Pathology: Muscle Diseases

Question 1

The two principal pathologic processes seen in skeletal muscle

Answer 1

Denervation atrophy and primary pathologic abnormalities of the skeletal muscle fiber itself (myopathy)

Question 2

Indications for muscle biopsy

Answer 2

suspected skeletal muscle disease w/ unexplained weakness, cramps or pain, or unexplained enzymatic evidence of skeletal muscle injury (CK)

Question 3

Spinal Muscular Atrophy

Answer 3

Group of mainly autosomal recessive motor neuron diseases that present in childhood or adolescence. NEUROGENIC ATROPHY
loss of motor neurons –> muscle atrophy and weakness

Question 4

Genetic defect –> Spinal muscular atrophy

Answer 4

Most forms of SMA are associated with mutations affecting survival motor neuron 1 (SMN1), a gene on chromosome 5 that is required for motor neuron survival

Question 5

Most common form of SMA

Answer 5

Werdnig-Hoffman Disease

Question 6

Muscular dystrophy

Answer 6

heterogeneous group of inherited disorders which result in muscle weakness and eventually muscle atrophy and wasting, with muscle replaced by fibrofatty tissue

Question 7

Two most common forms of childhood muscular dystrophy

Answer 7

X-linked disorders Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD)

Question 8

DMD and BMD are caused by mutations of an X-linked gene (Xp21 region) that encodes for ____________

Answer 8

a protein named dystrophin

Question 9

Dystrophin is located _______________, and dystrophin and the dystrophin associated protein complex form an interface between the _________________, transferring contractile force to the connective tissue.

Answer 9

in the cytoplasm adjacent to the sarcolemmal membrane

intracellular contractile apparatus (actin) and the extracellular connective tissue matrix

Question 10

Patients w/ DMD have ____ dystrophin, whereas BMD have _______ dystrophin

Answer 10

Patients with DMD have little or no dystrophin; patients with BMD have decreased amounts of dystrophin or a defective, abnormal form of dystrophin

Question 11

DMD and BMD are sometimes referred to as ____________

Answer 11

dystrophinopathies

Question 12

Sxs (observable) of DMD

Answer 12

symptoms by age 5
weakness in the pelvic girdle, followed by the shoulder girdle.
Waddling “duck-like” gait and place hands on knees to assist in standing (Gower’s maneuver).
“pseudohypertrophy” of the calf muscles (enlargement due to atrophic muscle being replaced by adipose tissue).

Question 13

Clinical outcomes DMD

Answer 13

Patients are often wheel chair dependant by 10-12 years. Complications include respiratory insufficiency with infections and cardiomyopathy, with median survival approximately age 35 years.

Question 14

DMD: Creatine kinase is ______ early in the disease, even before symptoms appear; electromyogram shows a ______ pattern

Answer 14

increased, myopathic (versus neurogenic)

Question 15

Electromyogram

Answer 15

test that measures the electrical activity of skeletal muscle

Question 16

Testing for DMD

Answer 16

Genetic tests are often used to establish the diagnosis (peripheral blood). Muscle biopsy can also be used to establish the diagnosis (western (protein) immunoblot for dystrophin).

Question 17

Clinical Outcomes BMD

Answer 17

Patients with BMD have a later onset with milder symptoms, and can survive well into the 40’s and beyond.

Question 18

Muscle biopsy in DMD and BMD show variation in _________, increased ____________, _____ and ________ of muscle fibers (it is believed that defects in the protein complex lead to membrane tears with influx of calcium), and muscle fiber _________. Eventually, the muscles become almost completely replaced by____________ and __________

Answer 18

Muscle biopsy in both conditions show variation in muscle fiber size, increased endomysial connective tissue, degeneration and necrosis of muscle fibers (it is believed that defects in the protein complex lead to membrane tears with influx of calcium), and muscle fiber regeneration. Eventually, the muscles become almost completely replaced by fat and connective tissue.

Question 19

Tx muscular dystrophy (DMD, BMD)

Answer 19

There is no cure, and in some cases patients are treated with immunosuppression. Definitive therapy would involve restoration of dystrophin levels in skeletal muscle and cardiac muscle.

Question 20

Female carriers of DMD,BMD

Answer 20

Female carriers can demonstrate increased creatine kinase levels, and can be at risk for cardiomyopathy.

