Peripheral Nerve and Skeletal Muscle Inflammatory Neuropathies



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Pathology Ch 27 1261-1267

Peripheral Nerve and Skeletal Muscle
Inflammatory Neuropathies characterized by inflammatory cell infiltrates in peripheral nerves, roots, and sensory/autonomic ganglia
Guillain-Barré Syndrome (Acute Inflammatory Demyelinating Polyradiculoneuropathy) characterized by weakness beginning in distal limbs but advancing to proximal muscles (ascending paralysis), and histologically by inflammation and demyelination of spinal nerves

Pathogenesis of GB thought to be acute-onset immune-mediated demyelinated neuropathy; sometimes preceded by flu-like illness from which person has recovered before becoming symptomatic

-infections with Campylobacter Jejuni, cytomegalovirus, EB virus, and mycoplasma pneumonia have been shown to be in association with GB syndrome

-lymphocytes from people with GB have been shown to produce demyelination in tissue cultures of myelinated nerve fibers; circulating antibodies play a part

Morphology of GB inflammation of peripheral nerve is dominant histological finding, manifested as perivenular and endoneurial infiltration by lymphocytes, macrophages

-most intense inflammation is in spinal and cranial motor roots and adjacent parts of spinal and cranial nerve

-segmental demyelination affecting peripheral nerves is primary lesion, but damage to axons is also present; macrophages penetrate schwann cells near nodes of ranvier to strip away myelin

Clinical Course of GB dominated by ascending paralysis; DTR’s absent early with some sensory involvement; nerve conduction velocity is slowed

-elevation of CSF protein due to inflammation and altered permeability of microcirculation within spinal roots

-inflammatory cells contained in roots, and there is little to no CSF pleocytosis
Chronic Inflammatory Demyelinating Polyradiculoneuropathy inflammatory demyelinating polyradiculoneuropathy can develop over several years with both sensory and motor polyneuropathy, although some patients show a predominant sensory or motor impairment; remission may occur with steroid treatment and plasmapheresis

-recurrent demyelination and remyelination with well-developed onion bulb structures


Infectious Polyneuropathies leprosy, diphtheria, and varicella zoster affect nerves

Leprosy (Hansen Disease) in lepromatous lepros, schwann celsl are invaded by Mycobacterium leprae, which proliferate and infect other cells

-evidence of segmental demyelination and remyelination and loss of both myelinated and unmyelinated axons

-as disease progresses, there is evidence of endoneurial fibrosis and multilayer thickening of perineurial sheaths; affected people develop symmetric polyneuropathy affecting the cool extremities (lower temps favor mycobacterial growth)

-infection involves pain fibers, and resulting loss of pain sensation contributes to injury, so traumatic ulcers can develop in extremities

-In tuberculoid leprosy, there is cell-mediated response to M. Leprae with nodules of granulomatous inflammation in the dermis

-inflammation injures cutaneous nerves in vicinity: axons, schwann cells, and myelin are lost



Diphtheria peripheral nerve involvement results from diphtheria exotoxin and begins with paresthesias and weakness; early loss of proprioception and vibratory sensation is common

-early changes seen in sensory ganglia, where incomplete blood-brain barrier allows entry of toxin

-selective demyelination of axons that extends into ant and posterior roots
Varicella-Zoster Virus most common viral infection of PNS, follows chicken pox and persists in neurons in sensory ganglia of spinal cord and brainstem  shingles is most frequent thoracic or trigeminal eruption

-may be transported along sensory nerves to the skin to establish active infection of epidermal cells, can appear with weakness; decreased T-cell immunity is important

-Affected ganglia show neuronal destruction and loss, accompanied by mononuclear inflammatory infiltrates; regional necrosis with hemorrhage may be found

-peripheral nerve shows axonal degeneration after the death of sensory neurons, and focal destruction of large motor neurons in anterior horns of cord may be seen


Hereditary Neuropathies group of heterogeneous, progressive, and disabling syndromes affecting peripheral nerves

  1. Hereditary Motor and Sensory Neuropathies (HMSNs) MOST COMMON form of hereditary neuropathy affecting both strength and sensation, caused by mutations in genes involved in peripheral nerve functions

  2. Adrenoleukodystrophy – defect in ABC transporter

  3. Familial amyloid polyneuropathies – defect in transthyretin gene

  4. Porphyria, acute intermittent or coproporphyria – enzymes in heme synthesis

  5. Refsum disease peroxisomal enzyme phytanoyl CoA hydroxylase defect

  6. Hereditary Sensory and Autonomic Neuropathies (HSANs) symptoms limited to numbness, pain, and autonomic dysfunction WITHOUT weakness (HSAN I-V)

  7. Familial Amyloid Polyneuropathies characterized by deposition of amyloid within PNS; show mutations in transthyretin gene and present similarly to HSAN; amyloid fibers composed of transthyretin, a protein in serum binding and transport of thyroid hormone

  8. Peripheral Neuropathy Accompanying Inherited Metabolic Disorders several hereditary metabolic disorders are accompanied by prominent peripheral neuropathy during disease

-the most common hereditary neuropathy, HMSN I, results in demyelination of peripheral nerve and slowing of axonal conduction
Hereditary Motor and Sensory Neuropathy Type I also referred to as charcot-marie-tooth (CMT) disease (demyelinating type) presenting in childhood

-characteristic progressive muscular atrophy of leg below knee causes term peroneal muscular atrophy; people may be asymptomatic but could present with distal muscle weakness, atrophy of leg below knee, or secondary orthopedic problems



