Chapter 26 Flashcards
1
Q
A
2
Q
Disorders of NMJs present with what?
A
Painless muscle weakness
3
Q
Disease of NMJ are most often due to what?
A
AutoAB that inhibit AChR, which are responsible for intiating signals that cause contraction of muscle.
4
Q
What toxins can cause damage to NMJ?
A
- Clostridium botulinum, botox blocks release of acetylcholine
- Curare muscle relaxant blocks AChR → flaccid paralysis
5
Q
2 Diseases of NMJ caused by autoAb that affect AChR
A
- Myasthenia gravis (grave weakness)
- Lambert-Eaton
6
Q
When is Myasthenia Gravis most common and in whom?
A
Bimodal age
- Younger adults = more common in W
- Older adults = more common in M
7
Q
Myastheina Gravis is caused by what?
A
AutoAB against:
- Post-synaptic ACh-R (85% cases)
- Muscle-specific receptor tyrosine kinase (15%)
8
Q
There is a strong association with AChR autoantibodies seen in Myathenia Gravis and which abnormalities?
Why>
A
- Thymic abnormalities: Thymoma (benign tumor of thyroid) and Thymic hyperplasia (often in younger patients)
- Thymoma and hyperplasia disrupt function of thymus, causing autoimmunity againt AChR in thymic myoid cells.
9
Q
Histology of thymic hyperplasia in patients with Myasthenia Gravis
A
- B-cell follicles in thymus
2.
10
Q
Myasthenia gravis patients with AChR autoantibodies usually present with what signs/sx’s?
A
Fluctuating generalized weakness that worsens with exertion and over course of day
- Begins with extraocular muscles: ptosis (drooping eyelids) and diplopia
11
Q
What feature of Myashtenia Gravis is not seen in any other myelopathies?
A
Weakness of extraocular muscles => ptsosis and diplopia
12
Q
What electrophysiologic findings help distinguish Myasthenia Gravis and Lambert-Eaton Myasthenic Syndrome?
A
- M.G. = ↓↓↓ muscle responses (blinking) after repeated stimulation
- L.E.M.S = ↑↑↑ muscle response (blinking) after repeated stimulation
13
Q
What is 1st line tx for Myasthenia Gravis and what other tx’s can be used to control the sx’s?
A
- 1st line = AChE inhibitors-> INC 1/2 life of ACh.
- Plasmapheresis and immunosuppressives (glucocorticoids, cyclosporine, rituximab) –> ↓ autoAb titers
- Thymectomy for those with thymoma
14
Q
How do patients with autoAB to AChR differ from those with Ab to muscle specific tyrosine kinase in Myasthenia Gravis?
A
Ab to muscle specific tyrosine kinase => more focal muscle involvement(neck, shoulder, facial, respiratory and bulbar muscles)
15
Q
Lambert-Eaton Myasthenic Syndrome is what?
A
An AI disorder OR paraneoplstic syndrome caused be Ab that block ACh release by inhibiting pre-synaptic Ca2+ channel
16
Q
50% of Lambert-Eaton Myasthenic Syndrome cases are associated with what underlying condition?
A
A paraneoplastic syndrome due to cancer (small-cell carcinoma of lung)
17
Q
Pt’s with Lambert-Eaton Myasthenic Syndrome typically present with what sx’s?
A
Weakness of the proximal extremities and autonomic dysfunction
18
Q
Durning embryogenesis, how does skeletal muscle develop?
A
- Mononucleated precursor cells (myoblasts) fuse ==> multinucleated myotubes
- Later mature into myofibers (muscle fibers) that vary in length and have thousands of nuclei
19
Q
In adult tissue, how are skeletal muscle myofibers arranged?
A
Fascicles, each associated with a small pool of tissue stem cells (satellite cells), that help with muscle regeneration after injury
20
Q
Types of skeletal muscle fibers and how are they arranged
A
Type I and type II, which are admixed in a checkerboard pattern in normal skeletal muscle
21
Q
What determines whether a skeletal myofiber is type 1 or 2?
A
Signal from the innervating motor neuron, meaning that all muscle fibers in a motor unit are the SAME type
22
Q
- What surrounds an individual muscle fiber/cell?
- What surrounds fascicles?
- What surrounds skeletal muscle (group of fascicles)?