Question 21

Myotonia

Answer 21

sustained involuntary contraction of a group of muscles

Question 22

Genetic basis for myotonic dystrophy

Answer 22

Autosomal dominant disorder - increased CTG trinucleotide repeat sequences on chromosome 19 (trinucelotide repeat disorder), which affects the mRNA for dystrophia myotonia protein kinase (DMPK). This results in defects affecting transcription of proteins for a chloride channel called CLC1, resulting in myotonia.

Question 23

Sxs of myotonic dystrophy

Answer 23

Patients often present in late childhood with abnormalities of gait, which eventually progresses to weakness of the hand and wrist; facial muscle atrophy leads to a typical facial appearance with a sagging face, ptosis (drooping upper eyelid), and open mouth. Other abnormalities include cataracts, frontal balding, gonadal atrophy, abnormal glucose tolerance, and cardiomyopathy.

Question 24

Testing for myotonic dystrophy

Answer 24

Muscle biopsy can show selective atrophy of type 1 fibers as well as ring fibers (both not specific); patients will also have elevated creatine kinase. Genetic test is available (peripheral blood).

Question 25

Ion channel myopathies

Answer 25

Group of inherited diseases caused by mutations affecting function of ion channel proteins. Depending on channel affected, clinical manifestations may include epilepsy, migraine, movement disorders with cerebellar dysfunction, peripheral nerve disease, and muscle disease. Mutations can affect potassium, sodium, calcium, and chloride channels, resulting in either hypotonia (decreased muscle tone) or hypertonia (increased muscle tone).

Question 26

Malignant hyperthermia - characterized by what, triggered by what

Answer 26

Malignant hyperpyrexia (malignant hyperthermia) is a rare clinical syndrome characterized by a marked hypermetabolic state (tachycardia, tachypnea, muscle spasms, and later hyperpyrexia) triggered by certain inhalational anesthetics.

Question 27

Malignant hyperthermia triggered by what

Answer 27

This condition is associated with several mutations that encode proteins that control levels of cytosolic calcium.

Question 28

Malignant hyperthermia process

Answer 28

Upon exposure to an anesthetic, the abnormal calcium channels allow uncontrolled release of calcium from skeletal muscle cells. This acute medical emergency leads to tetany, increased muscle metabolism, and excessive heat production.

Question 29

Congenital myopathies

Answer 29

Group of inherited myopathies defined largely on basis of pathologic findings in skeletal muscle biopsy - typically manifest at infancy (vs MD, after infancy)

Question 30

Myopathies associated w/ inborn errors of metabolism

Answer 30

Many types exist, including: Disorders of glycogen metabolism Disorders of lipid metabolism Mitochondrial myopathies, associated with mutations of mitochondrial enzymes (typically these disorders impair mitochondrial ATP generation, and thus affect tissues rich in cell types with high ATP requirements, such as cardiac cells and neurons).

Question 31

3 Subgroups of inflammatory myopathies

Answer 31

Infectious Associated w/ systemic inflammatory disease Noninfectious inflammatory disease

Question 32

Infectious inflammatory myopathy examples

Answer 32

trichinosis, necrotizing fasciitis and myositis due to group A streptococcus, clostridial gas gangrene

Question 33

Inflammatory myopathy associated w/ systemic inflammatory disease examples

Answer 33

systemic lupus erythematosis (SLE), polyarteritis nodosa, rheumatoid arthritis, sarcoidosis

Question 34

Noninfectious inflammatory myopathies examples

Answer 34

Dermatomyositis Polymyositis Inclusion Body Myositis

Question 35

autoimmune disease with immunologic injury and damage to small blood vessels and capillaries in the skeletal muscle, along with skin involvement and characteristic skin rash.

Answer 35

dermatomyositis

Question 36

dermatomyositis

Answer 36

autoimmune disease with immunologic injury and damage to small blood vessels and capillaries in the skeletal muscle, along with skin involvement and characteristic skin rash.

Question 37

dermatomyositis muscle biopsy

Answer 37

lymphocytic inflammation around small blood vessels and in the perimysial connective tissue, along with perifascicular myocyte atrophy secondary to ischemia. Necrotic muscle fibers with regeneration can also be seen.

