Peripheral Nerve and Skeletal Muscle Pathology Flashcards
Guillain-Barre Syndrome (acute inflammatory demyelinating polyneuropathy)
- life threatening resp paralysis
- weakness beginning in distal limbs that rapidly advanes to affect prox muscle function
- Inflammation and demyelination of spinal nerve roots and peripheral nerves
What is the pathogenesis of guillain-barre thought to be?
-an acute onset immune mediated demyelinating neuropathy
What precedes guillain-barre syndrome?
-an acute, influenza-like illness
What is the most prominent lesion in guillain barre?
-segmental demyelination affecting peripheral nerves is the most prominent lesion
clinical features of guillain barre?
- ascending paralysis and areflexia
- CSF ptn levels are elevated
tx for guilain barre
-plasmapheresis and IV immunoglobulin appear to be beneficial
Chronic Inflammatory Demyelinating poly(radiculo)neuropathy
-mot common chronic acquired inflammatory peripheral neuropathy, charcterized by symmetrical mixed sensorimotor polyneuropathy that persists for 2 months or more
Neuropathy associated with systemic autoimmune diseases
- RA
- SLE
- Sjogren
Lepromatous Leprosy
- schwann cells are invaded by mycobacterium leprae
- loss of sensation contributes to injury
- thus, large traumatic ulcers may develop
Tuberculoid leprosy
- active cell mediated immune response to M leprae
- dermal nodules containing granulomatous inflammation
lyme disease
- polyradiculopathy
- unilateral or bilateral facial nerve palsies
HIV/AIDS
-later stages are associated with a distal sensory neuropathy that is often painful
Diphtheria
-developing world
-peripheral nerve dysfunction results from the effects of diphtheria exotoxin
-
Varicella-Zoster Virus
- one of the most common viral infections of peripheral nervous system
- latent infection persists within neurons of sensory ganglia
- gets transported along the sensory nerves to the skin
- there, it infects keratinocytes, leading to a painful, vesicular skin eruption (shingles) in a distribution that follows sensory dermatomes
What is the most common cause of peripheral neuropathy?
- diabetes
- ascending distal symmetric
Uremic neuropathy
- renal failure
- axonal degeneration
- regeneration and recovery are common after dialysis
What is the most notorious cause of toxic neuropathies?
-chemotherapeutic agents
POEMS syndrome
- polyneuropathy
- organomegaly
- endocrinopathy
- monoclonal gammopathy
- skin changes
Hereditary motor and sensory neuropathies/Charcot Marie tooth disease (CMT)
- most common inherited peripheral neuropathy
- schwann cell hyperplasia and onion bulb formation
What chromosome is duplicated in CMT1A?
- 17
- PMP22
- 2nd decade of life
- slowly progressive distal demyelinating motor and sensory nueropathy
CMT1B
-caused by mutation in the myelin protein zero gene and accounts for about 9% of genetically
What kind of injury is found in CMT2?
-axonal rather than demyelinating injury
Hereditary neuropathy with pressure palsy
- deletion of gene encoding PMP22
- transient motor and sensory mononeruopathies that are triggered by compression of individual nerves at sites that are prone to entrapment
What is the characteristic morphologic feature for hereditary neuropathy with pressure palsy?
-swolen, bulbous myelin sheaths at the end of internodes (tomaculi)
Familial amyloid polyneuropathies
- characterized by amyloid deposition within peripheral nerves
- mutation of the the transthyretin gene
How do diseases of the NM junction present?
-with painless weakness
Myasthenia gravis
Autoantibodies against the postsynaptic Ach receptor at the NM junction
- more commonly seen in women
- competitive inhibition
- bimodal age distribution
what else will there be in a mysthenia gravis patient?
- thymic abnormalities
- thymectomy improves sx
clinical features of mysathenia gravis
- that worsens with use and IMPROVES WITH REST
- classically involves the eyes, leading to ptosis and diplopia
- sx improve with anticholinesterase agents
Lambert-Eaton myasthenic syndrome
- antibodies against presynaptic Ca2+ channels of the nm junction
- arises as a paraneoplastic syndrome, most commonly due to SMALL CELL CARCINOMA OF THE LUNG
- leads to impaired Ach release
what is required for Ach release?
-firing of presynaptic calcium channels
Clinical features of lambert-eaton syndrome
- pros muscle weakness that IMPROVES WITH USE
- eyes are usually spared
- Ach agents do not improve symptoms.. makes sense bc Ach isn’t the issue
- resolves with resection of the cancer
tx for lambert eaton
-drugs that increase AcH rlease by depolarizing synaptic membranes
What mutation will be there is congenital myasthenic syndromes?
-most commonly LOF in the gene encoding the e subunit of the AcH receptor
Botulinism
- C botulinum
- blocking the release of Ach from presynaptic neurons
what is a common name for muscle relaxants that block AcH receptors, resulting in flaccid paralysis?
- Curare
- used as poison on arrow tips
Dermatomyositis
- Inflammatory disorder of the skin and skeletal muscle
- unknown etiology
clinical features of dermatomyositis
- bilateral prox muscle weakness; distal involvement can develop late in disease
- rash of upper eyelids (heliotrope rash); malar rash may also be seen
- red papules on elbows, knuckles, and knees (gottron papules)
lab findings for dermatomyositis
- increased creatine kinase
- positive ANA and anti-Jo-1-antibody
- perimysial inflammation with perifascicular atrophy on biopsy
tx for dermatomyositis
-steroids
What other antibodies besides anti-Jo-1 antibodies would we find in dermatomyositis?
