
related to the large weight-bearing joints
of the lower extremity.
When situated in a critical area,
osteophytes may produce serious
disability. Spinal osteophytes, for
example, may narrow nerve
foramina, causing compression or
entrapment neuropathy with
severe pain and both motor and
sensory dysfunction.

Chondrocytes may be damged by aging and mechanical stresses. Genetic
factors may also play a role, particularly in the involvement of hands and
knees, as well as increased bone density and sustained high estrogen
Osteoarthritis is an insidious disease affecting patients of 50 and 60 years
Heberden nodules representing osteophytes in distal interpalangeal joints
are frequent in women.
There is no therapy to prevent or halt the progression of osteoarthritis.
With time, joint deformities will develop, but unlike rheumatoid arthritis
ankylosis will not occur.
The classical clinical indication of osteoarthritis is produced by osteophytes. The
subcutaneous bony swelling around the distal interphalangeal joints produces the
pathognomonic physical finding called Heberden's nodes.
                  Infectious Arthritis
 Microorganisms of any type can reach the joints by hematogenous
 dissemination. Joints can also become infected by direct inoculation or by
 contiguous spread from osteomyelitis or a soft tissue abcess.
1) Suppurative arthritis takes place during episodes of bacteriemia. Hemophilus
    influenza predominates in children under 2 years. S. aureus presents in older
    children and adults and gonococcus is prevalent during late adolescence.
2) Gonococcal arthritis occurs mainly in sexually active females.
    The patients show all the systemic symptoms seen in all the acute
     inflammatory processes like sudden onset of pain, redness and swelling of
 the involved joint, elevated ESR, fever, and leukocytosis.
 In 90% of suppurative arthritis, infection involves a single joint.
 Joint aspiration is typically purulent and cultures allow the identification of
 the causal agent.

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