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List of underlying causes

Much of the information regarding underlying causes of small fiber neuropathy is sourced from three pivotal scientific articles known as ‘reviews.’

These review articles offer comprehensive overviews of the subject, drawing from numerous primary studies. Ideally, from a rigorous scientific perspective, direct references to these primary sources would be made rather than relying on review articles. “Over time, the primary sources will be added step by step. Regardless, the origins of the information presented here are traceable and rooted in scientific literature.

Insights have also been obtained from OpenAI’s GPT-4 model, particularly when suggesting potential tests. It’s important to recognize that this model, a large language model, predicts word sequences based on patterns in vast datasets. Thus, information from it should be viewed as suggestions or ideas, not definitive truths.

Lastly, anecdotal accounts from individuals affected by small fiber neuropathy have been included. These narratives encompass personal experiences, diagnoses, or suspicions—either self-formed or shared by healthcare professionals. While these may not have a direct scientific basis, their inclusion offers valuable context and breadth to the understanding of the condition.

Metabolic:

ConditionTestsReferences
Diabetes MellitusFasting plasma glucose test1,4,5
Oral glucose tolerance test (OGTT)5
Hemoglobin A1c (HbA1c) test5
Random plasma glucose test5
Impaired glucose intoleranceOral glucose tolerance test (OGTT)1,6,5
Hyperlipidemia, Metabolic SyndromeLipid panel, cholesterol test3
Rapid Glycemic LoweringSimilar tests as diabetes, monitoring blood glucose levels3,5
Chronic Kidney DiseaseGlomerular filtration rate (GFR), urine albumin3

Autoimmune/Inflammatory:

ConditionTestsReferences
Sjögren’s syndromeAnti-Ro (SSA) and anti-La (SSB) antibodies test1,7,5
Salivary gland biopsy5
LupusAntinuclear antibody (ANA) test1,8,5
Anti-dsDNA test5
Anti-Ro (SSA) and Anti-La (SSB) test5
Complement levels test5
Rheumatic diseases (undifferentiated connective tissue disorders, rheumatoid arthritis, psoriasic arthropathy)Rheumatoid factor (RF) test1,9
Anti-cyclic citrullinated peptide (anti-CCP) test
Erythrocyte sedimentation rate (ESR) test
C-reactive protein (CRP) test
SarcoidosisAngiotensin-converting enzyme (ACE) test3,10,5
Chest X-ray5
Biopsy of affected tissue5
VasculitisANCA (antineutrophil cytoplasmic antibody) test1,3,5
C-reactive protein (CRP) test5
Erythrocyte sedimentation rate (ESR) test5
Biopsy of affected tissue5
Hypothyroidism, Autoimmune ThyroiditisTSH test3,5
Free T4 test5
Thyroid antibodies test5
Inflammatory bowel diseaseFecal calprotectin test1,3,5
Stool test for parasites and bacteria5
Colonoscopy with biopsy5
Celiac disease/gluten sensitivityTissue transglutaminase (tTG) antibody test1,2,3,5
Endomysial antibody (EMA) test5
Duodenal biopsy5
Mixed connective tissue diseaseAntinuclear Antibody (ANA) Test3,5
Anti-U1-RNP Antibodies Test5
Complete Blood Count (CBC)5
Erythrocyte Sedimentation Rate (ESR) and C-Reactive Protein (CRP) Tests5
Chest X-Ray or CT Scan5
Echocardiogram5
Churg-Strauss DiseaseBlood tests for eosinophilia3,5
Immunoglobulin E (IgE) test5
Other Immune-mediated (TS-HDS, FGFR-3, Plexin D1, Anti-Voltage-Gated Potassium Channel (VGKC) Antibody)Various specific antibody and immunological tests, depending on the suspected condition5
ConditionTestsReferences
Vitamin B12 deficiencyVitamin B12 blood test1,2,5
Methylmalonic acid (MMA) test5
Homocysteine test5
Vitamin B6 deficiencyVitamin B6 (pyridoxine) level test2,5
Vitamin B1 deficiencyVitamin B1 (thiamine) level test2,5
Vitamin E deficiencyVitamin E level test2,5
Vitamin B6 toxicityVitamin B6 level test2,5
Copper deficiency2

