Small Fibre Neuropathy

Small fibre neuropathy (SFN) is a painful neuropathy that selectively involves the thinly myelinated Aδ and unmyelinated C nerve fibres of the peripheral nervous sytem. 
These fibers play crucial roles in transmitting sensory information, such as pain and temperature, and in autonomic functions, such as regulating sweat glands and vascular tone. Damage to these fibres leads to sensory, autonomic, or combined symptoms. 
Small fibre neuropathy (SFN) and large fibre neuropathy belong to a group of diseases known as peripheral neuropathies. Polyneuropathy refers to cases where either the large fibres are affected, or both the large and small fibres are affected. SFN refers to isolated small fibre involvement. About 40-50% of patient with fibromyalgia meet the diagnostic criteria for SFN.Maslinska et al. Small fibre neuropathy as a part of fibromyalgia or a separate diagnosis? Int. J. Clin. Rheumatol. (2018) 13(6), 353-359. Full Text
==Nerve Anatomy==
Small fibre neuropathy results from damage to the nociceptive system. The majority of peripheral sensory nerves are unmyelinated C fibres and thinly myelinated Aδ fibres. Small fibre nerves also include the γ efferent fibres, and the preganglionic and postganglionic sympathetic C fibres. The large fibres in contrast are the Aβ afferents from the skin, muscle, and internal organs; and the α motor neurons.
==Aetiology==
Disorders known to contribute to SFN are listed below. SFN is a generalised sensory nerve disease process with abnormalities in the structure and function of affected nerve fibres. It is histopathologically characterized by degeneration of small nerve fibre endings. The small unmyelinated nerves are affected.
Conditions associated with SFN
Category 	Disease
Idiopathic (50%) 	
Metabolic 	
*Diabetes mellitus and glucose intolerance (up to 20% of cases)
*Vitamin B12 deficiency (5%)
*Copper deficiency
*B6 toxicity (causes a functional B6 deficiency due to competitive binding)
*Hypothyroidism
*Hyperlipidemia
*Chronic kidney disease
Immunological (up to 20%) 	
*Sjögren’s syndrome
*Sarcoidosis
*Systemic lupus erythematosus
*Coeliac disease
*Ehlers-Danlos SyndromeCazzato, Daniele et al. “Small fiber neuropathy is a common feature of Ehlers-Danlos syndromes.” Neurology vol. 87,2 (2016): 155-9. doi:10.1212/WNL.0000000000002847
Toxic agents and medications	
*Alcohol (this can eventually cause large fibre neuropathy) (3%)
*Antibiotics (metronidazole, nitrofurantoin, linezolid, isoniazid)
*Anticancer agents (bortezomib, platin)
*Antiretroviral drugs
Genetic diseases (10-15%) 	
*Sodium channelopathy (SCN9A most common, also SCN10A and SCN11A)
*Fabry’s disease
*Familial amyloid polyneuropathy (Hereditary TTR amyloidosis)
*Wilsons disease
*Late onset Pompe disease (acid maltase deficiency)
Other associations 	
* Fibromyalgia
* CRPS
* Parkinson's disease
* Paraproteinaemia
== Pathophysiology ==
The pathophysiology is through to relate to dysregulation of voltage gated sodium channels with resultant hyperexcitability of dorsal root ganglion neurons. The sodium channel members found in small nerve fibres are Nav1.7 (SCN9A), Nav1.8 (SCN10A), and Nav1.9 (SCN11A). 
A demyelinating process is thought to be unlikely as the condition only affects small nerve fibres. Distal axonal loss or extraordinarily neuronal degeneration are potential mechanisms.Raasing, Lisette R M et al. “Current View of Diagnosing Small Fiber Neuropathy.” Journal of neuromuscular diseases vol. 8,2 (2021): 185-207. doi:10.3233/JND-200490 Normally sodium enters the cell and then calcium and sodium are pumped out through the coupled sodium-calcium exchanger (NCX). With dysregulation (such as from a pathogenic variant leading to reversal of sodium-calcium exchanger) of this balance there may be excess calcium in the cell leading to axonal degeneration.
