Therapath Neuropathology

Small Fiber Neuropathy Overview

Symptoms of sensory small fiber neuropathy include numbness, hypersensitivity, and spontaneous painful or annoying sensations called paresthesias.

Background

Small fiber neuropathy (SFN) is caused by damage to the small, unmyelinated fibers in the peripheral nerves that innervate the skin and internal organs, including the cardiovascular system, gastrointestinal tract, and bladder, among others. These fibers convey pain and temperature sensations from the skin, and mediate autonomic functions.1,2 Dysfunction of the small nerve fibers can cause sensory or autonomic symptoms. The neurological examination and EMG and nerve conduction studies that measure the large nerve fibers are usually normal, so that the diagnosis requires examination of the small nerve fibers in the skin.3,4

Skin samples are routinely obtained by punch skin biopsy at standard sites, and the density of the small nerve fibers is determined by morphometry after immunostaining with an antibody to the axonal marker PGP- 9.5. Two standardized tests are available; the Epidermal Nerve Fiber Density (ENFD) test measures the density of the small sensory nerve fibers in the skin, and the Sweat Gland Nerve Fiber Density (SGNFD) test measures the density of the small autonomic nerve fibers in the sweat glands.5,6 The SGNFD test may also show a decrease in nerve fiber density in some patients with small fiber neuropathy whose ENFD test is normal.7

Making the diagnosis of SFN provides an explanation for the symptoms, and helps direct further testing for potentially reversible causes, whose treatment can result in amelioration of the neuropathy. Outcome studies have also found that providing an explanation of their symptoms and reassuring the patients that their evaluation is complete, is as important to patients as treatment of their neuropathic pain.8,9 Understanding the cause of their symptoms helps the patient accept their illness, cope with their symptoms, and be more receptive to their physician’s recommendations and treatments.

Biopsy procedure guide


Sensory And Autonomic Small Fiber Neuropathies; Symptoms And Differential Diagnosis

Symptoms of sensory small fiber neuropathy include numbness, hypersensitivity, and spontaneous painful or annoying sensations called paresthesias. The latter can present as tingling, burning, freezing, stinging, stabbing, itching, squeezing, tearing, buzzing, aching, or electric sensations that fluctuate in severity. The skin can be hypersensitive to pressure or touch, and innocuous stimuli can provoke unpleasant sensations, called dysesthesias; clothes can feel like sandpaper against the skin, and the pressure from wearing shoes or socks can cause pain and limit walking. These sensations can occur anywhere in the body, including the feet, arms, legs, torso, scalp, face, or even the mouth.10,11 At the same time, however, patients can experience a loss of sensation, and inability to feel painful stimuli, as when stepping on a sharp nail or burning the fingers on a hot stove, without being aware of the injury.

Symptoms of autonomic small fiber neuropathy include abnormal sweating or temperature regulation, lightheadedness or fainting when standing up from hypotension or tachycardia, gastroparesis with bloating and constipation or diarrhea, incomplete bladder emptying or difficulty initiating a stream, sexual dysfunction from hypo or hypersensitivity, dryness and thinning of the skin, hair loss in the legs, and ridged or brittle nails.12–14

The differential diagnosis includes other conditions that can cause pain including multiple sclerosis or myelopathy, Reflex Sympathetic Dystrophy, Regional Pain Syndrome (RSD), polymyalgia rheumatica, fibromyalgia, Erythromelalgia, Raynaud syndrome, restless leg syndrome, neuroma, fasciitis, or somatic pains resulting from anxiety or depression.15–21 Patients are sometimes diagnosed as having neuropathic pain, although that requires demonstration of the underlying disease or lesion.22 Autonomic symptoms can be misdiagnosed as being due to cardiac arrhythmia, colitis or irritable bowel syndrome, chronic bladder infections, skin allergies, or emotional stress.


