IMPORTANT

Features Specific to Certain Myopathies; Name the specific myopathies associated w/ each of the following features:

1.Perifascicular atrophy

2. Rimmed vacuoles

3. Ragged red fibers

4. Inflammation

5. Type I fiber predominance

1.Perifascicular atrophy - dermatomyositis

2. Rimmed vacuoles - Inclusion Body Myositis (IBM)

Oculopharyngeal Dystrophy (OPD)

distal myopathies

3. Ragged red fibers - mitochondrial myopathies

4. Inflammation - DM

PM

IBM

Vasculitis

5. Type I fiber predominance - myotonic dystrophy

congenital myopathies

Indications for Muscle Biopsy

1. What are some findings (physical exam and labs/tests) that would make you suspect presences of a muscle disease?

2. What are 4 systemic disorders w/ silent manifestations in muscle, and how does this actually help us as doctors?

1. weakness, pain, fatigue

Elevated serum CK

Myopathic EMG

2. a. Vasculitis

b. Sarcoidosis

c. Amylodiosis

d. Mitochondrial cytopathy

Easier to diagnose systemic diseases by taking a muscle biopsy than by examining any other body tissue

1. Multinucleated syncitia

2. Peripheral nuclei

3. Little fibrous tissue in the endomysium

4. Mixture of fiber types

What is found in each of the 3 CT compartments of skeletal muscle?

1. Endomysium

2. Perimysium

3. Epimysium

1. The muscle fibers themselves

capillaries

2. Septa

Nerves

BV's

3. Loose CT

Neurovascular Bundles

Fat

One Slow Fat Red Ox

Type 1 Fiber

slow twitch

lipid-rich

red appearance

oxidative

 Neurogenic Atrophy

Def?

Histopath characteristics of?

How do the characteristics of myopathic vs. neurogenic fibers compare?

wasting of a muscle due to damage to its peripheral nerve supply

Muscles shrink, so nuclei become much more prominent and clump together

myopathic = round fibers

variable fiber size

increased internal nuclei

selected type 2 fiber atrophy

endomysial fibrosis

neurogenic = angular

grouped atrophy (fiber type grouping too obviously)

nuclear clumping

Target fibers displayed

Target fibers (fibers w/ a central unstained zone surrounded by a densely stained intermediate zone, is a feature of acute denervation

Fiber type grouping

What is this, and when/why do you see this;  what pathologic event can follow fiber type grouping?

Normal muscle is like a checkerboard, you cant find 1 fiber that's surrounded w/ the same fiber type, BUT when there is denervation...

Fiber type grouping occurs - re-innervation by collateral axonal sprouting --> groups of fibers recieve innervation from the same neuron and become the same fiber type

Subsequent degeneration of the neuron innervating these newly grouped fibers results in grouped atrophy

Spinal Muscular atrophy

Inheritance? (including the chromo its on and gene)

What are 3 types of SMA?

Major histopath feature?

Autosomal recessive

mutation in SMN1 gene on chromosome 5 (suvival motor neuron 1 gene)

SMA Type 1 = Werdnig-Hoffman disease

SMA Type 2 or 3 = Early or late childhood

Histo shows panfascicular atrophy (major grouped atrophy)

Myasthenia Gravis

Where does this disease affect the neuromuscular pathway?

 Pathophys? (3 aspects)

2 associated physiologci changes?

3 symptoms?

Treatment option?

Its a disorder of the NMJ

Caused by autoimmune attack/destruction of Ach receptors

1. by fixing complement and causing direct injury to the receptors

2. increased internalization/degradation of R's

3. Inhibitng Ach binding

Assoc w/ thymic hyperplasia, thymoma

Symptoms:

Drooping eyelids (ptosis)

Double vision (diplopia)

Strength decreases w/ exercise

Symptoms improve w/ anticholinesterase agents

Lambert Eaton Syndrome

type of disorder

Pathophys

How does it differ from myasthenia gravis?

