Peripheral Nerve & Skeletal Muscle Pathology Flashcards by Sarah Gillen

There are 2 main responses of peripheral nerves to injury, determined by their target.

_______ _______ occurs with primary involvement of the Schwann cell and loss of myelin.

____ _____ occurs with involvement of the neuron and its axon, which may be followed by ________ _______ and ________ of muscle

Segmental demyelination

Axonal degeneration; axonal regeneration; reinnervation

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There are 2 principle pathologic processes seen in muscle:

_______ _______ follows loss of axon

_______ is a primary abnormality of muscle fiber itself

Denervation atrophy

Myopathy

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Segmental demyelination occurs with dysfunction of _____ cells or damage to the ______ sheath. There is no primary abnormality of axons and not all cells are affected.

Schwann; myelin

[disintigrating myelin is engulfed by schwann cells then macrophages; random internodes of myelin are remyelinated by multiple schwann cells, while the axon and myocytes remain intact]

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In the case of segmental demyelination, a ______ axon is the stimulus for remyelination. Precursor cells inside the endoneurium have the capacity to replace injured schwann cells. Newly myelinated internodes are shorter than normal. Histologically appear as “______ _____”, which are formed by concentric layers of schwann cytoplasm and redundant basement membrane surrounding thinly myelinated axon

Denuded

Onion bulbs

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A failure of the outgrowing axons to find their distal target can produce a “pseudotumor” called ______ _______: a non-neoplastic haphazard whorled proliferation of axonal processes and associated schwann cells that results in a painful nodule

Traumatic neuroma

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Axonal degeneration is the result of 1. Primary destruction of axon, and 2. Secondary disintigration of myelin sheath. Axon damage may be focal (trauma, ischemia) or generalized affecting whole neuron body (neuronopathy) or its axon (axonopathy).

With a focal lesion — traumatic transection of axon, the distal portion undergoes __________ _________

Wallerian degeneration

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______ ______ = small ovoid compartments produced when cells catabolize myelin and later engulf axon fragments

Myelin ovoids

[macrophages are then recruited for cleanup; proximal stump of severed nerve shows degenerative changes in most distal 2-3 internodes, then undergoes regeneration]

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When axonal degeneration occurs, muscle fibers in the motor unit lose neural input and undergo _______ ________.

Features of this process include _________ fibers —atrophic fibers that are smaller and triangular in shape, and _______ fibers which are a rounded zone of disorganized myofiebrs in the center

Denervation atrophy

“Angulated”; target

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In terms of nerve regeneration and reinnervation of muscle, schwann cells vacated by degenerating axons provide the guide for growth cone of regenerating fibers. A regenerating cluster consists of multiple closely aggregated, thinly myelinated, small-caliber axons.

Reinnervation of skeletal muscle changes its composition, altering distribution of the 2 major fiber types. The _____ ______ determines fiber type, and all muscle fibers of a single unit are the same type. Fibers of a single unit are distributed across the muscle in a _______ pattern

Motor neuron; checkerboard

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Type ____ fiber atrophy occurs with inactivity or disuse (limb fracture, pyramidal tract degeneration, neurodegenerative disease, etc), as well as with glucocorticoid therapy

Type 2

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Many diseases affect muscle, but myocytes only have a few pathologic reactions:

What are some of these reactions?

Segmental necrosis: destruction of portion of myoctye, followed by myophagocytosis

Loss of fiber leads to deposition of collagen and fat

Vacuolization, alterations in structural proteins or organelles, and accumulation of intracytoplasmic deposits

Regeneration

Hypertrophy (and muscle fiber splitting)

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Describe regeneration of muscle fiber

Satellite precursor cells proliferate and reconstitute the destroyed portion of the fiber; regenerating portion has large internalized nuclei in central location and prominent nucleoli; cytoplasm is laden with RNA

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Describe hypertrophy and muscle fiber splitting that occur with damage to muscle

