Peripheral nerve & Skeletal Muscle Flashcards
3 major connective tissue components of peripheral nerve:
- Epineurium: enclosed entire nerve
- Perineurium: multilayered, concentric connective tissue sheath that encloses each fascicle
- Endoneurium: surrounds individual nerve fibers
- Nerve: numerous fibers grouped into fascicles by connective tissue sheaths
- Fascicle contains both myelinated & unmyelinated nerve fibers
- Unmyelinated axons more numerous than myelinated
- Cytoplasm of 1 Schwann cell envelopes variable # of unmyelinated fibers (5‐10 axons in humans)
- PNS axons myelinated in segments (internodes) separated by Nodes of Ranvier • Single Schwann cell supplies myelin sheath for each internode
Segmental demyelination
Occurs when dysfunction of Schwann cell (ie hereditary motor & sensory neuropathy) of damage to the myelin sheath (ie Guillain‐Barre )
- No primary abnormality of axon
- Does not affect all Schwann cells
- Disintegrating myelin engulfed by Schwann cells then macrophages
NOTE: Random internodes of myelin are injured and are remyelinated by multiple Schwann cells, while the axon and myocytes remain intact
- Denuded axon = stimulus for remyelination
- Precursor cells inside endoneurium have the capacity to replace injured Schwann cells
- Newly myelinated internodes shorter than normal (several bridge demyelinated region)
- Onion bulbs: concentric layers of Schwann cytoplasm & redundant basement membrane surrounding thinly myelinated axon (cross section)
Traumatic neuroma
A failure of the outgrowing axons to find their distal target can produce a “pseudotumor” termed traumatic neuroma— a non‐neoplastic haphazard whorled proliferation of axonal processes and associated Schwann cells that results in a painful nodule
on histology: you would see parallel fibers that suddenling becoming Haphazarded
Axonal degeneration: result of primary destruction of axon (#1) with secondary disintegration of myelin sheath (#2)
Axon damage: focal (trauma, ischemia) or generalized affecting whole neuron body (neuronopathy) or its axon (axonopathy )
• Focal lesion (traumatic transection of axon); distal portion undergoes Wallerian degeneration
- Myelin ovoids: Schwann cells catabolize myelin & later engulf axon fragments, producing small oval compartments
- Macrophages then recruited for clean up
- Proximal stump of severed nerve shows degenerative changes in most distal 2‐3 internodes, then undergoes regeneration
Axonal degeneration → muscle fibers in motor unit lose neural input & undergo denervation atrophy
- “Angulated” fibers: atrophic fibers are smaller & triangular shape when denervation atrophy
- Target fibers: rounded zone of disorganized myofibers in center of fiber
Schwann cells vacated by degenerating axons provide guide for growth cone of regenerating fibers
- Regenerating cluster: multiple closely aggregated, thinly myelinated small‐caliber axons
- Reinnervation of skeletal muscle changes its composition, altering distribution of the 2 major fiber types
- Fiber type determined by neuron of the motor unit; fiber properties imparted via innervation
- Motor neuron determines fiber type; all muscle fibers of a single unit are the same type
- Fibers of a single unit are distributed across the muscle = checkerboard pattern
- Axons of unaffected neighboring motor unit extend sprouts to reinnervate the denervated myocytes & incorporate them into the healthy motor unit
- Newly adopted reinnervated fibers assume fiber type of their new siblings
- Type grouping: patch of contiguous myocytes having the same histochemical type
Nerve Regeneration
Group atrophy: type group becomes denervated
- Type 2 fiber atrophy: inactivity or disuse (limb fracture, pyramidal tract degeneration, neurodegenerative dz
- Type 2 atrophy also during glucocorticoid therapy = “steroid myopathy”
muscle types
Type 1: action: sustained force, strength: weight bearing, lipid: abundant, glycogen: scant, ultrastructure: many mitochondria, wide Z-band, physiology: slow-twitch, color: red, prototype: soleus
Type 2: action: sudden movements, strength: purposeful motion, lipid: scant, glucogen: abundant, ultrastructure: few mitochondria, narrow Z-band, physiology: fast-twitch, color: white, prototype: pectoral (pigeon)
Reactions of Muscle Fiber
- Many diseases affect muscle, but myocytes only have a few pathologic reactions
- Segmental necrosis: destruction of a portion of myocyte, followed by myophagocytosis (macrophages infiltrate region); loss of muscle fiber leads to deposition of collagen & fat
- Vacuolization, alterations in structural proteins or organelles, & accumulation of intracytoplasmic deposits; seen in many diseases
- Regeneration
- Hypertrophy -Muscle fiber splitting
- Regeneration: satellite precursor cells proliferate & reconstitute the destroyed portion of fiber; regenerating portion has large internalized (central location) nuclei with prominent nucleoli; cytoplasm laden with RNA is RED
- Hypertrophy: response to ↑ load; either through exercise or pathologic condition (fibers injured)
- Muscle fiber splitting: large fibers may divide longitudinally; cross section = single large fiber with a cell membrane traversing its diameter, often with adjacent nuclei
Patients with peripheral neuropathy (PN) generally describe the pain as tingling, stabbing, burning or “pins and needles”.
