Polyneuropathies: Histopathology & Common Etiologies

• Axonal polyneuropathy (the most common form) primarily involve the nerve axon.
• Key causes include diabetic neuropathy (the most common cause of neuropathy in the industrialized world), toxic neuropathies (eg, uremia and medications), immune, and B12 deficiency (the most common nutritional cause).
• Demyelinating polyneuropathy primarily affects the myelin sheath.
• Key causes are CIDP (chronic inflammatory demyelinating polyneuropathy), and some of the most common genetic neuropathies (CMT1 and CMTX).

• The most common presenting pattern of chronic polyneuropathy is a length-dependent peripheral neuropathy.
• These are commonly referred to as distal symmetric, dying-back, or stocking-glove distribution.

• Autonomic neuropathy manifests with autonomic dysregulation (blood pressure swings, gastroparesis, etc…).
• Small fiber polyneuropathy presents with burning pain in the feet but lacks large fiber sensory loss (ie, vibration and proprioception are intact).
• Sensory neuronopathy, aka ganglionopathy because it is a disease of the dorsal root ganglion; the sensory loss affects the upper extremities early on, because it affects the proximal portion of the nerve. Ataxia is a prominent feature, because of the profound loss of position sensation.
• Motor neuron disease, which causes a painless progressive lower motor neuron disease (ALS will also cause upper motor neuron findings).

• Neuron (the cell body), axon (which transmits signals to/from the cell body), and the nerve terminals.
• Within the cell body: nucleus and Nissl bodies, which are granular bodies that are the site of protein synthesis.
• Myelin sheaths wrap around the axon, which help increase action potential conduction speed.

• Axon has been transected.
• This disrupts transport, causes rapid inflow of extracellular ions (most notably calcium), axonal swelling and nerve degeneration.
• The distal portion of the axon disintegrates (is phagocytized) via Wallerian (aka anterograde) degeneration.
• Myelin ovoids, are fragments of myelin debris, which are formed because myelin degradation quickly follows the axon disintegration.
• Retrograde degeneration also occurs in the proximal direction to the first node of Ranvier. Retraction bulbs form at the proximal and distal stumps.
• Via proximodistal axon regeneration, axons sprout from the proximal nerve stump (called regenerative sprouting) to cross the transection site and then track down the distal nerve stump
• The cell body switches to chromatolysis (chromatin disintegration).
• The cell body swells; there is eccentric displacement of the nucleus; and the Nissl substance is marginalized to the periphery of the cell body.
• Chromatolysis is a reactive state of high protein synthesis to meet the demand of axon regeneration.

• Changes are segmental because many demyelinating neuropathies result in segmental damage.

#Axonal regeneration from regenerative sprouting:

• Numerous terminals coated with thin myelin sheaths – again, regenerative myelin thinner and the axon terminals are also thinner than normal.

Via proximodistal advancement, they crossed the transection site, elongated through growth cone advancement to enter Schwann cell tubes and advanced distally to reinnervate the original target site.

• Proximodistal advancement process occurs at ~ 1mm/day (or 1 inch/month).
• Muscle degeneration via fibrofatty transformation occurs at 20 - 24 months.
• Thus, nerve injury that occurs > than 24 inches from the muscle will not be successful – the muscle with undergo fibrofatty transformation before the regenerated axon will reach it.
• Also, note that reinnervation can fail from neuroma formation at the lesion site. Neuroma refers to axon tangling that occurs from fibroblast proliferation that obstructs or misdirects the regenerating axon sprouts.
• As well, the endoneurium (aka endoneurial tube) thickens during axon degeneration and it can unfortunately thicken to the point where the tube is too narrow for the axon to advance through it.

• Neuropraxia: Focal myelin injury (myelin disruption)

Axonotmesis: Axon injury with preservation of other nerve elements (endoneurium, perineurium, and epineurium). * Wallerian degeneration and nerve regeneration occur.

• Neurotmesis: Think – Disconnection of entire nerve (complete nerve trunk (peripheral nerve) injury) – all elements (axon, endoneurium, perineurium, and epineurium) are disconnected. Surgical repair is required.

• Grades 1 – 5
• Grade 1: Neuropraxia
• Grade 2: Axonotmesis
• Grade 3: Axonotmesis + Endoneurium
• Grade 4: Axonotmesis + Endoneurium + Perineurium
• Grade 5: Neurotmesis

• Chemical signals also induce collateral sprouting from neighboring uninjured axons. If the lesion to the nerve is incomplete, meaning there are still intact axons, then collateral sprouting can occur from them to improve innervation to the denervated tissue.

