Small Fiber Neuropathy

Small Fiber Neuropathy

Small fiber neuropathies are a heterogeneous group of disorders affecting peripheral afferent thinly myelinated, <7um diameter, Aδ-fibers and unmyelinated C-fibers.  Myelinated Aδ-fibers are responsible for cold temperature and sharp pain sensations, whereas the unmyelinated C fibers are involved inm sensation, heat pain, and autonomic function.  Large nerve fibers and roots are excluded.   

The highest diagnostic accuracy is achieved through a combination of skin biopsy for IENFD, clinical findings, and functional tests.  The diagnostic tests to identify small fiber neuropathy include skin biopsy, quantitative sensory, and autonomic testing.   A diagnosis of SFN would require abnormalities of at least two measures among QSART, QST, and skin biopsy.  Additional tests, such as those measuring small fiber-related evoked potentials and corneal confocal microscopy, might contribute to a better understanding of these neuropathies. Biochemical markers can also help in screening patients for the presence of small fiber neuropathy and to assess disease progression.

SFN cannot be diagnosed by nerve conduction studies—the standard diagnostic test for large fiber neuropathy—because the absence or reduced myelin of small fibers results in slow conduction velocities that are beyond the resolution of these studies.  Although nerve conduction studies cannot identify SFN, they are an essential step in the diagnostic investigation,  because they can establish whether large fibers are involved or not.  Furthermore, consecutive tests can show the reduction of SNAPs, reflecting progressive loss of large nerve fibers.  However, the involvement of large fibers does not exclude SFN, and overlap is common.  Recording techniques in nerve conduction studies affect how sensory neuropathies are classified; for example, orthodromic near-nerve recording of most distal nerves (eg, the medial plantar) can increase the sensitivity to detect subclinical large fiber involvement that would be otherwise missed by conventional surface techniques.

Diabetic Neuropathy Study Group of the European Association for the Study of Diabetes (NEURODIAB) categorized patients according to their diagnostic certainty of SFN:

Proposed diagnostic criteria for small fiber neuropathy

2008 criteria by Devigili and colleagues:

The diagnosis of SFN requires at least two of the following:

2017 Criteria by Blackmore and Siddiqi

Prevalence:  Small-fiber neuropathy (SFN) prevalence has been as high as 132/100,000 population in a recent study from Switzerland

Small fiber screening list

The Small Fiber Neuropathy and Symptoms Inventory Questionnaire includes 13 items:

History:  In small fiber neuropathies (SFNs) the thinly myelinated  (Aδ) and unmyelinated (C) fibers responsible for the transmission of thermal and noxious sensory input are affected.  Clinically, this nerve damage translates to symptoms of sharp, painful, or burning paresthesia; sensory loss or numbness; and the inability to discriminate between hot and cold sensations.  Symptoms may be vague, described as a tight feeling or abnormal sensation in the soles of the feet, intolerance of tactile stimuli (inability to wear socks or touch bedsheets), or a sensation of restless legs.  The distribution of symptoms may have a length dependent or non-length dependent pattern that affects the limbs, trunk, face, or it may have a combination of patterns.  Depending on the underlying cause, the onset of symptoms may be gradual, with slowly progressive worsening, or subacute with more rapid progression.  Pain may be prominent and disabling, and a recent large Italian cohort study of patients with painful diabetic neuropathy suggests that pain may be more common in women.  Dysautonomia is often a feature of SFN owing to impairment of the sympathetic and parasympathetic function of Aδ fibers and the postganglionic autonomic function of C fibers.  It is essential to ask patients about potential autonomic involvement including orthostasis; palpitations; abnormal sweating; dry mouth, eyes, or skin; gastrointestinal symptoms including cramping, diarrhea, or constipation; flushing or other changes of skin color; and erectile dysfunction.  A patient with SFN may have decreased temperature and pinprick sensation on examination, and potentially allodynia, dysesthesia, or hyperesthesia on sensory testing.  Motor strength, proprioception, and muscle stretch reflexes should be preserved in patients with pure SFN.  Skin may have a dry, atrophic, or discolored appearance.  Detailed history should be obtained, including alcohol use, family history of neuropathy, and use of neurotoxic medications such as metronidazole, misonidazole, nitrofurantoin, taxol, thalidomide, suramin, colchicine, and chemotherapeutic agents.  HIV, hepatitis C infection are well known to be associated with small fiber neuropathy, so relevant risk factors (eg, blood transfusions, sexual history, intravenous drug use) should be asked about.  Recent illnesses and vaccinations are another important line of questioning, as a small-fiber variant of Guillain-Barré syndrome has been described.  Autonomic symptoms must be asked. 