Disorder of the NMJ, a myasthenic syndrome

Its a paraneoplastic process (Dx of LE syndrome is an indication for cancer)

Fewer vesicles are released each time a presynaptic potential occurs (vs. myasthenia gravis, a postsynaptic issue)

Other differences from myasthenia gravis:

no clinical improvement w/ Ach agents

BUT there is enhanced neurotransmission w/ repetetive stimulation

Dysimmune (Inflammatory) Muscular Diseases

Name 3

Dermatomyositis

Polmyositis

Inclusion Body Myositis

Characteristics common to PM and IBM

Hallmark characteristic of DM

PM and IBM:  They are both primary inflammation diseases --> caused by invasion of the endomysial space

Macrophages and CD8 T Cells surround and phagocytose the muscle

DM involves a similar collection of inflammatory cells (MP's and CD4 T Cells), but they invade the Peri-mysial CT and cause perifascicular atrophy

Clinical Features of the Inflammatory Myopathies: Dermatomyosis

1. Weakness where?
2. Skin involvement?
3. Joint involvement?
4. Other systems involved
5. Risk of malignancy?

1. Proximal weakness, including dysphagia (difficulty swallowing)
2. Presents w/ periorbital edema, and a erthematous rash
3. Joint contractures and effusions
4. Arrythmias; interstitial lung disease
5. Increased risk of malignancy

1. Proximal, w/ dysphagia
2. No skin symptoms
3. joint involvement uncommon
4. Arrythmias and heart failure; interstitial lung disease
5. Increased risk of malignancy

Polymyositis

Characteristic histopath features?

Rx?

• Primary endomysial inflammation w/ immune cell infiltrates
• Variation in Fiber sizes
• Degeneration and necrosis (don't see this in neurogenic processes, this is characteristic of primary inflam disorders)
• Degenerated muscle is pale due to mitochondrial destruction --> blue muscle and plump nuclei indicates regeneration due to high RNA content

Respond to treatment w/ steroids

1.Where do you see Moth-Eaten Fibers in histopath?

2. How about split fibers & increased central nuclei?

1.Moth: characteristic of both myopathy or neuropathy

2. seen in all forms of myopathy

Dermatomyositis

2 clinical symptoms?

Seen in ppl of what ages?

Histo signs?

Describe muscular symptoms and progression.

1. Heliotrope rash (upper eyelid discoloration, periorbital edema)

2. Gottron's sign (erythematous rash on knuckles, elbows, knees)

Affects children and adults

Histo: Perifascicular atrophy, vasculitis

Muscle weakness is slow onset, bilaterlly symmetric, affects proximal muscles first; getting up from a seated position becomes increasingly difficult; fine movements by distal muscles are affected late in disease cours

Inclusion Body Myositis

Histopath?  

Most common primary muscle disease in who?

Symptoms common w/ what other disease?

Poorly responsive to what treatment that's effective in PM?

Rimmed Vacuoles

Endomysial Inflammation

Common in ppl over 50

Called Alzheimer's of the muscle

Don't treat w/ steroids, IBM patients are poorly responsive to immunosuppression

Muscular Dystrophies

def

Pathophys?

Inherited myopathies characterized by a progressive course w/ marked degenerative changes in the normal structure of the muclse

Caused by mutations in the genes encoding functionally related cytoskeletal proteins of the muscle fibers

Duchenne muscular dystrophy

Incidence?

Progression?

1 in 3500 live births

Walking is delayed, clumsiness; weakness begins in pelvic girdle muscles then extends to shoulder girdle; wheelchair dependence by age 12

Death from cardiomyopathy, w/ respiratory insufficiency & pneumonia in early 20's

Pathophys of DMD

2 characteristic physical features?

Most definitive histopath feature?