Hypertrophy is a response to increased load either due to exercise or pathologic condition (fibers injured)

Muscle fiber splitting — large fibers may divide longitudinally

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4 general types of peripheral neuropathy

Mononeuropathy — affects single nerve with deficits in restricted distribution

Polyneuropathy — multiple nerves, usually symmetric; deficits start at the feet and ascend with disease progression (“stocking and glove”)

Mononeuritis multiplex — several nerves damaged in haphazard fashion; common cause is vasculitis (polyarteritis nodosum)

Polyradiculoneuropathies — nerve ROOTS as well as peripheral nerves

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Bell’s palsy is a type of _________ of CN VII leading to facial muscle paralysis that generally resolves spontaneously. It is characterized by one-sided facial droop and is associated with conditions like _____ and _______

Mononeuropathy; URI; DM

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What is a neurogenic bladder and what are some associated conditions?

Neurogenic bladder = urinary condition in people who lack bladder control due to a brain, spinal cord, or nerve problem

May be result of MS, parkinsons, diabetes, infection, heavy metal poisoning, stroke, spinal cord injury, major pelvic surgery, spina bifida

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Acute onset immune-mediated inflammatory demyelinating polyneuropathy in which weakness begins in distal limbs, but rapidly advances to proximal muscles as “ascending paralysis”; DTRs disappear, there is inflammation and demyelination of spinal nerve ROOTS and peripheral nerves (radiculoneuropathy)

Guillain-barre

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2/3 of cases of guillain barre are preceded by an acute influenza-like illness caused by C.jejuni, CMV, EBV, M.pneumoniae, or prior vaccination. Inflammation of the peripheral nerve includes ______ and _______ infiltration by lymphocytes, macrophages, and few plasma cells. This inflammation and demyelination is widely distributed throughout the PNS.

______ ______ affecting peripheral nerves is the primary lesion

Overall characterized by presence of ________ antibodies

Perivenular; endoneurial

Segmental demyelination

Anti-myelin

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Describe the role macrophages play in demylination that occurs with GBS

Cytoplasmic processes of macrophages penetrate basement membrane of Schwann cells, particularly in vicinity of Nodes of Ranvier, and extend between myelin lamellae, stripping myelin sheath away from axon

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CSF changes in GBS

Increased CSF protein d/t altered permeability of microcirculation of spinal roots

[inflammatory cells remain confined the roots so there is little or no CSF pleocytosis]

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Most common acquired inflammatory peripheral neuropathy and how it is distinguished from GBS

Chronic inflammatory demyelinating polyradiculoneuropathy = symmetrical mixed sensorimotor polyneuropathy persisting >2 months

Distinguished from GBS based on time course and response to steroids

[dx also involves complement fixing IgG and IgM found on myelin sheath as well as sural nerve bx showing onion bulbs]

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Describe peripheral neuropathy caused by lepromatous leprosy

Schwann cells invaded by M.leprae; bacteria proliferates and infects other cells

Segmental demyelination and remyelination and loss of both myelinated and unmyelinated axons

Endoneurial fibrosis and multilayered thickening of perineural sheaths

Overall it is a symmetric polyneuropathy affecting cool extremities; tends to involve pain fibers leading to loss of sensation

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Describe peripheral neuropathy caused by tuberculoid leprosy

Active cell-mediated response resulting in grannulomatous nodules in derms, LOCALIZED nerve involvement, injury to cutaneous nerves, axons+schwann cells+myelin are lost, as well as fibrosis of perineurium and endoneurium

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How does diphtheria infection lead to peripheral neuropathy?

Diphtheria exotoxin affects peripheral nerves and begins with paresthesias and weakness

Affects sensory ganglia with early loss of proprioception and vibratory sensation

Selective demyelination of axons that extend into adjacent anterior and posterior roots, and into mixed sensorimotor nerves

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Most common viral infection of PNS, affecting sensory ganglia of spinal cord and brainstem leading to neuronal destruction and loss of affected ganglia, regional necrosis and hemorrhage, axonal degeneration, and focal destruction of large motor neurons in anterior horns or CN motor nuclei

Varicella-zoster virus

Infectious disease resulting in polyradiculoneuropathy in second and third stages, manifestations include unilateral or bilateral facial nerve palsies

Lyme disease

What type of peripheral neuropathy is caused by HIV?