Clinical distribution: 

Bedside and neurophysiological techniques to assess sensory function in small nerve fibers:

Conventional bedside sensory tests

Bedside testing of positive sensory signs includes increased pain (allodynia or hyperalgesia) in response to pressure, pinprick, heat, or cold.  Patients might complain of abnormal sensations to thermal stimuli (e.g., cold stimuli might be perceived as heat), and stimuli might also be accompanied by after-sensation (e.g., persistent sensation of pain lasting after the stimulus).  Negative sensory signs include reduced sensitivity to cold, heat, and noxious mechanical stimuli.

Modified Toronto Clinical Neuropathy Score (mTCNS) (highest diagnostic yield, with a sensitivity of 98% and a specificity of 97%)

Utah Early Neuropathy Scale (UENS) (diagnostic yield of 85% on sensitivity and 97% on specificity)

Michigan Neuropathy Screening Instrument

Neurophysiological and pathological techniques

Causes:  In 44%-55% of cases the cause of cryptogenic SFN.  Check for anti-sulfatide-ab, anti-trisulfated heparan disaccharide (TS-HDS), anti-fibroblast growth factor 3 (FGFR3-ab), anti-plexin D1.  IVIG shows disease-modifying effect in immune SFN with novel antibodies, especially Plexin D1SFN, as well as significantly improved pain. NLDENFD should be examined as well as LD-ENFD to see this effect. 

Most common causes:  Prediabetes/diabetes, Sjogren's syndrome, monoclonal gammopathy, sarcoidosis, paraneoplastic syndrome. 

Metabolic causes

Vitamin deficiency

Neurotoxic exposure or vitamin intoxication

Infections

Immunological causes (19%)

Hereditary causes

Genetic small fiber neuropathies:

Others

Idiopathic small fiber neuropathy:  30% to 53% of SFN cases, underlying cause remains unknown.  Novel antibodies are tested in these cases before labelling idiopathic SFN: anti-trisulfated heparan disaccharide (TS-HDS), anti-fibroblast growth factor-3, anti-plexin d1, and anti-interferon-induced GTP-binding protein Mx1 (MX1). 

Loss of small fibers can also occur in conditions that are not usually considered to have the essential characteristics of peripheral neuropathy: fibromyalgia, MND, Ehlers-Danlos syndrome, and Parkinson’s disease.

Preliminary Systemic screen: CBC with diff, CMP, HbA1c, OGTT, TSH, FT4, Vit B1, B6, B12, MMA, ESR, CRP, ANA, anti-ENA, ANCA, HIV, Lyme, HBV, HCV, COVID, celiac panel, paraneoplastic, UA, CXR.

Dxtic w/up for painful peripheral neuropathy (small fiber):  CXR, CBC, CMP, OGTT, FBS, Hb1Ac, SPEP with quantitation, SPEP with IFE, 24-h UPEP, UPEP with IFE, light chains, anti-Hu antibodies, ACE, syphilis EIA, TSH, FT4, vitamin B12, B6, MMA, HIV, COVID, ANA, ENA, C3, C4, total complements, antiphospholipid ab, anti-dsDNA, CRP, ESR, hepatitis panel, cryoglobulins, fasting lipids, antigliadin IgG and IgA, transglutaminase, alpha-galactosidase activity, TTR gene mutation, SCN9A/SCN10A/SCN11A gene mutations, apolipoprotein A1 (APOA1), and gelsolin (GSN) mutations.  TS-HDS, FGFR3.  EMG/NCS, autonomic function tests . Skin biopsy (IENFD, SGNFD), anterior fat pad aspirate, lip biopsy, nerve and muscle biopsies.  CSF studies.  24-hour urine heavy metal screen. 

Other supportive diagnostic tests include neurophysiologic tests: Laser evoked potentials (LEPs), contact heat evoked potentials (CHEPs), pain related evoked potentials (PREPs), autonomic tests of sudomotor function (QSART) (Sudoscan) and corneal confocal microscopy (CCM) for visualization of the corneal small fibers of trigeminal origin.  

Acute or subacute development of autonomic dysfunction

Autoimmune or connective tissue disorder

Infection:  HIV tests, Fluorescent treponemal antibody absorption test, Hepatitis B and C, CSF analysis

Diseases of the gut

Porphyria: Blood, urine, and stools for porphyrins

Neurotoxins: Urine and blood toxicology

Hereditary causes


Causes  - Ancillary investigations

Immune mediated

Metabolic

Infectious

Toxic

Hereditary

Other

Tx of painful neuropathies:

Regardless of cause of SFN, managing symptoms remains the key: 

A multidisciplinary approach that incorporates pain medications, physical therapy, and lifestyle modifications is ideal.  Integrative holistic treatments such as natural supplements, yoga, and other mind body therapies may also help.

