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Small Fibre Neuropathy: Difference between revisions

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Small fibre neuropathy (SFN) and large fibre neuropathy belong to a group of diseases known as [[Peripheral Neuropathy|peripheral neuropathies]]. [[Polyneuropathy|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.<ref name="Maslinska">Maslinska et al. Small fibre neuropathy as a part of fibromyalgia or a separate diagnosis? Int. J. Clin. Rheumatol. (2018) 13(6), 353-359. [https://www.openaccessjournals.com/articles/small-fiber-neuropathy-as-a-part-of-fibromyalgia-or-a-separate-diagnosis.pdf Full Text]</ref>
Small fibre neuropathy (SFN) and large fibre neuropathy belong to a group of diseases known as [[Peripheral Neuropathy|peripheral neuropathies]]. [[Polyneuropathy|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.<ref name="Maslinska">Maslinska et al. Small fibre neuropathy as a part of fibromyalgia or a separate diagnosis? Int. J. Clin. Rheumatol. (2018) 13(6), 353-359. [https://www.openaccessjournals.com/articles/small-fiber-neuropathy-as-a-part-of-fibromyalgia-or-a-separate-diagnosis.pdf Full Text]</ref>
See [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075405/ Raasing et al] for an in depth open access review.


==Nerve Anatomy==
==Nerve Anatomy==
The majority of peripheral sensory nerves are unmyelinated C fibres and thinly myelinated Aδ fibres.
{{See also|Basic Neurophysiology}}
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.
{{Sensory Nerve Fibres}}
{{Sensory Nerve Fibres}}
{{Nociception Receptors}}
{{Nociception Receptors}}


==Aetiopathology==
==Aetiology==
Disorders known to contribute to SFN are listed below.<ref name="Maslinska"/> 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.
Disorders known to contribute to SFN are listed below.<ref name="Maslinska"/> 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.


Line 45: Line 44:
**Wilsons disease
**Wilsons disease
**Sodium channelopathy
**Sodium channelopathy
== Pathophysiology ==
The pathophysiology is unknown. 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.<ref name=":0">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</ref>
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==
==Clinical Features==
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.  
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.  
Symptoms are typically length dependent, i.e. most notable in the distal extremities. However it can also present in a non-length dependent manner. Non-length dependent features may be more likely to have an immune mediated disease association.<ref>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.</ref> i


Classical symptoms include distal burnings, pain, numbness, paraesthesia, and autonomic symptoms. Autonomic symptoms can include sweating alterations, temperature dysregulation, dry mouth and eyes, and erectile dysfunction.  
Classical symptoms include distal burnings, pain, numbness, paraesthesia, and autonomic symptoms. Autonomic symptoms can include sweating alterations, temperature dysregulation, dry mouth and eyes, and erectile dysfunction.  
Line 57: Line 70:
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.<ref name="Maslinska"/>
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.<ref name="Maslinska"/>


==Diagnosis==
== Diagnostic Classification ==
Standard [[Nerve Conduction Studies|electrophysiologic testing]] is typically normal in SFN as the pathology lies in the small unmyelinated nerve fibres. Sural nerve biopsy may be only minimally abnormal, or even normal.<ref name="Maslinska"/>
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.<ref name=":0" />
 
The following classifications can be use.<ref name=":0" />
 
# ''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 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075405/ Raasing et al] for an in depth open access review of diagnostic methods.<ref name=":0" />
 
=== Screen for Systemic Causes ===
Blood tests may include HbA1c, serum electrophoresis, vitamin B12, full blood count, hepatitis B and C serology, celiac serology, copper, and ANA.
 
=== 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.<ref name=":0" />
 
=== Quantitative Sensory Testing ===
[[Media:Central sensitisation correlates.png|Quantitative sensory testing (QST)]] 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. 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.
 
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).


[[Media:Central sensitisation correlates.png|Quantitative sensory testing (QST)]] is an extension of the physical examination, and can be used to diagnose peripheral nervous system disorders. In QST the clinician determines the sensation and pain thresholds for cold and warm, vibration sense, and compares results to normative values. There are some important limitations. Either central or peripheral nervous system abnormalities can cause the same deficit. QST requires good cognitive function and good conscious patient reactions.<ref name="Maslinska"/>
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.<ref name="Maslinska" /> There are numerous other factors that can affect the results such as environmental conditions, gender, instructions, habituation, and motor performance.<ref name=":0" />


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. <ref name="Maslinska"/>
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. <ref name="Maslinska"/>


===Skin Biopsy===
=== Nerve Conduction Studies ===
Skin biopsy is the best diagnostic tool and current gold standard. 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 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.<ref name="Maslinska"/>
Standard [[Nerve Conduction Studies|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.
 
=== Skin Biopsy ===
Sural nerve biopsy may be only minimally abnormal, or even normal.<ref name="Maslinska" /> 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.<ref name="Maslinska" />


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.<ref name="Maslinska"/><ref>{{#pmid:20642627}}</ref>
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.<ref name="Maslinska"/><ref>{{#pmid:20642627}}</ref>


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.
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.


==Management==
==Management==

Revision as of 08:00, 19 August 2021

This article is still missing information.

Small fiber neuropathy (SFN) affects the small myelinated Aδ and unmyelinated C fibers. The potential affected fibres include sensory fibres, autonomic fibres, or both. This 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.[1]

Nerve Anatomy

See also: Basic Neurophysiology

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.

