This document discusses small fibre neuropathy (SFN), including definitions, causes, diagnostic criteria and tests, and management. SFN is defined as degeneration of small nerve fibres characterized by loss of small nerve endings. It can be caused by metabolic issues like diabetes, infections, toxins/drugs, immune or neurological disorders. Diagnosis involves clinical signs and symptoms, normal nerve conduction studies but abnormal quantitative sensory testing or skin biopsy showing reduced intraepidermal nerve fibres. Management focuses on treating underlying causes and pain management. Rarely, SFN can be caused by ion channel mutations affecting small nerve fibres.

1. SMALL FIBRE
NEUROPATHY:RECENT
ADVANCES IN APPROACH
Dr Prashant shringi
Senior Resident
Neurology

2. Small Fibre Neuropathy
• Small fibre neuropathy (SFN) is defined as a structural
abnormality of small fibre characterized pathologically by
degeneration of the distal terminations of small fibre nerve
endings

3. WHAT ARE THE SMALL FIBRES?
• Small fibres are small narrow diameter myelinated (Aδ)
and unmyelinated (C)nerve fibres of the peripheral
nervous system
• Somatosensory Aδ-fibres and C-fibres innervating skin
• Pass through the dermis where they innervate cutaneous
structures; both groups of fibres end as free nerve
endings in the epidermis.

5. • Functions:
• Aδ-fibres are responsible for conveying cold input and
nociceptive input.
• C-fibres convey innocuous warm sensations and possibly
innocuous cold sensations,and noxious input from a
variety of high threshold mechanical, thermal and
chemical stimuli

6. • Small fibres play an important role in the autonomic
nervous system,
• Because thin myelinated fibres contribute to preganglionic
fibres and C-fibres contribute to postganglionic fibres,
innervating structures such as sweat glands, blood
vessels and the heart.

7. Causes of SFN
• Primary

8. Causes of SFN
• Secondary
• Metabolic:
Impaired glucose tolerance
 Diabetes mellitus
 Rapid glycaemic control
Vitamin B12 deficiency
Dyslipidaemia
 Hypothyroidism
Chronic kidney disease

9. • Infections:
HIV
 Hepatitis C
 Influenza

10. • Toxins and drugs:
Anti-retrovirals
 Antibiotics—metronidazole, nitrofurantoin, linezolid
 Chemotherapy—bortezomib ,Flecainide
 Statin
 Alcohol
 Vitamin B6 toxicity

11. • Immune mediated:
Coeliac disease
Sarcoidosis
Sjögren’s syndrome
Rheumatoid arthritis
Systemic lupus erythematosus
 Vasculitis
 Inflammatory bowel disease
 Paraneoplastic
 Monoclonal gammopathy/amyloid

12. • Neurodegenerative:
Spinobulbar muscular atrophy (Kennedy disease)
Amyotrophic lateral sclerosis
Parkinson disease

13. • Commonest being diabetes mellitus, responsible for
approximately a third of all cases of SFN.
• In diabetes mellitus, a complex interplay of metabolic
factors, ischaemia and impaired recovery predispose
peripheral neurones, glial cells
• Vascular endothelial cells to damage that ultimately leads
to neuronal injury and peripheral neuropathy

14. • SFN features in a number of rare genetic conditions
• A recent study described variants of the SCN9A gene,
which encodes the Nav1.7 sodium channel in a third of
patients labelled as having idiopathic SFN.
• This voltage-gated ion channel is selectively expressed in
sensory and autonomic neurones.
• Faber CG, Hoeijmakers JG, Ahn HS, et al. Gain of function Nav1.7 mutations
in idiopathic small fiber neuropathy. AnnNeurol 2012;71:26–39.

15. • Nav1.7 variants associated with SFN cause enhanced
excitability of sensory neurons and eventual degeneration
of small fibres, which is probably mediated through
increased sodium load and reversal of sodium–calcium
exchange.

16. • Nav1.8 is a related voltage-gated sodium channel
selectively expressed in nociceptors.
• Variants in the SCN10A gene, which encodes the
Nav1.8 sodium channel, enhance the excitability of dorsal
root ganglion cells and are also associated with SFN.

