Diseases Of Peripheral Nerves

Gen Path – Dr. Yabut PNS and Skeletal muscle

Feb 02, 2008

DISEASES OF PERIPHERAL NERVE Inflammatory neuropathies ▪Characterized by inflammatory cell infiltrates in peripheral nerves, roots, and sensory and autonomic ganglia Guillain-Barre Syndrome (Acute Inflammatory Demyelinating Polyradiculoneuropathy) ▪Life-threatening dse f the PNS ▪Weakness beginning in the distal limbs rapidly advancing to affect proximal muscle fxn (ascending paralysis) Chronic Inflammatory Demyelinating Polyradiculoneuropath y

Pathogenesis ▪2/3 of cases preceded by acute, flu-like illness ▪Infections with Campylobacter jejuni, CMV, EBV, Mycoplasma pneumoniae ▪An immunological reaction is now generally favored as the underlying cause ▪Tx: plasmapheresis

Morphology ▪Inflammation of peripheral nerve ▪Perivenular and Endoneural infiltration by lymphocytes, macrophages, and a few plasma cells ▪Segmental demyelination affecting peripheral nerves is th primary lesion ▪Remyelination follows demyelination ▪Inflammatory foci and demyelination widely distributed throughout PNS (intensity is variable) ▪Histologically: inflammation and demyelination of spinal nerve roots and peripheral nerves (radiculoneuropathy)

Clinical Course ▪Ascending paralysis ▪DTR disappear early in the process ▪Sensory involvement can often be detected ▪Nerve conduction velocity slowed ▪Elevation of CSF protein due to inflammation ▪Altered permeability of microcirculation within spinal roots ▪There is little to no CSF pleocytosis

▪Often symmetric, mixed sensorimotor polyneuropathy ▪Biopsies of sural nerves show evidence of recurrent demyelination and remyelination w/ well-developed onion bulb structures

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Infectious Polyneuropathies ▪Leprosy, diphtheria, varicellazoster Pathogenesis Leprosy ▪Lepromatous leprosy: Schwann cells are often invaded by Mycobacterium leprae ▪Tuberculoid leprosy

Diphtheria

▪Peripheral nerve

involvement results from the effects of the diphtheria exotoxin

Varicella-Zoster Virus ▪One of the most common viral infections of the PNS

▪Latent infection of neurons in the sensory ganglia of the spinal cord and brainstem follows chickenpox, and reactivation leads to a painful, vesicular skin eruption in the distribution of sensory dermatomes (shingles), most frequently

Morphology

▪Lepromatous leprosy: there is

evidence of segmental demyelination and remyelination and loss of both myelinated and unmyelinated axons  endoneurial fibrosis ▪Tuberculoid leprosy: shows evidence of active cell-mediated immune response to M. leprae, with nodular granulomatous inflammation situated in the dermis  inflammation injures cutaneous nerves; axons, schwann cells and myelin are lost, there is fibrosis of perineurium and endoneurium ▪Earliest changes seen in the sensory ganglia ▪Incomplete blood-brain barrier allows entry of the toxin ▪There is selective demyelination of axons that extends into adjacent anterior and posterior roots as well as into mixed sensorimotor nerves ▪Weakness may be apparent ▪Affected ganglia show neuronal destruction and loss, usually accompanied by abundant mononuclear inflammatory infiltrates ▪Regional necrosis w/ hemorrhage may be found ▪Periperal nerve shows axonal

Clinical Course

▪Lepromatous leprosy: Pxs

develop a symmetric polyneuropathy that prominently involves pain fibers; the resulting loss of sensation contributes to injury  traumatic ulcers ▪Tuberculoid leprosy: Pxs have much more localized nerve involvement

▪Begins with paresthesias and weakness, early loss of proprioception and vibratory sensation

▪Decreased cell-mediated immunity is of major importance in some cases

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thoracic or trigeminal

degeneration after death of sensory neurons ▪Focal destruction of large motor neurons of the ant horns or cranial nerve motor nuclei may be seen