Pathogenesis and Molecular Genetics most common subtype is HMSN IA or CMT1A resulting from segmental trisomy; duplicated segment has gene encoding peripheral myelin protein 22 (PMP22), transmembrane protein on myelin

-mutations of these proteins result in demyelinating neuropathies of HMSNI

-mutations in another gene coding from myelin protein zero (MPZ) cause HMSN IB

Morphology of HMSN I demyelinating neuropathy with repetitive demyelination and remyelination with multiple onion bulbs, more pronounced in distal nerves than proximal

-redundant layers of schwann cell hyperplasia surrounding individual axons are associated with enlargement of involved peripheral nerves that are palpable – hypertrophic neuropathy



Clinical Course autosomal dominant, slow and progressive, normal life span
HMSN II axonal form of autosomal dominant CMT HMSN II presents with symptoms of HMSN I, although nerve enlargement is not seen and the disease presents at a later age; some cases caused by mutations in kinesin family member KIF1B

-nerve biopsy specimens in HMSN II show loss of myelinated axons; segmental demyelination of internodes is INFREQUENT


Dejerine-Sottas Neuropathy (HMSN III) slow progressive, autosomal recessive disorder beginning in childhood manifested by delay in developmental milestones, such as acquisition of motor skills

-in contrast to HMSN I and II where muscular atrophy is limited to leg, both the trunk and limb muscles are involved in Dejerine-Sottas disease

-on physical exam, enlarged peripheral nerves can be detected by inspection and palpation

-DTRs are depressed or absent, and nerve conduction is slow

-mutations in PMP2, MPZ, periaxin, and EGR2

-abundant bulb formation as well as segmental demyelination, evidence of axonal loss, axons remaining are diminished, and distal portions of peripheral nerves are most severely affected


Acquired Metabolic and Toxic Neuropathies metabolic alterations from endogenous disorders or exogenous agents can cause structural changes in peripheral nerves

Peripheral Neuropathy in Adult-Onset Diabetes Mellitus up to 50% of diabetics will get peripheral neuropathy; several clinicopathologic patterns have been recognized

-characterized by distal symmetric sensory or sensorimotor neuropathy, autonomic neuropathy, and focal/multifocal asymmetric neuropathy; sensorimotor/autonomic are found together

-caused by polyol pathway and nonenzymatic glycation of proteins

Morphology of Diabetic Neuropathy in people with distal symmetric sensorimotor neuropathy, predominant pathologic finding is axonal neuropathy; often some segmental demyelination. Relative loss of small, myelinated fibers and unmyelinated fibers, but large fibers also affected

Clinical Course most common in type 2 diabetes is symmetric neuropathy involving distal sensory and motor nerves; people develop decreased sensation in distal extremities with less evident motor abnormalities

-loss of pain sensation can result in development of ulcers which heal poorly due to diffuse vascular injury in diabetes

-has protean manifestations, including postural hypotension, incomplete emptying of bladder which results in recurrent infections and sexual dysfunctions
Metabolic and Nutritional Peripheral Neuropathies Most people with renal failure have a peripheral neuropathy (uremic neuropathy); typically a distal, symmetric neuropathy that may be asymptomatic or may be associated with muscle cramps, distal dysethesias, and diminished DTRs

-axonal degeneration is primary event with secondary demyelination

-can also develop in people with liver disease, chronic respiratory insufficiency, and thyroid dysfunction

-thiamine deficiency is associated with axonal neuropathy, called neuropathic beriberi

-axonal neuropathies occur with B12, B6, or E deficiency can cause axonal neuropathy; ethanol can lead to axonal neuropathy
Neuropathies Associated with Malignancies direct infiltration of peripheral nerve by tumor can cause mononeuropathy including brachial plexopathy if tumor is at apex of lung, obturator palsy from pelvic neoplasms, and cranial nerve palsies from intracranial tumors and tumors of the base of the skull

-a polyradiculopathy involving lower extremity may develop from meningeal carcinomatosis

-a diffuse, symmetric peripheral nerupathy may occur with distant carcinoma as a paraneoplastic event; most common is sensorimotor neuropathy characterized by weakness and sensory deficits often pronounced; associated with small cell carcinoma of lung
Toxic Neuropathies peripheral neuropathies can occur after exposure to industrial or environmental chemicals, biological toxins, therapeutic drugs; lead and arsenic are prominent
Traumatic Neuropathies peripheral nerves are commonly injured in course of trauma

-lacerations result from cutting injuries; fractures when long bone lacerates the nerve

-avulsions occur when tension is applied to peripheral nerve when force applied to limb

-regeneration does occur, but slowly; complicated by discontinuity between proximal and distal portions of nerve sheath

-axons, even in incorrectly positioned distal segments, grow in a tangle called traumatic neuroma; bundles of axons are randomly oriented but surrounded by schwann cells, fibroblasts, and perineurial cells

Compression Neuropathy (entrapment neuropathy) when peripheral nerve is compressed within anatomic compartment, such as in carpal tunnel syndrome (entrapment of median nerve at wrist by transverse carpal ligament)

-other nerves prone to compression are ulnar nerve at elbow, peroneal nerve at knee, radial nerve in upper arm, or in the foot affecting interdigital nerve at intermetatarsal sites (Morton neuroma)


Tumors of Peripheral Nerve both benign and malignant tumors can be derived from elements of nerve sheath


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