18. DIAGNOSTIC CRITERIA FOR SFN
• Possible:-Length-dependent symptoms and/or clinical
signs (pinprick and thermal sensory loss and/or
allodynia/hyperalgesia)
• Probable:-Length-dependent symptoms, clinical signs of
small fibre damage and normal nerve conduction studies
• Tesfaye S, Boulton AJ, Dyck PJ, et al. Diabetic neuropathies: update on
definitions, diagnostic criteria, estimation of severity, and treatments.
DiabetesCare 2010; 33:2285–2293.

19. • Definite-:Length-dependent symptoms, clinical signs of
small fibre damage, normal nerve conduction studies,
• altered intra-epidermal nerve fibre density at the ankle
and/or abnormal quantitative sensory testing of thermal
thresholds at the foot

20. • Lauria et al strongly recommend using these criteria in
SFN of any cause, irrespective of whether the neuropathy
is length- or non length dependent
• Daniele Cazzato and Giuseppe Lauria; Curr Opin Neurol 2017, 30:000–000

21. • Best evidence based for the diagnosing SFN is the
combination of clinical signs of small-fibre dysfunction and
reduced intra-epidermal nerve fibre density.

22. Electro diagnostic studies
• Major limitation of conventional nerve conduction studies
is that they primarily assess only large myelinated fibres
and cannot detect any change in small fibres.

23. • In pure SFN, conventional nerve conduction studies will
be normal and therefore their purpose is to exclude an
associated large fibre component

24. Microneurography
• Uses recording microelectrodes placed within nerve
fascicles and the ‘marking’ technique enables multiple
small fibres to be recorded from simultaneously.
• Functionality of small fibres can be directly determined

27. Quantitative sensory testing
• QST is a psychophysical investigative tool to assess the
function of the human somatosensory nervous system
• It is used to determine the functional impairment of small
nerve fibres by measuring warmth, cooling and pain
thresholds through noninvasive psychophysical tests

28. • Variety of mechanical and thermal challenges, non-
nociceptive and nociceptive, of measured intensity
provide an assessment of the function of Aβ-fibres, Aδ-
fibres and C-fibres
• Several variables, such as cold and warm thresholds,
pain thresholds can be measured

29. Quantitative sensory testing
• In assessing SFN, thermal detection and pain thresholds
are commonly used
• QST cannot differentiate between peripheral and central
causes of a sensory deficit

31. Skin biopsy
• Quantification of intra-epidermal nerve fibre density is the
most important advance in SFN diagnostics over the last
decade
• Most validated technique to diagnose SFN.

34. • A skin punch biopsy 3 mm in diameter can be taken from
any location on the body
•
• Typically taken 10 cm proximal to the lateral malleolus
for diagnostic purposes in SFN

35. • An additional frequently-used biopsy site is the proximal
thigh 20 cm below the iliac spine.
• An alternative method to the punch biopsy is to take a
sample of tissue via the skin blister technique.
• A potential benefit is that no topical anaesthesia is
needed, and bleeding is minimal.

36. • Small nerve fibre morphometric analysis is performed
using bright field immunohistochemistry or indirect
immunofluorescence
•
• Bright field immunohistochemistry is the most commonly
used technique for routine diagnostics

37. • skin sample is stained for an antigen called PGP 9.5 (an
ubiquitin hydrolase) that is found in all nerve fibre .

38. IENFD Measurement
• Intra-epidermal nerve fibre density measurements can be
established in most neuropathology laboratories as it uses
commonly used immuno histochemical techniques.

39. • Unmyelinated fibres located in the epidermis/dermis are
the terminal nerve endings of either Aδ-fibres or C-fibres
• Standard measure to assess for a SFN is to measure
intra-epidermal nerve fibre density, that is, the number of
fibres that cross the dermal–epidermal junction per
millimetre of epidermal surface.

40. • A decrease in intra-epidermal nerve fibre density with
values below the fifth centile relative to age and gender-
matched controls are considered diagnostic of SFN
• Decreases in intraepidermal nerve fibre density have
been correlated with neuropathy symptoms, and
abnormalities on sensory testing.