Hereditary Neuropathies ▪Grp of heterogenous, typically progressive, and often disabling syndromes that affect the peripheral nerves Pathogenesis Morphology Clinical Course Hereditary Motor ▪These disorders affect both ▪They present as a spectrum of and Sensory strength and sensation disorders, all caused by Neuropathies (sensorimotor neuropathies) mutations in genes whose (HMSN) products are involved in the ▪Most common formation and maintenance of myelin HMSN Type I ▪genetically heterogeneous ▪characteristic progressive ▪Patients may be ▪Most common muscular atrophy of the calf seen asymptomatic, but when they ▪In most pedigrees (known as hereditary in these patients gives rise to the present, it is often with HMSN IA or CMT1A), there is peripheral common clinical term peroneal symptoms such as distal a duplication of a large region neuropathy, muscular atrophy muscle weakness, atrophy of of chromosome 17p11.2-p12, Charcot-Marie-Tooth the calf, or secondary ▪CMT1 is a demyelinating resulting in "segmental (CMT) disease, orthopedic problems of the trisomy" of the duplicated neuropathy, both by nerve hypertrophic form foot (such as pes cavus) region conduction velocity studies and (HMSN I), usually ▪The disorder is usually pathologically ▪ presents in autosomal-dominant, and ▪Histologic examination: shows childhood early although it is slowly the consequences of repetitive adulthood progressive, the disability of demyelination and remyelination, sensorimotor deficits and with multiple onion bulbs, more associated orthopedic pronounced in distal nerves than problems such as pes cavus in proximal nerves are ▪Hypertrophic neuropathy usually limited in severity, and a normal life span is typical HMSN II

▪neuronal form of autosomal-

▪Nerve biopsy specimens in this

▪less common than HMSN I, 3

Dejerine-Sottas Disease (HMSN III)

dominant Charcot-Marie-Tooth disease that presents with signs and symptoms similar to those of HMSN I, although nerve enlargement is not seen and the disease presents at a slightly later age

disorder show loss of myelinated axons as the predominant finding ▪Segmental demyelination of internodes is infrequent

and in some families (designated CMT2A), it is linked to chromosome 1p35p36

▪slowly progressive,

▪muscular atrophy is limited to

▪genetically heterogeneous,

autosomal-recessive disorder that begins in early childhood, manifested by delay in developmental milestones, such as the acquisition of motor skills

the leg, both trunk and limb muscles ▪enlarged peripheral nerves can be detected by inspection and palpation ▪deep tendon reflexes are depressed or absent, and nerve conduction velocity is slowed

and arises from distinct mutations in the same myelinassociated genes that are mutated in HMSN I [genes encoding peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ), periaxin (PRX), and early growth response 2 (EGR2)]

Pathology

Morphology

Hereditary sensory and autonomic neuropathies (HSAN) Familial amyloid polyneuropathies (FAP)

Peripheral neuropathy accompanying inherited metabolic disorders

Clinical Course

▪symptoms are usually limited

▪characterized by the deposition of amyloid w/in the PNS

to numbness, pain and autonomic dysfunction such as orthostatic hypotension ▪Most exhibit mutations of the transthyretin gene (18q11.2q12.1) ▪Clinical presentation similar to HSAN

See table 27-3 (below)

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Acquired Metabolic and Toxic Neuropathies Pathogenesis Peripheral ▪most common peripheral Neuropathy in Adultneuropathy: symmetric Onset DM neuropathy that involves ▪Prevalence distal sensory and motor depends on nervesdecreased duration of dse sensation in the distal extremities with less ▪They are evident motor categorized as abnormalities distal symmetric development of ulcers that sensory or sensorimotor heal poorly  a major

Morphology ▪In patients with a distal symmetric sensorimotor neuropathy, the predominant pathologic finding is an axonal neuropathy ▪there is often some segmental demyelination ▪There is a relative loss of small myelinated fibers and of unmyelinated fibers, but large fibers are also affected

