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Peripheral Neuropathy: Advanced Topics

Notes

Peripheral Neuropathy: Advanced Topics

Sections




Overview

Here, we will address advanced topics in neuropathy.

To begin, start a table.

Histopathology

In regards to histopathology, remind ourselves that we divide neuropathies into:

Axonal

  • Axonal neuropathies, such as: diabetic neuropathy, toxic neuropathies (such as, uremia and medications), immune, and B12 deficiency (the most common nutritional cause).

Demyelinating

  • And also into demyelinating polyneuropathy: which primarily affects the myelin sheath.
    • Indicate key causes as AIDP, acute inflammatory demyelinating polyneuropathy (aka Guillain-Barre Syndrome), and the chronic form, CIDP, chronic inflammatory demyelinating polyneuropathy, and a some of the most common genetic neuropathies (CMT1 and CMTX), which we address later.

Patterns

Length-Dependent

  • And remind ourselves that the most common presenting pattern of chronic polyneuropathy is a length-dependent peripheral polyneuropathy – a distal symmetric, dying-back, or stocking-glove distribution of neuropathy.

Common Diagnostic Testing

EMG/NCS

Overview

In this part, let's address common diagnostic testing neuropathy. First, let's see how EMG/NCS helps divide neuropathies into their underlying histopathology of axon vs myelin, list:

  • Normal
  • Axonal
  • Demyelinating

Normal

Indicate that key parameters are a normal amplitude, onset time, and speed ("conduction velocity").

  • To graph this, draw an X-axis for time and show a hump-shaped compound motor action potential (CMAP).
  • Indicate its distal latency, which is the time from the stimulus (when the nerve is stimulated) to the start of the wave form (when the muscle activates).
  • Then, indicate the amplitude of the muscle action potential is the peak height of its wave form.
  • Add a more proximal CMAP from when the nerve is stimulated farther away from its target (more proximally).
  • Indicate that the calculation of the speed of nerve transmission, called conduction velocity (measured in meters/second) is the distance between the two stimulation sites divided by the time difference between the proximal latency and the distal latency (the time of onset of the second wave form minus the first),

Axonal

With that as a background, let's address axonal neuropathies (aka axonopathies), which represent the vast majority of chronic neuropathies.

  • Draw the X-axis.
  • Then, re-draw the two CMAP waveforms but show that their amplitudes are much lower; this is what happens when there are fewer axons innervating a muscle – the motor unit potential is smaller.
  • Indicate that the distal latency is normal and the conduction velocity is normal, although some slowing would be seen.

Demyelinating

Now, for demyelinating neuropathies, indicate that the most common cause is CIDP and that the most common genetic neuropathies are CMT1 and CMTX, which we address further in the next section.

  • Make the first waveform of a normal amplitude but have a prolonged distal onset latency (ie, it takes longer for the stimulus to make the muscle fire because the nerve is slower).
  • Make the second waveform fire later than the healthy one (again, it takes longer to elicit a response from the muscle) and also make its amplitude shorter than the first waveform.
    • This reduction between the first and second waveforms represents a block in nerve transmission along its length, so-called conduction block (so the waveform is severely reduced in size).
  • Most notably, however, indicate that the nerve, overall, is slow.
    • Nerves with thick myelin sheaths travel quickly; those without, such as those that are demyelinated, travel slowly.
  • We can also see temporal dispersion (a ratty and broader waveform) in demyelinated nerves because the muscle receives its innervation from the various axons over a more widespread time-period.
  • In summary, findings in demyelinating neuropathies include: prolonged distal latency, reduction in conduction velocity, conduction block, and temporal dispersion.

Laboratory Testing

In this last section, we'll address laboratory testing in peripheral neuropathy, which will allow us to review key clinical aspects of neuropathy.

Highest Yield

First, let's address serologies with the highest yield in making an actionable diagnosis.