Characteristics of sensory nerve fibres
Nerve fibre Myelinated axons Diameter (µm) Conduction velocity (m/s) Sensory information Usefulness of electroneuromyography Usefulness of QST
Aα Yes   13-20   80-120 Proprioception, muscle spindle primary endings (Ia), golgi tendon organs (Ib) (and alpha motor neurons)   Yes (H reflex) No
Aβ   Yes   6-12   33-75 Discriminative mechanoreception (touch, vibration), proprioception, pain modulation (block nociceptive information, allodynia in sensitisation) Yes (sensory nerve conduction) Yes
Aγ   Yes   4-8   15-40 Touch, pressure (and gamma motor neurons) No
Aδ Thin 1-5 3-30 "rapid" pain, crude touch, pressure, temperature. AMH type I for rapid mechanical pain (high heat threshold >53C), AMH type II for rapid heat pain (lower heat threshold 43-47C). No Yes
C No 0.3-1.5 0.5-2.0 "slow" pain, touch, pressure temperature (and postganglionic autonomic). Polymodal. No Yes
Overview of different nociception receptors with corresponding small nerve fibre type[2]
Receptor Type Fibre Group Modality
Cutaneous and subcutaneous mechanoreceptors Touch
Hair down Aδ Light stroking
Thermal receptors Temperature
Cold receptors Aδ Skin cooling (25°C)
Warm receptors C Skin warming (41°C)
Heat nociceptors Aδ Hot temperatures (>45°C)
Cold nociceptor C Cold temperatures (<5°C)
Nociceptors Pain
Mechanical Aδ Sharp, pricking pain
Thermal-mechanical Aδ Burning pain
Thermal-mechanical C Freezing pain
Polymodal C Slow, burning pain
Polymodal Muscle and Skeletal Mechanoreceptors Limb proprioception
Stretch-sensitive free endings Aδ Excess stretch or force

Aetiology

Disorders known to contribute to SFN are listed below.[1] 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.

  • Idiopathic
  • Metabolic
    • Diabetes mellitus and glucose intolerance
    • Vitamin B12 deficiency
    • Copper deficiency
    • Hypothyroidism
    • Hiperlipidemia
    • Hipervitaminosis B6
    • Chronic kidney disease
  • Dysimmunity/inflammatory diseases
    • Sjögren’s syndrome
    • Sarcoidosis
    • Systemic lupus erythematosus
    • Celiac disease
    • Ehlers-Danlos Syndrome[3]
  • Infectious
    • HIV
    • Hepatitis C
    • Ebstein-Barr virus
    • Lyme disease
    • Leprosy
  • Toxic agents and medications
    • Alcohol (this can eventually cause large fibre neuropathy)
    • Antibiotics (metronidazole, nitrofurantoin, linezolid, isoniazid)
    • Anticancer agents (bortezomib, platin)
    • Antiretroviral drugs
  • Genetic diseases
    • Fabry’s disease
    • Familial amyloid polyneuropathy (transthyretin)
    • Wilsons disease
    • Sodium channelopathy

Pathophysiology

The pathophysiology is unknown. 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.[4]

There are four stages of neuropathy in unmyelinated nerve fibres

  1. Mild proliferation: Increase in number of isolated small Schwann cell projections which are irregular in shape.
  2. Fibre loss: decreased fibre numbers along with increased empty Schwann cells.
  3. 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
  4. 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

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.

Symptoms are typically length dependent, i.e. most notable in the distal extremities. However it can also present in a non-length dependent manner. Non-length dependent features may be more likely to have an immune mediated disease association.[5] i

Classical symptoms include distal burnings, pain, numbness, paraesthesia, and autonomic symptoms. Autonomic symptoms can include sweating alterations, temperature dysregulation, dry mouth and eyes, and erectile dysfunction.

Patients with SFN may have severe symptoms but a normal physical and neurological examination. Proprioception, light touch, and vibration sense may also be normal. Some patients may have decreased pinprick, decreased thermal sensation, hyperalgesia in the affected region, and slightly decreased vibratory sense.

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).

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.[1]

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.[4]

The following classifications can be use.[4]

  1. Possible SFN: symptoms or clinical signs of small fibre damage
  2. Probable SFN: symptoms or clinical signs of small fibre damage and normal sural nerve conduction studies
  3. 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.[4]

Screen for Systemic Causes

Blood tests may include HbA1c, serum electrophoresis, vitamin B12, full blood count, hepatitis B and C serology, celiac serology, copper, and ANA.

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.[4]

Quantitative Sensory Testing

Quantitative sensory testing (QST) 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. 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.

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.[1] There are numerous other factors that can affect the results such as environmental conditions, gender, instructions, habituation, and motor performance.[4]

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. [1]

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.

Skin Biopsy

Sural nerve biopsy may be only minimally abnormal, or even normal.[1] 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.[1]

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.[1][6]

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.

Management

There is no known cure for SFN. 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.[1] 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.

See Also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 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
  2. ↑ Kandel ER, Schwartz JH, Jessel TM. Principles of Neural Science. 4th ed. Appleton & Lange; 2000
  3. ↑ Cazzato, 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
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 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
  5. ↑ 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.
  6. ↑ Lauria et al.. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. European journal of neurology 2010. 17:903-12, e44-9. PMID: 20642627. DOI.

Literature Review

Library.pngLiterature Review

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