Muscular Disorders L2

What can we determine from the information in this patient case:

A 35 year old woman reports difficulty climbing stairs, difficulty lifting objects over her head, and fatigue when brushing her har.

Her condition involves proximal muscles ~ muscles closer to the trunk

The presentation is bilateral which indicates a systemic condition

What does the term constitutional system indicate?

That there are multiple systems involved. Systemic disturbance.

What are the steps in reaching a diagnosis?

Take the patient’s history

Complete a physical examination

Make a list of differential diagnoses (DDx)

Complete diagnostic testing

Diagnosis

Name five muscle weakness differentials related to the CNS:

Stroke

Multiple sclerosis

Spinal cord lesions

Motor neuron disease

ALS - amyotrophic lateral sclerosis

Name five muscle weakness differentials related to the PNS:

guillain-barre syndrome (paralysis from toes upwards)

radiculopathy

peripheral neuropathy

diabetes

herneated disc

Name two muscle weakness differentials related to the neuromuscular junction:

myasthenia gravis

lambert-eaton syndrome

Name six muscle weakness differentials related to muscle (myopathy):

inflammatory

genetic

endocrine

metabolic

toxic/drug induced

infectious

Innate muscular disease is often _____ and ______.

proximal

bilateral

Define myopathy:

a disease primarily damaging muscle fibers, resulting in muscle weakness and impaired muscle function.

Myopathy is a disease primarily damaging _______, resulting in _____ and impaired _____.

muscle fibers

muscle weakness

muscle function

What does myopathy present as?

weakness of the muscles

fatigue of the muscles

exercise intolerance

+/- myalgia

What is the term for muscle pain?

myalgia

Myopathy commonly involves the _____ muscles.

proximal

T/F: Distal muscles are rarely affected with myopathy.

False. distal muscles become involved later in the course of illness

What is the pathway for myopathy to occur?

Injury to the muscle fiber (sarcoplasmic membrane)

Cell membrane damage

Leakage of intracellular contents

Release of creatine kinase into the bloodstream

Elevated CK in diagnostic testing is indicative of muscle injury

Creatine kinase if primarily found in _____.

skeletal muscles

What is the normal function of creatine kinase?

To provide immediate bursts of energy (physiologically)

Provides energy rapidly during high demand

What are the three places creatine kinase is found?

brain

heart, skeletal muscle

What are common diagnostic tests for muscle injuries?

Blood tests: CK, autoantibodies

Magnetic resonance imaging (soft tissue)

Electromyography (EMG) measures muscle-neural conduction which is good to diagnose neural/muscle disorders

Muscle biopsy

What is another term for inflammatory myopathy?

Myositis

What is the definition of myositis?

a rare autoimmune disorder characterized by inflammation of the SKM

Myositis is a rare __________ characterized by inflammation of the ____.

autoimmune disorder

SKM

What autoimmune disorder is characterized by proximal bilateral SKM weakness?

myositis

What does chronic SKM inflammation lead to?

progressive weakness

What are the two major types of myositis?

polymyositis

dermatomyositis

How is the presentation of polymyositis and dermatomyositis different?

Dermatomyositis has skin-related presentations

T/F: The etiology of myositis is well known and easy to diagnose.

False. the etiology is unknown.

The underlying autoimmune reaction is seen in genetically susceptible individuals ~ may have an HLA subtype difference

The epidemiology for myositis in the US: The ___________ population are disproportionately affected by _______ type of myositis.

African American

polymyositis

For myositis, the ratio of Female to Male individuals affected is:

F>M

2:1

What time of day is polymyositis symptoms typically the worst?

worse in the morning

Patients with polymyositis may have difficulty with what two actions?

difficulty rising from a chair

difficulty climbing up stairs

Polymyositis is defined as:

Chronic, slow onset, bilateral proximal muscle weakness

What is the term for difficulty swallowing?

dysphagia

How many patients with polymyositis will experience dysphagia?

1/3 patients

What is the term for difficulty in articulating words due to disease of the central nervous system?

dysarthria

When oropharyngeal muscles are involved in the polymyositis disorder, what three things might the patient present with?

dysphagia

dysarthria

aspiration risk

T/F: Patients with polymyositis may experience myalgia.

