Laboratory Evaluation of Peripheral Neuropathy

K.H. Vincent Lau, MD


Semin Neurol. 2019;39(5):531-541. 

In This Article

Acute or Subacute Peripheral Neuropathy

Acute Demyelinating Polyneuropathy

Rapidly developing proximal preceding distal limb weakness with sensory symptoms and loss of reflexes warrants consideration of acute inflammatory demyelinating polyradiculopathy (AIDP). The related entity of acute motor axonal neuropathy (AMAN) presents with predominantly distal preceding proximal motor weakness without sensory changes, with or without hyporeflexia. For these subtypes of Guillain-Barré syndrome (GBS), albuminocytologic dissociation remains the only consistent biomarker supportive of the diagnosis[31]—CSF protein is elevated in approximately 50% of patients in the first week, increasing to 80% of patients in the second week. AMAN has been associated with IgG antibodies against GM1, GD1a, GalNAc-GD1a, and GD1b.[75] However, antibodies are not routinely checked, as their status is unlikely to change management decisions, especially with the delay in results. In patients with GBS who had exposure in endemic areas, testing for Zika virus may be considered.[76]

When there is clinical suspicion for the Miller Fisher syndrome variant of GBS characterized by the clinical triad of ophthalmoplegia, areflexia, and ataxia, anti-GQ1b may be checked, found in approximately 80 to 90% of patients.[77] Most recently, anti-GD1b was found to have low specificity for various other neuropathies—IgM to anti-GD1b antibodies were found with varying prevalence in the entities of GBS, paraneoplastic syndrome with anti–Hu-associated neuropathy and MGUS, while IgG to anti-GD1b antibodies were found in GBS and Miller-Fisher-GBS overlap but not in healthy controls or other autoimmune diseases.[78] Similarly, the results for antibodies are nonspecific and are unlikely to be available by the time of management decisions.

Acute or Subacute Axonal Polyneuropathy

The differential diagnosis for acute or subacute axonal polyneuropathies includes infections with West Nile virus (WNV), rabies, HIV, CMV, and Lyme, as well as porphyria and heavy metals toxicity. WNV causes a clinical presentation consistent with damage to anterior horn cells[79] with variable limb involvement from one to all four,[80] while rabies affects the peripheral motor neurons prior to central nervous system involvement.[81] WNV infection can be evaluated with CSF studies. Rabies is generally tested on the animal to which a patient may have been exposed, via direct fluorescent antibody testing against the rabies virus.[82] HIV, CMV, and Lyme can also cause variable presentations of acute or subacute polyneuropathies.

Porphyria can present acutely with a predominantly axonal motor neuropathy, often with proximal, preferentially upper extremity involvement.[83] Laboratory screening includes urine porphobilinogen quantification and measurement of urine porphyrin excretion.[84]

Heavy metals can also cause polyneuropathy that is typically axonal. Arsenic causes gastrointestinal distress along with a length-dependent, painful, sensory polyneuropathy.[13] Levels are checked in the urine, but in more insidious cases, it may only be detected in hair and nail samples. The pesticide thallium also causes gastrointestinal distress along with painful sensory involvement followed by motor neuropathy mimicking GBS. Alopecia is a late symptom. Evaluation of heavy metals is appropriate in the setting of suspected exposure. In cases of rapidly developing symptoms for which other diagnostics have been exhausted, a nerve biopsy may be indicated.[27]

Acute Mononeuropathy or Multiple Mononeuropathies

The pattern of peripheral neuropathy consistent with multiple mononeuropathies is elicited on history, examination, and neurophysiological studies. The differential diagnosis for primary axonal mononeuropathies includes vasculitidies, infection, amyloidosis, sarcoidosis, and lead toxicity, and for primarily demyelinating mononeuropathies the differential diagnosis includes multifocal-acquired demyelinating sensory and motor neuropathy (MADSAM) and hereditary neuropathy with liability to pressure palsy (HNPP).

In terms of vasculitidies, the relative prevalence of multifocal neuropathy among patients with the following conditions is listed in decreasing order: polyarteritis nodosa (PAN), microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, granulomatosis and polyangiitis, and giant cell arteritis. Associated laboratory investigations include ESR, C-reactive protein, ANA, antineutrophil cytoplasmic antibodies, and cryoglobulins. One-third of patients with PAN have hepatitis B or C antibodies.[22] If laboratory testing is unrevealing, nerve and muscle biopsy is the gold standard for diagnosis of peripheral nerve vasculitis.[85,86] In a recent study, 11 of 14 patients had confirmation of the underlying etiology of a presentation of multiple mononeuropathies with nerve biopsy, finding vasculitic neuropathy in six cases and perineuritis in two cases. Atypical presentations of CIDP and MADSAM were found in the remaining three.[87]

Other causes include infections. In addition to hepatitis, HIV, CMV, and Lyme can also cause multiple mononeuropathies.[24,88] Amyloidosis should be considered in patients who present with bilateral carpal tunnel syndrome if other features such as autonomic dysfunction are present. Laboratory testing may reveal abnormal SPEP and IFE; fat pad biopsy or pathological examination of structures near sites of neuropathy may also reveal amyloid deposits, for example, with examination of the flexor retinaculum after carpal tunnel release surgery.[89,90] Hereditary amyloidosis may be diagnosed with genetic testing with the transthyretin gene.[91] Sarcoidosis also causes multiple mononeuropathies, with laboratory testing possibly demonstrating elevated serum or CSF ACE as previously discussed.[25] Another cause of focal neuropathy is lead toxicity, which should be evaluated in patients with possible exposure history. The classic presentation is radial nerve palsy causing weakness of wrist and finger extensors. Laboratory investigation involves measuring serum lead level, while other supporting evidence includes anemia on complete blood count and abnormal peripheral smear with anisopoikilocytosis and basophilic stippling.[92,93]

HNPP has a distinguished phenotype with presentation of recurrent, episodic, generally painless focal mononeuropathies that may be caused by minor trauma. Neurophysiological studies demonstrate decreased motor nerve conduction velocities, prolonged distal motor latencies predominantly at sites of common nerve entrapment, and abnormal sensory nerve action potentials even in clinically unaffected nerves.[94,95] Genetic testing is available evaluating for PMP22 gene deletion; a recent study used next-generation sequencing-based copy number variation analysis to test asymptomatic newborns and found a genetic prevalence of 58.9 per 100,000, which is unsurprising given the combination of underdiagnosis and likely incomplete penetrance of the disease.[96] As for MADSAM, laboratory testing is similar to that for CIDP as detailed in a previous section.

The initial presentation of an acute focal mononeuropathy may represent the first of multiple mononeuropathies. As such, given the treatability of many of the etiologies, most of the above studies for acquired causes may be performed even as an initial evaluation.