The force the muscle can exert is a reflection of the fibers that innervate it NOT the number of axons available – thus these muscles are innervated by fewer axons but equivalent fibers, called the anterior horn cell innervation ratio. On EMG, we see that these motor units are larger because they have to innervate a larger number of muscle fibers. * The innervation ratio can increase to 5-fold normal via collateral sprouting.

• Via collateral sprouting, the muscle fiber pattern changes to reflect the anterior horn cells that innervate it because the fiber type is determined not by the anterior horn cell.
• There is a loss of the normal checkerboard pattern typically seen on muscle biopsy.

• The outer covering of the peripheral nerve (the nerve trunk) is called the epineurium (specifically, the superficial epineurium).
• Nerve fascicles are encased in perineurium, which is an impermeable sheath that forms a protective barrier around the nerve fascicle: a blood-nerve barrier.
• Internal to the perineurium is the endoneurium, which is a loose connective tissue.
• Deep epineurium that surrounds the fascicles.
• In each fascicle, we see perineurial septa, which carry vasculature to the nerve fibers.
• Myelinated nerve fibers in the fascicles:
• Nerve fiber axon.
• Myelin sheath.
• Schwann cell (each of which myelinates at most one axon internode).
• Unmyelinated (or thinly-myelinated) axons which bundle into so-called Remak bundles.

• The most common finding in neuropathy is zonal axon loss, meaning a drop-out in the number of axons.

• Wallerian Degeneration. Axons have a thin myelin sheath and thickening of the endoneurium but, dissolution of the axons (empty space within the axon) creates a void of nerve filaments.
• Axon Atrophy. Disintegration of normal axonal structures (eg, neurofibrils) is a common occurrence in smoldering axonal neuropathies.
• Axonal Regeneration.

• The most obvious finding is simply a low density of myelinated axons.
• Onion-bulb formation. Axons with a thin layer of myelin surrounded by concentric rings of Schwann cell cytoplasm, called onion-bulb formation.
• This, in conjunction with surrounding axons devoid of myelin, is a clear histopathological finding of demyelinating neuropathy, such as occurs in CMT1a.
• Tomacula. Thickened myelin sheath around a reduced-caliber axon; tomacula are focal thickenings of myelin.
• Tomacula means "sausage", which is how these myelin fragments appear in longitudinal (teased-fiber) preparation.
• Tomacula characteristically occur in Hereditary Neuropathy with Liability for Pressure Palsy (HNPP).

• Epineural vessel with inflammatory changes; that vasculitis is an important cause of neuropathy, specifically mononeuritis multiplex.

• The neuropathy typically begins in the toes and ascends.
• When the neuropathy reaches mid-shin, it begins in the fingertips and ascends; hence this is a "distal symmetric", "dying-back", or "stocking-glove distribution" neuropathy.
• Also, see toe hammering/clawing and pes cavus (high arch) foot for descriptions of musculoskeletal changes in chronic neuropathy.

• The most common cause of peripheral neuropathy in the industrialized world. It accounts for ~ one-third of the neuropathies in the US and occurs in ~ one-half of all patients with diabetes. Note that in addition to the classic sensorimotor peripheral polyneuropathy, DM can cause small fiber neuropathy, a focal radiculoplexus neuropathy (which we address along with the acute neuropathies), and there is an often-forgotten phenomenon of insulin neuritis, wherein with the initiation of insulin triggers a painful neuropathy of small and autonomic fibers.
• The classic sensorimotor peripheral polyneuropathy is an axonal neuropathy with some myelin loss, as well. The pathologic underpinnings in DM 1 are, as one might guess, hyperglycemia; however in DM 2, the pathophysiology appears to be multifactorial and relates to a combination of metabolic syndrome, hyperglycemia, and microvascular ischemia/hypoxia – this is important because good glycemic control can help slow the progression of neuropathy and promote stabilization but not to the extent we hope.
• A multifactorial approach to all causative aspects of the DM 2 is necessary. Individuals with pre-diabetic hyperglycemic neuropathy are strongly encourage to take measures to avoid developing diabetes because once it sets-in, there is little that can be done to stop its progression.

• It manifests with distal burning pain and atrophy due to a high volume of alcohol over long periods of time.
• Contrast this to rhabdomylosis – acute muscle necrosis, which occurs in the setting of acute alcohol intoxication.

