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:
Possible: Symptoms or clinical signs of SFN or both
Probable: Clinical signs of SFN with normal NCS
Definite: Clinical signs of SFN, normal sural NCS, and abnormal QST thresholds at the foot and/or reduced IENFD at the ankle.
Proposed diagnostic criteria for small fiber neuropathy
2008 criteria by Devigili and colleagues:
The diagnosis of SFN requires at least two of the following:
Clinical signs of small fiber impairment (pinprick and thermal sensory loss, hyperalgesia, or allodynia, or a combination thereof) with a distribution consistent with peripheral neuropathy (length dependent or non-length dependent)
Abnormal warm or cooling threshold (or both) at the foot on QST
Reduced IENFD at the distal leg
2017 Criteria by Blackmore and Siddiqi
Definite SFN: abnormal neurologic examination (impaired pain or thermal sensation) and any two of QSART, QST, or HRV
Probable SFN: abnormal neurologic examination and either QSART, QST, or HRV
Possible SFN: abnormal neurologic examination or QSART or QST
Prevalence: Small-fiber neuropathy (SFN) prevalence has been as high as 132/100,000 population in a recent study from Switzerland
The Small Fiber Neuropathy and Symptoms Inventory Questionnaire includes 13 items:
Changed sweating pattern
Diarrhea
Constipation
Micturition problems (eg, incontinence and hesitation)
Dry eyes
Dry mouth
Dizziness on standing from sitting or supine position
Palpitations
Hot flashes
Sensitive skin
Burning feet
Heat intolerance,
Restless legs.
Each item has four response options:
0=never, 1=sometimes, 2=often, and 3=always.
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:
Length dependent pattern: (LD-SFN)
SFN can present as a polyneuropathy (ie, a topographical distribution with bilateral symmetric disturbances usually in distal parts of the limbs)
Somatic symptoms include burning feet and neuropathic pain. Other symptoms include intermittent pain, electrical shocks or shooting, tingling, hyperesthesia, allodynia, or dysesthesias. Simultaneously, SFN can affect autonomic nervous system, which further complicates the clinical picture. Autonomic symptoms include postural dizziness, syncope, palpitations, dry eyes and mouth, disturbances in perspiration, constipation, urinary retention, and erectile dysfunction.
Cold, warm, light touch, or pinprick in a characteristic stocking-glove distribution, with intact deep tendon reflexes and preserved proprioception and sensation to vibration.
Distal-to-proximal gradient is often seen in patients with impaired glucose intolerance or diabetes. However, symptoms remain limited to the feet in most patients with pure SFN. In patients with type 2 diabetes, SFN symptoms can occur early in the course of the disease and are followed by gradual large fiber involvement.
Non-length dependent pattern: (NLD-SFN)
Diffuse patchy distribution that can affect- various parts of the body such as face, tongue, scalp, upper limb, and trunk before it involves lower limbs.
Account for 20%-25% of the total SFN population.
Focal neuropathy affecting one nerve (ie, a mononeuropathy)
Multifocal neuropathy (ie, as mononeuropathy multiplex)
Proximal distribution as a ganglionopathy.
Symptoms may be either reduced or increased in small fiber function corresponding to a single or to multiple nerves.
Childhood SFN presents differently, as mot of these forms are due to genetic mutations-gain-of-function or loss-of-function. The former presents with pain, itch, and autonomic lability, whereas the latter presents with painless injuries, infections, and death. Episodic hand redness, pain, and hyperhidrosis can occur in early-onset SFN, and adolescents may present with profound GI symptoms such as nausea, vomiting, and cachexia. Pupillary abnormalities may also occur and neuropathic itch may be so severe that painless foot ulcers may result from relentless scratching.
Bedside and neurophysiological techniques to assess sensory function in small nerve fibers:
Conventional bedside sensory tests
Cotton
Brush
Monofilaments
Needle or pinprick
Thermorollers
Tuning fork and reflex hammer
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
Nerve biopsy
Skin biopsy
The pathological hallmark of SFN is decreased density of intraepidermal nerve fibers (reduced IENFD), which has sensitivity and specificity of 90% to 97% of respectively. Patients with erythromelalgia or oxaliplatin-induced acute neuropathy can have altered small fiber function without loss of intraepidermal nerve fibers.
