Peripheral Neuropathy

Peripheral Neuropathy

Sections

Axon Injury & Regeneration
Nerve Regeneration Details
Common Causes of Neuropathy
References

In this tutorial, we will learn about the most common acute and subacute immune-mediated polyneuropathies, most notably Guillain-Barré syndrome.

Overview

Start a table. Indicate that there are generally two forms of acutely presenting neuropathies:

• Demyelinating, typically Guillain-Barré syndrome (GBS), also called acute inflammatory demyelinating polyneuropathy – importantly, because it is inflammatory, it responds to immune-modulating therapy.
• Axonal. Notably, the immune-mediated axonopathies, which are most commonly due to the primary vasculitis (eg, polyarteritis nodosa) and secondary vasculitis (eg, rheumatoid arthritis).

Guillain-Barré syndrome: acute inflammatory demyelinating polyneuropathy

In part one, we'll address acute inflammatory demyelinating polyneuropathy, which still most commonly goes by the eponym: Guillain-Barré syndrome.

Overview

Write out that this acute polyneuropathy characteristically presents with ascending numbness and weakness and lower motor neuron findings (eg, muscle cramps).

• They occur one to two weeks following a viral respiratory or GI illness (~70% of the time).
  • Campylobacter jejuni, which causes diarrhea, is the most common infectious agent (up to 40% of cases in the US are due to Campylobacter jejuni).

Presenting Pattern: Ascending Numbness/Weakness

Let's illustrate the classic presenting pattern, now.

• Draw a human figure.
• First, draw a lower lumbosacral spine in pain because low back (and/or thigh pain) is one of the most common presenting features.
• This presenting symptom should remind us to rule-out spinal cord compression or cauda equina syndrome in patients with GBS-like presentations.
• Next, draw an ascending arrow from the feet to the head because the classic pattern in GBS is symmetric, ascending numbness, followed by severe weakness (often to the point of paralysis) and diminished or absent muscle stretch reflexes over a 2 – 4 week time period.
  • Note that because GBS is actually a polyradiculopathic neuropathy (meaning that both the nerve roots and nerves are affected), it can present with proximal (rather than distal) weakness. - As well, note that the large fiber sensory exam, itself, can be surprisingly preserved in patients despite the prominent numbness, which can be misleading.
• Next, draw a heart to represent the autonomic dysfunction (gastric hypomotility, urinary retention, cardiac dysrhythmias, and blood pressure swings) that can plague patients with GBS.
• Draw a swinging pendulum to remind ourselves that there can be rapid swings in heart rate and blood pressure.
  • To remember these swings, it's helpful to imagine competing vagal nerve dysfunction and surges in the sympathetic nervous system.
• Now, draw a face with facial weakness and bilateral ptosis to represent the oculobulbar palsies that occur in roughly half of GBS cases.
  • In addition to the ptosis we've drawn, patients can have ocular dysmotility and pupillary changes.
• Finally, draw a chest cage with a paralyzed diaphragm to indicate respiratory failure.
  • Almost one-third of patients will develop phrenic nerve failure with resultant diaphragmatic paralysis and require mechanical ventilation.
  • Even in the absence of diaphragmatic paralysis, patients can require intubation for airway protection from the bulbar dysfunction, itself.

Treatment

This leads us to treatment in GBS.

• Indicate that we use plasmapheresis or IVIG as immunotherapies.
  • The argument as to which is more preferred is beyond our scope here but it should be noted that to date there is not evidence for the combined use of these treatments (although this is often done in clinical practice) and it's also important to realize that steroids have been shown to be detrimental in GBS treatment.
• Most importantly, management involves monitoring for respiratory failure with frequent respiratory measurements (forced vital capacity and negative inspiratory force).
• And monitoring for other aspects of autonomic dysfunction, as well. These include:
  • Cardiovascular swings, which can occur rapidly, so we have to be careful not to overcorrect any single finding because the pendulum can rapidly swing the other way.
  • Cardiac dysrhythmias, which can be so severe as to require a temporary pacemaker to avoid asystole and sudden cardiac death.
  • Ileus, which is so common, that all patients require a good, proactive bowel protocol.

Nerve Conduction Physiology

Overview

To understand the diagnostic work-up of GBS, we need to understand myelin physiology.

• Write out that nerve conduction velocity directly relates to both axon and myelin thickness.
  • This is because the time it takes for an action potential to propagate down an axon is related to how often it needs to be regenerated and how long it takes for this regeneration to occur (speed of channel opening and closing).
  • In practice, consider that the more heavily myelinated a nerve is, the faster its speed; and the more proximal a nerve is, the thicker it is, and thus the faster its speed.

Unmyelinated Axons

First, let's address unmyelinated axons, which are slow.

• Draw a section of the axon with numerous voltage-gated ion channels along its length.
  • We can more easily imagine the sodium shifts along an axon when we break it up into discrete segments (although, in reality, the axon is a continuous structure).