- Mononeuropathies: affects a single nerve, deficits in a restricted distribution
- Trauma, entrapment, infections…
- Polyneuropathies: multiple nerves, usually symmetric
- Deficits start at the feet & ascend with disease progression
- Hands usually deficits same time as knee = “stocking & glove” distribution
• Mononeuritis multiplex: several nerves damaged in haphazard fashion
- Vasculitis is a common cause of this pattern (polyarteritis nodosum = PAN)
• Polyradiculoneuropathies: nerve roots as well as peripheral nerves
- Diffuse symmetric in proximal & distal parts of the body
Bell’s Palsy
- Mononeuropathy: CN VII → facial muscle paralysis
- 15‐60 yo; generally resolves spontaneously
- One sided facial droop within 48‐72 hrs of initial sx
- Assoc with URI & DM
- SX: facial tingling, mid‐severe headache/neck pain, memory problems, balance issues, ipsilateral limb paresthesias, ipsilateral limb weakness, & sense of clumsiness
- DDX for facial weakness: stroke, brain tumor, Ramsay Hunt syndrome (type 2 herpes zoster oticus), & Lyme Dz
- Neurogenic bladder: a number of urinary conditions in people who lack bladder control due to a brain, spinal cord or nerve problem
- This nerve damage can be the result of diseases such as multiple sclerosis (MS), Parkinson’s disease or diabetes.
- It can also be caused by infection of the brain or spinal cord, heavy metal poisoning, stroke, spinal cord injury, or major pelvic surgery.
- People who are born with problems of the spinal cord, such as spina bifida, may also have this type of bladder problem.
- Nerves in the body control how the bladder stores or empties urine, and problems with these nerves cause overactive bladder (OAB), incontinence, and underactive bladder (UAB) or obstructive bladder, in which the flow of urine is blocked.
Acute Inflammatory Neuropathy
Guillain‐Barre
Acute inflammatory demyelinating polyneuropathy
- Life threatening dz of PNS
- Weakness beginning in distal limbs, but rapidly advancing to proximal muscles: “ascending paralysis”
- Deep tendon reflexes disappear
- Inflammation & demyelination of spinal nerve roots & peripheral nerves (radiculoneuropathy )
- Acute onset immune‐mediated demyelinating neuropathy
⅔ cases preceded by acute influenza‐like illness; recovered when neuropathy starts
• Campylobacter jejuni, cytomegalovirus, Epstein‐Barr virus, Mycoplasma pneumoniae, or prior vaccination
- Inflammation of peripheral nerve: perivenular & endoneurial infiltration by lymphs, macrophages & few plasma cells
- Inflammation & demyelination widely distributed throughout PNS
- Segmental demyelination affecting peripheral nerves = primary lesion
- Anti‐myelin antibodies
- Cytoplasmic processes of macrophages penetrate basement membrane of Schwann cells, particularly in vicinity of Nodes of Ranvier, & extend between myelin lamellae, stripping myelin sheath away from axon
- ↑CSF protein due to altered permeability of microcirculation of spinal roots
- Inflammatory cells remain confined to the roots, thus little or no CSF pleocytosis (cells)
- Mortality has ↓ from 25→2‐5%; respiratory paralysis, autonomic instability, cardiac arrest…
- Plasmapheresis, IVIg (intravenous immunoglobulin) beneficial
- 20% of hospitalized pt have long‐term disability
Chronic Inflammatory Demyelinating Poly(radiculo)neuropathy
- Most common acquitted inflammatory peripheral neuropathy
- Symmetrical mixed sensorimotor polyneuropathy, persists > 2 months (signs & sx MUST be present for at least 2 months)
- Relapses & remissions evolve over years
- Clinical remission: immunosuppressive tx (glucocorticoids, IVIg, plasmapheresis, & biologic agents against T or B‐cells)
DDX: Time course & response to steroids distinguish this from Guillain‐ Barre
- Complement fixing IgG & IgM found on the myelin sheath
- Sural nerve bx = ONION BULBS
- Onion bulbs: mult layers of Schwann cells wrap around an axon like the layers of an onion
Infectious polyneuropathies
Leprosy (Hansen Disease)
- Lepromatous leprosy: Schwann cells invaded by Mycobacterium leprae; bacteria proliferates & infects other cells
- Segmental demyelination & remyelination & loss of both myelinated & unmyelinated axons
- Endoneurial fibrosis & multilayered thickening of perineural sheaths
- Symmetric polyneuropathy affecting cool extremities (lower temp favors Mycobacterium growth)
- Involves pain fibers, loss of sensation contributes to injury
- Large traumatic ulcers
Tuberculoid leprosy: active cell‐mediated response
- granulomatous nodules in dermis
- localized nerve involvement
