Corneal Confocal Microscopy in the Diagnosis of Small Fiber Neuropathy: Faster, Easier, and More Efficient Than Skin Biopsy?

Chronic pain may affect 30–50% of the world’s population and an important cause is small fiber neuropathy (SFN). Recent research suggests that autoimmune diseases may be one of the most common causes of small nerve fiber damage. There is low awareness of SFN among patients and clinicians and it is difficult to diagnose as routine electrophysiological methods only detect large fiber abnormalities, and specialized small fiber tests, like skin biopsy and quantitative sensory testing, are not routinely available. Corneal confocal microscopy (CCM) is a rapid, non-invasive, reproducible method for quantifying small nerve fiber degeneration and regeneration, and could be an important tool for diagnosing SFN. This review considers the advantages and disadvantages of CCM and highlights the evolution of this technique from a research tool to a diagnostic test for small fiber damage, which can be a valuable contribution to the study and management of autoimmune disease.

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Alpha-synuclein oligomers and small nerve fiber pathology in skin are potential biomarkers of Parkinson’s disease

npj Parkinson s Disease ◽

10.1038/s41531-021-00262-y ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Elena Vacchi ◽

Camilla Senese ◽

Giacomo Chiaro ◽

Giulio Disanto ◽

Sandra Pinton ◽

...

Keyword(s):

Skin Biopsy ◽

Nerve Fiber ◽

Temporal Dynamics ◽

Alpha Synuclein ◽

Small Fiber Neuropathy ◽

Proximity Ligation Assay ◽

Anatomical Site ◽

Small Fiber ◽

Intraepidermal Nerve Fiber Density ◽

Small Nerve

AbstractThe proximity ligation assay (PLA) is a specific and sensitive technique for the detection of αSyn oligomers (αSyn-PLA), early and toxic species implicated in the pathogenesis of PD. We aimed to evaluate by skin biopsy the diagnostic and prognostic capacity of αSyn-PLA and small nerve fiber reduction in PD in a longitudinal study. αSyn-PLA was performed in the ankle and cervical skin biopsies of PD (n = 30), atypical parkinsonisms (AP, n = 23) including multiple system atrophy (MSA, n = 12) and tauopathies (AP-Tau, n = 11), and healthy controls (HC, n = 22). Skin biopsy was also analyzed for phosphorylated αSyn (P-αSyn) and 5G4 (αSyn-5G4), a conformation-specific antibody to aggregated αSyn. Intraepidermal nerve fiber density (IENFD) was assessed as a measure of small fiber neuropathy. αSyn-PLA signal was more expressed in PD and MSA compared to controls and AP-Tau. αSyn-PLA showed the highest diagnostic accuracy (PD vs. HC sensitivity 80%, specificity 77%; PD vs. AP-Tau sensitivity 80%, specificity 82%), however, P-αSyn and 5G4, possible markers of later phases, performed better when considering the ankle site alone. A small fiber neuropathy was detected in PD and MSA. A progression of denervation not of pathological αSyn was detected at follow-up and a lower IENFD at baseline was associated with a greater cognitive and motor decline in PD. A skin biopsy-derived compound marker, resulting from a linear discrimination analysis model of αSyn-PLA, P-αSyn, αSyn-5G4, and IENFD, stratified patients with accuracy (77.8%), including the discrimination between PD and MSA (84.6%). In conclusion, the choice of pathological αSyn marker and anatomical site influences the diagnostic performance of skin biopsy and can help in understanding the temporal dynamics of αSyn spreading in the peripheral nervous system during the disease. Skin denervation, not pathological αSyn is a potential progression marker for PD.

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Small Nerve Fiber Damage and Langerhans Cells in Type 1 and Type 2 Diabetes and LADA Measured by Corneal Confocal Microscopy

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.62.6.5 ◽

2021 ◽

Vol 62 (6) ◽

pp. 5

Author(s):

Luca D'Onofrio ◽

Alise Kalteniece ◽

Maryam Ferdousi ◽

Shazli Azmi ◽

Ioannis N. Petropoulos ◽

...

Keyword(s):

Type 2 Diabetes ◽

Confocal Microscopy ◽

Nerve Fiber ◽

Langerhans Cells ◽

Fiber Damage ◽

Corneal Confocal Microscopy ◽

Small Nerve

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Faculty Opinions recommendation of Early detection of nerve fiber loss by corneal confocal microscopy and skin biopsy in recently diagnosed type 2 diabetes.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718289800.793492653 ◽

2014 ◽

Author(s):

Rayaz Malik

Keyword(s):

Type 2 Diabetes ◽

Confocal Microscopy ◽

Early Detection ◽

Skin Biopsy ◽

Nerve Fiber ◽

Corneal Confocal Microscopy

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Corneal nerves in diabetes—The role of the in vivo corneal confocal microscopy of the subbasal nerve plexus in the assessment of peripheral small fiber neuropathy

Survey of Ophthalmology ◽

10.1016/j.survophthal.2020.09.003 ◽

2020 ◽

Cited By ~ 1

Author(s):

Anna M. Roszkowska ◽

Carmelo Licitra ◽

Giuseppe Tumminello ◽

Elisa I. Postorino ◽

Michele R. Colonna ◽

...

Keyword(s):

Confocal Microscopy ◽

Small Fiber Neuropathy ◽

Nerve Plexus ◽

Small Fiber ◽

Corneal Confocal Microscopy ◽

Corneal Nerves ◽

Subbasal Nerve Plexus

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Small Fiber Neuropathy: Clinicopathological Correlations

Behavioural Neurology ◽

10.1155/2020/8796519 ◽

2020 ◽

Vol 2020 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Endre Pál ◽

Krisztina Fülöp ◽

Péter Tóth ◽

Gabriella Deli ◽

Zoltán Pfund ◽

...

Keyword(s):

Diabetes Mellitus ◽

Genetic Alterations ◽

Small Fiber Neuropathy ◽

Endocrine Disorders ◽

Fiber Density ◽

Fiber Damage ◽

Small Fiber ◽

Patient Reported ◽

Common Causes ◽

Patient Reported Measures

Small fiber neuropathy develops due to the selective damage of the thin fibers of peripheral nerves. Many common diseases can cause this condition, including diabetes, infections, autoimmune and endocrine disorders, but it can occur due to genetic alterations, as well. Eighty-five skin biopsy-proven small-fiber neuropathy cases were analyzed. Forty-one (48%) cases were idiopathic; among secondary types, hypothyreosis (9.4%), diabetes mellitus (7%), cryoglobulinemia (7%), monoclonal gammopathy with unproved significance (4.7%), Sjögren’s disease (3%), and paraneoplastic neuropathy (3%) were the most common causes. Two-thirds (68%) of the patients were female, and the secondary type started 8 years later than the idiopathic one. In a vast majority of the cases (85%), the distribution followed a length-dependent pattern. Intraepidermal fiber density was comparable in idiopathic and secondary forms. Of note, we found significantly more severe pathology in men and in diabetes. Weak correlation was found between patient-reported measures and pathology, as well as with neuropathic pain-related scores. Our study confirmed the significance of small fiber damage-caused neuropathic symptoms in many clinical conditions, the gender differences in clinical settings, and pathological alterations, as well as the presence of severe small fiber pathology in diabetes mellitus, one of the most common causes of peripheral neuropathy.

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