41. • Intraepidermal nerve fibre density has been measured in
a wide variety of conditions and show consistent results.
• In studies where SFN was clinically suspected, IEFND
assessment had a sensitivity of 90%, specificity of
95%, positive predictive value of 95% and negative
predictive value of 91% for the diagnosis of SFN

42. • Qualitative assessments of small nerve fibres, such as
axonal swellings as a marker of pre-degenerative
changes or weaker PGP 9.5 staining.
• Less Reliable

43. • Skin biopsy with intra-epidermal nerve fibre density
measurements is the diagnostic modality of choice for
SFN
• Nerve biopsy is virtually never performed for a pure SFN

44. Corneal confocal microscopy
• In vivo corneal confocal microscopy is noninvasive
technique to assess small fibre innervation
• It can measure and assess corneal innervation

45. • How it works?:-
• Cornea is innervated by Aδ-fibres and C-fibres that
originate from the ophthalmic division of the trigeminal
nerve
• Cornea is the most densely innervated part of the human
body and offers a unique window to small fibre
innervation, as corneal living tissue can be assessed at a
cellular level.

46. • Corneal nerve fibre bundle density inversely correlates
with severity of neuropathy
• Fewer the nerve fibre bundles the more severe the
neuropathy

47. • Corneal nerve fibre bundle density and tortuosity have
been assessed most extensively in patients with diabetes
mellitus.
• Also in Fabry’s disease, Charcot–Marie–Tooth disease,
idiopathic SFN and in non-length dependent neuropathy

48. • Corneal confocal microscopy is a new and promising non-
invasive means of assessing structural integrity of small
fibres

49. Quantitative sudomotor axon reflex test
• Technique assesses the integrity of postganglionic
sympathetic cholinergic sudomotor nerves through the
iontophoresis of acetylcholine that stimulates cutaneous
unmyelinated C-fibres, and sweating quantified by a
sudometer.

50. • When abnormal QSART findings were associated with
local autonomic symptoms, the technique allowed
increasing the diagnostic yield for SFN based on skin
biopsy and QST

51. Nociceptive evoked potentials
• Following types of nociceptive evoked potentials
Laser-evoked potentials (LEPs)
Contact heat-evoked potentials (CHEPs)
Pain-related evoked potentials (PREPs) involves the
preferential stimulation of Aδ-fibres

52. Laser-evoked potentials
• To obtain LEPs, the skin is stimulated with short radiant
heat pulses that are emitted by a CO2 laser
• Brain potential at the vertex can be subsequently
recorded.

53. • Late LEPs reflect Aδ-fibre activation (200–400-ms latency
range),
•
• Ultra-late LEPs reflect C-fibre activation (1000-ms latency
range), with the amplitude of cerebral response
correlating with the reported intensity of the perceived
pain.

54. • Abnormal LEP can represent a disorder of the peripheral
nerve, nerve plexus, nerve root, or spinal or brainstem
nerves, and the technique seems to be diagnostically
useful in SFN.

55. Contact heat-evoked potentials (CHEPs)
• Heat-foil CHEP stimulator with extremely rapid heat rising
time (70 °C/s), elicitation of pain and CHEPs can be
achieved
• Compared with LEPs, contact heat stimulators cause
mechanical activation of the skin and stimulate a larger
surface area, which makes missed stimulation of fibres
less likely, even when only a few intact fibres remain

56. • Stimulus of contact heat stimulators is natural and can be
controlled very precisely
• Furthermore, the technology is easy to use in the clinic,
does not require eye protection, and has a low risk of
causing skin irritation
• Late CHEPs are associated with Aδ-fibre activation, and
ultra late CHEPs with C-fibre activation

57. Pain-related evoked potentials
• PREPs is less time-consuming and easier to perform.
• PREPs are obtained through the use of a concentric
planar electrode that delivers electrical stimuli only to the
superficial layer of the dermis
• Stimulus primarily depolarizes superficial nociceptive Aδ-
fibres, thereby excluding the possibility of activation of
deeper non-nociceptive fibres

58. • In patients with HIV-related SFN, a correlation between
reduced IENFD and abnormal PREPs was found.
• Obermann, M. et al. Correlation of epidermal nerve fiber density with
pain-related evoked potentials in HIV neuropathy. Pain 138, 79–86
(2008).

