Chapter 27: Diseases of the NMJ and Skeletal Muscle Flashcards
Disorders of NMJs present with what?
Painless muscle weakness and fatigue
Myastheina Gravis is associated with autoantibodies against what?
- ACh receptors on post-synaptic membrane (85% cases)
- Muscle-specific receptor tyrosine kinase (15%)
There is a strong association with the AChR autoantibodies seen in Myathenia Gravis and which abnormalities?
Thymic abnormalities: Thymoma and Thymic hyperplasia
What is the histology of thymic hyperplasia?
B-cell follicles in the thymus associated with thymic hyperplasia
What is the classic age of onset of myasthenia gravis?
- bimodal age
- 2:1 W:M in younger adults;
- Older adults, male predominance
Myasthenia gravis patients with AChR autoantibodies usually present with what signs/sx’s?
- Fluctuating weakness that worsens with exertion and over course of day
-Diminished responses after repeated stimulation
- Diplopia** and **ptosis due to involvement of extra-ocular muscles
What electrophysiologic findings help distinguish Myasthenia Gravis and Lambert-Eaton Myasthenic Syndrome?
- M.G. = Diminished muscle responses after repeated stimulation
- L.E.M.S = Increased muscle response after repeated stimulation
Patients with myasthenia gravis with antibodies to muscle specific tyrosine kinase exhibit more _______?
they exhibit more focal muscle involvement
What is 1st line tx for Myasthenia Gravis and what other tx’s can be used to control the sx’s?
- 1st line = Acetylcholinesterase inhibitors
- Plasmapheresis and immunosuppressives (glucocorticoids, cyclosporine, rituximab) –> ↓ autoAb titers
Lambert-Eaton Myasthenic Syndrome is an autoimmune disorder due to what?
Antibodies block ACh release by inhibiting pre-synaptic Ca2+ channel
50% of Lambert-Eaton Myasthenic Syndrome cases are associated with what underlying condition?
Malignancy; most often small-cell carcinoma of lung (neuroendocrine carcinoma of the lung)
Pt’s with Lambert-Eaton Myasthenic Syndrome typically present with what sx’s?
Weakness of the extremities and autonomic dysfunction
-symptoms may precede diagnosis of cancer, sometimes by years
What is the treatment for Lambert-Eaton Myasthenic Syndrome?
drugs that increase ACh release by depolarizing synaptic membranes and immunosuppressive agents
What are congenital myasthenic syndromes?
rare disorders, most commonly autosomal recessive
-marked by varying degrees of muscle weakness
What is the most common causative mutation of congenital myasthenic syndromes?
loss of function mutations in gene encoding E-subunit of ACh receptor
Many patients with congenital myasthenic syndromes present when and how?
in the perinatal period with poor muscle tone, external eye muscle weakness, and breathing difficulties
what is the clinical presentation of congenital myasthenic syndromes?
response to drugs such as acetylcholinesterase inhibitors, and prognosis depend largely on the underlying mutation
what are 2 examples of a toxin that causes a disorder at the NMJ?
Clostridium botulinum → botox (neurotoxin) blocks release of acetylcholine
-Curare
what is the gram stain of clostridium botulinum?
anaerobic gram-positive
What is Curare and what is its effect on the NMJ?
- a plant derived muscle relaxant that blocks AChR
- leads to flaccid paralysis
what is the small pool of tissue stem cells in the fascicles referred to as?
What is their role?
- satellite cells
- can contribute to muscle regeneration following injury
There are 3 patterns of muscle atrophy, what are they?
- Neurogenic
- Dermatomyositis
- Prolonged corticosteroid treatment and disuse
Type II fiber atrophy with sparing of type I fibers is seen with what?
Prolonged corticosteroid therapy or disuse
Clusters or groups of atrophic skeletal muscle fibers are seen in which disorders?
Neurogenic diseases
Primary myopathic injuries are associated with 3 distinct sets of morphologic changes. What are they?