A
- Endomysium
- Perimysium
- Epimysium
23
Q
What causes skeletal muscle atrophy?
A
- Loss of innervation
- Disuse
- Cachexia
- Old age
- Primary myopathies
24
Q
Type II fiber atrophy with sparing of type I fibers is seen with what?
A
- Prolonged corticosteroid therapy
- Disuse
25
Clusters or groups of atrophic skeletal muscle fibers are seen in which disorders?
**Neurogenic diseases**
26
How can **skeletal muscle myofibers** be injured?
1. Directly injured (**myopathic injury**)
2. Disruption of muscle innervation (**neurogenic disease**), which leads to _fiber type grouping_ and _grouped atrophy_
27
**Myopathic injury (directly injury)** to skeletal muscles causes what changes in the muscle?
1. **Segmental myofiber degeneration** and **regeneration**
2. **Hypertrophy of myofiber** = adaptation to exercise or chronic myopathic conditions
3. **Cytoplasmic inclusions,** like vacuoles, aggregates of protein, clusters of organnelles.
28
What is a **marker** for damage to skeletal muscle?
**Creatine Kinase**
29
**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** randomly distributed in cytoplasm
30
Name 3 primary **_Non-Infectious_ Inflammatory Myopathies**
1. **Polymyositis**
2. **Dermatomyositis**
3. **Inclusion body myositis**
31
What is **Dermatomyositis**?
When does it MC occur?
* **Systemic AI disease** that involves **skin** and **muscle**
* **Adults: 40s-60s**
32
Skin changes in **Dermatomyositis**
1. **Distinctive skin rash:** _lilac_ or _heliotrope_ discoloration of eyelids + periorbital edema
2. **Telangiectasies (dilated capillaries)** in nail folds, eyelids and gums
3. **Grotten lesions:** scaling erythemous patches over the knuckles, elbows and knees.
33
Muscle changes in **Dermatomyositis**
1. **Weakness of _proximal_ muscles 1st** =\> difficulty rising from chair, climbing stairs
2. 1/3 dev **dysphagia** (oropharyngeal & esophageal m) =\> _problem swallowing_
3. **10% interstitial lung dz**, vasculitis
4. **Cardiac involvement** common, rarely leads to _cardiac failure_
34
Which autoantibody type in **Dermatomyositis** is associated with prominent _Grotton papules_ and _heliotrope rash_?
**Anti-Mi2 antibodies**
35
Which autoantibody type in **Dermatomyositis** is associated with _interstitial lung disease_, _non-erosive arthritis_, and a rash known as _"mechanic's hands?_"
**Anti-Jo1 Ab**
36
Which autoantibody type in **Dermatomyositis** is associated with _paraneoplastic_ and _juvenile cases?_
**Anti-P155/P140 Ab**
37
Histology in **Dermatomyositis**?
1. **Perfascicular atrophy** = atrophic myofiber grouped periphery of fascicles
* Mononuclear infiltrate perimysial CT
38
Patients with **dermatomyositis** have ↑ of?
↑ risk of **_visceral cancer_**
**15-24%** adults with dermatomyositis have an assoc malignancy, may be viewed as **paraneoplastic**
39
What is the most common **inflammatory myopathy** in **children** and average age of onset?
**Juvenile Dermatomyositis;** average age **7YO**
40
**Juvenile Dermatomyositis** is more likely to have what findings compared to the adult-type; how does this affect prognosis?
1. **GI involvement**
2. **Calcinosis** and **lipodystrophy** (have a better prognosis)
41
When is the onset of **Polymyositis** and what are the signs/sx's; how is it distinguished from Dermatomyositis?
1. **Adult onset** w/ myalgia and weakness; _NO cutaneous features_
2. **Symmetrical** **proximal** muscle involvement
42
Which **inflammatory myopathy** is more associated with _perimysial infiltration_ vs. _endomysial infilatration_?
* **Dermatomyositis** = _perimysial_ (CD4+ T cells)
* **Polymyositis** and **Inclusion body myositis** = _endomysial_ _mononuclear infiltrate of_ (CD8+ T cells), affecting _random fibers_
43
When does **Inclusion Body Myositis** typically present?