There may also be a mitochondrial role with trauma and ageing. In small nerve fibres mitochondrial density is normally quite high. Dysfunctional mitochondria have been found in painful neuropathies especially in HIV, diabetes, and chemotherapy induced neuropathies.
There are four stages of neuropathy in unmyelinated nerve fibres
# Mild proliferation: Increase in number of isolated small Schwann cell projections which are irregular in shape.
# Fibre loss: decreased fibre numbers along with increased empty Schwann cells. 
# Regeneration: Signs of regeneration of unmyelinated fibres along with fibre loss. There is an increase in the total number of unmyelinated fibres and small fibres with a diameter of below 0.8μm
# Advanced regeneration: Empty Schwann cells return to normal. There is only an increase of small nerve fibres with a diameter of below 0.8μm, and small isolated projections of Schwann cells.
SFN associated with diabetes may have a different underlying cause. This may involve axon swelling, and there can be progression to proximal large fibre or polyneuropathy.
==Clinical Features==
Patients have "positive" and "negative" symptoms related to Aδ and C fibre degeneration - i.e. pain, loss of temperature sensation and/or autonomic symptoms. This is in contrast to large fibre neuropathy which affects light touch, vibration, and joint-position sense. 
Symptoms suggesting small fiber neuropathy (SFN)
Sensory symptoms
* Pain (burning sensations, tingling, painful cold sensation, shooting pain, pins and needles)
* Dysesthesia (e.g. sensation of feet constriction)
* Allodynia in response to rubbing
* Hypoesthesia to heat, cold, and pinprick
Dysautonomic symptoms
* Hypo/anhydrosis
* Hyperhydrosis
* Sicca syndrome
* Erythromeralgia
* Cutaneous vasoparalysis
* Gastrointestinal symptoms (early gastric empty, constipation, diarrhea, intestinal pseudo-obstruction)
* Urinary incontinence or retention
* Erectile dysfunction
* Disorders of accommodation with blurred vision, photophobia, tonic pupil
* Orthostatic hypotension, orthostatic intolerance
=== History ===
Pain is the dominant symptom in most patients, often described as burning in character and superficial to the skin. 
The neuropathy pattern is most commonly a length dependent polyneuropathy with the pain being most notable in the distal lower limbs, maximal in the feet. Most patients with the length-dependent pattern don't have pain in the head, torso, abdomen, groin, and buttocks. The pain progressively ascends to more proximal sites, and later involves the upper limbs in a similar fashion of starting distally before spreading proximally. This pattern is most commonly seen in diabetics or those with neurotoxin exposure. 
However it can also present as a non-length dependent polyneuropathy (e.g. involving all limbs at the onset of symptoms, asymmetrical involvement, or patchiness) or an asymmetric mono-multiplex neuropathy (i.e. affecting one more sensory peripheral nerve).
It can be clinically distinguished from erythromelalgia in that the erythema if it occurs is relatively mild, and there is no clear exacerbation/relief link to warmth/cold respectively. 
In non-length dependent polyneuropathy there is proximal, diffuse, or patchy distribution of different parts of the body. This may include the face, mouth, scalp, trunk and upper limbs before or at the same time as the lower limbs are affected. Non-length dependent features may be more likely to have an immune mediated disease association such as Sjogren's Syndrome and as a paraneoplastic phenomenon.Khan S, Zhou L. Characterization of non-length-dependent small-fiber sensory neuropathy. Muscle Nerve. 2012 Jan;45(1):86-91. doi: 10.1002/mus.22255. PMID: 22190313. 
In mono-multiplex neuropathy type presentations there may be burning mouth syndrome, notalgia paraesthetica, meralgia paraesthetica, vulvodynia, and Wartenberg neuropathy. 
Patients may also complain of allodynia or dysaesthesia type symptoms with intolerance to bed sheets, shoes, and clothes. 
Autonomic symptoms are due to dysfunction of C-fibres and thinly myelinated Aδ fibres and can include sweating alterations, temperature dysregulation, dry mouth and eyes, orthostatic intolerance or tachycardia, erectile dysfunction.
40-50% of patients with fibromyalgia meet the diagnostic criteria for SFN. In one small study, fibromyalgia patients with SFN were more likely to report dysautonomia and paraesthesias.
=== Examination ===
A thorough sensory examination is required and this includes multi-modal testing for allodynia as well as testing for hyperpathia.