  • Indicate that of all serologies, diabetic screening has the highest likelihood of being positive, since it's the most common cause of neuropathy in the industrialized world.
  • Next, indicate that vitamin B12 testing is of reasonable yield and should be complemented with methylmalonic acid (MMA) and homocysteine levels, if the patient is taking B12 supplementation, as a way to ensure the supplementation is effective.
  • Now, indicate that serum immunofixation (as well as serum protein electrophoresis) are used to identify a paraproteinemia.
    • The most common abnormality is MGUS, which has the potential to transition to multiple myeloma.
    • Serum immunofixation, along with serum protein electrophoresis, are also used to identify amyloidosis (but direct visualization with tissue biopsy is mandatory).

Lesser Yield

Next, let's address some other common tests in peripheral neuropathy that are of lesser yield.

  • First, renal function.
    • Indicate that in end-stage renal disease (GFR < 30), there can be a uremic neuropathy. Consider that milder forms of renal disease should not be attributed as the causative agent of neuropathy.
  • Next, hepatic function.
    • Indicate that this is best used as a marker of chronic alcohol abuse because hepatotoxicity, itself, isn't a well-defined cause of neuropathy.
  • Now, TSH/FreeT4, which are used to identify hypothyroidism as the cause of neuropathy but, in reality, hypothyroidism isn't a well-defined etiology for neuropathy.
  • Next, folate, which helps to look for a general nutritional deficiency.
    • Although one would guess that folate deficiency (like B12 deficiency) is an important cause of neuropathy, isolated folate deficiency actually isn't a well-defined etiology of neuropathy.

Genetic Testing

Now, let's focus on genetic testing, which is used to test for inherited neuropathies (although, remember that ~ one-third of autosomal dominant CMT is sporadic (no family history)). The number of known genetic causes of neuropathy is sky-rocketing but we can reduce our discussion to just four major genes and five major diagnoses.

  • First, indicate PMP22 (peripheral myelin protein 22) duplication, which causes CMT1a: the most common genetic neuropathy.
    • Indicate that it is an autosomal dominant demyelinating peripheral polyneuropathy; nearly all of the CMTs are autosomal dominant (CMT4 is autosomal recessive and CMTX is X-linked dominant).
    • Although CMT1a is a genetic neuropathy, a high proportion of patients have a sporadic mutation and thus they may lack a family history of disease.
  • Next, indicate PMP22 deletion (deletion of one copy of chromosome 17p11.2), which is the cause of HNPP, for Hereditary Neuropathy with Liability for Pressure Palsy.
    • Indicate that it is an autosomal dominant, multifocal demyelinating neuropathy, which, as its name suggests, causes segmental demyelination at compressible sites.
    • As a helpful mnemonic for the genetics of PMP22, associate the deletion of a chromosome with the deletion of a segment of myelin and we can recall the PMP22 deletion causes HNPP and PMP22 duplication causes CMT1a.
  • Now, indicate that MPZ (myelin protein zero) mutation results in CMT1b, another autosomal dominant, demyelinating neuropathy.
  • Next, indicate that GJB1 (gap junction protein beta 1) mutation results in CMTX, which is an X-linked dominant (XLD) demyelinating neuropathy.
    • It helps to add that GJB1 makes connexin-32, which is an important channel forming protein (these gap junction proteins join the gaps between proteins).
    • It hastens cellular transport and signal communication.
    • Thus, dysfunction in this conduction-related protein produces a demyelinating disorder.
  • Now, indicate that a mutation in MFN2 (mitofusin 2) results in CMT2a, which is an autosomal dominant axonal neuropathy.
    • To remember that this is an axonopathy, it helps to know that MFN2 plays a key role in multiple aspects of mitochondrial health and transport, which is key to cellular energy physiology.
    • Without morphologically healthy mitochondria, neurons die, which results in axonopathy.

Specific Patterns of Neuropathy

Finally, let's address how we tailor select serologies to specific patterns of neuropathy. This is not intended to be exhaustive but rather illustrative of some key patterns and their causative illnesses.