Mononeuritis multiplex [later stages of HIV are associated with distal sensory neuropathy]

Most common cause of peripheral neuropathy

Diabetes

What is the most common pattern of peripheral neuropathy in diabetic pts?

Ascending distal symmetric sensorimotor polyneuropathy

Pathogenesis of the neuropathy caused by DM

Segmental demyelination: decreased number of axons as well as degeneration of myelin sheaths and regenerative axonal clusters There is a relative loss of small myelinated fibers and unmyelinated fibers, but large fibers are also affected Endoneurial arterioles show thickening, hyalinization, and intense PAS positivity

Types of neuropathy associated with uremia

Distal symmetric neuropathy — may be asymptomatic, muscle cramps, distal dysesthesias, decreased DTRs Axonal degeneration is usually primary event; regeneration and recovery common after dialysis

Types of neuropathy associated with thyroid dysfunction

Hypothyroid —> compression mononeuropathies (carpal tunnel), distal symmetric predominantly sensory polyneuropathy Rarely, hypERthyroidism is associated with syndrome resembling GBS

Neuropathies are often associated with malignancies due to local effects, complications of tx, paraneoplastic syndromes, or tumor derived Ig. This may occur due to direct infiltration as in brachial plexopathy with apical lung neoplasm or obturator palsy with pelvic tumor. In terms of paraneoplastic neuropathy, sensorimotor neuronopathy is most common and is seen in ______________

Small cell lung cancer

Neuropathy associated with monoclonal gammopathy (B-cell neoplasms)

POEMS: polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes

Compression neuropathy affecting median nerve due to entrapment by transverse carpal ligament, leads to numbness and paresthesias of tip of thumb and first 2 digits

Carpal tunnel syndrome

Compression neuropathy affecting radial nerve of upper arm, often due to sleeping in an awkward position

Saturday night palsy

Compression neuropathy manifesting as metatarsalgia due to interdigital nerve entrapment; histological lesion is perineural fibrosis

Morton neuroma

Most common inherited peripheral neuropathy

Charcot-Marie-Tooth (CMT) [genes involved include CMT1 or CMT2 which are autosomal dominant forms, or CMTX which is X-linked]

Inherited peripheral neuropathy resulting in amyloid deposition within peripheral nerves

Familial amyloid polyneuropathy

Regardless of the cause, disorders that impair function of the neuromuscular junction tend to present with painless ______. _______ that inhibit key neuromuscular junction proteins are the most common cause of disrupted transmissions, as found in myasthenia gravis and lambert-eaton

Weakness Autoantibodies

2 Toxins that affect neuromuscular junctions

Clostridium botulinum — blocks release of ACh Curare — muscle relaxant that blocks AChR —> flaccid paralysis

Condition characterized by immune-mediated los of Ach receptors. 85% have Abs against AChR, while the rest have Ab against sarcolemmal protein muscle specific receptor tyrosine kinase

Myasthenia gravis

There is a strong association between AChR autoAb seen in myasthenia gravis and _______ abnormalitis

Thymic [10% of pts with MG have thymoma, 30% have thymic hyperplasia]

Clinical presentation of myasthenia gravis

Fluctuating generalized weakness that worsens with exertion and over the course of the day Diminished responses after repeated stimulation Weakness begins with extraocular muscles — drooping eyelids and double vision (not seen in other myopathies!) Note: those with Ab to muscle specific RTK exhibit more focal muscle involvement (neck, shoulder, facial, respiratory, bulbar)

Tx for myasthenia gravis

Acetylcholinesterase inhibitors Plasmapheresis and immunosuppressives Thymectomy for those with thymoma

Condition characterized by antibody block of acetylcholine release by inhibiting presynaptic calcium channel

Lambert-eaton myasthenic syndrome

Lambert-Eaton myasthenic syndrome may be a paraneoplastic process of what primary cancer?