Underlying Causes, Treatmant And Prognosis

The causes of small fiber neuropathy are diverse, and in some cases, the neuropathy is the first manifestation of an underlying systemic disease. The most common cause is diabetes mellitus or glucose intolerance.20 Other causes include metabolic syndrome, hypothyroidism, Sjögren’s syndrome, lupus, scleroderma, mixed connective tissue disease, sarcoid, vasculitis, inflammatory bowel disease, psoriasis, unspecified inflammatory conditions, Guillain-Barre syndrome, nutritional deficiencies such as B12 deficiency, celiac disease, Lyme disease, HIV-1 infection, Hepatitis C infection, Fabry disease including in female carriers, amyloid, alcohol abuse, neurotoxic drugs including statins, toxins, or vaccinations.23–50

In cases where no cause can be found, the neuropathy is called idiopathic. In some cases, a progressive neuropathy that affects both the small and large nerve fibers can first present as small fiber neuropathies before progressing to involve the large fibers, at which point it can also cause electrodiagnostic abnormalities. A listing of the known causes of small fiber neuropathy, and the corresponding diagnostic tests, is provided in Table I.

One large study reported that in approximately 40% of patients, no cause for the neuropathy was found on initial evaluation, but in a 2 year follow-up study, a potential cause was identified in 25% of these patients. Thirteen percent of patients went on to develop a large fiber neuropathy.24 Progression of the underlying neuropathy can be evaluated by repeating the biopsy and monitoring the ENFD.

Therapy in patients with small fiber neuropathy is directed at both the underlying cause, if one can be identified, and at ameliorating the symptoms. Some acute onset, otherwise idiopathic small fiber neuropathies were reported to respond to prednisone, presumably because they were caused by inflammatory mechanisms.39 Painful paresthesias can be treated using oral medications for neuropathic pain such as Lyrica or Cymbalta, or with topical medications such as Lidoderm.

Causes of Small Fiber Neuropathy Evaluation
Diabetes Mellitus,  glucose intolerance, hypothyroidism, chronic renal disease Fasting glucose, glycosylated hemoglobin, glucose tolerance test, thyroid functions, renal functions
Sjogren’s syndrome SSA-Ro and SSB-La antibodies, salivary or lacrymal duct biopsy
Lupus erythematosus, scleroderma, mixed connective tissue disease, psoriasis ANA, dsDNA antibodies, SCL-70 antibodies, Sm antibodies, RNP antibodies, biopsy
Vasculitis Biopsy of skin, nerve, or muscle, ANCA, cryoglobulins, HCV, RF
Sarcoid Chest radiogram, biopsy
Autoimmune autonomic ganglionopathy Anti-ganglionic nicotinic AChR antibodies
Inflammatory bowel disease History, small or large bowel biopsy
Nutritional deficiency or B6 toxicity Serum B12, B6, or B1 vitamins
Celiac disease Gliadin and transglutaminase antibodies, duodenal biopsy
Lyme disease Serological tests for Lyme antibodies
HIV-1 infection, HCV infection Serological tests for HIV-1 or HCV antibodies
Fabry disease Alpha-galactosidase A activity
Amyloidosis; primary or hereditary Biopsy, free light chains, transthyretin mutations
Alcohol abuse History
Drugs, toxins History of exposure, urine or blood levels

