Chapter 12

PERIPHERAL NERVE PATHOLOGY

SPECIFIC NEUROPATHIES

DIABETIC NEUROPATHIES


Arteriole in diabetic nerve

Vascular thickening of an endoneurial arteriole in diabetes.

The most common cause of neuropathy in clinical practice is diabetes. Peripheral neuropathy develops in more than half of long term diabetics and goes in tandem with other complications, such as retinopathy and nephropathy. Diabetes causes several types of neuropathy, which include chronic symmetrical polyneuropathy, proximal neuropathy (diabetic amyotrophy), mononeuropathies, and cranial radiculopathies. The most common is a symmetrical sensorimotor neuropathy which causes pain, sensory loss, weak or absent tendon reflexes and, to a lesser extent, weakness. The pathological findings in this diabetic polyneuropathy are axonal loss, axonal regeneration, and in some patients, demyelination. Small axons are affected more severely.A prominent finding in diabetic neuropathy is thickening of endoneurial arterioles due to increased deposition of basement membrane material, similar to changes that occur in brain arterioles and glomerular capillaries. The pathogenesis of diabetic neuropathies is poorly understood. Ischemia is probably an important factor. Nonenzymatic glycation of neural structures and other biochemical changes in diabetes probably play a role also.

INFLAMMATORY DEMYELINATIVE NEUROPATHIES

These uncommon neuropathies are presumed to be immune disorders in which antibodies and activated T-lymphocytes, reacting with antigens present on peripheral nerves, elicit an inflammatory and macrophage reaction that destroys myelin and axons. The strongest evidence of a humoral immune reaction in these neuropathies is that plasma exchange results in significant clinical improvement. The participation of cellular immunity is underlined by the pesence of T-lymphocytes around blood vessels in affected nerves. The two main entities in this group are the Guillain-Barré syndrome and chronic inflammatory demyelinative neuropathy. An experimental model of demyelinative neuropathy, experimental allergic neuritis (EAN), can be produced by injecting animals with myelin and Freund adjuvant or purified peripheral myelin protein P2. EAN is a cell-mediated immune reaction.


Guillain-Barré syndrome

GBS. Inflammation in peripheral nerve.

The Guillain-Barré Syndrome(GBS) is not a single disease entity. It includes several variants: Acute inflammatory demyelinative polyneuropathy (AIDP), acute motor axonal neuropathy (AMAN), and the Miller-Fisher syndrome (MFS). AIDP accounts for 90% of GBS. It is rare but represents a medical emergency in which prompt diagnosis may save lives. It begins with paresthesias in the toes and fingertips, followed by rapidly advancing weakness and areflexia. Weakness reaches a plateau within four weeks, after which recovery begins. Some cases are fulminant, evolving in one or two days. At the height of their disease, many patients are completely paralyzed and unable to breathe. Even with modern intensive care, approximately 5% of patients die from respiratory paralysis, cardiac arrest (probably due to autonomic dysfunction), sepsis, and other complications. Ten percent of those who recover have residual weakness. Though easy to diagnose in its classical form, GBS is often missed because of atypical clinical features which include ophthalmoplegia, ataxia, sensory loss, and dysautonomia. Plasma exchange (presumably removing the offending antibodies) and intravenous immunoglobulin are the treatments of choice. The two key laboratory abnormalities in GBS are decreased nerve conduction velocity or conduction block and elevated CSF protein with relatively few cells (albuminocytologic dissociation).

Peripheral nerves show perivenular mononuclear cells, demyelination (myelin proteins are the source of elevated CSF protein), and macrophages. Axonal damage, which accounts for the permanent deficits, is variable and may be severe. The pathology is most severe in spinal roots and plexuses and less pronounced in more distal nerves. In the phase of recovery, the nerve contains thin myelin sheaths, indicating myelin regeneration. AMAN shows axonal damage with little inflammation.

About 20% to 30% of GBS cases are preceded by an infection with Campylobacter Jejuni. This association is more established in AMAN. An equal number are preceded by Cytomegalovirus (CMV) infection. The rest are preceded by Mycoplasma and other infections, or vaccinations. The bacterial wall of C. jejuni contains GM1 ganglioside. Anti-ganglioside antibodies, generated in the course of the infection, cross-react with GM1 ganglioside present in the axonal membrane at the nodes of Ranvier and in paranodal myelin. This contact elicits inflammation that damages these structures. Anti-GM1 antibodies are found in the serum of GBS patients. GBS following CMV infections has anti-GM2 antibodies.