Skin biopsy can also measure sweat gland nerve fiber density (SGNFD)
Skin biopsy is 88% sensitive and 91% specific.
However, if the SFN is not ruled out but less likely if the skin biopsy shows normal IENFD. I usually repeat the test a year later if the symptoms persist. Check the percentile values to determine if there has been a decline in the IENFD.
Quantitative sensory testing
Quantitative sudomotor axon reflex test
Corneal confocal microscopy
Microneurography
Electrical-evoked potentials
Laser-evoked potentials
Sympathetic skin response
Skin wrinking tests
Tilt-table, HRV with deep breathing and Valsalva ratio to test cardiovagal function.
Contact heat-evoked potentials
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
Diabetes, impaired glucose tolerance, and rapid glycemic control in the setting of chronic hyperglycaemia (treatment-induced neuropathy of diabetes): 7.7%
Hypothyroidism
Hypertriglyceridemia
Uremia at onset
AIP
Vitamin deficiency
Vitamin B12 (4.7%)
Thiamine, Vit B6, pantothenic acid, and niacin deficiencies
Neurotoxic exposure or vitamin intoxication
Alcohol
Antiretroviral agents
Chemotherapeutic agents
Organic solvents
Pyridoxine B6 intoxication
Statins
Anecdotal cases: antiarrhythmic drugs (flecainide), antibiotics (metronidazole, nitrofurantoin, linezolid, ciprofloxacin), ingestion of Clostridium botulinum toxin, heavy metals (arsenic, thallium, lead), and tumour necrosis factor α inhibitors
Infections
Hepatitis C virus
HIV
Influenza
Leprosy
Severe sepsis, septic shock, and critical illness
Anecdotal cases: Epstein-Barr virus, herpes simplex infection, mycoplasma pneumonia, rubella, syphilis, vaccination for rabies, varicella or Lyme disease, and hepatitis B virus, SARS-CoV-2 causing a "long-haul" syndrome of SFN, possibly COVID-19 vaccine -associated SFN.
Chagas disease
Immunological causes (19%)
Autoimmune autonomic ganglionopathy
Celiac disease
Guillain-Barré syndrome, monoclonal gammopathies, and primary amyloidosis (immunoglobulin light chain associated)
Paraneoplastic syndrome
Sarcoidosis
Scleroderma
Sjögren’s syndrome
Systemic lupus erythematosus
Vasculitis
Multiple myeloma
Hereditary causes
Familial amyloid polyneuropathy (transthyretin amyloidosis)
Hereditary sensory and autonomic neuropathies
Fabry disease
Mutations in COL6A5 and genes encoding voltage-gated sodium channels
Pompe’s disease. It is rare and can be classified into infantile Pompe disease (IPD) and late onset Pompe's disease (LOPD). IPD presents with cardiomyopathy, respiratory failure, and proximal muscle weakness. Death occurs within the first 2 years of life. LOPD has an emerging course and occurs when there is partial deficiency of acid alpha glucosidase (GAA). Neuropathy has rarely been associated with IPD, but SFN was reported in LOPD in 2015.
Genetic small fiber neuropathies:
HSAN-IV: Autosomal recessive, congenital onset with insensitivity to pain anhidrosis caused by genetic variation in NTRK1.
HSAN-V: Autosomal recessive, congenital onset with insensitivity to pain caused by genetic variation in NGF-beta.
HSAN-III (familial dysautonomia, Riley day syndrome): Autosomal recessive; almost exclusive to patients of Eastern European Jewish ancestry, early childhood manifesting with tearless crying, dry mouth, diarrhea/constipation, labile blood pressure, reduced taste, pain, and temperature. It is caused by genetic variation in IKBKAP.
Cold-induced sweating syndrome: Autosomal recessive. Congenital onset manifest with cold-induced sweating. It is caused by genetic variation in CRLF1.
HSAN-I: Autosomal dominant. Subtle onset in children, teens, worsens during life. Manifest with reduced sensitivity to touch, pain, and thermal stimuli; muscle weakness; atrophy; distal ulcers. It is caused by a genetic variation and SPTLC1 and SPTLC2. Oral L-serine overloading reduces 1-deoxysphingolipids and modestly improves adults who have been no longer affected. Much earlier diagnosis and treatment consideration as recommended.