References

1.
Stewart J, Low P, Fealey R. Distal small fiber neuropathy: results of tests of sweating and autonomic cardiovascular reflexes. Muscle Nerve. 1992;15(6):661-665. [PubMed]
2.
Novak V, Freimer M, Kissel J, et al. Autonomic impairment in painful neuropathy. Neurology. 2001;56(7):861-868. [PubMed]
3.
Lacomis D. Small-fiber neuropathy. Muscle Nerve. 2002;26(2):173-188. [PubMed]
4.
Herrmann D, Ferguson M, Pannoni V, Barbano R, Stanton M, Logigian E. Plantar nerve AP and skin biopsy in sensory neuropathies with normal routine conduction studies. Neurology. 2004;63(5):879-885. [PubMed]
5.
Joint T. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. J Peripher Nerv Syst. 2010;15(2):79-92. [PubMed]
6.
Gibbons C, Illigens B, Wang N, Freeman R. Quantification of sweat gland innervation: a clinical-pathologic correlation. Neurology. 2009;72(17):1479-1486. [PubMed]
7.
Hays A, Harrington W. Sweat gland nerve fiber density in 523 patients with peripheral neuropathy. J Periph Nerve Soc . 2011.
8.
Petrie K, Frampton T, Large R, Moss-Morris R, Johnson M, Meechan G. What do patients expect from their first visit to a pain clinic? Clin J Pain. 2005;21(4):297-301. [PubMed]
9.
McCracken L, Evon D, Karapas E. Satisfaction with treatment for chronic pain in a specialty service: preliminary prospective results. Eur J Pain. 2002;6(5):387-393. [PubMed]
10.
Walk D, Zaretskaya M, Parry G. Symptom duration and clinical features in painful sensory neuropathy with and without nerve conduction abnormalities. J Neurol Sci. 2003;214(1-2):3-6. [PubMed]
11.
Lauria G, Majorana A, Borgna M, et al. Trigeminal small-fiber sensory neuropathy causes burning mouth syndrome. Pain. 2005;115(3):332-337. [PubMed]
12.
Low P, Vernino S, Suarez G. Autonomic dysfunction in peripheral nerve disease. Muscle Nerve. 2003;27(6):646-661. [PubMed]
13.
Freeman R. Autonomic peripheral neuropathy. Neurol Clin. 2007;25(1):277-301. [PubMed]
14.
Waldinger M, Venema P, van G, Schweitzer D. New insights into restless genital syndrome: static mechanical hyperesthesia and neuropathy of the nervus dorsalis clitoridis. J Sex Med. 2009;6(10):2778-2787. [PubMed]
15.
Oaklander A, Rissmiller J, Gelman L, Zheng L, Chang Y, Gott R. Evidence of focal small-fiber axonal degeneration in complex regional pain syndrome-I (reflex sympathetic dystrophy). Pain. 2006;120(3):235-243. [PubMed]
16.
Caro X, Winter E, Dumas A. A subset of fibromyalgia patients have findings suggestive of chronic inflammatory demyelinating polyneuropathy and appear to respond to IVIg. Rheumatology (Oxford). 2008;47(2):208-211. [PubMed]
17.
Paticoff J, Valovska A, Nedeljkovic S, Oaklander A. Defining a treatable cause of erythromelalgia: acute adolescent autoimmune small-fiber axonopathy. Anesth Analg. 2007;104(2):438-441. [PubMed]
18.
Kumar N, Davis M. Erythromelalgia: an underrecognized manifestation of small-fiber neuropathy. Mayo Clin Proc. 2006;81(8):1001. [PubMed]
19.
Manek N, Holmgren A, Sandroni P, Osborn T, Davis M. Primary Raynaud phenomenon and small-fiber neuropathy: is there a connection? A pilot neurophysiologic study. Rheumatol Int. 2011;31(5):577-585. [PubMed]
20.
Polydefkis M, Griffin J, McArthur J. New insights into diabetic polyneuropathy. JAMA. 2003;290(10):1371-1376. [PubMed]
21.
Gemignani F, Brindani F, Vitetta F, Marbini A. Restless legs syndrome and painful neuropathy-retrospective study. A role for nociceptive deafferentation? Pain Med. 2009;10(8):1481-1486. [PubMed]
22.
Treede R, Jensen T, Campbell J, et al. Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology. 2008;70(18):1630-1635. [PubMed]
23.
Zhou L, Li J, Ontaneda D, Sperling J. Metabolic syndrome in small fiber sensory neuropathy. J Clin Neuromuscul Dis. 2011;12(4):235-243. [PubMed]
24.
Devigili G, Tugnoli V, Penza P, et al. The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology. Brain. 2008;131(Pt 7):1912-1925. [PubMed]
25.
Penza P, Lombardi R, Camozzi F, Ciano C, Lauria G. Painful neuropathy in subclinical hypothyroidism: clinical and neuropathological recovery after hormone replacement therapy. Neurol Sci. 2009;30(2):149-151. [PubMed]