Chronic inflammatory demyelinative polyradiculoneuropathy (CIDP) follows a chronic or relapsing course over many months or years and may cause severe permanent disability. Nerve conduction studies show decreased conduction velocity, conduction block, and prolonged distal latencies and F waves. In the active phase of the disease, the CSF shows elevated protein without increased cells. Pathologically, peripheral nerves show demyelination, thin (incompletely regenerated) myelin, and hypertrophic changes due to recurrent attacks of demyelination with intervals of repair. In chronic cases, there is significant axonal loss. Inflammation is variable, sometimes absent. The pathology is most severe in proximal nerve segments and spinal roots and may not be full blown in the sural nerve biopsy. CIDP is thought to represent an autoimmune T-cell and antibody reaction against unknown myelin antigens. Its treatment consists of plasma exchange, intravenous immunoglobulin, and corticosteroids.

The GBS and CIDP are the counterparts of MS for the peripheral nervous system. They are important, because timely intervention with plasma exchange can prevent death in the GBS and severe permanent disability in CIDP. There are standardized criteria for their diagnosis, based on the clinical, CSF, nerve conduction, and biopsy findings.

HEREDITARY NEUROPATHIES

Seventy percent of neuropathies in children are inherited and 30% are acquired. The reverse is true of adults. The inherited neuropathies include lysosomal storage diseases, peroxisomal disorders, mitochondrial disorders, familial amyloidoses, and other entities. Neuropathy, in these diseases, is a component of a systemic metabolic defect. The inherited neuropathies include also two groups called Hereditary Motor and Sensory Neuropathy (HMSN) and Hereditary Sensory and Autonomic Neuropathy (HSAN), in which neuropathy is the main or only abnormality (see teble below).


Hypertrophic neuropathy

Charcot-Marie-Tooth neuropathy, EM. Hypertrophic changes-onion bulb formation. Onion bulbs are concentric layers of Schwann cell processes and collagen around an axon.


Hypertrophic neuropathy

Charcot-Marie-Tooth neuropathy, thick epoxy section, Toluidin Blue stain. Hypertrophic changes-onion bulb formation.

The most common HMSN and the most common overall familial neuropathy is Charcot-Marie-Tooth disease (CMT). CMT affects 1 in 2500 persons and is autosomal dominant. It causes weakness and atrophy of distal muscles, especially those innervated by the peroneal nerve ("stork leg"), pes cavus, and sensory loss. It begins in childhood or adolescence and progresses slowly, involving other nerves. It is compatible with a normal lifespan. Nerve conduction studies show decreased conduction velocity. The nerve biopsy in CMT1 shows demyelination, myelin regeneration (thin myelin), axonal loss, and onion bulbs. In longstanding cases there is gross thickening of nerves, hence the term hypetrophic neuropathy.


HSAN III

HSAN III-Familial Dysautonomia. Small myelinated and unmyelinated axons are absent.

The name CMT denotes a specific entity but is used also to encompass the entire group of HMSN. In that group, the phenotype described above is referred to as CMT1. Other, less frequent HMSNs are listed in the table. The HSANs are characterized by sensory dysfunction (depressed reflexes, altered pain and temperature perception) and variable autonomic dysfunction (GER, postural hypotention without tachycardia, excessive sweating). HSAN III (Familial Dysautonomia/Riley Day syndrome) in particular shows also hypothermia, no axon flare on intradermal histamine injection, lack of fungiform papillae in the tongue, and other abnormalities. Nerves in HSAN III lack small myelinated and unmyelinated axons, and sensory and autonomic ganglia show loss of ganglion cells.

INHERITED NEUROPATHIES

    HMSN/CMT
  • CMT1-demyelinative, hypertrophic
  • CMT2-axonal (connective tissue diseases).
  • Hereditary neuropathy with pressure palsies
  • Dejerine-Sottas neuropathy
  • Congenital hypomyelinating neuropathy
  • Roussy-Levy syndrome

  • HSAN
  • HSAN I-Hereditary sensory radicular neuropathy
  • HSAN II-Congenital sensory neuropathy
  • HSAN III-Familial dysautonomia/Riley Day syndrome
  • HSAN IV-Congenital insensitivity to pain with anhidrosis

The HMSNs are characterized by great genetic heterogeneity. There are autosomal dominant, recessive, and X-linked forms. CMT1 alone is genetically diverse. Its most common autosomal dominant form is due to duplication of a segment of chromosome 17 (17p11.2-p12) that contains the gene for a 22 kd peripheral myelin protein, PMP22. This protein probably plays a role in Schwann cell differentiation. CMT1 patients have three copies of the normal gene and presumably produce 1.5 times as much PMP22 as normal people do. Other forms of CMT1 are recesssive or X-linked and are caused by point mutations of the PMP22, Cx32, and Myelin Protein Zero (MPZ) genes. Other HMSNs are equally diverse with mutations of the same gene causing different phenotypes and mutations of different genes causing the same phenotype.