- injures cutaneous nerves
- axons, Schwann cells & myelin lost
- fibrosis of perineurium & endoneurium
Infectious polyneuropathies
Diphtheria exotoxin affects peripheral nerves & begins with paresthesias & weakness
- Incomplete immunization & waning adult immunity
• Early loss of proprioception & vibratory sensation
• Sensory ganglia
- Selective demyelination of axons that extend into adjacent anterior & posterior roots, & into mixed sensorimotor nerves
- Peripheral neuropathy assoc with prominent bulbar & respiratory muscle dysfunction → death or long term disability
Infectious polyneuropathies
Varicella‐Zoster Virus
- Most common viral infection of PNS
- Sensory ganglia of spinal cord & brainstem
- Reactivation of latent infection: painful vesicular skin eruption in distribution of sensory dermatomes: shingles
- Neuronal destruction & loss of affected ganglia; abundant mononuclear infiltrate; regional necrosis & hemorrhage may be found
- Axonal degeneration of peripheral nerves after death of sensory neurons
- Focal destruction of large motor neurons in anterior horns or cranial nerve motor nuclei may be seen at corresponding levels
lyme disease- • Second & third stages of dz • Polyradiculoneuropathy • Unilateral or bilateral facial nerve palsies
HIV-• Mononeuritis multiplex • Demyelinating that resemble Guillain‐Barré or chronic inflammatory demyelinating polyradiculoneuropathy • Later stages of HIV infection assoc with distal sensory neuropathy
Acquired Metabolic & Toxic Neuropathies: Diabetes
Diabetes is the most common cause of peripheral neuropathy
Several patterns: ascending distal symmetric sensorimotor polyneuropathy, most common
• Prevalence of complication depends on duration of the DZ
Most common: symmetric neuropathy involving distal sensory & motor nerves
- Numbness, loss of pain sensation, difficulty with balance
- Paresthesias & dysesthesias = positive sx = painful sensations
- Neuropathy→ morbidity due to ↑susceptibility to foot & ankle flexion, chronic skin ulcers
- Diffuse vascular injury major cause of morbidity in diabetes
- DM causes Segmental demyelination
- ↓ # axons; degen myelin sheaths & regenerative axonal clusters
- relative loss of small myelinated fibers & unmyelinated fibers
- large fibers also affected
- endoneurial arterioles show thickening, hyalinization & intense PAS positivity
• Dysfunction of autonomic nervous system in 20‐40%, almost always assoc with distal sensorimotor neuropathy
- Postural hypotension, incomplete emptying of bladder (↑infections), & sexual dysfunction
Other metabolic, hormonal, nutritional or toxic neuropathies
Uremic: most people with renal failure have a periph neuropathy
- Distal symmetric neuropathy: may be asymptomatic, muscle cramps, distal dysesthesias, ↓deep tendon reflexes
- Axonal degeneration usually primary event; regeneration & recovery common after dialysis
- Thyroid dysfunction: hypothyroidism →compression mononeuropathies (carpel tunnel), distal symm predominantly sensory polyneuropathy
- Rarely hyperthyroidism assoc with syndrome resembling Guillain‐Barré
- Vit B12, vit B1, vit B6, folate, vit E, copper, & zinc
- EtOH, heavy metals (Pb, mercury, arsenic, thallium), organic solvents
Neuropathies assoc with Malignancy
- Neuropathies from local effects, complications of tx, paraneoplastic effects, or tumor derived Ig (B‐cell tumors)
- Direct infiltration or compression of periph n
- brachial plexopathy from neoplasm apex of lung
- Obturator palsy (pelvic tumor), cranial n palsy, …
- Paraneoplastic neuropathies
- Sensorimotor neuronopathy most common = small cell lung CA
- Neuropathies assoc with monoclonal gammopathies (B‐cell neoplasms)
• POEMS: polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, & skin changes
• Deposition of paraprotein between noncompacted myelin lamellae
- Traumatic neuropathies
- Traumatic neuroma: regenerates slowly; discontinuity complicates
- Axons continue to grow despite misalignment → small bundles of axons randomly oriented, but surrounded by organized layers of Schwann cells, fibroblasts & perineural cells
- Compression/entrapment neuropathy
- Carpel tunnel syndrome: median nerve, transverse carpal ligament
- freq bilateral, women
- Numbness & paresthesias tip of thumb & first 2 digits
• Saturday night palsy: radial nerve upper arm, fall asleep awkwardly
Other compression neuropathies:
Ulnar nerve @ elbow; peroneal nerve @ knee,
- Morton neuroma: metatarsalgia, histological lesion=perineural fibrosis
- Interdigital nerve @ intermetatarsal sites, W > M