- segmental myofiber degeneration and regeneration
- myofiber hypertrophy
- cytoplasmic inclusions
What is occurring in segmental myofiber degeneration and regeneration?
creatine kinase is being released into the blood
Regenerating myofibers are rich in what and stain how in H&E stained sections; characteristic nuclei and nucleoli that are seen?
- RNA and stain basophilic
- Enlarged nuclei and prominent nucleoli
Regeneration can restore normal muscle following an acute, transient injury, but in chronic disease states regeneration often fails to keep pace with damage. What do the muscles often show in these disease states?
- endomysial fibrosis (collagen deposition)
- dropout of myofibers
- fatty replacement
What are the 3 noninfectious inflammatory myopathies?
polymyositis, dermatomyositis, and inclusion body myositis
What is the histologic hallmark of dermatomyositis?
perifascicular atrophy
what is polymyositis?
- diagnosis of exclusion
- T-cell mediated autoimmune disease affecting skeletal muscles;
- lacks the features of dermatomyositis or inclusion body myositis
many cases traditionally viewed as polymyositis are now regarded as what?
immune-mediated necrotizing myopathy (IMNM) or as a connective tissue disease- associated myositis
What is inclusion body myositis?
-slowly progressive disease associated with distinct inclusions termed “rimmed vacuoles”
What is occurring in dermatomyositis and when does it usually present?
there is damage to small blood vessels leading to muscle injury
-Adults: 4th-6th decade
How does dermatomyositis present?
distinctive skin rash: lilac or heliotrope discoloration of upper eyelids associated with periorbital edema
- telangiectasis in nail folds, eyelids, and gums
- grotten lesions: scaling erythematous eruption or dusky patches over knuckles, elbows, and knees
Which autoantibody type in Dermatomyositis is associated with prominent Gottron papules and heliotrope rash?
Anti-Mi2 antibodies
Which autoantibody type in Dermatomyositis is associated with interstitial lung disease, non-erosive arthritis, and a rash known as “mechanic’s hands?”
Anti-Jo1 antibodies
Which autoantibody type in Dermatomyositis is associated with paraneoplastic and juvenile cases?
Anti-P155/P140 antibodies
Myofiber atrophy accentuated at the periphery of fascicles known as perfascicular atrophy is seen with what disorder?
Dermatomyositis
Patients with dermatomyositis are at an increased risk of what?
visceral cancer
-15-24% of adults with dermatomyositis have an associated malignancy, may be viewed as paraneoplastic
Biopsies and immunohistochemical studies of muscle and skin in Dermatomyositis will show deposition of what?
Complement MAC (C5b-9) within capillary beds + infiltrate rich in CD4+ T helper cells
What are the signs and sx’s of dermatomyositis and some complications which may be seen?
- Slow onset symmetric muscle weakness often w/ myalgias affecting the proximal ms. 1st (difficulty rising from chair or climbing stairs)
- ⅓ of pt’s have dysphagia and another 10% with interstitial lung disease —> can cause death
- Cardiac involvement = common, rarely leads to failure
What is the most common inflammatory myopathy in children and average age of onset?
Juvenile Dermatomyositis; average age 7 y/o
Juvenile Dermatomyositis is more likely to have what findings compared to the adult-type; how does this affect prognosis?
Calcinosis and lipodystrophy; have a better prognosis
Various rashes have been described in Dermatomyositis, but which 2 are the most characteristic?
- Heliotrope rash: Lilac colored discoloration of upper eyelids assoc. w/ periorbital edema
- Gottron papules: scaling erythematous eruption or dusky patches over knuckles, elbows and knees
Which inflammatory myopathy is more associated with perimysial infiltration vs. endomysial infilatration?
- Dermatomyositis = perimysial (CD4+ T cells)
- Polymyositis and Inclusion body myositis = endomysial (CD8+ T cells)
What is immune-mediated necrotizing myopathy (IMNM) aka necrotizing autoimmune myopathy?