Clinical Course ▪Another manifestation of diabetic neuropathy is dysfunction of the autonomic nervous system; this affects 20% to 40% of diabetics, nearly always in association with a distal sensorimotor neuropathy ▪Some pxs develop peripheral neuropathy that manifests as a disorder of

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neuropathy, autonomic neuropathy, and focal or multifocal assymtric neuropathy

cause of morbidity

▪Endoneurial arterioles show

thickening, hyalinization, and intense periodic acid-Schiff (PAS) positivity in their walls and extensive reduplication of the basement membrane

single indiv cranial or peripheral nerves (mononeuropathy) or several indiv nerves of asymmetric distribution (multiple mononeuropathy/mononeuro pathy multiplex)

Metabolic and Nutritional Peripheral Neuropathies

▪As many as 65% of pxs w/

▪Typically a distal, symmetric

▪Thiamine deficiency

renal failure have clinical evidence of peripheral neuropathy before dialysis (uremic neuropathy) ▪Axonal degeneration is the prmary event, w/ degenerating fibers and fiber loss ▪Can also develop in pxs w/ chronic liver dse, chronic respi insufficiency, and thyroid dysfxn

neuropathy ▪May be asymptomatic or may be assoc w/ muscle cramps. Distal dysesthesias, and diminished DTRs

characterized by axonal neuropathyneuropathic beriberi ▪Can also occur w/ def in vit. B12, B6, and E

Neuropathies associated with Malignancy

▪Most common cause of

▪Brachial plexopathy 

Toxic Neuropathies

▪Can occur after exposure

mononeuropathy: Direct infiltration of peripheral nerve by tumormay be presenting symptom of Cancer

neoplasms of lung apex ▪Obturator palsy pelvic malignant neoplasms ▪Cranial nerve palsies intracranial tumors ▪Polyradiculopathy cauda equine involved by meningeal carcinomatosis

to industrial, envi, chem., biologic toxins or therapeutic drugs Traumatic Neuropathies ▪Peripheral nerves commonly injured in the course of trauma ▪Laceration: result from cutting injuries and can complicate fractures when a sharp fragment of bone lacerates the nerve

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▪Avulsions: occur when tension is applied to a peripheral nerve, often as the result of a force applied to one of the limbs.

Regeneration occurs slowly. o Traumatic neuroma (pseudoneuroma or amputation neuroma): mass of tangled axonal processes ▪Compression neuropathy (entrapment neuropathy): occurs when a peripheral nerve is compressed, often w/in anatomic compartment o Most common: carpal tunnel syndrome: results from compression of the median nerve at the level of the wrist DISEASES OF SKELETAL MUSCLE Denervation Atrophy ▪Caused by any process that affects the ant horn cell or its axon Pathogenesis Spinal Muscular Atrophy ▪All forms of SMA are /Infantile Motor Neuron associated with a locus on Disease (SMA) chromosome 5 that ▪Progressive neurologic harbors survival motor illnesses that selectively neuron gene SMN1 affect the ant horn cells in the spinal cord and cranial nerve motor neurons, resulting in their loss

in the PNS Morphology ▪Typical histologic finding: large number of atrophic fibers ▪Muscle fiber atrophy often involves entire fascicle, and is called panfascicular atrophy

Clinical Course

▪Most common form:

Werdnig-Hoffmann disease (SMA type 1)  onset at birth or w/in 4 mos and leads to death w/in first 3 yrs of life ▪SMA2 (shorter survival) and SMA3 (often survive to adulthood) present at later ages (3-15 mos for SMA2 and after 2 yrs in SMA3)

Muscular Dystrophies ▪A heterogenous grp of inherted disorders, often beginning in childhood ▪Characterized clinically by progressive muscle weakness and wasting ▪Histologically, advanced cases are characterized by the replacement of muscle fibers by fibrofatty tissue ▪X-Linked Muscular Dystrophy, Autosomal Muscular Dystrophy and Myotonic Dystrophy