Action Potential: Review

• The axon has a resting membrane potential of -70mV.
• Neuron depolarization triggers sodium channel opening.
• The influx of sodium further depolarizes the axon to the excitation threshold.
• Then, all of the sodium channels open and sodium ions rush in.
• Following this, there is repolarization, which involves potassium ions exiting the axon and sodium channels closing.
• At this point, the sodium ions drift down to the next segment and depolarizes it.

Depolarization and Action Potential Generation

Here, we'll focus on the sodium shifts and action potential generation.

• Apply an initial stimulus (at the axon hillock).
• Show that it rapidly decrements.
• Then show that it is regenerated at the next set of voltage-gated ion channels.

Now, let's look at what happens with sodium during depolarization:

• Show that with the initial depolarization, sodium enters the axon.
• Indicate that this influx produces and action potential and there is a significant sodium influx.
• Then, show that the sodium ions drift down the axon and produce the next depolarization.
• Indicate that this process slowly repeats itself along the unmyelinated axon.
  • The stimulus regeneration at each channel is a slow process (the channels have to open for the ions to enter).

Myelinated Axon

Indicate that myelinated axons are fast because myelin lengthens the intervening segments between action potentials and hastens nerve transmission.

• So now, redraw an axon and cover it in segments of myelin sheath (called internodes).
• Label one of the nodes of Ranvier (in between the myelin sheaths) and draw voltage-gated ion channels within at these nodal regions.
• Show depolarization and illustrate that the myelin sheath acts as an insulator, thus because the current does not need to be regenerated as often, it can travel farther down the axon, faster.
• With curved arrows, show that the action potential appears to "jump" from node to node, called saltatory conduction.

Gasser Classification Scheme of Nerve Thickness & Speed

Let's apply this knowledge to the Gasser classification scheme, which divides nerves into groups: A, B, or C (a second classification scheme also exists, the Lloyd scheme, but it applies to sensory nerves, only).

• Group A fibers have thick myelin sheaths, large diameter, and have conduction speeds of up to 120 m/s.
• Group B fibers are lightly myelinated, intermediate diameter, and have conduction speeds of around 10 m/s.
• Group C fibers are non-myelinated, small diameter, and have conduction speeds of 1 m/s or less.

Laboratory Testing in Guillain-Barré Syndrome

With this knowledge as a background, let's turn our attention to laboratory testing in the work-up of GBS.

Cerebrospinal Fluid (CSF)

Indicate that CSF testing is the primary, key helpful diagnostic test; it demonstrates a mildly elevated protein (~ 60) in the setting of a normal WBC (<50), which is called cytoalbuminologic dissociation.

• CSF protein is elevated because the attack affects proximal roots, which lie within the spinal canal, thus the proteinaceous debris increases the CSF protein level.

Electromyography(EMG)/Nerve Conduction Studies (NCS)

Then, show that EMG/NCS testing shows demyelination.

• Take note, however, that the classic changes, such as prolonged distal onset latency, reduced conduction velocity, and conduction block can take several days to a couple of weeks to appear, so we look for other changes early on such as abnormal F-waves and H reflexes.

Imaging

Indicate that we should get imaging of the spine (ideally, MRI) (and we will also get one of the brain), mostly to rule-out other potential mimickers such as cord compression and carcinomatous meningitis but also to assess for evidence of cranial nerve or nerve root enhancement.

HIV

Indicate that HIV testing is warranted in GBS because HIV seroconversion, itself, can trigger an acute inflammatory demyelinating polyneuropathy (AIDP).

Key Mimickers

Beyond these tests, we should have a working knowledge of some key mimickers to ensure that they are fully ruled out…

• Compressive myelopathy, which can present with an acute/subacute flaccid paraparesis (spinal shock).
• Tick paralysis, which typically manifests with an abrupt (sometimes overnight) development of severe weakness (which can be asymmetric) or ataxia.
  • Less commonly, it can manifest with a GBS-like ascending paralysis.
  • Like GBS, tick paralysis will often cause sensory symptoms with negligible sensory exam findings and loss of muscle stretch reflexes.
• Viral myelitis, which can initially present with a flaccid paralysis.
  • As well, consider that, especially in the immune-suppressed, CMV can cause an associated a radiculomyelitis that mimics GBS very closely: ascending flaccid paralysis with sensory loss. Prominent bladder and bowel incontinence is an associated finding.
• Critical illness neuropathy can mimic GBS.
  • As its name suggests, it occurs in the setting of severe physiological stress.
• Acute intermittent porphyria can cause an acute attack of cranial neuropathies and quadriparesis that resembles GBS.
  • It is preceded by a few days of colicky abdominal pain and behavioral disturbance.
  • Distinguishing features are the marked asymmetry found in porphyria; predilection for proximal muscles; and a characteristic shield-like sensory loss over the chest.
  • Screening involves 24-hour testing looking for abnormal levels of porphyrin in the urine or feces.
  • Numerous medications are implicated as the cause of a porphyria attack, they include: barbiturates, sulfonamides, and certain antiepileptics (eg, valproic acid, carbamazepine, and primidone).
  • Alcohol is also an important potential trigger.
• Lastly, always consider B12 deficiency myelopathy, especially given its treatability.