26.
Magri F, Buonocore M, Oliviero A, et al. Intraepidermal nerve fiber density reduction as a marker of preclinical asymptomatic small-fiber sensory neuropathy in hypothyroid patients. Eur J Endocrinol. 2010;163(2):279-284. [PubMed]
27.
Chai J, Logigian E. Neurological manifestations of primary Sjogren’s syndrome. Curr Opin Neurol. 2010;23(5):509-513. [PubMed]
28.
Chai J, Herrmann D, Stanton M, Barbano R, Logigian E. Painful small-fiber neuropathy in Sjogren syndrome. Neurology. 2005;65(6):925-927. [PubMed]
29.
Omdal R, Mellgren S, Gøransson L, et al. Small nerve fiber involvement in systemic lupus erythematosus: a controlled study. Arthritis Rheum. 2002;46(5):1228-1232. [PubMed]
30.
Gøransson L, Tjensvoll A, Herigstad A, Mellgren S, Omdal R. Small-diameter nerve fiber neuropathy in systemic lupus erythematosus. Arch Neurol. 2006;63(3):401-404. [PubMed]
31.
Poncelet A, Connolly M. Peripheral neuropathy in scleroderma. Muscle Nerve. 2003;28(3):330-335. [PubMed]
32.
Olney R. Neuropathies associated with connective tissue disease. Semin Neurol. 1998;18(1):63-72. [PubMed]
33.
Bakkers M, Faber C, Drent M, et al. Pain and autonomic dysfunction in patients with sarcoidosis and small fibre neuropathy. J Neurol. 2010;257(12):2086-2090. [PubMed]
34.
Lacomis D, Giuliani M, Steen V, Powell H. Small fiber neuropathy and vasculitis. Arthritis Rheum. 1997;40(6):1173-1177. [PubMed]
35.
Zafrir B, Zimmerman M, Fellig Y, Naparstek Y, Reichman N, Flatau E. Small fiber neuropathy due to isolated vasculitis of the peripheral nervous system. Isr Med Assoc J. 2004;6(3):183-184. [PubMed]
36.
Lee J, Shun C, Hsieh S, Hsieh S. Skin denervation in vasculitic neuropathy. Arch Neurol. 2005;62(10):1570-1573. [PubMed]
37.
Gondim F, Brannagan T, Sander H, Chin R, Latov N. Peripheral neuropathy in patients with inflammatory bowel disease. Brain. 2005;128(Pt 4):867-879. [PubMed]
38.
Narayanaswami P, Chapman K, Yang M, Rutkove S. Psoriatic arthritis-associated polyneuropathy: a report of three cases. J Clin Neuromuscul Dis. 2007;9(1):248-251. [PubMed]
39.
Dabby R, Gilad R, Sadeh M, Lampl Y, Watemberg N. Acute steroid responsive small-fiber sensory neuropathy: a new entity? J Peripher Nerv Syst. 2006;11(1):47-52. [PubMed]
40.
Seneviratne U, Gunasekera S. Acute small fibre sensory neuropathy: another variant of Guillain-Barré syndrome? J Neurol Neurosurg Psychiatry. 2002;72(4):540-542. [PubMed]
41.
Brannagan T, Hays A, Chin S, et al. Small-fiber neuropathy/neuronopathy associated with celiac disease: skin biopsy findings. Arch Neurol. 2005;62(10):1574-1578. [PubMed]
42.
Polydefkis M, Yiannoutsos C, Cohen B, et al. Reduced intraepidermal nerve fiber density in HIV-associated sensory neuropathy. Neurology. 2002;58(1):115-119. [PubMed]
43.
Tembl J, Ferrer J, Sevilla M, Lago A, Mayordomo F, Vilchez J. Neurologic complications associated with hepatitis C virus infection. Neurology. 1999;53(4):861-864. [PubMed]
44.
Dütsch M, Marthol H, Stemper B, Brys M, Haendl T, Hilz M. Small fiber dysfunction predominates in Fabry neuropathy. J Clin Neurophysiol. 2002;19(6):575-586. [PubMed]
45.
Torvin M, Winther B, Feldt-Rasmussen U, et al. Functional and structural nerve fiber findings in heterozygote patients with Fabry disease. Pain. 2009;145(1-2):237-245. [PubMed]
46.
Liguori R, Di S, Bugiardini E, et al. Small fiber neuropathy in female patients with fabry disease. Muscle Nerve. 2010;41(3):409-412. [PubMed]
47.
Zambelis T, Karandreas N, Tzavellas E, Kokotis P, Liappas J. Large and small fiber neuropathy in chronic alcohol-dependent subjects. J Peripher Nerv Syst. 2005;10(4):375-381. [PubMed]
48.
Lo Y, Leoh T, Loh L, Tan C. Statin therapy and small fibre neuropathy: a serial electrophysiological study. J Neurol Sci. 2003;208(1-2):105-108. [PubMed]
49.
Kuo H, Huang C, Tsai Y, Chu C, Hsieh S, Chu N. Acute painful neuropathy in thallium poisoning. Neurology. 2005;65(2):302-304. [PubMed]
50.
Souayah N, Ajroud-Driss S, Sander H, Brannagan T, Hays A, Chin R. Small fiber neuropathy following vaccination for rabies, varicella or Lyme disease. Vaccine. 2009;27(52):7322-7325. [PubMed]