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Pathogenesis X-Linked Muscular Dystropy (Duchenne MD and Becker MD) ▪DMD: most severe and more common form  manifest by age 5

▪Both are caused by

Autosomal Muscular Dystrophies (AMD)

▪Some affect specific

Myotonic Dystrophy (MD) ▪Myotonia: sustained involuntary contraction of a grp of muscles is the cardinal neuromuscular symptom in this dse

abnormalities in a gene located in Xp21 region and encodes 427-kDa protein termed dystrophin ▪DMD: almost or completely no dystrophin ▪BMD: diminished dystrophin

muscle grps, and the specific diagnosis is based largely on the pattern of clinical weakness ▪Limb Girdle MD ▪an autosomal-dominant trait ▪the disease tends to increase in severity and appear at a younger age in succeeding generations, a phenomenon termed anticipation ▪Myotonic dystrophy is associated with a trinucleotide CTG repeat expansion on chromosome 19q13.2-13.3 ▪This expansion affects the mRNA for the dystrophila myotonia-protein kinase

Morphology Histopathologic abnormalities: ▪Variation in fiber size ▪Increased numbers of internalized nuclei ▪Degeneration, necrosis, and phagocytosis of muscle fibers ▪Regeneration of muscle fibers ▪Proliferation of endomysial connective tissue ▪DMD: fibers that have lost their normal crossstriations (wala nito sa BMD)

▪Skeletal muscle may

show variation in fiber size ▪Striking increase in the number of internal nuclei, which on longitudinal section may form conspicuous chains ▪Ring fiber, with a subsarcolemmal band of cytoplasm that appears distinct from the center of the fiber ▪ring fiber may be associated with an irregular mass of sarcoplasm

Clinical Course

▪Boys with DMD normal at brith, walking is delayed ▪Weakness begins in the pelvic girdle muscles ▪Psuedohypertrophy: enlargement of calf muscles associated with weakness ▪Death resultsfrom respi insuff, pulmo infx, and cardiac decompensation

▪disease often presents in late childhood abnormalities in gait secondary to weakness of foot dorsiflexors and subsequently progresses to weakness of the hand intrinsic muscles and wrist extensors ▪Atrophy of muscles of the face and ptosis ▪Cataracts ▪Other associated abnormalities: frontal balding, gonadal atrophy, cardiomyopathy, smooth muscle involvement, decreased plasma

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(DMPK)

(sarcoplasmic mass) IgG, and abnormal glucose tolerance test response ▪Histochemical techniques: relative ▪Dementia has been reported in atrophy of type 1 fibers some cases early in the course of the disease in some cases ▪Of all the dystrophies, only MD shows pathologic changes in the intrafusal fibers of muscle spindles, with fiber splitting, necrosis, and regeneration ▪Malignant hyperpyrexia (malignant hyperthermia): a rare clinical syndrome characterized by a dramatic hypermetabolic state (tachycardia, tachypnea, muscle spasms, and later, hyperpyrexia) o Triggered by induction of anesthesia o May occur n predisposed indivs with hereditary mscle dses

Ion Channel Myopathies (Channelopathies) ▪A grp of familial dses characterized by myotonia, relapsing episodes of hypotonic paralysis, or both ▪Hypotonia variants associated with elevated, depressed, or normal serum potassium levels ar the time of the attack are termed heperkalemic, hypokalemic, and normokalemic periodic paralysis, respectively ▪Pathogenesis: Congenital Myopathies o These dses are caused by mutations in genes ▪A grp of disorders defined largely on the basis of the that encode ion channels pathologic findings w/in muscle o Hyperkalemic periodic paralysis: mutations in ▪Onset in early life the gene that encodes a skeletal muscle ▪Nonprogressive or slowly progressive course sodium channel protein (SCN4A)regulates entry of Na into muscle during contraction ▪Proximal or generalized muscle weakness o Hypokalemic periodic paralysis: mutations in ▪Hypotonia the gene that encodes a voltage-gated ▪Arthrogryposis calcium channel -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------Myopathies Associated with Inborn Errors of Metabolism • Many are found in the setting of disorders of glycogen synthesis and degredation Pathology Morphology Clinical Course Lipid Myopahties • Principal morphologic • Abnormalities of the characteristic is carnitine transport accumulation of lipid system or w/in myocytes deficiencies of the • Myofibrils are mitochondrial separated by vacuoles Dehydrogenase