Guillain-Barré Syndrome Variants

Acute motor axonal neuropathy (AMAN)

Acute motor axonal neuropathy (AMAN) (aka Chinese paralytic illness), which has a more rapid and severe progression than AIDP, and acute motor and sensory axonal neuropathy (AMSAN): both of these axonal variants are highly associated with Campylobacter Jejuni infection.

Miller Fisher Syndrome (MFS)

Miller Fisher Syndrome (MFS), which consists of the triad AOA, which stands for ataxia, ophthalmoplegia, and areflexia and highlights the prominent, early oculobulbar involvement, ataxia out of proportion to weakness, and lower motor neuron findings of areflexia (rather than upper motor neuron signs found in cerebellar disorders). Anti-GQ1b IgG testing is a helpful diagnostic tool in this disorder.

Axon Injury & Regeneration

We'll draw a schematic of a nerve in three states: Healthy, Wallerian Degeneration, and Nerve Regeneration.

Healthy Nerve

Draw the neuron (the cell body), axon (which transmits signals to/from the cell body), and indicate the nerve terminals.

• Within the cell body, draw a nucleus and Nissl bodies, which are granular bodies that are the site of protein synthesis – we'll see how they are affected by Wallerian degeneration in a moment.
• Draw myelin sheaths around the axon, which help increase action potential conduction speed – we address this further in the acute neuropathies tutorial.

Wallerian Degeneration

For Wallerian (aka anterograde) degeneration, redraw the cell body and the myelinated proximal nerve stump.

• Distal to this, show that the axon has been transected.
  • This disrupts transport, causes rapid inflow of extracellular ions (most notably calcium), axonal swelling and nerve degeneration.
• Indicate that the distal portion of the axon disintegrates (is phagocytized) via Wallerian (aka anterograde) degeneration.
• Show myelin ovoids, fragments of myelin debris, 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.
• Now, show that 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 – we'll address this along with nerve regeneration.
• Before that, however, show that 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.

Nerve Regeneration

First, redraw the cell body and axon and show the nucleus and Nissl bodies.

• Draw a few normal myelin sheaths.
• Then, show segmental remyelination, which results in stretches of short, thin (ie, hypomyelinated) internodes.
• The changes are segmental because many demyelinating neuropathies result in segmental damage.

Next, illustrate axonal regeneration from regenerative sprouting:

• Show numerous terminals coated with thin myelin sheaths – again, regenerative myelin thinner and the axon terminals are also thinner than normal.
  • We saw these sprouts emerged from the damaged proximal stump in the previous diagram. 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.

Nerve Regeneration Details

Regeneration Timing

• 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, we'll see that 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.

Seddon Classification System of Nerve Injury

• 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.

Sunderland Classification System of Nerve Injury

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

Collateral Sprouting

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.

Common Causes of Neuropathy

Presenting Pattern: Length-dependent

Show that the most common presenting pattern of chronic neuropathy is a length-dependent pattern.

• Draw a human figure to show what we mean; indicate that the neuropathy typically begins in the toes and ascends. - Indicate that 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.

Common Causes: "DANG THERAPIST"

The causes of neuropathy are so numerous that we'll focus on a key selection of them via an acronym: DANG THERAPIST.

"D" for diabetes mellitus

• We list it first because it is 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.

"A" for alcohol

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

"N" for nutritional

• 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.

"G" for Guillain-Barré syndrome (along with its chronic form, CIDP).

We address GBS in detail in the acute polyneuropathies tutorial.

"T" for toxic

• 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.

"H" for Hereditary.

• 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.

"E" for endocrinopathies other than diabetes.

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

"R" for Rheumatologic.

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

"A" for amyloidosis.

• It involves amyloid deposition in the peripheral nerves along with systemic organ involvement, which causes weight loss, nephrotic syndrome, heart failure, and hepatomegaly.
• Draw a green apple in a red background to remind ourselves of the apple-green birefringence that amyloid deposits demonstrate 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.

"P" for porphyria and plasma cell disorders

Porphyria

• Draw a red blood cell to remind ourselves that porphyria results from enzyme defects in heme synthesis.
  • It presents with abdominal pain and psychiatric symptoms and peripheral neuropathy appears ~ a month after onset.

Plasma Cell Disorders (paraproteinemias)

• MGUS. The most common cause of a paraproteinemia is monoclonal gammopathy of undetermined significance (MGUS).
• POEMS syndrome. Another important, albeit rare, cause is POEMS syndrome (aka osteosclerotic myeloma), which stands for Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Gammopathy, and Skin changes.
• Multiple myeloma. Draw an arrow toward a crab to show that it has a 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.

"I" for infectious

• 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.

"S" for sarcoidosis.

• 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.

"T" for tumor

• 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).

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