59. • Results from a study in patients with diabetes suggest
that measurement of PREP may contribute to early
detection of SFN
• Although this study did not include assessment of IENFD
by skin biopsy
• Mueller, D. et al. Electrically evoked nociceptive potentials for early
detection of diabetic small-fiber neuropathy. Eur. J. Neurol. 17, 834–841
(2010.

60. Intraepidermal electrical stimulation
• For IES, a pushpin-like electrode of 0.2 mm in length is
gently pressed against the skin, inserting the needle tip
adjacent to the thin nerve endings in the skin.
• After delivery of an electrical stimulus the evoked
potential is measured in the same way as in the other
nociceptive evoked potentials

61. Autonomic testing
• Ewing battery for cardiovascular autonomic reflex testing
is easy to perform.
• Low sensitivity for the detection of autonomic dysfunction
in patients with SFN

62. Sudomotor and vasodilator function tests include the -
Quantitative Sudomotor Axon Reflex Test (QSART)
Thermoregulatory Sweat Test
Sympathetic Skin Response (SSR)
Skin Vasomotor Reflex (SVR)
 Axon Reflex Flare Size (ARFS)

63. • QSART seems to be sensitive in SFN, but as the
application of this test requires specific skills and
instrumentation
• SSR and SVR are simple methods and can be used in
any clinical neurophysiology laboratory, although their
diagnostic value in SFN is reported to be poor

64. • The ARFS is a noninvasive method, the results of which
seem to correlate with IENFD.
• Technique is used to measure the size of axon-reflex
flare following electrical stimulation that simultaneously
activates axon reflexes of sudomotor fibres and
nociceptors.

65. • This mode of stimulation causes the release of
vasodilating calcitonin gene-related peptide from C-fibre
endings and acetylcholine from sympathetic nerve
endings

68. Management

70. PAINFUL CHANNELOPATHIES
• There are several rare heritable conditions where small
fibres are dysfunctional (leading to severe pain) .
• Peripheral small fibres are structurally intact with no
evidence of a small fibre neuropathy

71. Ion channel dysfunction
Channelopathies have recently been linked to multiple pain
syndromes
A recent study has demonstrated the presence of single amino
acid substitutions of the voltage-gated sodium channel Nav1.7—
which is preferentially expressed within DRG and sympathetic
ganglion neurons—in a substantial fraction of patients with
idiopathic SFN.
Faber, C. G. et al. Gain of function Nav1.7 mutations in idiopathic small fiber neuropathy.
Ann. Neurol. 71, 26–39 (2012).

72. • Gain of function mutations of the genes SCN9A or
SCN10A that encode the voltage-gated sodium channels
Nav 1.7 and Nav 1.8 are associated with previously
unexplained small fibre neuropathy.
• A total of 28.6% of patients with idiopathic SFN were
found to carry a gain-of-function variant in Nav1.7.

73. • Nav1.7 mutations have also been linked to inherited
erythromelalgia (IEM) and paroxysmal extreme pain
disorder
• Two diseases that show some clinical similarities with
SFN

74. Refrences
• Hoeijmakers, J. G. et al. Nat. Rev. Neurol. 8, 369–379 (2012);
published online 29 May 2012n doi:10.1038/nrneurol.2012.97
• Themistocleous AC, et al. Pract Neurol 2014;0:1–12.
doi:10.1136/practneurol-2013-000758, British Medical Journal
• Daniele Cazzato and Giuseppe Lauria; Curr Opin Neurol 2017,
30:000–000
• Medscape.com
• Page 3 of 18 Saxena AK, Nath S, Kapoor R (2015) Diabetic
Peripheral Neuropathy: Current Concepts and Future Perspectives. J
Endocrinol Diab 2(5): 1-18.

75. • THANK YOU