Patients with SFN may have severe symptoms but a normal physical and neurological examination. However there may be positive and negative signs. Most affected patients have a combination of positive signs (e.g. hyperalgesia, and allodynia), and negative signs (e.g. diminished pin prick and temperature sense). The majority of peripheral sensory nerves are unmyelinated C fibres and thinly myelinated Aδ fibres. There is no clear way of diagnosing pathology in these fibres.
Proprioception, light touch, and vibration sense may be normal in pure SFN. Some patients may have decreased pinprick, decreased thermal sensation, hyperalgesia in the affected region, and slightly decreased vibratory sense.
== Diagnostic Classification ==
There is no gold standard for diagnosis. One suggestion is making the diagnosis based on 2/3 abnormal findings of clinical features, quantitative sensory testing, and skin biopsy; or quantitative sudomotor axon-reflex test (QSART) as an alternative to skin biopsy.
=== Diagnostic Criteria ===
The following two diagnostic criteria have been published - Besta and Neurodiab
Besta Criteria (2008).
Presence of at least two of the following:	Absence of the following:
* Clinical signs of small fiber neuropathy, including pinprick and thermal sensory loss or reduction and/or the presence of positive signs (allodynia and hyperalgesia)
* Abnormal thermal threshold assessed at the foot by QST
* Reduced IENFD at the distal leg	
* Reduced vibratory sensation
* Loss of deep tendon reflexes
* Altered sensory nerve conduction
Neurodiab Criteria (2010)
Possible SFN	symptoms or clinical signs of small fibre damage
Probable SFN	symptoms or clinical signs of small fibre damage and normal sural nerve conduction studies
Definite SFN	symptoms or clinical signs of SFN-damage, normal sural nerve conduction studies and decreased intra-epidermal nerve fibre density (IENFD) and/or abnormal quantitative sensory testing (QST) thermal thresholds
==Investigations==
See Raasing et al for an in depth open access review of diagnostic methods.
=== Screen for Systemic Causes ===
A large cohort study used the following tests to find a cause in around 50% of patients.
First line tests: FBC, UEC, LFTs (alcohol abuse), HbA1c, TSH (hypothyroidism), Vitamin B12, celiac serology, ANA/ENA (Sjogrens, SLE, rheumatic disease), serum protein electrophoresis and serum light chains (amyloidosis), HIV, Hepatitis C, ACE and CXR (sarcoidosis) 
Second line tests to consider if appropriate: Alpha-galactosidase A activity (Fabry disease), antineuronal antibodies (paraneoplastic syndromes) 
Third line tests: Genetic testing. Channelopathies SCN9A, SCN109A, and SCN11A. Fabry disease, hereditary sensory and autonomic neuropathies, TTR amyloidosis. Genetic testing is extremely difficult to access in New Zealand. 
=== Questionnaires ===
These tools are obviously limited by their subjective nature. Neuropathic pain can be diagnosed using the Douleur Neuropathique 4 (DN4), and other similar instruments. There are multiple specific questionnaires for small fibre neuropathy, with validation done in different populations.
Two screening tools have also been developed that correlate with intraepidermal nerve fibre density. These are the SFN screening list, and SFN symptom inventory questionnaire (SFN-SIQ).
SFN screening list seems to have been primarily validated in sarcoidosis patients Small studies showed promise for SFN-SIQ for example a study of 86 patients with suspected pure SFN showed a sensivitiy of 86% and specificity of 70% with a cut off of 6.5. Unfortunately a larger study of 3842 patients referred to an SFN expertise centre showed a poor UAC of 0.601 with no clinically relevant cut off point. The authors concluded that it should only be used to measure symptoms.
=== Nerve Conduction Studies ===
Standard electrophysiologic testing is typically normal in SFN as the pathology lies in the small unmyelinated nerve fibres. However nerve conduction studies can be used to exclude large fibre involvement. This is recommended over the other QST procedures for testing large fibres.
=== Testing for Sensory Symptoms ===
==== Quantitative Sensory Testing ====
 is an extension of the physical examination, and can be used to diagnose peripheral nervous system disorders. Testing involves thermal, pressure, vibration, and electrical stimulation, with the full battery of tests involving 13 parameters. The results are compared to normative values. 