Duloxetine 30 mg PO daily for 1 week, then 60 mg PO daily for 4 weeks to evaluate efficacy.  Also recommend BAK gel which is a compounded preparation of Baclofen 10 mg + amitryptiline 40 mg + and ketamine 20 mg to be prepared in gel (1.31 gm tube/container).  It can be topically applied to painful dysesthetic areas, bid for 4 weeks. 

Mexilitine 150 mg PO tid can be tried in erythromelalgia caused by SCN9A mutations.  Carbamazepine, and oxcarbazepine can also be used. 

Lacosamide in SCN10A mutations. 

Corticosteroids immunotherapy has effectively treated young patients with rapid-onset painful SFN.  Inflammatory causality was proposed when comprehensive evaluations revealed neither familial, diabetic, nor toxic causes but rather histories of other autoimmune illnesses and inflammatory blood test markers.  Corticosteroids and IVIG benefit a significant percentage of the patients.  Overall 80% benefit from immunotherapy.

For autoimmune SFN: 

Corticosteroids were found to be effective in 67% cases;

IVIg was effective in 63% of cases .


Non-length dependent SFN (NLD-SFN): 

Diagnosis of NLD-SFN is based on clinical features consistent with normal length dependent topography associated with proximal IENFD loss.  The topographic pattern of NLD-SFN is likely related to ganglionopathy restricted to the small neurons of the dorsal root ganglia.  It is often associated with systemic diseases, but about half the time is idiopathic.

Patient with NLD-SFN likely represent about 20-25% of total small fiber neuropathy patient and more commonly in women, with onset at younger age than distal small fiber neuropathy.

The clinical presentation is characterized by neuropathic pain and other dysesthesias related to small fiber involvement, such as burning, tingling, coldness, itching, intolerance to bedsheets or socks, occurrence and an atypical, not distally predominant distribution.  Positive sensory symptoms are often intermittent and migratory, varying throughout the day, and usually worse at night.  Signs of thermal and pain sensory loss are more subtle than large fiber signs and may be overlooked.  Several combination of topographic patterns are seen, classifiable as patchy, asymmetrical, upper limb predominant, proximally predominant, and diffuse.  Widespread pain and dysesthesias seem to be more commonly associated with an acute subacute presentation.

Ongoing burning pain, is the most common symptom of small fiber neuropathy and it seems to be related to peripheral sensitization, especially in regenerating fibers and thus, would be more likely to occur in distal small fiber neuropathy.  Fluctuating, migrating symptoms can be related to nonspecific mechanisms, such as perineural granulomas involving small cutaneous nerves as in  sarcoidosis.  Burning pain or other small fiber related symptoms may present with a strictly circumscribed distribution in conditions classified as focal small fiber neuropathy.  Included in the subgroup are common diseases such as postherpetic neuralgia, notalgia and meralgia paresthetica, burning mouth syndrome, and possibly others.

Fibromyalgia represents an intriguing example of small fiber pathology,  in that the "neuropathic" pain although often prominent, is only part of a constellation of symptoms.  Prevalence of SFN with fibromyalgia is about 49%. 

In 44%-55% of cases the cause of cryptogenic SFN.  Check for anti-sulfatide-ab, anti-trisulfated heparan disaccharide (TS-HDS), anti-fibroblast growth factor 3 (FGFR3-ab), anti-plexin D1.  IVIG shows disease-modifying effect in immune SFN with novel antibodies, especially Plexin D1SFN, as well as significantly improved pain. NLDENFD should be examined as well as LD-ENFD to see this effect. 

Migratory sensory neuritis of Warternberg

Migrant sensory neuritis pattern occurs in multifocal patches of sensory loss and allodynia, related to stretch of the skin.  Based on the very few biopsies in Wartenberg's syndrome, there is usually perineurial inflammation and some of those may be non-systemic vasculitic neuropathies.   Probalby treat it like vasculitis with steroids started immediately with each episode, slow taper, and perhaps, MMF, and AZA for prophylaxis.  Another approach may be to treat the paresthesias symptomatically with gabapentin.   


Erythromelalgia

Erythromelalgia is characterized by attacks of severe burning pain, erythema, and warmth of the extremities, primarily the feet and, to a lesser extent, the hands.  The distress is provoked by environmental heat, exercise, and dependency; it is relieved by exposure to cold and elevation of the extremity.  Primary and secondary forms of erythromelalgia exist.  Secondary erythromelalgia has been linked to a wide variety of diseases, the most common of which are certain myeloproliferative disorders: polycythemia vera and essential thrombocythemia.   

