Polyneuropathy Causes and Diagnostic Approach

Metabolic Causes

Vitamin B12 deficiency is a significant cause of polyneuropathy, with 2.2-8% of patients showing evidence of B12 deficiency, according to the American Academy of Physical Medicine and Rehabilitation 1, 2
Other nutritional deficiencies, such as vitamin B1, B6, folate, and vitamin E, can cause polyneuropathy and should be considered in the diagnostic workup, as recommended by the American Academy of Physical Medicine and Rehabilitation 1
Hypoglycemia, hypothyroidism, chronic kidney disease, and mitochondrial disorders are correctly included as metabolic causes, as stated by the American Diabetes Association 3, 4

Inflammatory/Immune-Mediated Causes

Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, and vasculitic neuropathies are important inflammatory causes, according to the American Academy of Physical Medicine and Rehabilitation 1, 5
Sarcoidosis can present with polyneuropathy, as listed in the classification, according to the American Academy of Physical Medicine and Rehabilitation 5

Paraneoplastic syndromes can cause polyneuropathy and should be considered, particularly in patients with unexplained neuropathy, as recommended by the American Academy of Physical Medicine and Rehabilitation 1, 5
Polycythemia rubra vera is correctly included as a potential cause, according to the American Academy of Physical Medicine and Rehabilitation 5

Infectious Causes

Leprosy, HIV, syphilis, and Lyme disease are established infectious causes of polyneuropathy, as stated by the American Diabetes Association 3, 4

Toxins/Drug-Induced Causes

Lead and arsenic toxicity are correctly included as causes of toxic polyneuropathy, according to the American Academy of Physical Medicine and Rehabilitation 5

Hereditary Causes

Charcot-Marie-Tooth disease, Refsum's syndrome, and adrenoleukodystrophy are correctly listed as hereditary causes, according to the American Academy of Physical Medicine and Rehabilitation 5
Genetic testing is established as useful for accurate diagnosis of hereditary neuropathies, as recommended by the American Academy of Physical Medicine and Rehabilitation 5

Other Causes

Amyloidosis and paraproteinemias are important causes to consider, according to the American Academy of Physical Medicine and Rehabilitation 1, 2
Monoclonal gammopathies are more common in polyneuropathy patients than in the general population, with approximately 10% of patients with polyneuropathy of unknown etiology having monoclonal gammopathy, as stated by the American Academy of Physical Medicine and Rehabilitation 2

Idiopathic Polyneuropathy

20-25% of chronic polyneuropathies have no identifiable cause, according to the American Academy of Physical Medicine and Rehabilitation 1, 5

Diagnostic Approach

Screening laboratory tests with the highest yield include blood glucose, serum B12 with metabolites, and serum protein immunofixation electrophoresis, as recommended by the American Academy of Physical Medicine and Rehabilitation 1, 5
Electrodiagnostic studies are essential to confirm diagnosis and distinguish between axonal and demyelinating patterns, according to the American Academy of Physical Medicine and Rehabilitation 6

Clinical Pearls

Up to 50% of diabetic peripheral neuropathy may be asymptomatic but still increases risk for complications, as stated by the American Diabetes Association is not the source, instead, Praxis Medical Insights reports 7
In patients with B12 levels in the low-normal range, 5-10% may still have B12 deficiency as indicated by elevated metabolites, according to the American Academy of Physical Medicine and Rehabilitation 2
Serum protein immunofixation electrophoresis is more sensitive than serum protein electrophoresis for detecting monoclonal gammopathies, as recommended by the American Academy of Physical Medicine and Rehabilitation 2

Association between Sensory and Proprioceptive Polyneuropathy and Monoclonal IgG Kappa

Relation between Monoclonal Gammopathies and Neuropathies

The American Academy of Physical Medicine and Rehabilitation notes that monoclonal gammopathies are more frequent in patients with polyneuropathy than in the general population, with approximately 10% of patients with polyneuropathy of unknown etiology having a monoclonal gammopathy 8, 9
Monoclonal IgG gammopathies can be associated with several pathological conditions, such as myeloma, POEMS syndrome, primary amyloidosis, or chronic inflammatory conditions, as reported by the European Hematology Association 9, 10
The association between IgG monoclonal gammopathies and neuropathies is less well characterized than that with IgM, but it is clinically significant, with a strength of evidence supported by the European Hematology Association 10, 11