Small cell carcinoma of lung

Clinical presentation of lambert eaton

Proximal muscle weakness and autonomic dysfunction Repetitive stimulation increases muscle response (note: opposite of MG!!)

Skeletal muscle atrophy is a common feature of many disorders. Causes include loss of innervation, disuse, cachexia, old age, and primary myopathies. When atrophy is severe there is a loss of muscle mass. Neurogenic disease is characterized by fiber type grouping and group atrophy. Dermatomyositis is a ________ atrophy.

Perifascicular

Skeletal muscle disorders may be via myopathic or neurogenic injury. Segmental myofiber degeneration and regeneration result in release of ______ ______ in to the blood which is a marker of muscle damage. Regenerating fibers rich in RNA exhibit ______ staining with enlarged nuclei and prominent nucleoli randomly distributed in cytoplasm.

Creatine kinase; basophilic

Dermatomyositis is associated with skin and muscle changes occurring in adults in 4-6th decade. Describe the skin rash associated with this condition

Distinctive skin rash with lilac or heliotrope discoloration of upper eyelids associated with periorbital edema Telangiectasias of nail folds, eyelids, and gums Grotton lesions = scaling erythematous eruption or dusky patches over knuckles, elbows, and knees

Describe muscle and cardiopulm manifestations that accompany the skin rash of dermatomyositis

Proximal muscles affected first (difficulty rising from a chair, climbing stairs, etc) 1/3 develop dysphagia (oropharyngeal and esophageal mm) 10% have interstitial lung disease and vasculitis Cardiac involvement is common and may lead to cardiac failure

Autoantibodies present in dermatomyositis

Anti-Mi2 (causes heliotrope rash and Grotten papules) Anti-jo1 (“mechanics hands”) Anti-P155/P140 (paraneoplastic and juvenile forms)

Dermatomyositis is associated with an increased risk of _______ ______, and thus may be viewed as a paraneoplastic syndrome

Visceral cancer

Histologic appearance of dermatomyositis

Perifascicular atrophy — atrophic fibers grouped at periphery of fascicles Mononuclear infiltrate in perimysial CT

Most common myopathy in children with avg age of onset at 7 y/o

Juvenile dermatomyositis [involves GI tract, calcinosis and lipodystrophy; anti-P155/P140]

Adult onset condition characterized by symmetric proximal myalgias and weakness WITHOUT cutaneous features; considered a dx of exclusion

Polymyositis

Polymyositis is associated with _________ cells in the endomysium, and necrotic and regenerating fibers scattered throughout the fascicle. The endomysial mononuclear infiltrate and random distribution of affected fibers differentiate this condition from ______

CD8+ T cells; dermatomyositis

Disease of late adulthood (>50y/o) and the most common inflammatory myopathy in pts >65 y/o; characterized by slowly progressive and asymmetric muscle weakness most severe in quadriceps and distal upper extremities, and rimmed vacuoles on histology

Inclusion body myositis [muscle weakness starts with DISTAL mm., esp the extensors of the knee and flexors of the wrist; also associated with dysphagia from esophageal and pharyneal m. involvement]

Myopathy is the most common complication of what class of Rx drugs?

Statins!

Antimalarial drugs associated with drug-induced lyososomal storage myopathy that affects type 1 fibers and manifests as slowly progressive muscle weakness

Chloroquine | Hydroxychloroquine

Thyrotoxic myopathy is associated with acute or chronic _______ muscle weakness and may manifeest as _____ ________ which consists of swelling of the eyelids, edema conjunctiva, and diplopia

Proximal; exophthalmic ophthalmoplegia

Binge drinking may produce what myopathies?