True

T/F: Patients with polymyositis experience proximal and distal muscle weakness at the beginning of the disease.

False. distal muscle weakness presents later in disease onset.

What cells are directed against muscle antigens in polymyositis pathogenesis?

cytotoxic CD8+ cells

Which myositis disorder is caused by cytotoxic CD8+ cells directed against muscle antigens?

polymyositis

What infiltrates the endomysium in polymyositis pathogenesis?

CD8+ T cells and macrophages cause endomysial infiltration

Where is inflammation found in polymyositis?

Around each muscle fiber in the endomysium

What is the function of CD8+ T cells and macrophages in polymyositis pathogenesis?

endomysial infiltration

T/F: in polymyositis, there is a direct attack on the necrotic muscle fibers.

False. There is a direct attack on the non-necrotic muscle fibers that leads to inflammation.

What is the end result of polymyositis on the muscle?

Polymyositis eventually destroys the muscle fibers, leading to necrosis.

When evaluating a polymyositis muscle biopsy, what would you expect to see?

Endomysial infiltration - partial invasion of lymphocytes within/around the muscle fibers

How does dermatomyositis differ clinically from polymyositis?

It is the same as polymyositis clinically EXCEPT for skin findings

What are four clinical skin findings of dermatomyositis?

heliotrope rash

gottron papules

shawl and V sign

mechanics hands

What are the two most common clinical skin presentations of dermatomyositis?

Helitrope rash

Gottron papules

What skin presentation caused by dermatomyositis is shown here?

gottron papules - erythmatous, scaly rash on the DIP, MIP, PIP knuckles

What skin presentation caused by dermatomyositis is shown here?

heliotrope rash - a bilateral, violet or bluish-purple rash on the upper eyelids, sometimes extending to the lower eyelids. It may be raised, shiny, bumpy, or patchy, and can be accompanied by swelling, burning, or itching

What skin presentation caused by dermatomyositis is shown here?

Shawl and V sign - photosensitivity due to sun on back and chest

What skin presentation caused by dermatomyositis is shown here?

Mechanics hands

Dermatomyositis pathogenesis is a _______ response.

humoral mediated

Which myositis is an antibody-mediated activation of the complement system leading to MAC deposits into the endomysial vasculature and within the perimysium?

dermatomyositis

Describe the pathogenesis of dermatomyositis.

An antibody-mediated activation of the complement system leading to MAC deposits (B cells, CD4 T cells, T-helper cells) into the endomysial vasculature, which causes blood vessel inflammation, capillary destruction, and little to no blood supply reaching the muscle fascicle leading to atrophy.

What MAC deposits are deposited into the endomysium and perimysium vasculature with dermatomyositis?

B cells

CD4 T cells

T helper cells

What does the activation of antibody-mediated activation of the complement system and MAC deposition into the endomysial and perimysial vasculature lead to?

Blood vessel inflammation

capillary destruction

microinfarction

Perifascicular atrophy due to decreased or total lack of blood supply to the muscle fascicle

What is defined as obstruction of the blood supply to an organ or region of tissue, typically by a thrombus or embolus, causing local death of the tissue..

Infarction

T/F: In dermatomyositis, the skin is affected due to antibody-mediated activation of the complement system leading to MAC depositions.

False. the skin is affected due to the activation of IFN-1.

it is not a downstream response

In dermatomyositis, IFN-1 leads to:

the clinical presentation of affected/involved skin

When looking at a muscle biopsy of a patient with dermatomyositis, what would you expect to see?

the destruction of blood vessels ~ infiltration of inflammatory cells surrounding the vessel

perifascicular atrophy seen as thick white bands through the muscle fibers.

What are the diagnostic tests used for myositis?

Muscle biopsies - confirmatory diagnosis

Elevated CK - nonspecific

Autoantibody tests

What are the three autoantibody tests used for myositis?