**- Late adulthood; typically \>50 y/o**
- Most common cause of **inflammatory myopathy in pt's \>65 y/o**
44
What are the typical signs/sx's of **Inclusion Body Myositis?**
1. **Slowly progressive _asymmetric_** muscle weakness, most severe in **quadriceps** (knee extensors) and **_distal_ upper extremities (**flexors of wrist and fingers**)**
2. **Dysphagia** is not uncommon
45
Morphological changes that are specific for **Inclusion Body Myositis?**
1. **- "Rimmed vacuoles"** = cytoplasmic inclusions with red/granular rimming + basophilic granules around periphery + endomysial fibrosis
46
What is the first-line tx for **inflammatory myopathies** (i.e., dermatomyositis and polymyositis)?
**Corticosteroids**
47
Which drugs cause _drug-induced lysosomal storage myopathy_ =\> with **slowly progressive muscle weakness** which predominantly affects **type I fibers**?
_Anti-malarial drugs:_ **Chloroquine** and **hydroxychloroquine**
48
**Myopathy** is a common compliation of what drugs, _not_ related to the dose or type?
**_Statin_**: atorvastatin, simvastatin, pravastatin.
49
What is **ICU myopathy** (aka **myosin deficit myopathy)?**
**Critical illness + corticosteroid treatment**
50
**Thyrotoxic myopathy** causes what?
1. Acute or chronic _proximal_ muscle weakness
2. Exopthalmic opthalmoplregia: swelling of eyelids, conjunctiva and diplopia
3. Hypothryoirism
51
**Binge drinking** can cause what myopathy?
1. **Rhabdomyolysis**
2. Myoglobinuria
3. Renal failure
4. Acute myalgia
52
Types of **Inherited Diseases of Skeletal Muscle**
When do they present?
1. **Congenital myopathies** = persent _in infancy_ with muscle defects that are static or get better over time
2. **Muscular dystrophies** = progressive muscle damage that appears _AFTER infancy,_ often associated with developmental abnormalities of the CNS + progressive muscle damage
53
1. What is the inheritance and gene is affected in Duchene and Beckers muscular dystropgy?
2. Most commonly sporadic or familial?
3. Both have INC risk of developing what?
* **X-linked**
* **DMD gene** on **Xp21** =\> encodes **dystrophin**
* **2/3 = familial**
* **Cardiomyopathy**
54
How do the type of mutations of 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
55
Which is more common and more severe: **Duchenne** or **Becker**?
**Duchenne**: more common = more severe
56
Which lab value can aid in the diagnosis of **Duchenne** and **Becker muscular dystrophy?**↑↑
**↑↑↑ CK**
57
Where does weakness associated with **Duchenne muscular dystrophy** begin and how does it progress?
* Females carriers = asymptomatic
* **Symptoms appear before 5YO**
* Begins in _pelvic girdles -_--\> extends to _shoulder girdles_
* **Pseudohypertrophy** of calves: enlargement of lower leg muscles due to weakness: initially =\> ↑ bulk due to ↑ size of muscle fibers initially; later =\> muscle is replaced by ↑ fat & CT
* **Wheelchair bound by 10-12 YO**
58
Where does weakness associated with **Beckers muscular dystrophy** begin and how does it progress?
1. Begins in late childhood/adolescene
1. Begins in pelvic girdles ---\> extends to shoulder girdles
2. **Pseudohypertrophy** of calves often present (same as Duchennes)
2. Nearly NL lifespan
3. INC risk of cardiac disease
59
Histology of DMD and BMD
1. Variation in fiber size
2. ↑ # internalized nuclei
3. Degeneration, necrosis, & phagocytosis of muscle fibers
4. Regeneration of muscle fibers
5. Proliferation of endomysial connective tissue
6. occasionally (DMD), enlarged, rounded hyaline fibers that have lost their cross-striations (rare in BMD)
**7.Later stages,** muscle almost totally replaced by fat & connective tissue
60
What will immunohistochemical staining for dystrophin show in **Duchenne** vs. **Becker muscular dystrophy?**
- **Duchenne**: _absence_ of normal dystrophen staining pattern
- **Becker**: shows _reduced_ staining
61
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"
62
What is a key feature of **Myotonic Dystrophy?**
**Myotonia**: sustained involuntary contraction of a group of muscles; elicited by percussing the thenar eminence =\> _"Stifness or difficulty releasing grip"_
63
**Myotonic dystrophy** is caused by what?
**AD**: expansions of **CTG triplet repeats** in 3'-noncoding region of **DMPK gene**
64
How does **Myotonic Dystrophy** present signs and sx's?