-autoimmune disease that is often associated with distinct autoantibodies
What are the symptoms of immune-mediated necrotizing myopathy (IMNM)?
subacute muscle weakness typically associated with significantly increased creatine kinase levels
what would a muscle biopsy show in a patient with immune-mediated necrotizing myopathy (IMNM)?
fairly prominent myofiber necrosis and regeneration while inflammatory cell infiltrates are usually absent or minimal despite the autoimmune nature of the disease
In many cases, IMNM is associated with autoantibodies against what?
HMG-CoA reductase
-their formation is often attributed to prior statin exposure
When is the onset of Polymyositis and what are the signs/sx’s; how is it distinguished from Dermatomyositis?
- Adult onset w/ myalgia and weakness; NO cutaneous features
- Symmetrical proximal muscle involvement
What cells are seen in polymyositis?
CD8+ cytotoxic T cells in the endomysium, random distribution of necrotic and regenerating fibers scattered throughout the fascicle
When does Inclusion Body Myositis typically present?
- Disease of late adulthood; typically >50 y/o
- Most common cause of inflammatory myopathy in pt’s >65 y/o
What are the typical signs/sx’s of Inclusion Body Myositis?
- Slowly progressive muscle weakness most severe in quadriceps and distal upper extremities; asymmetric
-starts with involvement of DISTAL muscles, esp extensors of knee (quadriceps) and flexors of wrist and fingers
- Dysphagia is not uncommon
What are 2 morphological changes that are specific for Inclusion Body Myositis?
- Abnormal cytoplasmic inclusions, “rimmed vacuoles”
- Endomysial fibrosis and fatty replacement
What is the first-line tx for inflammatory myopathies (i.e., dermatomyositis and polymyositis)?
Corticosteroids
How do you treat a patient who has an inflammatory myopathy if they are steroid resistant?
immunosuppressive drugs (azathioprine and methotrexate)
What is the effect of steroids or immunosuppressive treatment on inclusion body myositis?
-it usually responds poorly
what is the leading prescribed medication known to be the culprit of myopathy?
Statins
Which drugs are associated with slowly progressive muscle weakness which predominantly affects type I fibers?
Chloroquine and hydroxychloroquine
Thyrotoxic myopathy presents most commonly as what?
an acute or chronic proximal muscle weakness that may precede other signs of hyperthyroidism
-such patients may also present with exophthalmic ophthalmoplegia (swelling of the eyelids)
How does alcohol lead to myopathy?
binge drinking may produce rhabdomyolysis, myoglobinuria, and renal failure
How do you differentiate between congenital myopathies, muscular dystrophies, and congenital dystrophies?
congenital myopathies: presents in infancy with muscle defects that tend to be static or improve over time
muscular dystrophies: progressive muscle damage, sx after infancy
congenital dystrophies: present in infancy, associated with developmental abnormalities of the CNS as well as progressive muscle damage
What chromosome is the DMD gene found on? What is the product?
Xp21
dystrophin
Female carriers for muscular dystrophy are at risk for what?
increased CK, risk for developing cardiomyopathy
How do the type of mutations of Dystrophin differ between Duchenne and Becker muscular dystrophy?
- Duchenne: deletions or frame shift mutations –> total absence
- Becker: synthesis of a truncated version, which retains some function
What will immunohistochemical staining for dystrophin show in Duchenne vs. Becker muscular dystrophy?
- Duchenne: absence of normal sarcolemmal staining pattern
- Becker: shows reduced staining
What morphological changes are seen with disease progression in Duchenne and Becker muscular dystrophy?
Muscle tissue is replaced by collagen and fat cells = Fatty replacement or change”
Regenerating fibers
Where does weakness associated with Duchenne muscular dystrophy begin and how does it progress?
