Peripheral neuropathy is a very old and often straightforward problem for neurologists. Its presentation is well-defined, and neurologists are at their theatrical best when they map out the classical glove-and-stocking distribution of impaired temperature and touch sensation. They proficiently demonstrate distal muscle weakness and wasting, and masterfully elicit absent reflexes or areflexia.

Stripped hand on a stick. Tysone Moore on Flikr.
Stripped hand on a stick. Tysone Moore on Flikr.


Below the surface however, peripheral neuropathy is anything but straightforward. It has a wide variety of subtypes and causes, and its classification now has subclassifications of subclassifications. Research is continually demonstrating how complex peripheral neuropathy really is, and here are 4 concepts to illustrate this complexity.

1. IgG4-related peripheral neuropathy
Cold Spring Harbor 012. Vik Nanda on Flikr.
Cold Spring Harbor 012. Vik Nanda on Flikr.


As soon as neurologists make the clinical diagnosis of peripheral neuropathy, they reach for the blood request form. They almost mindlessly tick off tests which include immunoglobulins, the building block of antibodies. The nerve damage arising from excessive amounts of immunoglobulins is called paraproteinaemic neuropathy. This simple paradigm, high immunoglobulins equalling paraproteinaemic neuropathy, is however set to change. And this is going by a paper in Neurology titled Immunoglobulin G4-related pathologic features in inflammatory neuropathies. The article showed that IgG4 levels are elevated in a subgroup of people with neuropathy, but these people have vasculitic neuropathy rather than straightforward paraproteinaemic neuropathy. Because the treatment of vasculitis differs from that of paraproteinaemia, this finding is completely changing the rules of the game.

 2. More genes please, we're neurologists
Framed Embroidery Chromosome Art. Hey Paul Studios on Flikr. By Database Center for Life Science (DBCLS), CC BY 3.0,
Framed Embroidery Chromosome Art. Hey Paul Studios on Flikr. By Database Center for Life Science (DBCLS), CC BY 3.0,


Hereditary neuropathy is a quagmire for neurologists, but it hasn’t always been that way. In the good old days, (and I have enough grey hairs to say this), a neurologist just needed to have a smattering knowledge of one or two genetic mutations that cause Charcot Marie Tooth disease (CMT), and a vague familiarity with CMT’s genetic cousin, hereditary neuropathy with liability to pressure palsy (HNPP). It used to be a few minutes of counselling, an aliquot of blood, and a confirmatory blood test 6 months later. Not anymore this life of luxury; CMT alone is now classified into multiple subtypes, each subtype caused by a multitude of genetic mutations. And the genetic neuropathists are not done yet; the articles below show the broadening scope of genetic neuropathies we have to contend with. Your neurologist really deserves your sympathies!


3. Nodopathies
By Dr. Jana - ;, CC BY 4.0,
By Dr. Jana – ;, CC BY 4.0,


Still in nostalgic mood, there was a time when a neurologist just needed to know if a neuropathy was axonal (affecting the main nerve fiber), or demyelinating (involving the nerve ensheathing layer called myelin). Confine that classification to the history books because nodopathy is toppling the prevailing order. This is from a paper titled Nodopathies of the peripheral nerve: an emerging concept, in the Journal of Neurology, Neurosurgery and Psychiatry (JNNP). The authors of the paper are scathing of the traditional classification which, they say, is ‘inadequate or even misleading’. Why? Because many cases of typical demyelinating neuropathy demonstrate clear axonal changes. The authors explain this paradox by describing the anatomy of myelinated nerves which are made up of domains: node, paranode, juxta-paranode and inter-node. And it is the node which bucks the trend because it resolutely refuses to be ensheathed by myelin. And this singular act of defiance will be the source of anguish for generations of medical students and doctors, not to mention neurophysiologists.

4. Growth factor receptor antibodies

When requesting immunoglobulins and other blood tests, neurologists only needed to tick boxes in standard blood request forms. This life of ease and luxury has been on the way out because the standard blood request form no longer accommodates the ever-expanding causes of peripheral neuropathy. What was previously the almost mindless ticking of B12 and folate is fast becoming anxiety-provoking for the neurologist. It is one thing to remember the test to request, it is another to justify this to your friendly biochemist that this test is worth the cost. But what could a neurologist do when researchers keep coming up with more causes of neuropathy. Take anti-FGFR3 antibodies for example, again from a paper in the JNNP titled antifibroblast growth factor receptor 3 antibodies in sensory neuropathy. The authors have no idea how their findings threaten a cosy B12-and-folate relationship between neurologist and biochemist!

Teased Myelinated Medullated Nerve 2. Green Flames 09 on Flikr.
Teased Myelinated Medullated Nerve 2. Green Flames 09 on Flikr.


Looking for a comprehensive approach to the management of peripheral neuropathy? I haven’t come across anything better than Clinical Approach to Peripheral Neuropathy in  Continuum…but you need to have access. For a hands-on take on genetic neuropathies, A Practical Approach to the Genetic Neuropathies is the place to start. Thankfully, this is open access.


6 thoughts on “What’s looming at the frontline of peripheral neuropathy?

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