Toxic:

ConditionTestsReferences
Chemotherapeutic agents (taxanes, platinum family, vinca alkaloids, thalidomide, bortezomib, epothilones, and arsenic trioxide)Complete blood count (CBC)2
Kidney function tests, liver function tests
Electrocardiogram (ECG)
Nerve conduction studies
Antibiotics (isoniazid, linezolid, oxazolidinones, nitrofurantoin, metronidazole, and fluoroquinolones)Complete blood count (CBC)2,3
Kidney function tests
Liver function tests
Anti-retroviral medicationsComplete blood count (CBC)3
Liver function tests
Kidney function tests
Gout medications (colchicine, allopurinol)Complete blood count (CBC)2
Kidney function tests
Liver function tests
Heavy metal toxicity (lead, arsenic, mercury, thallium)Heavy metal levels in blood and urine2,3
Blood lead level test
Excessive alcohol useAlcohol level test2,3
Liver function tests
Complete blood count (CBC)
Neurotoxic drugsComplete blood count (CBC)3
Liver function tests
Kidney function tests
Nerve conduction studies
Cholesterol-lowering medications (Statins)3
Gadolinium toxicity11

Infectious:

ConditionTestsReferences
LymeEnzyme-linked immunosorbent assay (ELISA) test2,5
Western blot test5
Human immunodeficiency virus (HIV)HIV antibody test2,5
Viral load test5
Herpes simplex virus (HSV)HSV antigen test2,5
HSV culture test5
HSV DNA test5
Varicella zoster virus (VZV)VZV antibody test2
VZV antigen test
Cytomegalovirus (CMV)CMV antibody test2,5
CMV antigen test5
Hepatitis-C virus (HCV)HCV antibody test, HCV RNA test2
Hepatitis-B virus (HBV)HBV antibody test2,5
HBV surface antigen test5
LeprosySkin biopsy2,5
Nerve biopsy5
Bacterial culture5

Hereditary:

ConditionTestsReferences
Fabry’s diseaseEnzyme assay test for alpha-galactosidase12,5
Genetic testing for GLA mutations5
Mutation in sodium channels (SCN9A, SCN10A, SCN11A)Genetic testing for specific mutations2,5
Wilson’s disease(No specific tests listed under this condition)13
Ehlers-Danlos syndrome/joint hypermobility syndrome(No specific tests listed under this condition)2,14
HSAN (Hereditary Sensory and Autonomic Neuropathy)Genetic testing3
Clinical evaluation
Tangier DiseaseBlood tests for HDL cholesterol levels3
Genetic testing
Pompe DiseaseEnzyme assay test for acid alpha-glucosidase3
Genetic testing

Other causes:

ConditionTestsReferences
Monoclonal gammopathySerum protein electrophoresis (SPEP)15,2
Immunofixation electrophoresis (IFE) test
Bone marrow biopsy
FibromyalgiaNo specific blood test, diagnosis based on symptoms and medical history16
Paraneoplastic and cancer related2
Amyloidosis (transthyretin or familial (TTR), light chain (AL), secondary/autoimmune (AA))Genetic testing for TTR mutations2
Biopsy to identify amyloid deposits
Degenerative (associated with Parkinson’s disease or multisystem atrophy)2
Idiopathic1,2
Post viral illness11
Vaccine injury11

Footnotes

  1. Raasing LRM, Vogels OJM, Veltkamp M, van Swol CFP, Grutters JC. Current View of Diagnosing Small Fiber Neuropathy. J Neuromuscul Dis. 2021;8(2):185-207. doi:10.3233/JND-200490 2 3 4 5 6 7 8 9 10 11