- Begins in pelvic girdles —> extends to shoulder girdles
- Pseudohypertrophy of calves often present
- symptoms before age 5
- Wheel-chair bound around age 10-12
Which lab value can aid in the diagnosis of Duchenne and Becker muscular dystrophy?↑↑
↑↑↑ CK
When does Becker muscular dystrophy present? What are the symptoms?
late childhood adolescence; nearly normal lifespan; cardiac disease
What is the pathologic hallmark of DMD?
pseudohypertrophy: enlargement of muscles of lower leg associated with weakness; increased bulk due to increased size of muscle fibers initially; by the end it is bc of increased fat and CT deposition
What is limb-girdle muscular dystrophy?
muscle weakness that preferentially involves proximal muscle weakness
-multiple AD and AR entities
What is myotonic dystrophy?
a multisystem disorder: SKM weakness, cataracts, endocrinopathy, and cardiomyopathy
What is a key feature of Myotonic Dystrophy?
Myotonia: sustained involuntary contraction of a group of muscles; can be elicited by percussion on thenar eminence
-“stiffness”, difficulty releasing grip
Myotonic dystrophy is caused by what?
Expansions of CTG triplet repeats in 3’-noncoding region of DMPK gene
What is seen on histology of myotonic dystrophy?
ring fibers and sarcoplasmic mass
How does Myotonic Dystrophy present signs and sx’s?
Gait, then atrophy of facial muscles = ptosis and “hatchet face,” frontal balding, cataracts, cardiomyopathy
What is the triad of findings seen with Emery-Dreifuss Muscular Dystrophy?
1) Slowly progressive humeroperoneal weakness
2) Cardiomyopathy w/ conduction defects
3) Early contractures of the achilles, spine, and elbows
Emery-Dreifuss Muscular Dystrophy is due to mutations in genes that encode what and what is the inheritance of EMD1 and EMD2?
- Genes that encode nuclear lamina proteins
- X-linked = EMD1
- Autosomal dominant = EMD2
Carnitine palmitoyltransferase II deficiency is associated with what pattern of muscle damage?
- Episodic muscle damage with exercise and fasting
- Defect in transport of FFAs —> mitochondria
Milder deficiencies of acid maltase lead to what type of myopathy in adults?
Myopathy preferentially involving respiratory and truncal muscles
What is McArdle disease?
myophosphorylase deficiency
glycogen storage disease, episodic muscle damage with exercise
what is pompe disease?
a severe deficiency of acid maltase
generalized glycogenesis of infancy
Skeletal muscle involvement in Mitochondrial Myopathies can manifest with what findings; involvement of what is common and can be a clue to the diagnosis?
- Weakness + ↑ CK or rhabdomyolysis
- Extraocular muscle involvement = common and clue to dx
- Chronic progressive external opthalmoplegia = common feature
SKM and other tissues rich in ATP requirements affected
Morphologically what is the most consistent pathologic change seen in skeletal muscle of the Mitochondrial Myopathies; which stain can be used?
- Abnormal aggregates of mitochondria under the sarcolemma producing appearance of “ragged red fibers”
- Trimchrome stain*
What is spinal muscular atrophy?
a neuropathic disorder, loss of motor neurons → muscle weakness and atrophy
how does spinal muscular atrophy present?
infants with neurologic or neuromuscular disease may present with generalized hypotonia = “floppy baby”
What is the inheritance pattern of spinal muscular atrophy?
autosomal recessive
What is seen in cases of spinal muscular atrophy?
large zones of atrophic myofibers mixed with scattered NL or hypertrophied myofibers
round atrophic fibers and innervated hypertrophied fibers
what gene is mutated in cases of spinal muscular atrophy? What chromosome is this on?
SMN1
Chromosome 5
Wernig-Hoffman (SMA type 1) is due to destruction of what and what is the presentation?
- Destruction of anterior horn cells in the spinal cord
- Onset at birth, floppy baby, death <3 yo
- Muscle weakness of truncal and extremity ms. initially; followed by chewing, swallowing and breathing difficulties
What are the characteristic morphological changes seen with Spinal Muscular Atrophy (SMA)?
Large zones of severely atrophic myofibers mixed with scattered normal sized fibers or hypertrophied myofibers, found individually or in small groups
RYR1 mutations are associated with what?
Malignant hyperthermia –> hypermetabolic state: tachycardia + tachypnea + muscle spasms and later hyperpyrexia