Congenital hypomyelinating neuropathy

Congenital hypomyelinating neuropathy. The Schwann cell touches the axon but makes no myelin. There are rings of basement membrane.

Autosomal dominant and autosomal recessive mutations of PMP22, MPZ, and other genes cause Dejerine-Sottas neuropathy, a severe infantile demyelinative hypertrophic neuropathy associated with developmental delay and severe slowing of nerve conduction velocity. Congenital hypomyelinating neuropathy (CHN), caused by mutations of PMP22, MPZ, EGR2, and other genes is characterized by neonatal hypotonia, arthrogryposis, developmental delay, and absence of onion bulbs. Instead, CHN nerves have concentric rings of basement membrane. The molecular abnormalities of HMSN underline the importance of myelin proteins for the structural stability of myelin and show how diverse genetic abnormalities can cause a similar phenotype.


Amyloid neuropathy

Familial amyloid neuropathy. Amyloid deposition in nerve. Sirius red stain.

Familial amyloid neuropathies(FAP) are a group of familial systemic amyloidoses with involvement of peripheral nerves. The most common FAP is caused by an autosomal dominant mutation of the transthyretin gene on 18q11. The mutant protein is deposited in the form of amyloid and damages peripheral nerves, the heart, kidneys, gastrointestinal tract, and other organs. In nerves, amyloid damages first and most severely small fibers, causing loss of pain and temperature sensation and autonomic dysfunction. Transthyretin is produced in the liver. Liver transplantation arrests the progression of the disease.

Myeloma and other monoclonal plasma cell proliferations result in the production of abnormal amounts of immunoglobulins and immunoglobulin chains. In some of these conditions, immunoglobulins form amyloid deposits which damage nerve fibers mechanically. In others, immunoglobulins have antibody activity against MBP and other myelin proteins and cause a demyelinative neuropathy. Other plasma cell dyscrasias and dysproteinemias cause vasculitis.

VASCULITIC NEUROPATHY


Necrotizing arteritis

Churg-Strauss syndrome. Necrotizing arteritis and eosinophilia in a nerve biopsy.

Polyarteritis nodosa and other vasculitides often involve peripheral nerves causing single or multiple mononeuropathies (due to nerve ischemia), asymmetric polyneuropathy, and distal symmetric polyneuropathy. A sural nerve biopsy along with a muscle biopsy are the best tissues for establishing the diagnosis of vasculitis. The nerve biopsy is diagnostic in over half of patients with systemic vasculitis and clinical neuropathy, and the diagnostic yield increases with the addition of a muscle biopsy. Such biopsies show necrotizing arteritis, perivascular inflammatory infiltrates, hemorrhage and hemosiderin deposition, neovascularization in epineurial arteries, and variable changes in nerve fascicles, depending on the severity and stage of neuropathy. The muscle shows vasculitis and denervation atrophy.

SMALL FIBER NEUROPATHY

Small fiber neuropathy (SFN) refers to a set of symptoms caused by damage of unmyelinated and small myelinated axons that convey pain and temperature sensation and serve autonomic functions. These symptoms are burning or shooting pain and tingling, loss of pain and temperature sensation, and autonomic abnormalities (loss of or excessive sweating, color and other skin changes) affecting the extremities in a stocking-glove distribution. There may also be visceral autonomic dysfunction (tachycardia, erectile dysfunction, constipation, urinary retention). The most common cause of SFN is diabetes and related entities, including impaired glucose tolerance and insulin-induced neuropathy. Other causes include vitamin deficiencies, drug toxicity, monoclonal gammopathy, hypothyroidism, alcoholism, Sjogren syndrome, Lyme disease, sarcoidosis, amyloidosis, Fabry disease, and paraneoplastic neuropathies. Some SFNs are genetic and are caused by sodium channel mutations and some are caused by autoantibodies to potassium channels. Many of these entities affect also larger nerve fibers and can cause weakness and loss of vibration and position sense. When large fibers are affected, electrodiagnostic studies are abnormal. If only small fibers are affected, which is often the case at the onset of these neuropathies, electrodiagnostic studies are normal, and the best way to confirm the diagnosis is a skin biopsy, stained with antibodies to Protein Gene Product 9.5, an axonal marker. Normal skin contains axons that cross the dermis, traverse the basement membrane, and branch into the epidemis. In SFN, these fibers are decreased or lost. Thus, epidermal nerve fiber density (ENFD) is a sensitive and reliable index of SFN.


Further Reading

Updated: May, 2017

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