Mutation in the dystrophin gene, on the short arm of the X chromosome

dystrophin protein links cytoskeletal actin to membrane proteins, stabilizing the membrane

1. Gower's sign - must push against themselves to pull themselves up to standing position

2. Calf muscl pseudohypertropy - but its fat accumulation

Increase in CT (fibrosis) is definitive feature

also, fiber size variation, and replacement of muscle fibers w/ fat

Definitive molecular diagnosis: lack of staining when immunostaining for dystrophin 

Facioscapulohumeral Muscular Dystrophy (FSH)

Inheritance?

Genetic basis?  --> functional correlation?

Clinical findings?

Histopath?

Auto dominant inheritance

Involves the telomere region of chromo 4, decrease in number of DNA repeats

*Severity of disease relates to size of reduction

Features:

Proximal arm/distal leg weakness

Scapular winging

Weakness can be very A-symmetric

Could never whistle --> associated facial weakness is highly characteristic of FSH

Histo:

Very large and small fibers

fibrosis

Inflam/immune invasion

Myotonic Dystrophy

Inheritance? (special characteristic)

Some manifestations unrelated to muscle?

Histopath?

Auto Dominant w/ Anticipation

expansion of CTG repeats in the DMPK gene on chrom 19

Also affects the heart, brain, lens, testicular atrophy, frontal balding, insulin/glucose issues

Histo:  Shows ring fibers w/ stripes around their periphery

marked increase in internal nuclei

Congenital myopathies

colloquial name?

How do they differ from the dystrophies?

aka floppy baby syndromes

Unlike the dystrophies, congenital myopathies are:

non-progressive

exhibit proximal weakness w/ hypotonia

arthrogriposis (claw hand)

Nemaline (Rod) Myopathy

Features?

histopath?

a congenital myopathy

classic features of congenital myopathies

Histo:

dark-red blue structures (nemaline rods), these are accumulations of z-discs

Central Core Disease

Clinical features

Inheritance?  Genetic assoc to another condition?

Histopath

Mitochondrial Disorders

inheritance?

How do they affect children vs. adults

Characteristic histopath feature?

syndromes assoc w/ defects in oxidative phosphorylation

Can be mitochondrial or nuclear inheritance

Adults: experience myopathy w/ variable CNS involvement

Children:  psychomotor delay, hypotonia, acidosis, cardiorespiratory failure

Histo ragged red fibers - damaged at the periphery w/ excess mitochondria

EM - 'parking lot' appearance w/ paracrystalline inclusions

Myophosphorylase deficiency

aka?

What type of disorder is this?

Pathophys, and how can you test for this?

Histopath?

(McArdle's disease, Glycogen storage disease V)

Disorder of carbohydrate metabolism

deficient in the enzyme that removes glucose residues from the glycogen molecule

patient will be negative for phosphorylase reaction

Histo: buildup of peripheral glycogen vacuoles

Pompe Disease

aka?

What type of disease is this?

form in neonates vs. form in kids & adults?

(Acid maltase deficiency)

Disorder of carbohydrate metabolism

Hypotonic and cardiomegalic form in neonates

Myopathic form in kids and adults (limb girdle dystrophy w/ resp involvement)

excessive storage in lysosome vacuoles

Malignant Hyperthermia

What is it?

Inheritance?

What triggers it?

Histo?

Disorder of skeletal muscle Ca homeostasis; mutations in Ca-channel proteins that mediate excitation-contraction coupling

Auto dominant (rare but potentially lethal from renal failure)

Muscle contracture and high fever and rhabdomyolysis (muscle breakdown) upon exposure to anesthetics or muscle relaxants

Histo reveals very damaged disorganized muscle

Parasitic myositis

what parasite causes this?

Histo?

Tichinella spiralis

Histo: you can spot larvae encysted in muscle cells

Distal Axonal Degeneration

aka?

What is it?

Distribution of sensory/motor changes?

What reflexes are lost early?

What diseases?

aka Dying Back

length dependent vulnerability (distal weakness)

ankle reflexes are lost early

stocking glove distribution of sensory changes

Seen in most metabolic, toxic, and heritable neuropathies