  • First, indicate that a good rheumatologic/vasculitic work-up is key to the evaluation of mononeuritis multiplex. We address this pattern in detail in the acute neuropathies tutorial but, in brief, we need to look for numerous potential culprits, the most common being: rheumatoid arthritis, systemic and nonsytemic vasculitis, HIV, mixed cryoglobulinemia (from hepatitis C infection), SLE and other connective tissue diseases.
  • Next, indicate that a B6 level and anti-Hu antibody are indicated in sensory neuronopathy: pyridoxine toxicity causes a diffuse proprioceptive sensory loss and Anti-Hu antibody is a paraneoplastic disorder that can cause sensory neuronopathy.
  • Now, indicate that CSF analysis is fundamental for the work-up of CIDP. Radicular inflammatory demyelination results in an elevated protein in the CSF because the protein degradation occurs within the CSF. The WBC is normal.
  • Lastly, indicate that biopsies are sometimes indicated, in addition to nerve biopsies (which are typically the sural nerve), skin biopsy is done for small fiber neuropathy and tissue biopsy in amyloidosis is done from an affected organ is done to look for amyloid deposits.

Mononeuritis Multiplex: Presenting Pattern

Draw an individual with asymmetric focal neuropathies: wrist drop on one side and foot drop on the other.

  • The typical presentation is a stepwise (aka stuttering) course of multiple mononeuropathies, meaning multiple abrupt painful neuropathies in single nerve distributions; hence mononeuritis multiplex.
    • In the leg, this is most often the peroneal nerve, manifesting with foot drop.
    • In the arm, this is most often the ulnar nerve.
    • Note that atypical presentations occur; those with a distal symmetric pattern can be especially challenging to diagnose because they look like more garden-variety polyneuropathy.

Common Causes of Vasculitic Neuropathy

  • Next, indicate that we divide the most common causes of vasculitic neuropathy into the primary vasculitides and the secondary vasculitides (meaning the vasculitis is secondary to some other rheumatologic illness).

Most common primary vasculitides

The most common primary vasculitides are:

  • Polyarteritis nodosa (PAN), which causes a neuropathy in ~ 75% of cases.
    • PAN commonly affects key visceral arteries, potentially resulting in GI or renal aneurysms, hypertension, and also numerous skin manifestations that are shared with the following key vasculitis microscopic polyangiitis.
    • As an aside, a minority of cases of PAN are associated with hepatitis B infection (whereas we'll see there is a key association between hepatitis C and mixed cryoglobulinemia).
  • Microscopic polyangiitis (MPA), which shares many features with PAN (for a long period they were considered a single entity).
    • MPA is one the ANCA-positive microscopic vasculitides and, unlike polyarteritis nodosa, is often associated with necrotizing glomerulonephritis and pulmonary capillitis.
  • Nonsystemic vasculitis neuropathy, which can be thought of as PAN restricted to the nerve, itself (hence: nonsystemic), with evidence of vasculitis in the medium and small-size arteries of the epinerium and perineurium.

Primary Vasculitides (by vessel size)

Let's take a moment, now, to categorize the various vasculitides based on their vessel size. We'll use the heart to help us define these vessel sizes.

  • Draw a heart with the left side of the heart opened-up (show the valves and their attachments).
  • Draw the aorta and the great vessels: brachiocephalic trunk (which produces the right subclavian and right common carotid), left common carotid artery, and left subclavian artery to represent the vessels that are affected in large vessel vasculitides, such as giant cell arteritis and Takayasu arteritis.
  • Then, draw a coronary artery and branch to indicate the medium vessel vasculitides, such as polyarteritis nodosa (PAN), and Kawasaki disease, which affect these sized vessels.
  • Finally, draw some tiny microvasculature for the microscopic vasculitides, such as microscopic polyangiits (MPA), Wegener's granulomatosis (WG), and Churg-Strauss syndrome (CSS). These diseases all have overlapping clinical features and a strong association with anti-neutrophil cytoplasmic antibodies (ANCA).