Due to the time consuming nature of full QST, specific thermal threshold testing (TTT) can be used to test small fibre function instead. In TTT an electrode is used that has a baseline temperature of 32C and this can increase up to 50C or down to 0C. There are two testing methods.
* Method of limits (reaction time dependent): start at the baseline temperature and increase or decrease the temperature. The test button is pressure twice, first when the temperature change is felt, and second when it becomes painful.
* Method of levels (reaction time independent): there are two buttons for yes or no. For each stimulus the patient is asked whether the thermode becomes colder or not. There is no pain threshold testing in method of levels, only thermal detection.
The feet are tested first because they are more commonly abnormal than the hands. If the feet have abnormal thresholds then the hands don't need to be tested. However if the feet are normal then the hands need to be tested. Most studies seem to use the Medoc devices which appear to be quite expensive.
Normative values for TTT: normal temperature detection thresholds lay above 41C (C fibres) and below 25C (Aδ fibres), and temperature pain thresholds lay above 45C (Aδ fibres) and below 5C (C fibres).
There are some important limitations to QST in general. There is great inter-observer variability and a lack of world-wide standardisation with iportant differences in methods between normative values.. Either central or peripheral nervous system abnormalities can cause the same deficit. QST requires good cognitive function and good conscious patient reactions. There are numerous other factors that can affect the results such as environmental conditions, gender, instructions, habituation, and motor performance.
The Quantitative Sudomotor Axon Reflex Test (QSART) is used to evaluate autonomic function, in particular the peripheral sympathetic cholinergic nervous system. It measures the response of the autonomic sudomotor nerves. Iontophoresis is used to introduce acetylcholine into the skin, which stimulates the sweat glands. The volume of sweat produced is measured. Some patients with SFN have increased sweat production. 
==== Skin Biopsy ====
Sural nerve biopsy may be only minimally abnormal, or even normal. It is performed using a 3mm punch under sterile technique. It can be taken from any body part, but the standard biopsy is 10cm above the lateral malleolus in the region of sural nerve innervation to enable evaluation of the loss of the most distal sensory endings that are typical of length dependent axonal neuropathy. Another site is the upper thigh (20cm distal to the iliac spine). The guidelines on performing the skin biopsy were established by the European Federation of Neurological Societies in 2005. The biopsy should be 3mm thick to enable assessment of both the epidermis and dermis. Suturing is not required. Risks include infection, tenderness at biopsy site, delayed healing, bleeding, allergy.
The biopsy sample is stained immunohistochemically with antibodies against protein gene product 9.5 (PGP 9.5). This protein is a marker for peripheral nerve fibres and neuroendocrine cells. Most cutaneous nerve fibres are unmyelinated, but in the dermis of hair skin 10% are small diameter myelinated fibres (A-delta fibres). A fibre count is done, and single axons are counted that cross or originate at the epidermal-dermal junction. The result is the Epidermal Nerve Fibre Density (ENFD). Reduced ENFD has a 90% specificity and 82.6% sensitivity for small fibre neuropathy.
In New Zealand the PGP9.5 stain doesn't appear to be available, but it may be possible to request an epidermal nerve fibre density assessment through other stains. It is viewed as a controversial investigation by pathologists in New Zealand.
==== Corneal Confocal Microscopy ====
This is a non-invasive test as an alternative to skin biopsy. It is comparable to skin biopsy in that you are looking for reduced nerve fibre density in SFN.
=== Testing for Autonomic Symptoms ===
There are a variety of tests for autonomic symptoms. The most applicable for clinical care are cardiovagal tests, water induced skin wrinkling, neuropad, sudoscan, pupillometry, and bladder function tests.
==== Water-induced and EMLA-induced Skin Wrinkling ====
The patient places both hands in a bath of water heated to 40 degrees. The wrinkling is graded for the second to fifth fingers. Grade 0: wrinkling absent; grade 1: slight wrinkling and the fingertip is not smooth; grade 2: two or less lines of shallow wrinkling on the fingertip; grade 3: three or more lines of clear cut lines of wrinkling on the fingertip; grade 4: wrinkling completely distorts the pulp of the fingertip. The grade is averaged across fingers.
