What are the causes of small fiber neuropathy in patients with underlying medical conditions such as diabetes, autoimmune disorders, or a history of chemotherapy?

Causes of Small Fiber Neuropathy

Small fiber neuropathy results from a broad spectrum of metabolic, immune-mediated, infectious, toxic, hereditary, and idiopathic conditions, with diabetes and impaired glucose tolerance being the most common identifiable causes, though nearly half of cases remain idiopathic despite thorough evaluation.

Primary Etiologic Categories

Metabolic Disorders

• Diabetes mellitus and impaired glucose tolerance are the most prevalent metabolic causes, with chronic hyperglycemia triggering oxidative stress, inflammation, and microvascular dysfunction that preferentially damages small unmyelinated C and thinly myelinated Aδ fibers before affecting large fibers 1, 2.
• Hypothyroidism represents another significant metabolic cause, accounting for approximately 9.4% of secondary small fiber neuropathy cases 3.
• Up to 50% of diabetic peripheral neuropathy may be asymptomatic, and small fiber damage occurs early even when conventional nerve conduction studies remain normal 1, 2.

Immune-Mediated and Autoimmune Conditions

• Sjögren's disease is a recognized autoimmune cause, accounting for approximately 3% of secondary cases 3.
• Cryoglobulinemia contributes to approximately 7% of secondary small fiber neuropathy cases 3.
• Monoclonal gammopathy of undetermined significance (MGUS) accounts for approximately 4.7% of cases 3.
• Growing interest in immune-mediated forms could help identify potentially treatable subgroups 4.

Toxic and Drug-Induced Causes

• Chemotherapy agents are well-established causes of small fiber neuropathy through direct toxic effects on nerve fibers 4, 5.
• Various other drugs and toxins can cause small fiber damage, with the list of associated exposures continuing to expand 4, 5.

Infectious Causes

• Human immunodeficiency virus (HIV) infection is a recognized chronic infectious cause of small fiber neuropathy 5.
• Other chronic infections have been associated with small fiber damage 4.

Genetic and Hereditary Causes

• Sodium channelopathies involving variants in SCN9A, SCN10A, and SCN11A genes (encoding Nav1.7, Nav1.8, and Nav1.9 sodium channel subunits) have been identified in small fiber neuropathy patients 6, 4.
• TRPA1 gene variants have also been found, expanding the spectrum of underlying genetic conditions 4.
• These genetic discoveries provide insight into pathophysiological mechanisms and reveal overlapping clinical presentations with other sodium channelopathies 6.

Paraneoplastic Syndromes

• Paraneoplastic neuropathy accounts for approximately 3% of secondary small fiber neuropathy cases 3.

Idiopathic Small Fiber Neuropathy

• Idiopathic cases represent 41-48% of all small fiber neuropathy, making it the single largest category when no underlying cause can be identified despite thorough evaluation 3, 7.
• At 2-year follow-up, a potential cause can be determined in approximately 25% of initially idiopathic cases, emphasizing the importance of continued surveillance 7.
• The aetiology remains frequently unknown despite advances in diagnostic capabilities 6, 7.

Critical Diagnostic Considerations

Pattern Recognition

• Length-dependent distribution is observed in approximately 85% of cases, typically presenting with distal, symmetric symptoms that are nocturnally exacerbated 8, 3.
• Small fiber damage precedes large fiber damage in diabetic neuropathy, with intraepidermal nerve fiber density significantly reduced even when nerve conduction studies are normal 9, 1.

Gender and Severity Differences

• Two-thirds (68%) of patients are female, though men demonstrate significantly more severe pathology, particularly in diabetes 3.
• Secondary small fiber neuropathy typically starts approximately 8 years later than idiopathic forms 3.

Progression and Natural History

• At 2-year follow-up, approximately 13% of small fiber neuropathy patients show involvement of large nerve fibers, while 45.6% remain stable 7.
• Spontaneous remission of neuropathic pain occurs in only 10.9% of patients, while symptoms worsen in 30.4% 7.

Common Pitfalls to Avoid

• Do not rely solely on nerve conduction studies, as these only assess large myelinated fiber function and will be completely normal in isolated small fiber neuropathy, leading to missed diagnoses 8, 1, 2.
• Do not assume normal electrophysiology excludes significant neuropathy when small fibers are preferentially affected 1.
• Screen all type 2 diabetics at diagnosis and type 1 diabetics after 5 years, then annually thereafter, as up to 50% may be asymptomatic 1.