Secondary Vasculitides

The major secondary causes of vasculitic neuropathy are:

  • Rheumatoid arthritis (which is overwhelmingly the most common)
  • Other connective tissue disorders, such as systemic lupus erythematosus, sarcoidosis, Sjögren's disease.
  • Lastly, include mixed cryoglobulinemia, which is often triggered by hepatitis C infection, and, if symptomatic, most commonly presents with palpable purpura, along with arthralgias, asthenia, nephropathy, and neuropathy. The presence of serum cryoglobulins confirms the diagnosis.

Fiber Types

Now, denote that there are certain neuropathies that only affect single fiber types.

Autonomic neuropathy

Autonomic neuropathy, which manifests with autonomic dysregulation (blood pressure swings, gastroparesis, etc…).

Small fiber polyneuropathy

Small fiber polyneuropathy, which presents with burning pain in the feet but lacks large fiber sensory loss (ie, vibration and proprioception are intact).

Sensory neuronopathy

Sensory neuronopathy, aka ganglionopathy because it is a disease of the dorsal root ganglion, denote that the sensory loss affects the upper extremities early on, because it affects the proximal portion of the nerve, and also denote that ataxia is a prominent feature, because of the profound loss of position sensation.

Motor neuron disease

Motor neuron disease, which causes a painless progressive lower motor neuron disease (ALS will also cause upper motor neuron findings). We cover these disorders in their own section.

Diabetic Amyotrophy (Lumbosacral Plexus Neuropathy)

Now, let's transition to the radiculoplexus neuropathies.

Lumbosacral Plexus Anatomy

Let's remind ourselves of key lumbosacral plexus anatomy.

  • Draw the lower lumbar vertebral column and sacrum.
  • Then, draw the right pelvic bone and the femur.
  • Then, draw the inguinal and sacrospinus ligaments.
  • Show that the femoral nerve, supplied by L2–L4, exits the pelvis, passes in between the psoas and iliacus muscles, underneath the inguinal ligament, and down the anterior thigh to innervate the anterior compartment muscles: thus it is susceptible to psoas hematoma and other sources of compression.
  • Show that the obturator nerve, also supplied by L2–L4, descends medial to the femoral nerve, down the medial aspect of the thigh to innervate the medial compartment muscles.
  • Finally, show that the sciatic nerve, which is derived from L4–S3, exits the pelvis via the greater sciatic foramen and descends posterior to the femur.

Diabetic Amyotrophy (Lumbosacral Plexus Neuropathy)

  • Indicate that in diabetic amyotrophy, patients have an inflammatory attack of the lumbosacral plexus that presents with thigh or hip pain.
  • On exam, there is most commonly unilateral involvement of the upper lumbar plexus: the L2 – L4 roots (the femoral and obturator nerves).
  • There is weakness much more so than sensory loss and there is an absent knee jerk (aka patellar reflex).

Neuralgic Amyotrophy (Brachial Plexopathy)

Finally, let's look at brachial plexopathy. We'll draw key aspects of the brachial plexus.

Brachial Plexus Anatomy

Begin with some anatomical landmarks:

  • Include the clavicle, cut away, so we can see the plexus divisions, which lie beneath it.
  • Then, draw the axillary artery (a continuation of the subclavian artery), which climbs over the first rib.

Now let's see how the brachial plexus forms within this space:

  • C5 and C6 form the upper trunk (U).
  • C8 and T1 form the lower trunk (L).
  • C7 makes up the middle trunk (M).

Now, for the cords, which get their name from their relationship to the axillary artery.