EMLA can be used as an alternative to induce skin wrinkling. Apply 1g to the distal digit tips of the 2nd to 5th fingers, and leave it to soak into the skin for 30 minutes after covering with Tegaderm.
In both cases, with sympathetic nerve dysfunction, there is less wrinkling seen due to prevention of vasovonstriction. Studied in patients with sensory neuropathy, the diagnostic accuracy depends on the cut off of the comparison standard of reduced intraepithelial nerve fibre density. Overall both tests have good positive predictive values, but poor negative predictive values. There was no correlation between grade of wrinkling and nerve density. For wrinkling grading, a score of 12 or more for each hand was used as the cut off for normal, and a difference of 4 or more difference per hand was used as a cut-off for a different score.Wilder-Smith EP, Guo Y, Chow A. Stimulated skin wrinkling for predicting intraepidermal nerve fibre density. Clin Neurophysiol. 2009 May;120(5):953-8. doi: 10.1016/j.clinph.2009.03.011. Epub 2009 Apr 16. PMID: 19375384.
==== Cardiovagal Tests ====
One abnormal cardiovagal test is possible cardiovascular autonomic neuropathy, two positive tests is definite, and severe is defined as orthostatic hypotension in addition to definite.
Heart rate response to valsalva (parasympathetic) is a test where the RR interval is measured on ECG to determine heart rate variability. There are five phases: ; phase (0) deep inspiration, phase (I) onset of strain, phase (II) continued strain, phase (III) release, phase (IV) recovery. The ratio is calculated by taking the shortest RR interval in phase II and dividing it by the longest in phase IV. An abnormal result is a lack of bradycardia during phase IV and a decreased valsalva ratio.
Heart rate response to postural change (parasympathetic) is where the patient changes from supine to upright and the heart rate is measured. A normal result is where the heart rate increases initially and then reduces. The 30:15 ratio is calculated, taking the bradycardia at 30 seconds and dividing it by the tachycardia at 15 seconds. Normally the heart rate increases by 10 seconds. In autonomic dysfunction there is no bradycardia.
Heart rate response to deep inspiration (parasympathetic) is looking for variability of the amplitude of individual electrical complexes on ECG with deep inspiration.
Blood pressure response to valsalva (sympathetic): In autonomic dysfunction there is no overshoot in blood pressure and bradycardia reflex.
Blood pressure response to postural change (sympathetic): The blood pressure should increase by 10mmHg after 1-2 minutes.
=== Sudoscan and Body Scan ===
These are non-invasive tools for detecting autonomic dysfunction by measuring electrochemical skin conductance of hands and feet through reverse iontophoresis. In a study of diabetics the Sudoscan had a sensitivity of 78% and specificity of 92% for detecting SFN. Body scan is an at home version which has comparable accuracy.
=== Genetic disease ===
The following genetic tests have been proposed in some cases.
* Sodium channelopathy - SCN9A, SCN10A, SCN11A genes (gain of function mutations). Most variants area associated with distal pain.
* Familial amyloidosis - Transthyretin gene 
* Fabry disease - Enzymatic assay for alpha-Gal A activity / Genetic test of alpha-Gal A (GLA)
Of the above the sodium channelopathies are the most common. Unfortunately there is no great difference between those with pathogenic variants and those with no variant. The only association is that those with a channelopathy are more likely to have a family history and have pain aggravated by warmth.
==Management==
There is no known cure for SFN and the results of medication are usually disappointing with a lot of side effects. Standard neuropathic pain medications can be trialled such as gabapentinoids, topiramate, TCAs, and SNRIs. The combination of a TCA and gabapentinoid may be more effect than monotherapy. Opioids are not recommended, but weak opioids such as codeine or tramadol can be considered for short periods of use only. Topical lidocaine or capsaicin has been used.
In those with a SCN9A pathogenic variant, lacosamide can be used with modest effect, with 40% feeling very much improved vs 12% with placebo in a small RCT.
== Resources ==
Euro-NMD Painful Neuropathies Lecture
==See Also==
*Fibromyalgia
*Erythromelalgia
*Polyneuropathy
==References==
Category:Polyneuropathies
Category:Partially complete articles