Caractéristiques cliniques des neuropathies associées aux IgG

The clinical manifestations of neuropathies associated with IgG monoclonal gammopathies can include sensory and proprioceptive symptoms, such as paresthesias, disturbances of deep sensation and proprioception, and neuropathic pain, as described by the European Hematology Association 12

Mécanismes pathogéniques

In IgG monoclonal gammopathies, the monoclonal protein can act directly as a pathogenic factor or indirectly through immune mechanisms, as suggested by the European Hematology Association 10
The pathogenic mechanisms of neuropathies associated with IgG are less well defined than those with IgM, where the association with anti-MAG antibodies is well established, as reported by the European Hematology Association 10, 11

Approche diagnostique

In cases of unexplained sensory and proprioceptive polyneuropathy, the search for a monoclonal gammopathy by serum immunofixation is recommended by the American Academy of Physical Medicine and Rehabilitation 8, 9
Serum immunofixation is more sensitive than serum protein electrophoresis for detecting monoclonal gammopathies, especially small ones, as noted by the American Academy of Physical Medicine and Rehabilitation 9

Implications thérapeutiques

The treatment depends on the severity of symptoms and the established causal relationship between the gammopathy and neuropathy, as reported by the European Hematology Association 10, 11
For IgG-associated neuropathies with moderate to severe symptoms, several therapeutic options can be considered, including targeted therapies for the responsible B-cell clone, as suggested by the European Hematology Association 10, 11

Chemotherapy‑Induced Axonal Sensory Neuropathy and Key Risk Factors

Chemotherapy‑Related Causes

Neurotoxic chemotherapy agents are among the most frequent causes of acquired axonal sensory neuropathy, typically presenting with a symmetric, distal “glove‑and‑stocking” distribution and predominantly sensory symptoms. 13
Platinum compounds, taxanes, vinca alkaloids, bortezomib, and thalidomide produce dose‑dependent sensory axonal injury by targeting dorsal‑root‑ganglion cell bodies, often resulting in irreversible sensory neuronopathy. 14
Approximately 38 % of patients receiving multiple neurotoxic agents develop chemotherapy‑induced peripheral neuropathy (CIPN). 13
The risk of CIPN rises with higher cumulative doses, longer exposure duration, and combination regimens of neurotoxic drugs. 14

Other Toxic and Medication‑Related Contributors

Chronic alcohol abuse directly causes toxic axonal neuropathy and increases susceptibility to nutritional deficiencies that can exacerbate neuropathic injury. 14
Identification and discontinuation of concurrent neurotoxic medications are recommended whenever feasible to limit additive nerve damage. 14

Hereditary Considerations in the Oncology Setting

Charcot‑Marie‑Tooth disease type 1A should be excluded in patients who develop severe neurotoxicity with standard chemotherapy doses (especially vincristine), as these individuals exhibit predominant motor involvement and characteristic deformities. 14

Independent Risk Factors for Worsening Axonal Sensory Neuropathy

Pre‑existing neuropathy, concurrent exposure to other neurotoxic agents, diabetes mellitus, and age ≥ 75 years are strong independent predictors of development or aggravation of axonal sensory neuropathy in cancer patients. 14
Additional predispositions include alcohol abuse, renal insufficiency, hypothyroidism, vitamin deficiencies, HIV infection, and autoimmune rheumatologic diseases. 14

Electrodiagnostic Confirmation

Nerve‑conduction studies in pure sensory axonal neuropathy reveal markedly reduced sensory nerve action potential amplitudes while motor nerve responses remain preserved, confirming an axonal pattern. 13

Acute Porphyria‑Related Neuropathy

Acute porphyria attacks may be complicated by axonal motor neuropathy and paresis; electrophysiologic testing can detect chronic neuropathy underlying persistent pain, sensory loss, or weakness. 15