HSAN IIA, B, and C: Autosomal recessive. Birth or early adulthood. Manifest with pain sensory loss in distal mutilation. It is caused by a genetic variation in ATL1, ATL3, DNMT1, RAB7, ATSV, WNK1, and FAM134B.
Fabry disease is an X-linked lysosomal storage disorder caused by deficiency of the enzyme α-galactosidase A. Affected patients have an impaired ability to degrade membrane glycosphingolipids containing a terminal α-glycosidic galactose, especially globotriaosylceramide/ceramide trihexoside (GL3), which accumulates in tissues. Storage in the vascular endothelium increases the risk for cerebrovascular accidents (CVA) and myocardial microvascular ischemia in the heart causes dysrhythmias, hypertrophic cardiomyopathy, and valvular insufficiency; in the kidney leads to progressive renal insufficiency and eventually failure; in the peripheral nervous system gives rise to gastrointestinal dysmotility, hypohidrosis, temperature intolerance, dysregulation of vascular tone, and characteristic acroparesthesias of the hands and feet. Obstructive lung disease and impaired exercise tolerance are also seen. Fabry disease causes significant morbidity and mortality in hemizygous males. Acroparesthesias and gastrointestinal upset reduce emotional well-being and productivity. Patients become deconditioned due to exercise intolerance. Proteinuria and renal insufficiency begin in the third to fourth decades of life in males. Death occurs typically in the fifth decade; renal failure is the most common cause of death in patients with Fabry disease, followed closely by stroke and myocardial infarction. As recently as 2001, women with heterozygous mutations in the α-gal A gene were thought to be asymptomatic carriers of the disease due the presence of functional α-gal A enzyme synthesized from the normal allele. Symptoms in heterozygotes were attributed to skewed X-inactivation of the normal allele. Recently, several groups have reported that carrier women develop symptoms of Fabry disease at a higher rate than can be predicted simply by skewed X-inactivation and are at a higher risk of premature death. Enzyme replacement agalasidase alfa (Replagal) and agalasidase beta (Fabrazyme).
Hereditary Transthyretin amyloidosis (hATTR): Autosomal dominant. Seen in adults (20 to 80 years). Manifest with pain, autonomic symptoms, carpal tunnel syndrome, and restrictive cardiomyopathy. There is aggregation of insoluble potentially toxic, fibrosis that precipitate in tissues. It is caused by genetic variation and transthyretin (TTR) gene. Affected adults are afflicted with abnormalities in the peripheral nervous system, cardiomyopathy and to a lesser extent in other organs. The most frequent variant reported is Val30Met. Patients present at less than 50 years of age and endemic areas like Portugal, Japan, and Cyprus, but have late onset in other known endemic areas. Other mutations of the TTR gene usually lead to a late onset phenotype. hATTR polyneuropathy occurs when TTR accumulates in the peripheral nervous system, often causing an autonomic and/or axonal length dependent sensorimotor neuropathy. Without appropriate treatment, and with progression of the disease to involve the large nerve fibers, patients may have progressive difficulty walking, and typically die within approximately 12 years of disease onset. Autonomic dysfunction is a key component of H ATTR, occurring more in early onset disease compared with late onset, and severely varies according to the mutation. Overall the peripheral neuropathy of which ATTR is a progressive axonal and length dependent sensorimotor and autonomic neuropathy. Patisiran (small interfering RNA) and Inotersen (antisense oligonucleotide) lower transthyretin formation. Transthyretin stabilizers such as tafamidis, diflunisal, and tolcapone inhibit release of monomers that form amyloid.
Ehlers-Danlos Syndrome. It is a heritable soft connective tissue disorder that is categorized into 13 variants according to the clinical presentation. Patients present with generalized joint hypermobility, skin texture abnormalities, and visceral and vascular fragility or dysfunction. Hypermobility (hEDS), classic (cEDS), and vascular (vEDS) forms of EDS are the most common. Most patients have neuropathic pain that is moderate to severe in intensity. Nerve conduction studies are normal in all patients, and all of them have reduction of IENFD that was consistent with small fiber neuropathy.