- anti Mi2 antibodies: prominent gottron papules and heliotrope rash
- anti-P155/P140 antibodies: for paraneoplastic and juvenile cases
- anti Jo-1 will have interstitial lung disease and “mechanics hands”
What is the key morphologic feature of dermatomyositis?
- perfascicular atrophy… characteristic of dermatomyositis
- polymyositis is endomysial
What is the most common inflammatory myopathy in children?
-dermatomyositis
Polymyositis
- inflammatory disorder of skeletal muscle
- resembles dermatomyositis clinically, but skin is NOT involved
- endomysial inflammation (CD8+ T cells) with necrotic muscle fibers is seen on biopsy
- adult onset
- symmetric proximal muscle involvement
What is believed to play a major role in dermatomyositis but not polymyositis?
-vascular injury
Inclusion body myositis
- late adulthood
- most common inflammatory myopathy in pts older than 65
- quadriceps and distal upper extremity muscle weakness
- most myositis associated autoantibodies are absent
- anti cN1A
- doesnt’ respond to steroids
What are the leading culprits of toxic myopathies?
- statins
- myopathy is the most common complication of statins
X-linked muscular dystrophy
- degeneative disorder characterized by muscle wasting and replacement of skeleatl muscel by adipose tissue
- due to defects in dystrophin gene
what is dystrophin important for?
-anchoring the muscle cytoskeleton to the ECM
Duchenne muscular dystrophy
- due to deletion of dystrophin
- presents as prox muscle weakness at 1 year of age, progresses to involve distal muscles
- calf pseudohypertrophy is characteristic
- serum creatine kinase is elevated
What does death result from in Duchenne?
- cardiac or respiratory failure
- the myocardium is commonly involved
Becker muscular dystrophy
- due to mutated dystrophin
- clinically results in milder disease
- so, it’s not totally deleted
where is the dystrophin gene?
-on the X chromosome
what will we see on IF for Duchenne and Becker
- Duchenne: absence of normal sarcolemmal staining pattern
- Becker: reduced staining
clinical presentation for duchenne?
- clumbsy boys who can’t keep up with their peers
- beckerpresents in later childhood
Myotonic dystrophy
-auto dominant multisystem disorder associated with skeletal muscle weakness, cataracts, endocrinopathy, and cardiomyopathy
pathogenesis of myotonic dystrophy
-expansions of CTG triplets in region of DMPK gene
Emery-Dreifuss Muscular dystropy
- caused by mutation sin genes that encode nuclear laminal proteins
- triad of slowly progressive humeroperoneal weakness, cardiomyopathy associated with conduction defects, and early contractures of the achilles tendon, spine, and elbows
- inner face of nuclear membrane
Fascioscapulohumeral dystrophy
- characteristic pattern of muscle inovlvement that includes prominent weakness of facial muscles and muscles of the shoulder girdle
- DUX4 overexpression on chrom 4
Limb-Girdle muscular dystrophy
-characterized by muscle weakness that preferentially involves proximal muscle groups
Carnitine palmitoyltransferase 2 deficiency
- most common disorder of lipid metabolism to cause episodic muscle damage with exercise or fasting
- impaired transport of free fatty acids into mitochondria
Myophosphorylase deficiency (McArdle disease)
- common glycogen storage disease
- episodic muscle damage with exercise
acid maltase deficiency
- impaired lysosomal conversion of glycogen to glucose
- glycogen accumulates within lysosomes
- severe form results in generalized glyogenosis of infancy… Pompe disease
mitochondrial myopathies
- impair the ability of mitochondria to generate ATP
- involvement of extraocular eye muscles in common … good clue for dx
- chronic progressive external opthalmoplegia is a common feature
- “ragged red fibers”: abnormal aggregates of mitochondria
Spinal muscular atrophy mutation?
- auto recessive
- LOF in SMN1 gene
Schwannomas
- benign tumors that exhibit schwann cell differentiation and often arise directly from peripheral nerves
- component of NF2
- chromosom 22: merlin on the NGS gene
- immunoreactivity for S-100
What are Verocay bodies?
- in schwannomas
- nuclear free zones that lie between the regions of nuclear palisading
Neurofibromas
- benign nere sheath tumors that are more heterogenous in composition than schwannomas
- only the schwann cells in this disease show complete los of NF1 gene product
- bland Schwann cells admixed with stromal cells such as mast cells, perineurial cells, CD34+ spindle cells, and fibroblasts
what is the NF1 gene product?
- neurofibromin
- suppresses RAS activity by stimulating GTPase
Malignant peripheral nerve sheath tumors (MPNSTs)
- high grade tumors
- arise in NF1 (1/2 of them do)
- pporly defined tumor masses that frequently infiltrate along the axis of the parent nerve and ivade adjacent soft tissues
- divergent differentiation
Which MPNST has rhabdomyoblastic morphology?
-Triton tumor
Neurofibromatosis 1
- pigmented nodules of the irs
- cutaneous hyperpigmented macules (cafe au laits pots
- LOF in NF1 on chrom 17: encodes neurofibromin
- In the absence of NF-1, RAS remains trapped in its active state
- auto dominant
Neurofibromatosis 2
- auto dominant
- bilateral 8th nerve schwannomas
- multiple meningioma
- much less common that NF1
- NF2 gene product: merlin
What are the 3 kinds of neurofibromas
- Superficial cutaneous neurofibromas: pedunculated nodules…if multiple.. NF1
- Diffuse neurofibromas: large plaquelike elevation of skin… NF1
- Plexiform neurofibromas: NF1 associated… bag of worms
Where do most schwannomas occur?
- at the CPA, where they are attached to the vestibular branch of the 8th nerve
- that is where the tinnitus and hearing loss come from
- “acoustic neuroma”: not from 8ht nerve…. not a neuroma…. idiots