• Especially from deficiencies of certain vitamins, such as B12, which more notably produces a myelopathy with mixed dorsal column and corticospinal tract findings (subacute combined degeneration) than a neuropathy.

• Uremia from ESRD
• Medications. Most notably:
• Chemotherapies, for instance the platinum-containing drugs (eg, cisplatin), as well as the vinca alkaloids (eg vincristine), thalidomide, etc…
• HIV medications can cause a distal-predominant primary axonal sensory neuropathy, which was fortunately more common with the older-line HIV meds (didanosine, zalxitabine, and stavudine) and less common with the newer-line medications.
• Some other medications to watch out for, especially at higher doses or longer-term use are amiodarone, colchicine, and nitrofurantoin.
• As well, since leprosy is a leading cause of neuropathy world-wide, it's important to know that a mainstay of its treatment, dapsone, can cause an acute motor neuropathy.
• Vitamin B6 (pyridoxine) excess can be toxic and cause a sensory neuronopathy.
• In contrast, isoniazid treatment can cause B6 depletion, which can also produce a neuropathy.
• Heavy metals:
• Arsenic, which causes an acute painful neuropathy in the setting of GI symptoms (nausea, vomiting, and abdominal pain (similar to porphyria) and lead, which most notably causes an acute motor neuropathy with early weakness of finger and wrist extension.

• It generally refers to Charcot-Marie-Tooth (CMT).
• Consider that a large population of patients that have CMT have sporadic (de novo) autosomal dominant mutations (rather than inherited). We call CMT genetic neuropathy to remind ourselves that there doesn't not have to be a family history of neuropathy.

• For instance hypothyroidism (although this association is fairly weak).

• Most notably: systemic lupus erythematosus, rheumatoid arthritis, rheumatologic causes of vasculitis.

• It involves amyloid deposition in the peripheral nerves along with systemic organ involvement, which causes weight loss, nephrotic syndrome, heart failure, and hepatomegaly.
• Amyloid deposits demonstrate apple-green birefringence under polarized light in Congo red stained preparations.
• Note that the most common form of amyloidosis is light-chain amyloidosis due to plasma cell dyscrasia.

• Porphyria results from enzyme defects in heme synthesis.
• It presents with abdominal pain and psychiatric symptoms and peripheral neuropathy appears ~ a month after onset.
• Paraproteinemia refers to monoclonal gammopathy, which is a plasma cell dyscrasia.
• The most common cause of a paraproteinemia is monoclonal gammopathy of undetermined significance (MGUS).
• Low but real risk of conversion to multiple myeloma.
• CRAB is the acronym for end-organ damage from multiple myeloma. It stands for: hyperCalcemia, Renal failure, Anemia and Bone lesions.
• For reference, MGUS is defined as:
• Monoclonal spike on serum protein electrophoresis (SPEP) of less than 3 g/dL
• Bone marrow infiltration by monoclonal malignant plasma cells (PC) of less than 10% and
• Absence of any end-organ damage from multiple myeloma.

• Specifically indicate HIV, leprosy (which is the leading cause of neuropathy in the nonindustrialized world), CMV (which notably causes a radiculitis), and lyme, which we remember by drawing an Ixodes tick.
• As an aside, tick paralysis is a key differential diagnosis in the evaluation of GBS.

• It can cause a wide-variety of neuropathies, and is one of the causes of the rare pattern of bilateral facial nerve palsy.
• The causes of acquired bilateral facial nerve palsy include, but are not limited to: infectious causes (eg lyme disease (most commonly), HIV, syphilis, EBV, and others), GBS, meningeal inflammation/infection/carcinomatosis, diabetes mellitus, vasculitis, multiple neurofibromas.
• The histopathological hallmark of sarcoidosis is the noncaseating (ie, non-necrotizing) granuloma, which is a focal, compact conglomeration of inflammation cells that arise with the target can't be degraded or as an autoimmune hypersensitivity response.

• It notably includes cancers (eg, lymphoma, which causes a profound radiculopathy), chemotherapy (we list certain causative agents above in the notes), and paraneoplastic disease (eg, anti-Hu sensory neuronopathy, which causes a severe proprioceptive deficit, manifesting with sensory ataxia) as well as POEMS syndrome (aka osteosclerotic myeloma), which stands for Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Gammopathy, and Skin changes.