Cation channelopathy: Autosomal dominant. Usually prepubertal age. Manifest with episodic or chronic pain, itch, sensory loss, and vasomotor and autonomic symptoms. It is a channelopathy; initial gain of function, with possible early or late loss of function encoding sodium channels NaV1.7 (SCN9A), NaV1.8 (SCN10A), and NaV1.9 (SCN11A), HCN1, TRPA1 (transient receptor potential ankyrin 1), TRPM3, TRPV3, TRPV4, fibulin-5 (FBLN5) and Piezo2. TRPA, SCN9A, COL6A5 (collagen type VI alpha 5 chain), TRPV4 (transient receptor potential cation channel subfamily V member 4), Piezo2 (Piezo-type mechanosensitive ion channel component) variants are associated with neuropathic itch. Positive subtype specific sodium channels are in progress. Patients are mostly middle aged and present with moderate to severe burning pain.
FBLN5 variants have been found in CMT "plus" disease which is an autosomal dominant form of CMT. Patients present in the 4-5th decade with a mild to severe large-fiber demyelinating neuropathy, skin hyperelasticity, and age related macular degeneration. Fibulin expressed in FBLN5 in the extracellular matrix plays an essential role in elastic fiber assembly.
SCN9A. The frequency of SCN9A potentially pathogenic variants was reported to be 5.1%. It is due to a gain of function pathogenic variant in the SCN9A gene encoding the NaV1.7 alpha-subunit. All patients presented with pain that mainly started in the distal extremities, mostly aggravated by warmth, and most had autonomic symptoms. Patients with the RH185 variant presented with less prominent autonomic symptoms. RH185 renders dorsal root ganglion neurolysis hyperexcitable, does not produce detectable changes within sympathetic neurons. 1739V, in comparison, renders the dorsal root ganglion hyperexcitable and sympathetic neurons hypoexcitable. 1739V is associated with a wide variety of phenotypes, ranging from congenital insensitivity to pain to small fiber neuropathy. Patients may sometimes complain of muscle cramps, paroxysmal itch, and associated with development of diabetes. G856D (c.2567G>A) variant for as described in 2012 in a 35-year-old man with erythema, burning pain, and muscle cramps in the hands since childhood that spread to the feet, cheeks, and ears. Dysautonomia symptoms were prominent. Physical examination showed small hands and feet. There is signs of acromesomelia and distal extremity redness and pain. This variant leads to hyperexcitability of DRG neurons, and possibly contributed to distal limb underdevelopment. Recently, novel single nucleotide polymorphism of SCN9A was described with response to immunotherapy.
SCN10A. Gain of function variants in SCN10A including for Nav1.8 was described. Patients have burning and intense paroxysmal itching in the feet with severe allodynia and hyperalgesia in the feet and legs. The L554P channel variant was a missense mutation in exon 11 of the SCN10A gene. Excitability of small DRG neurons expressing L554P was increased. Patient can also develop swelling of the feet and various autonomic dysfunction symptoms.
SCN11A. It has been reported to occur in 2.9% of SFN patients. Pathogenic variants of the Nav1.9 alpha subunit. Tingling and burning aresthesias in distal extremities.
HSAN type I, II, and III.
Porphyria. Porphyria are a group of metabolic disorders arising from a defect in the heme biosynthetic pathway. Clnical presentation is diverse and neuropathies, and an acute intermittent porphyria (AIP). AIP is an autosomal dominant disease due to deficiency of hydroxmethylbilane synthase (encoded by HMBS gene). Most, if not at all, peripheral neuropathy is described have concomitant involvement of the large nerve fibers, suggesting that he does not appear SFN. However, autonomic neuropathy was responsible for variety of symptoms during the acute attack and the majority of patients with AIP. Manifest with autonomic dysfunction without large fiber peripheral neuropathy or focal CNS impairment.
Fragile X associated tremor ataxia syndrome (FXTAS) is a movement disorder characterized by tremor and/or ataxia, cognitive involvement, neuropathy, and autonomic dysfunction. FXTAS are carriers of the mutation the fragile X mental retardation 1 (FMR1) gene located at xq27.3 which causes fragile X syndrome. The association of SFN with fracture tasks is known since 2015. Although it is underrecognized. Numbness, neuropathic pain, and autonomic dysfunction are common, and usually occurs before motor symptoms.