1. **Gait, then atrophy of facial muscles** = ptosis and "hatchet face,"
2. **Frontal balding,**
3. **Cataracts,**
4. **Cardiomyopathy**
5. **Endocrinopathy**
65
**Histology** in Myotonic Dystropgy
1. Ring fiber
2. Sarcoplasmic Mass
66
What are diseases of lipid and glycogen metabolism?
Inborn errors of lipid or glycogen metabolism affect SKM
1. **Carnitine palmitoyltransferase II**
2. **McArdle Dz (myophosphorylase def)**
3. **Pompe Dz (Acid maltase def)**
67
When does a patient with a **disease of lipid/glycogen metabolism** get symptoms of muscle dysfunction?
1. **Exercise or fasting**
2. Or **slowly progressive muscle damage**
68
**Carnitine palmitoyltransferase II deficiency** is associated with what pattern of muscle damage?
* - **Episodic** muscle damage with **exercise and fasting**
69
_Milder_ deficiencies of **acid maltase** lead to what type of myopathy in _adults_?
Myopathy preferentially involving **respiratory** and **truncal** **muscles**
70
_Severe_ **acid maltase deficiency** causes what?
**Pompe disease** =\> generalized _glyocogenesis_ of _infancy_
71
Skeletal muscle involvement in **Mitochondrial Myopathies, which cause problems making ATP,** can manifest with what findings; involvement of what is common and can be a clue to the diagnosis?
1. - **Weakness** + **↑ CK** or **rhabdomyolysis**
2. - **Extraocular muscle involvement** = common and clue to dx
3. - **Chronic progressive external opthalmoplegia** = common feature
72
Morphologically what is the most consistent pathologic change seen in skeletal muscle of the **Mitochondrial Myopathies;** which stain can be used?
**Ragged red fibers:** Abnormal aggregates of mitochondria under the sarcolemma (red) + distortion of myofibrils (ragged)
## Footnote
**- Trimchrome stain\***
73
On **EM**, _ragged red fibers_ seen in _skeletal muscle_ due to **Mitochondrial Myopathies** are described how?
**Paracrystalline parking lot inclusions**
74
**Wernig-Hoffman (Spinal Muscular Atrophy type 1)** is due to destruction of what and what is the presentation?
- Destruction of anterior horn **motor neurons** in the spinal cord =\> muscle weakess and atropgy
- Onset at birth: generalized hypotonia (floppy infant), death \<3 yo
- Initially =\> muscle weakness of _truncal and extremity_ ms ==\> followed by chewing, _swallowing and breathing_ difficulties
75
**Spinal Muscular Atrophy** is also called what?
Inheritance
**Infantile Motor Neuron Disease**
* **AR** mutation of Survival Motor Neuron 1 (**SMN1**) on **Chr 5**
76
Characteristic morphological changes seen with **Spinal Muscular Atrophy (SMA)?**
* **Mix** **of**:
* Large zones of **round atrophic myofibers (panfascicular atrophy)**
* Scattered **NL sized fibers** or **hypertrophied myofibers** that are STILL innervated, found individually or in small groups
77
**Ion channel myopathies** are what?
Inheritance?
Symptoms?
* Mutations affecting function of **ion channel proteins**
* Most **AD**
* SX:
* **epilepsy,**
* **migraine,**
* **movement DOs with cerebellar dysfunction,**
* **peripheral n dzs**
* **muscle dz**
* **•↑ or ↓ excitability** → hypotonia or hypertonia
78
What triggers **malignant hyperthermia** in patients with _RYR1 mutation?_
**Anesthetics** (usu **halogenated inhalational agents**) ==\> **↑efflux of Ca⁺²** from sarcoplasmic reticulum→ **tetany** & **excessive heat production**
79
What is an **ion channel myopathy (channelopathy)?**
**Malignant Hyperthermi**a due to a RYR1 mutation
80
**RYR1 mutations** are associated with what?
**Malignant hyperthermia** --\> pts go into _hypermetabolic state_: tachycardia + tachypnea + muscle spasms and later hyperpyrexia
81
**Ion channel myopathies** that cause **hypotonia** may have what associated findings?
1. **↑,↓ or NL serum K+** (potassium)
82