Anti-nucleic antibodies (ANA) - found in 80-90% of patients. it is SENSITIVE, not specific

Anti-Jo1 antibodies (against histones) in 30% of patients. it is SPECIFIC, not sensitive.

If a patient has Anti-Jo1 antibodies, what additional disease are they at risk of developing? What percentage of patients has this disease?

Interstitial lung disease

90% of patients with anti-jo1 antibodies will develop ILD

Which autoantibody test is specific, not sensitive?

anti-jo1 antibody test

Which autoantibody test is sensitive, not specific?

anti-nucleic antibody test

What are two additional autoantibody tests used to diagnose myositis?

anti-Mi2

anti-SRP

Myositis is linked to malignancy, with the most common being in the:

lung

What types of supportive management are available for patients with myositis?

physical

occupational

speech therapy

Both polymyositis and dermatomyositis are associated with increased risk of cancer. The most common two types being:

adenocarcinoma

squamous cell carcinoma

Where are malignancies associated with myositis often found?

lung

thyroid

breast

cervical (most prevalent)

What is the first line of medical management for myositis?

glucocorticoids - prescribed for patients with a decreased immune response for inflammation management

What is a risk associated with glucocorticoids?

risk of delayed wound healing

What are the common chronic therapy medications provided to patients with myositis?

Immunosuppressives: methotrexate, azathioprine

What management methods are recommended for dermatomyositis rash?

photoprotection

hydroxychloroquine (has an immunological component)

What is a muscular dystrophy?

a genetic myopathy

What is the term used for a group of inherited diseases that cause progressive muscle degeneration?

muscular dystrophies

Define muscular dystrophy.

A group of inherited diseases that cause progressive muscle degeneration

What is the common cause of muscular dystrophies?

Mutations involving muscular genes.

Muscular dystrophy is commonly due to mutations involving muscular genes. What ratio is hereditary and what ratio is sporatic?

hereditary 2/3

sporatic 1/3

A patient presenting with a muscular dystrophy will have a chief complaint of:

muscular compaints that affect specific muscle groups

T/F: With muscular dystrophy, the pelvic girdle musculature is affected least.

False. pelvic girdle musculature (thigh and gluteal muscles) are commonly involved.

What are the two most common types of muscular dystrophy?

Duchene Muscular Dystrophy (DMD)

Becker Muscular Dystrophy (BMD)

Between the two most common types of muscular dystrophies, which is more severe and which is of lesser severity?

DMD is most severe

BMD is least severe

What is the largest known protein-coding gene in the human DNA?

Dystrophin

What is dystrophin’s function?

acts as an anchor, connecting each muscle cell's structural framework (cytoskeleton/filamental actin) with the lattice of proteins and other molecules outside the cell (extracellular matrix/sarcoplasmic membrane).

Where is dystrophin gene found?

On the short arm of the X-chromosome

In which muscle types can dystrophin protein be found?

skeletal

cardiac

Dystrophin anchors intracellular _____ to the ______, stabilizing the sarcolemma.

actin

extracellular matrix

What is the downstream effects of a genetic mutation involving dystrophin?

genetic mutation

dysfunctional protein ~ disturbance of cellular signaling pathways

necrosis of affected muscles

replacement of the affected muscle tissue with connective and fatty tissue

weak muscles that appear large (pseudohypertrophy)

What does the term pseudohypertrophy refer to?

weak muscles that appear large

If the dystrophin gene experiences a nonsense or frameshift mutation, what happens to the protein?

the entire protein area is deleted and the protein is not there

What disorder is caused by a nonsense or frameshift mutation of the dystrophin gene?

Duchenne Muscular Dystrophy

If the dystrophin gene experiences a missense mutation, what happens to the protein?

Part of it may be altered or missing

the protein is still there, just not at 100%

What disorder is caused by a missense mutation of the dystrophin gene?

Becker Muscular Dystrophy

Which is more severe, DMD or BMD?

DMD is more severe

Which has a later onset in adolescence, DMD or BMD?

BMD

Which has an earlier onset between 2-5 years of age, BMD or DMD?

DMD

Which is the milder form of a muscular dystrophy, DMD or BMD?

BMD