Primary erythromelalgia can be inherited or idiopathic.  The inherited form of erythromelalgia is an autosomal dominant neuropathy caused by a gain-of function mutation in the SCN9A, SCN10A, and SCN11A gene, which encodes the alpha subunit of the voltage-gated NaV 1.7, NaV 1.8, and NaV 1.9 sodium channel, respectively. This peripheral channel is expressed within the dorsal root ganglion of the sympathetic ganglion neurons. This mutation leads to hyperexcitability of the nociceptive fibers causing them to fire at subthreshold stimuli.  This, in turn, leads to a previously nonpainful stimulus eliciting a painful response 

Erythromelalgia in thrombocythemia occurs in association with essential thrombocytosis and polycythemia vera.  

Secondary erythromelalgia has been attributed to a number of different medical conditions. The most prevalent being myeloproliferative disorders, including essential thrombocytosis, polycythemia vera, and myelofibrosis. Other underlying causes include infectious agents (HIV, influenza, syphilis, and poxvirus), autoimmune diseases (systemic lupus erythematosus and rheumatoid arthritis), diabetes mellitus type 1 and 2, solid tumors (astrocytoma, colon, and breast cancer), medications (bromocriptine, nifedipine, verapamil, topical isopropanol, pergolide, simvastatin), gout, multiple sclerosis, hypertension, venous insufficiency, pernicious anemia, thrombotic thrombocytopenic purpura, mushroom intoxication, and mercury poisoning. The symptoms of patients with secondary erythromelalgia are often milder and are relieved after the treatment of the underlying disease. 

Primary erythromelalgia typically presents in the first two decades of life in comparison to secondary erythromelalgia, which has a mean onset of 49.1 years.  

Patient's with erythromelalgia typically report swollen, red, burning feet with dramatic improvement with cooling; they sometimes come with an iced-water bucket to clinic. Warm/hot temperatures precipitate the attacks, as they are due to sudden vasodilation. The pain is typically severe and burning in nature.

Erythromelalgia represent spontaneous activity of damage sensory C-fibers that transmit unprovoked pain signals centrally while releasing vasoactive substances P and calcitonin gene related peptide distally to cause neurogenic inflammation.

Erythromelalgia may occur with or without a small fiber neuropathy, in either case treatment is the same, except you'd do a work up for small fiber neuropathy etiologies if present. You'd want to rule out an underlying myeloproliferative disorder. It is rare for erthyromelalgia to be genetic, but checking for underlying mutations is reasonable.

Differential diagnosis for primary and secondary erythromelalgia include polyneuropathy (large or small fiber neuropathy), acrocyanosis, peripheral arterial disease, lipodermatosclerosis, Raynaud phenomenon, cellulitis, gout, Fabry disease, vasculitis, and frostbite. These disorders should be distinguished from erythromelalgia with the help of typical features associated with these disorders like angiokeratomas and corneal opacities in Fabry disease, history of fever/trauma in cellulitis that responds quickly to antibiotics, high uric acid in gout, and abnormal nerve conduction test results in polyneuropathy.  The episodes of Raynaud phenomenon are precipitated by cold exposure and relieved by warming.  A presentation limited to the face, which is extremely rare, can often be mistaken and mistreated as rosacea, seborrheic dermatitis, or contact dermatitis.

Complex regional pain syndrome (CRPS), which is also known as reflex sympathetic dystrophy, can mimic many of the symptoms of erythromelalgia.  However, CRPS is more often unilateral and can present more proximally in a limb, while erythromelalgia is more likely to be symmetric and located in the distal limb.  In addition, CRPS is often preceded by trauma or surgery, whereas episodes of erythromelalgia can often be triggered by heat and relieved with cooling agents.

Management of erythromelalgia can be quite challenging and necessitates an interprofessional approach.  Treatment should encompass patient education, behavior modifications, and the avoidance of triggers.  Various treatment options have been suggested, though none are fully curative, rather aimed at symptom management and improving quality of life.  While treatment of erythromelalgia is primarily focused on symptom control, secondary erythromelalgia can improve or resolve with treatment of the underlying disease process.  The mainstay of therapy for both primary and secondary erythromelalgia aims to avoid triggers, most often heat, exercise, and standing.  Commonly used strategies include remaining in cool environments, decreased physical activity, limb elevation, and avoiding excess clothing.  In addition, some patients find relief with cool water immersion or portable fans.  It should be noted that excessive cooling via ice water immersion can lead to maceration, infection, and ulceration.