Others
Monoclonal gammopathy
ALS
PD
RBD
PAF
DLB
FM
EDS
OSA
Vaccination
Fragile X syndrome
Wilson disease
CRPS (focal form of SFN)
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
Ganglionic acetylcholine receptor antibodies
Onconeuronal antibodies (anti-Hu antibodies, anti-CV2 antibody, voltage-gated calcium channel antibody, voltage-gated potassium channel antibody, Purkinje cell cytoplasmic antibody type 2)
Autoimmune or connective tissue disorder
Rheumatoid factor, Antinuclear antibody, Antineutrophil cytoplasmic antibody screening, Cryoglobulin, Interleukin-2 receptor antibody, Total and free calcium ion, Serum and urine protein immunofixation electrophoresis, CSF analysis
Sjögren’s syndrome: Anti-RO (SSA), anti-La (SSB)
Infection: HIV tests, Fluorescent treponemal antibody absorption test, Hepatitis B and C, CSF analysis
Diseases of the gut
Antibodies for celiac disease (gliadin, transglutaminase, and endomysial), Vitamin B and E concentrations
anti-gliadin test is least specific
Porphyria: Blood, urine, and stools for porphyrins
Neurotoxins: Urine and blood toxicology
Hereditary causes
Leucocyte α-galactosidase A enzyme activity in men and genetic tests in women for suspected Fabry disease when systemic features of the disease are present
Genetic testing for SCN9A and SCN10A in patients with suspected Nav1.7α, 1.8α, or 1.9α sodium channelopathies: 16.7% of SFN.
Genetic testing for familial transthyretin amyloidosis, ABCA1 gene for Tangier disease.
Tangier disease: rare, AD disorder of lipid metabolism. Low or normal serum cholesterol, normal or elevated triglyceride level, nearly absent HDL and apoprotein A-1. Syringomyelia-like syndrome with episodes of sharp, lancinating pain usually in the
Causes - Ancillary investigations
Immune mediated
Sarcoidosis: ACE, chest radiography, histopathology
Sjögren’s syndrome: Anti-SSA/anti-SSB antibodies, Schirmer test, Rose Bengal test, lip and salivary gland biopsy
Systemic lupus erythematosus: ANA, antiphospholipid antibodies, complement levels, ESR, CRP, anti-dsDNA and anti-Smith antibodies
Celiac disease: Antigliadin antibodies (serum IgA endomysial and tissue transglutaminase antibody), IgG deamidated gliadin peptide, small bowel biopsy
Inflammatory bowel disease: (Crohn’s disease and ulcerative colitis) Inflammatory markers, endoscopy, barium studies
Paraneoplastic: (ganglionic acetylcholine receptor antibody mediated) Voltage gated potassium channel antibodies, CASPR-2, and anti-Hu antibodies, ganglionic acetylcholine receptor antibodies
“Apparently autoimmune” small fiber neuropathy: Presence of systemic autoimmune disease, abnormal blood markers of autoimmunity (ANA, ESR, SSA/SSB antibodies, or low complement levels)
Metabolic
Impaired glucose tolerance and impaired fasting glucose: Two hour glucose tolerance test, fasting blood sugar, glycosylated hemoglobin
Diabetes: Glycosylated hemoglobin, two hour glucose tolerance test, fasting blood sugar
Treatment induced neuropathy in diabetes (insulin neuritis): Clinical diagnosis in the setting of rapid correction of hyperglycemia
Hyperlipidemia (mostly hypertriglyceridemia): Lipid profile including fasting triglyceride level
Hypothyroidism: TSH, free T4 and T3
Infectious
HIV: HIV viral load, and CD4 cell count
Hepatitis C virus: Hepatitis C virus antibody, hepatitis C PCR
Cryoglobulinemia (often associated with hepatitis C): Cryoglobulins
Leprosy: Serum antibodies to phenolic glycolipid-I, skin or nerve biopsy for acid fast bacilli
Toxic
Numerous implicated drugs (anti-retrovirals, metronidazole, nitrofurantoin, linezolid, flecainide, statins): History of drug exposure
Alcohol: History of excessive alcohol use for a long duration.
