Polyneuropathty - Diagnostic Testing

Laboratory Testing

Highest Yield

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

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.
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.
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

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.

Indicate that this is best used as a marker of chronic alcohol abuse because hepatotoxicity, itself, isn't a well-defined cause of neuropathy.

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.
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.

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.

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.

MPZ (myelin protein zero) mutation results in CMT1b, another autosomal dominant, demyelinating neuropathy.
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.

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

This is not intended to be exhaustive but rather illustrative of some key patterns and their causative illnesses.

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.
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.
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.
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.