Some studies have shown that topical lidocaine patches, compounded topical amitriptyline-ketamine, and topical capsaicin applied three times daily may improve the pain associated with erythromelalgia.  While 0.2% midodrine compounded in a moisturizing cream applied thrice a day might improve redness associated with erythromelalgia. Topical therapy should be continued for two to four weeks to assess the efficacy.

Aspirin is the drug of choice for erythromelalgia associated with thrombocytopenia or myeloproliferative disorder.  Other NSAIDs like anagrelide may be used as an alternative.  Diagnosing and treating the underlying myeloproliferative disorder is of utmost importance for the improvement of erythromelalgia.  In this patient population, the addition of hydroxyurea (chemotherapy) to reduce the platelet count may also improve the symptoms of erythromelalgia, while phlebotomy might be useful for patients with polycythemia vera.

Primary erythromelalgia can be particularly resistant to treatment.  Medications affecting the voltage-gated sodium channels (lidocaine, mexiletine, and carbamazepine) have shown promise in primary erythromelalgia.  There is some evidence for the use of mexiletine 100 mg to 200 mg three times a day.  An alternative regimen consists of carbamazepine 300 mg twice per day with gabapentin, which is titrated up to 300 mg five times a day.  Secondary erythromelalgia may be responsive to aspirin, 81 mg to 640 mg daily, and is often used as a first-line agent.

Other agents that may be effective in treating primary and secondary erythromelalgia include gabapentin, pregabalin, venlafaxine, amitriptyline, iloprost, and misoprostol, calcium channel blockers, and beta-blockers.  However, these agents are less well studied, and no specific treatment regimen has been proposed.  Alternative therapies used rarely for refractory cases are epidural infusions of bupivacaine/ropivacaine, transcranial magnetic stimulation, subcutaneous injection of botulinum toxin A, and thoracic or lumbar sympathectomy.

Some studies postulate that pain rehabilitation programs and patient counseling can improve physical and emotional functioning in a patient with erythromelalgia.

Approach to the management in steps: (a) Avoid triggers (b) Aspirin for one month (c) Topical drugs for two to four weeks (c) Systemic drugs like gabapentin or pregabalin or venlafaxine for two to four months (d) Consider other systemic drugs and pain rehabilitation programs.

Try the next step only after the failure of previous steps and treat underlying myeloproliferative disorder if present.

My approach for treatment:

1- Counsel about proper cooling techniques to avoid skin burns from ice (indirect contact with skin, limit to 5 min every 1-2 hours).

2- I have always start with topical creams as they can be very effective. There are a lot of options (guided by our dermatology colleagues). Amitriptyline 2% with Ketamine 0.5% would be a good one to start with. Lidocaine patches can be helpful. We sometimes use topical midodrine (not sure if available outside Mayo as it is compounded by our pharmacy). And many other options that differentially target  vasodilation versus neuropathic pain etc. that our dermatology colleagues mastered and each of them has their own preferred agents.

If these fail, we move on to systemic treatment and in addition to neuropathic pain meds, some patients may respond to Aspirin.  


Algorithmic approach in investigation of Small Fiber Neuropathy

Normal muscle strength and tendon reflexes

SUSPICION OF SFN > NCS > abnormal > NOT SFN

NCS > NORMAL > SKIN BIOPSY for PGP 9.5 Staining for IENFD: positive > SFN; negative > unlikely SFN but cannot be ruled out.  

NCS > NORMAL > Small fiber sensory/autonomc function tests: 

SFN:

Preliminary Systemic screen: CBC with diff, CMP, HbA1c, OGTT, TSH, FT4, Vit B1, B6, B12, MMA, ESR, CRP, ANA, anti-ENA, SLE, ANCA, HIV, Lyme, HBV, HCV, COVID, celiac panel, paraneoplastic, UA, CXR.

IVIG and SFN

In the review of evidence from 2008 to 2021, the American Association of neuromuscular and Electrodiagnostic Medicine (AANEM) published a new consensus statement updating its recommendations for the use of IVIG for neuromuscular disorders.  The updated statement advises against using IVIG for small fiber neuropathy that is idiopathic or related to tr-sulfated heparin disaccharide antibodies (TS-HDS-ab) or fibroblast growth factor receptor 3 (FGFR3-ab) among other evidence-based guidelines.

CONCLUSION: Based on two Class I studies, IVIG is not effective for treating SFN that is idiopathic or associated with TS-HDS or FGFR-3 autoantibodies. There is also insufficient evidence to support IVIG for treating SFN due to other autoimmune conditions.