Hereditary
Sodium channel mutations: SCN9A, SCN10A, and SCN11A mutations
Fabry disease: Alpha-galactosidase enzyme assay, GAL DNA sequencing (especially in women, in whom the enzyme assay may be normal)
Familial amyloidosis: Genetic testing for transthyretin (TTR), apolipoprotein A1 (APOA1), and gelsolin (GSN) mutations
Hemochromatosis: High serum ferritin
Ehlers-Danlos syndrome: Clinical diagnosis
Other
Sporadic amyloidosis: Serum protein electrophoresis, immunofixation, serum free light chains, abdominal fat pad biopsy, rectal mucosa biopsy
Fibromyalgia: American College of Rheumatology diagnostic criteria (2010)
Idiopathic (cryptogenic): Diagnosis of exclusion
Despite extensive evaluation, 20-50% of cases of SFN are ultimately classified as idiopathic.
The most common causes include diabetes, immunologic conditions, sodium channel mutations, and vitamin B12 deficiency.
Although immunologic conditions were found in 19% of a cohort of 921 patients with SFN, which exceeds the prevalence in the general population, the exact pathogenic role of isolated autoantibodies remains unclear.
In one series, the highest yield blood tests in SFN that appeared to be “initially idiopathic” were erythrocyte sedimentation rate (ESR), antinuclear antibodies (ANA), C3 complement values, and autoantibodies that are associated with Sjögren’s syndrome and celiac disease. It has been recommended that patients are screened for glucose intolerance, vitamin B12 deficiency, and sodium channel mutations even if there is a known underlying cause.
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:
Objectively confirmed SFN
Disabling symptoms that are not improving.
History and/or lab tests excluding other causes.
History and/or lab tests consistent with dysimmunity.
Corticosteroids were found to be effective in 67% cases;
Inpatient treated with IV methylprednisolone 1 g/day for 3-5 days
Outpatient got prednisone 1 g/kg/day x 4 weeks the brief taper.
IVIg was effective in 63% of cases .
ISFN-1 (isolated small fiber neuropathy type I) is nonlength dependent pathology. Sjogren's, immune mediated neuropathies such as FGFR3, TS-HDS, CISP.
ISFN-2 (length dependent small fiber neuropathy): DM, Sjogren's, sarcoid, monoclonal gammopathies.
ISFN-3 (Multifocal forms): Glucose dymetabolism, cryoglobulinemia, systemic vasculitis, sarcoid, HIV, Wartenberg sensory neuritis.
Autonomic form: IENFD is normal. SGNFD: reduced. Monoclonal gammopathy, AAG (anti-ganglionic rcp-ab, GAD65-ab), inherited amyloid (TTR), AL amyloid.
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.
SFN and autonomic neuropathies
Anne Louise Oaklander | Small Fibers, Big Pain || Radcliffe Institute - YouTube
CRL, Todd Levine SFN algorithm
2010 Fibromyalgia Diagnostic Criteria_Excerpt.pdf (rheumatology.org)
https://acttion.nfshost.com/static/conceppt/4_18/Gibbons.pptx
https://clinicaltrials.gov/study/NCT04153422?cond=Small%20Fiber%20Neuropathy&page=2&rank=19
Algorithmic approach in investigation of Small Fiber Neuropathy
Positive sensory symptoms:
Tingling, burning, prickling, shooting pain, aching
Allodynia, hyperesthesia and cramps
Worse at night and may interfere with sleep
Dynamic, punctate, static or thermal allodynia
Hyperalgesia
Feeling of distorted sensation or after sensation
Negative sensory symptoms:
Numbness, tightlness and coldness
Imparied thermal and pain sensitivity
Autonomic symptoms:
Increased/decreased sweating, facial flushing, skin discoloration, dry eyes and dry mouth, changes in skin temperature, orthostatic hypotension, urinary or enteric symptoms, blurring of vision, sexual dysfunction.
Miosis, tonic pupils
Signs of dysautonomia icluding pupil abnormalities, abnormal sweating, skin flushing or discoloration, orthostatic hypotension, heart frequency
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:
Tilt table testing with HRVDB
Stimualted skin wrinkling with water/EMLA
TST
QST
QSART
LEP
Other functional test as indicated.
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.