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Mitochondrial Myopathies (Oxidative Phosphorylation Diseases)

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enzyme systems accumulation of lipid droplets w/in muscles Mutations in mitochondrial genome (mtDNA) May present in young adulthood and manifest with proximal muscle weakness, and sometimes, external opthalmoplegia

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Vacuoles occur predominantly in Type 1 fibers

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Most consistent morphologic finding: aggregates of abnormal mitox that occur under the sarcolemma in early stages Ragged red fibers Parking lot inclusions

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Point mutations in DNA (maternal pattern of inheritance, myoclonic epilepsy with ragged red fibers or MERRF, Leber Hereditary optic Neuropathy or LHON, mitox encephalopathy with lactic acidosis and strokelike episodes or MELAS) Mutations in genes encoded by nuclear DNA (autosomal dominant/recessive, Subacute necrotizing encephalopathy or Leigh syndrome , infantile X-linked cardioskeletal myopathy or Barth syndrome) Deletions or duplications of mtDNA (chronic progressive external ophthalmoplegia, Kearns-Sayre syndrome)

Inflammatory Myopathies Noninfectious Inflammatory Myopathies • Characterized by injury and inflammation of the skeletal muscle Pathogenesis Morphology Dermatomyositis • Capillaries seem to be • Inflammatory the target infiltrates located predominantly around • CD4+ Tcells present in small bloodvessels and muscle in perimysial connective tissue • Perifascicular atrophy

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• • Polymyositis

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Appears to be causedby cell-

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CD8+ lymphocytes and other lymphoid cells

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Clinical Course Skin and skeletal muscle Classic rash takes the form of a lilac or heliotrope discoloration of upper eyelids w/ periorbital edema Muscle weakness slow in onset Proximal muscles affected first Lack of cutaneous involvement

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Inclusion Body Myositis

mediated injury of myocytes • CD8+ Tcells • CD8+ Tcells found

surround and invade healthy muscle fibers • •

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Occurs mainly in adults

Presence of rimmed vacuoles Vacuoles present w/in myocytes

Toxic Myopathies Thyrotoxic Myopathy • Presents most commonly as an acute or chronic proximal muscle weakness that may precede the onset of other signs of thyroid dysfxn • Exophthalmic ophthalmoplegia • Fiber atrophy, increased number of internal nuclei, glycogen aggregates, deposition of mucopolysaccharides in the connective tissue • Myofiber necrosis, regeneration and interstitial lymphocytosis Ethanol Myopathy • Binge drinking of alcohol • Acute toxic syndrome of rhabdomyolysis with accompanying myoglobinuria w/c may lead to renal failure Drug-Induced Myopathies • Steroid myopathy • Muscle fiber atrophy, predominantly affecting type 2 fibers • Choloroquine can produce a proximal myopathy in humans

Diseases of the NMJ Myasthenia Gravis • One of the best defined forms of autoimmune disease

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Pathogenesis Immune-mediated loss of Ach receptors and having characteristic temporal and anatomic patterns as well as drug responses

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Morphology Disuse changes with type 2 fiber atrophy

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Clinical Course Weakness begins with extraocular muscles Ptosis, diplopia Generalized weakness

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Lamberton-Eaton Myasthenic Syndrome

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Usually develops as a paraneoplastic process, most commonly with small cell CA of the lung

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Proximal muscle weakness along with autonomic dysfxn Autoimmunity to calcium channel causes disease

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