Question 38

_________________ are involved in capillary damage in dermatomyositis

Answer 38

Activated B and T cells and antibodies with complement activation are involved in the capillary damage Dermatomyositis

Question 39

Clinical manifestations of dermatomyositis

Answer 39

muscle weakness and skin rash | possible extramuscular manifestations (interstitial lung disease, dysphagia, myocarditis)

Question 40

classic rash of dermatomyositis

Answer 40

a violaceous discoloration of upper eyelids associated with periorbital edema, accompanied by a scaling erythematous eruption or dusky red patches over the knuckles, elbows, and knees (Gottron papules).

Question 41

muscle weakness pattern of dermatomyositis

Answer 41

Muscle weakness typically affects proximal muscles first and is symmetric, often accompanied by myalgias (muscle pain).

Question 42

15-25% of patients with dermatomyositis have _______________.

Answer 42

an underlying malignancy (screen newly diagnosed patients for malignancy!)

Question 43

Dermatomyositis - juvenille

Answer 43

Juvenile form of the disease exists, more often is accompanied by abdominal pain and involvement of the gastrointestinal tract.

Question 44

Dermatomyositis testing/lab and treatment

Answer 44

Patients will have elevated creatine kinase; treat with immunosuppressive agents.

Question 45

Muscle and systemic involvement is similar to that seen in dermatomyositis, except for the lack of skin involvement.

Answer 45

polymyositis

Question 46

Polymyositis - lab and treatment

Answer 46

Patients will have elevated creatine kinase; treat with immunosuppressive agents.

Question 47

Polymyositis pathogenesis

Answer 47

Pathogenesis is believed to be caused by immunologic injury to muscle by activated CD8+ cytotoxic T cells. Autoantibodies similar to that seen in dermatomyositis may be present, such as anti-Jo1, which is directed against histidyl t-RNA synthetase.

Question 48

polymyositis pathology

Answer 48

Muscle biopsy shows lymphocytic inflammation surrounding and invading muscle fibers, without the perifascicular atrophy seen in dermatomyositis. Necrotic and regenerating muscle fibers are found throughout the fascicle. No vascular injury is seen.

Question 49

polymyositis vs dermatomyositis

Answer 49

Muscle and systemic involvement is similar to that seen in dermatomyositis, except for the lack of skin involvement.

Question 50

Polymyositis mostly seen in _______

Answer 50

adults

Question 51

Inclusion body myositis pathogenesis

Answer 51

uncertain, as it is not known whether this is an inflammatory condition or a degenerative process with secondary inflammation

Question 52

Inclusion body myositis clinical presentation

Answer 52

Often begins with the involvement of distal muscles, in contrast to dermatomyositis and polymyositis. Muscle involvement may be asymmetric. Older people

Question 53

Inclusion body myositis muscle biopsy

Answer 53

Muscle biopsy shows rimmed vacuoles (not specific), along with lymphocytic inflammatory infiltrate.

Question 54

Inclusion body myositis lab/treatment

Answer 54

Modest elevations of creatine kinase are present. | There is often no beneficial effect with immunosuppressive agents.

Question 55

Toxic myopathies examples

Answer 55

Thyrotoxic, ethanol, drug-induced

Question 56

Thyrotoxic myopathy

Answer 56

hyperthyroidism is associated with increased levels of thyroid hormone, which can cause muscle degeneration/necrosis with regeneration. Patients can get exophthalmic opthalmoplegia with swelling and enlargement of the ocular muscles. In hypothyroidism, patients may get muscle fiber atrophy.

Question 57

Ethanol myopathy

Answer 57

binge drinking can produce an acute toxic syndrome of rhabdomyolysis, with rapid breakdown of skeletal muscle. Also, if pass out - on hard surface - pressure necrosis

Question 58

Drug-induced myopathy

Answer 58

steroids, whether associated with Cushings syndrome or therapeutic use, can produce muscle fiber atrophy, predominately of type 2 fibers. Choroquine, used for treatment of malaria, can produce a proximal myopathy. Satins, used to reduce cholesterol, can also produce myopathy. Statin use is one of the most common causes of prescription drug-induced myopathy!

Question 59

_________ use is one of the most common causes of prescription drug-induced myopathy!

Answer 59

Statin

Question 60

autoimmune disease caused by immune mediated loss of function of the acetylcholine receptor (AChR).