Rhabdomyolysis Myoglobinuria + renal failure Acute myalgia

Inheritance pattern of Duchenne muscular dystrophy and becker muscular dystrophy

X-linked

Gene affected in DMD

Xp21 (dystrophin) [2/3 of cases are familial; female carriers are asymptomatic but show increased creatine kinase and risk of developing cardiomyopathy]

Primary difference between DMD and BMD

DMD pts have NO dystrophin BMD pts have a decreased amount of dystrophin [thus DMD presents before age 5 and wheelchair bound by 10-12; BMD presents later in childhood and exhibits nearly normal lifespan w/increased risk of cardiac dz]

Manifestation of DMD and/or BMD in which there is enlargement of muscles of lower legs associated with weakness; increased bulk is due to increased size of muscle fibers initially due to attempt to compensate for lack of dystrophin

Pseudohypertrophy

Histology of DMD and BMD

Variation in muscle fiber size, increased number of internalized nuclei Degeneration, necrosis, and phagocytosis of muscle fibers Regeneration of muscle fibers Proliferation of endomysial CT Occasionally, DMD shows enlarged rounded hyaline fibers taht have lost cross striations In later stages, muscle is almost completely replaced by fat and CT

Sustained involuntary contraction of a group of muscles that can be elicited by percussion on thenar eminence

Myotonia

Symptoms of myotonic dystrophy as well as 2 major histologic features

Stiffness — difficulty releasing grip Skeletal m. weakness, cataracts, endocrinopathy, and cardiomyopathy Atrophy of facial muscles — ptosis and “hatchet face”, frontal balding, cataracts, cardiomyopathy Histology: ring fiber, sarcoplasmic mass

Inheritance of myotonic dystrophy and genes affected

Autosomal dominant CTG trinucleotide repeat expansion 19q13.2-q13.3 myotonic dystrophy protein kinase (DMPK)

___________ muscular dystrophy results from mutations in genes that encode nuclear lamina proteins. There is an X-linked form (______) and an autosomal dominant form (________)

Emery-Dreifuss; EMD1; EMD2

Triad associated with emery-dreifuss muscular dystrophy

Slowly progressive humeroperoneal weakness Cardiomyopathy associated with conduction defect Early contractures of the Achilles tendon, spine, and elbows

Limb-girdle muscular dystrophy is muscle weakness that preferentially involves ______ muscle groups. There are multiple AD and Ar entities. Age of onset and severity of disease vary greatly

Proximal

Many inborn errors of lipid or glycogen metabolism affect skeletal muscle. Two general patterns of muscle dysfunction include symptoms with exercise or fasting, and slowly progressive muscle damage. What is the most common enzyme deficiency that falls in this category, manifesting as episodic muscle damage with exercise and fasting?

Carnitine palmitoytransferase II deficiency

_______ is a glycogen storage disease characterized by myophosphorylase deficiency, leading to episodic muscle damage with exercise

McArdle Disease

Acid maltase deficiency is considered a milder adult form of ______disease, affecting respiratory and trunk muscles

Pompe

General symptoms associated with mitochondrial myopathies

Weakness, increased serum CK, or rhabdomyolysis Extraocular muscle involvement commonly seen Chronic progressive external ophthalmoplegia also common

Leber hereditary optic neuropathy is caused by a _______ mutation in mitochondrial DNA

Point

______ syndrome (subacute necrotizing encephalopathy) and ______ syndrome (infantile x-linked cardioskeletal myopathy) are mitochondrial myopathies associated with genes encoded by nuclear DNA

Leigh; Barth

________ syndrome is a mitochondria myopathy associated with weakness of extraocular muscles including ophthalmoplegia, pigmentary degeneration of retina, and complete heart block; caused by deletions or duplications of _____ DNA

Kearns-Sayre; mitochondrial

Characteristic histologic finding associated with mitochondrial myopathy

Ragged red fibers [aggregates of abnormal mitochondria under the sarcolemma, distortion of myofibrils]