  2. Farhad K. Current Diagnosis and Treatment of Painful Small Fiber Neuropathy. Curr Neurol Neurosci Rep. 2019;19(12):103. Published 2019 Nov 26. doi:10.1007/s11910-019-1020-1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28

  3. Zeidman LA. Advances in the Management of Small Fiber Neuropathy. Neurol Clin. 2021;39(1):113-131. doi:10.1016/j.ncl.2020.09.006 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

  4. Alam U, Jeziorska M, Petropoulos IN, et al. Diagnostic Utility of Corneal Confocal Microscopy and Intra-Epidermal Nerve Fibre Density in Diabetic Neuropathy. Vol 12.; 2017. doi:10.1371/journal.pone.0180175

  5. Generated by OpenAI’s GPT-4 LLM on [2023-09-17]. Readers should treat insights from this GPT-4 as a guide/suggestion, not a definitive answer. 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61

  6. Khoshnoodi MA, Truelove S, Burakgazi A, Hoke A, Mammen AL, Polydefkis M. Longitudinal Assessment of Small Fiber Neuropathy: Evidence of a Non-Length- Dependent Distal Axonopathy. Vol 73.; 2016. doi:10. 1001/jamaneurol.2016.0057

  7. Zouari HG, Wahab A, Ng Wing Tin S, S`ene D, Lefaucheur JP. The Clinical Features of Painful Small- Fiber Neuropathy Suggesting an Origin Linked to Primary Sjögren’s Syndrome. Pain Pract. 2019;19(4):426-34. doi:10.1111/papr.12763

  8. Gøransson LG, Tjensvoll AB, Herigstad A, Mellgren SI, Omdal R. Small-diameter nerve fiber neuropathy in systemic lupus erythematosus. Arch Neurol. 2006;63(3):401-4. doi:10.1001/archneur.63.3.401

  9. Devigili G, TugnoliV, Penza P, et al. The Diagnostic Criteria for Small Fibre Neuropathy: From Symptoms to Neuropathology. Vol 131.; 2008. doi:10.1093/brain/awn093

  10. Bakkers M, Faber CG, Drent M, et al. Pain and Autonomic Dysfunction in Patients with Sarcoidosis and Small Fibre Neuropathy. Vol 257.; 2010. doi:10.1007/s00415- 010-5664-7

  11. Potential causes that have been reported by individuals within a Small Fiber Neuropathy Facebook group . These are anecdotal experiences and have not been scientifically validated. 2 3

  12. Biegstraaten M, Hollak CEM, Bakkers M, Faber CG, Aerts JMFG, van Schaik IN. Small fiber neuropathy in Fabry disease. Mol Genet Metab. 2012;106(2):135-41. doi:10.1016/j.ymgme.2012.03.010

  13. Sturniolo GC, Lazzarini D, Bartolo O, et al. Small fiber peripheral neuropathy in wilson disease: An in vivo documentation by corneal confocal microscopy. Investig Ophthalmol Vis Sci. 2015;56(2):1390-5. doi:10.1167/iovs.14- 15004

  14. Cazzato D, Castori M, Lombardi R, et al. Small fiber neuropathy is a common feature of Ehlers-Danlos syndromes. Neurology. 2016;87(2):155-9. doi:10.1212/ WNL.0000000000002847

  15. Farhad K, Traub R, Ruzhansky KM, Brannagan TH. Causes of neuropathy in patients referred as “idiopathic neuropathy.” Muscle and Nerve. 2016;53(6):856-61. doi:10.1002/mus.24969

  16. Lawson VH, et al. Fibromyalgia syndrome and small fiber, early or mild sensory polyneuropathy. Muscle Nerve. 2018; This study confirms the presence of small fiber neuropathy in a subset of patients with fibromayalgia and also shows evidence of early large fiber neuropathy in these patietns.