Answer 60

Myasthenia Gravis

Question 61

Autoantibodies in Myasthenia Gravis

Answer 61

AChR autoantibodies can be detected in most patients (85%). Some patients have antibodies directed against a sarcolemmal protein, muscle specific receptor tyrosine kinase. AChR autoantibodies lead to degradation of the receptors; muscle specific tyrosine kinase autoantibodies interfere with the function of the receptor.

Question 62

Myasthenia gravis associated with ___ abnormalities

Answer 62

Myasthenia gravis is often associated with thymic abnormalities, with thymic hyperplasia in 30% and thymoma (tumor of the thymus) in 10%.

Question 63

Clinical presentation Myasthenia gravis

Answer 63

Muscle weakness may be generalized, or localized to the extraocular muscles (ptosis).

Question 64

Diagnosis Myasthenia gravis

Answer 64

Detection of the above autoantibodies in the appropriate clinical setting; electrophysiologic studies can also be helpful, as well as bed-side tests in those patients with ptosis (ice pack test, edrophonium test).

Question 65

Tx MG

Answer 65

Treatment is with anticholinesterase drugs, immunosuppressive agents, plasmapheresis in acute cases, and thymectomy in those with thymic tumors.

Question 66

Lambert-Eaton Myasthenia pathogenesis

Answer 66

autoantibodies directed against presynaptic calcium channels, which block acetylcholine release. In contrast to myasthenia gravis, rapid repetitive stimulation of the affected muscle increases the muscle response.

Question 67

Lambert-Eaton Myasthenia often seen as a ________________ syndrome, with ____________ present in 60% of cases (often _____________).

Answer 67

This condition is often seen as a paraneoplastic syndrome, with malignancy present in 60% of cases (often small cell lung carcinoma).

Question 68

Lambert-Eaton Myasthenia Dx

Answer 68

Patients may have detectable “voltage gated calcium channel autoantibodies” and show no improvement with anticholinesterase agents; electrophysiologic studies are quite helpful in distinquishing this entity from myasthenia gravis, along with the presence of non-thymic malignancies.

Question 69

Creatine Kinase

Answer 69

cytosolic enzyme which converts creatine to phosphocreatine; in the process ATP is converted to ADP

Question 70

Creatine kinase exists as three isoenzymes:

Answer 70

CK-BB, CK-MB, and CK-MM (B = brain, M = muscle) .

Question 71

Skeletal muscle primarily expresses _____(98%) with very low levels of______; however, as skeletal muscle is damaged and regeneration occurs, skeletal muscle can exhibit increased _______ expression.

Answer 71

Skeletal muscle primarily expresses CK-MM (98%) with very low levels of CK-MB; however, as skeletal muscle is damaged and regeneration occurs, skeletal muscle can exhibit increased CK-MB expression.

Question 72

Cardiac muscle expresses______ (70%) and ______ (20-25%). ______ is expressed at low levels in many tissues.

Answer 72

Cardiac muscle expresses CK-MM (70%) and CK-MB (20-25%). CK-BB is expressed at low levels in many tissues.

Question 73

________ is released into the interstitial space and blood when cells are damaged.

Answer 73

Creatine kinase is released into the interstitial space and blood when cells are damaged.

Question 74

Elevations of creatine kinase are seen in a variety of conditions

Answer 74

Acute myocardial infarct or other myocardial injury (e.g. myocarditis) Skeletal muscle diseases such as inflammatory myopathies, muscular dystrophies, rhabdomyolysis, skeletal muscle trauma Cerebrovascular accidents, head injury

Question 75

__________ isoenzyme was once used primarily for the diagnosis of acute myocardial infarct, along with cardiac troponin I. Why not?

Answer 75

CK-MB While cardiac troponin I is specific for cardiac muscle, CK-MB is not. As such, cardiac troponin I is the preferred enzyme to measure for detection of myocardial injury.

Question 76

______ is helpful in the assessment of skeletal muscle injury, in the absence of cardiac disease or other conditions that may cause increased CK.

Answer 76

Total CK

Question 77

Protein found in skeletal muscle and cardiac muscle. | As with creatine kinase, elevations occur when cardiac muscle or skeletal muscle is damaged.

Answer 77

Myoglobin

Question 78

In rhabdomyolysis, elevated levels of myoglobin can cause ________________

Answer 78

acute tubular necrosis with acute renal failure (myoglobinuria).