Neuropathic disorder (and prototypic neuronopathy) resulting in loss of motor neurons, which manifests as muscle weakness and atrophy

Spinal muscular atrophy

Infants with neurologic or neuromuscular disease may present with generalized hypotonia (“floppy infant”). On the DDx for this is spinal muscular atrophy, which is a disease that destroys the ________ of the spinal cord. It is inherited in _____ _____ pattern, and although it begins in childhood or adolescence, loss of fibers can begin in utero. It is associated with the ____ gene on Chr5

Anterior horn cells Autosomal recessive SMN1 (survival motor neuron 1)

On histology, spinal muscular atrophy appears as large zones of atrophic myofibers mixed with scattered normal or hypertrophied myofibers (the latter retain their innervation). What is the most common type of spinal muscular atrophy and what are the clinical manifestations?

Wernig-Hoffman (SMA type 1) Onset at birth, floppy baby, death <3 y/o Muscle weakness of truncal and extremity muscles initially, followed by chewing, swallowing, and breathing difficulties

An important ion channel myopathy is malignant hyperthermia, which is caused by a mutation in _______. This leads to a hypermetabolic state including tachycardia, tachypnea, muscle spasms, and hyperpyrexia. It can be triggered by anesthetics, usually __________ inhalational agents. The anesthetic triggers increased efflux of _____ from the ______ leading to tetany and excessive heat production

RYR1 Halogenated Ca++; SR

Inheritance and pathologic findings associated with RYR1 mutation leading to malignant hyperthermia

Autosomal dominant Pathologic finding is central-core disease, meaning cytoplasmic cores represent demarcated central zones in which normal arrangement of sarcomeres is disrupted and mitochondria are decreased in number

Autosomal dominant familial tumor syndrome characterized by neurofibromas of peripheral nerves, optic nerve gliomas, lisch nodules, and cafe au lait spots

Neurofibromatosis type 1

Autosomal dominant familial tumor syndrome associated with bilateral acoustic schwannomas (CN VIII), may affect cerebellopontine angle, increased meningiomas, ependymomas, affects merlin protein

Neurofibromatosis type 2

Disease associated with pineoblastoma and leukokoria

Retinoblastoma [pineoblastoma = trilateral retinoblastoma]

Autosomal dominant disease associated with hemangioblastoma of cerebellum/spine, retinal angioma, cysts of pancreas, liver, and kidneys, renal cell carcinoma, pheochromocytoma, and polycythemia

VHL

Autosomal dominant disease associated with subependymal giant cell astrocytoma, ash-leaf spots, shagreen patches, retinal astrocytoma, and affects hamartin protein leading to hamartomas (cortical tubers)

Tuberous sclerosis

Disease associated with medulloblastoma, basal cell carcinoma, and affects PTCH gene

Nevoid basal cell carcinoma (Gorlin) syndrome

Syndrome associated wtih dysplastic gangliocytoma of the cerebellum, facial trichilemmoma, and affects PTEN gene

Lhermitte-Duclos/Cowden syndrome

Syndrome associated with malignant glioma and affects P53

Li-fraumeni

Autosomal recessive condition affecting ATM gene/protein affecting DNA repair after radiation injury, and characterized by neurologic and vascular lesions

Ataxia-telangiectasia

What kind of peripheral nerve sheath tumor?: Cerebellar pontine angle Acoustic neuroma NF2: loss of merlin Antoni A = spinde cells, verocay bodies = palisading nuclei around “nuclear free zones” Antoni B = hypocellular, myxoid ECM

Schwannoma

_______ are peripheral nerve sheath tumors that can be sporadic or NF-1 associated. May be superficial cutaneous, diffuse, or plexiform (“bag of worms”) with malignant transformation to _____ possible

Neurofibroma; MPNST

85% HG tumors, 1/2 arise in NF1 pts, subtypes include triton tumor with rhabdomyoblastic differentiation

MPNST