  • The posterior trunk divisions form the posterior cord, which passes posterior to the axillary artery to form the axillary nerve (Ax.) and ultimately the radial nerve (R), which innervates the extensor surface of the upper extremity.
  • The anterior division of the lower trunk forms the medial cord, which passes medial to the axillary artery, and forms the ulnar nerve (U), which innervates the medial flexors distal to the elbow.
  • The anterior divisions of the upper and middle trunks form the lateral cord, which passes lateral to the axillary artery to form the musculocutaneous nerve (Mu.) and joins with a branch of the medial cord to form the median nerve (M), which innervates the lateral flexors distal to the elbow.

Neuralgic Amyotrophy (Brachial Plexopathy)

  • Neuralgic amyotrophy, which parallels diabetic amyotrophy. There are two forms: idiopathic, commonly known as Parsonage-Turner syndrome, and a hereditary form. Note that we discuss the individual brachial plexopathies elsewhere.
  • Indicate that it presents with shoulder pain.
  • On exam, there is most often upper plexus multiple mononeuropathies.
  • Again, the weakness is greater than the associated sensory loss.
  • And there is a diminished triceps and/or biceps reflex.

Note that steroids are often used for pain control in both lumbosacral and brachial plexopathies.

Histopathology of Neuropathy: Nerve cross-section

Now, let's draw the histopathology of neuropathy in nerve cross-section. On the left, we'll draw a healthy nerve fascicle, on the right, we'll draw key findings in various forms of neuropathy.

Healthy Nerve Fascicle

  • First, draw the outer covering of the peripheral nerve (the nerve trunk), called the epineurium (specifically, the superficial epineurium).
  • Then, draw two nerve fascicles 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, draw the endoneurium, which is a loose connective tissue.
  • Now, fill in the deep epineurium that surrounds the fascicles and add some vasculature: a vein and artery.
  • In each fascicle, include perineurial septa, which carry vasculature to the nerve fibers.
  • Now, draw various groups of myelinated nerve fibers in one of the fascicles:
    • Indicate the nerve fiber axon.
    • Then, the myelin sheath.
    • Then, include a Schwann cell (each of which myelinates at most one axon internode).
  • Next, draw some unmyelinated (or thinly-myelinated) axons, which bundle into so-called Remak bundles.

Zonal Axon Loss

Now, let's address specific findings in neuropathy.

  • First, in one partition of the nerve fascicle, show a scant number of axons and indicate that the most common finding in neuropathy is zonal axon loss, meaning a drop-out in the number of axons.

Axonal Neuropathy

Next, let's show some specific axon changes that occur in axonal neuropathy:

  • Wallerian Degeneration. Show an axon with a thin myelin sheath and thickening of the endoneurium but show dissolution of the axons (empty space within the axon), which represents the void of nerve filaments.
  • Axon Atrophy. Draw a small caliber axon with a myelin sheath of normal thickness. We can imagine a disintegration of normal axonal structures (eg, neurofibrils) as a common occurrence in smoldering axonal neuropathies and also as secondary changes in demyelinating neuropathies, as well.
  • Axonal Regeneration. Draw a cluster of small-caliber axons that are thinly myelin to represent axonal regeneration – we drew this phenomenon in detail in our nerve schematic.

Demyelinating Neuropathy

Now, let's address demyelinating neuropathies wherein the most obvious finding is simply a low density of myelinated axons.

  • Onion-bulb formation. Draw an axon 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. Draw a highly thickened myelin sheath around a reduced-caliber axon; tomacula are focal thickenings of myelin.
  • Show that tomacula means "sausage", which is how these myelin fragments appear in longitudinal (teased-fiber) preparation.
  • Indicate that tomacula characteristically occur in Hereditary Neuropathy with Liability for Pressure Palsy (HNPP). In the next part of this tutorial, we'll see that HNPP involves a mutation on the same gene as CMT1a (the PMP-22 gene).

Vasculitic Neuropathy

Finally, show an epineural vessel with inflammatory changes to show that vasculitis is an important cause of neuropathy, specifically mononeuritis multiplex.

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