Diabetes Metab J.  2018 Aug;42(4):255-269. 10.4093/dmj.2018.0056.

Diagnosing Diabetic Neuropathy: Something Old, Something New

• Petropoulos IN
• Ponirakis
• Khan A
• Almuhannadi H
• Gad H
• Malik RA

• KMID: 2418714
• DOI: http://doi.org/10.4093/dmj.2018.0056

Abstract

There are potentially many ways of assessing diabetic peripheral neuropathy (DPN). However, they do not fulfill U.S. Food and Drug Administration (FDA) requirements in relation to their capacity to assess therapeutic benefit in clinical trials of DPN. Over the past several decades symptoms and signs, quantitative sensory and electrodiagnostic testing have been strongly endorsed, but have consistently failed as surrogate end points in clinical trials. Therefore, there is an unmet need for reliable biomarkers to capture the onset and progression and to facilitate drug discovery in DPN. Corneal confocal microscopy (CCM) is a non-invasive ophthalmic imaging modality for in vivo evaluation of sensory C-fibers. An increasing body of evidence from multiple centers worldwide suggests that CCM fulfills the FDA criteria as a surrogate endpoint of DPN.

Keyword

Complications; Diabetic neuropathies; Diagnosis

MeSH Terms

Biomarkers
Diabetic Neuropathies*
Diagnosis
Drug Discovery
Microscopy, Confocal
Peripheral Nervous System Diseases
United States Food and Drug Administration
Biomarkers

Figure

• 

  Fig. 1 Corneal confocal microscopy images of the subbasal nerve plexus from a control subject (A) and patients with mild (B), moderate (C), and severe (D) diabetic neuropathy demonstrating a progressive reduction in corneal nerve fibers (red arrows) and corneal nerve branches (yellow arrows).

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102. Azmi S, Ferdousi M, Alam U, Petropoulos IN, Ponirakis G, Marshall A, Asghar O, Fadavi H, Jones W, Tavakoli M, Boulton AJM, Jeziorska M, Soran H, Efron N, Malik RA. Small-fibre neuropathy in men with type 1 diabetes and erectile dysfunction: a cross-sectional study. Diabetologia. 2017; 60:1094–1101. PMID: 28357503.

103. Kalteniece A, Ferdousi M, Petropoulos I, Azmi S, Adam S, Fadavi H, Marshall A, Boulton AJM, Efron N, Faber CG, Lauria G, Soran H, Malik RA. Greater corneal nerve loss at the inferior whorl is related to the presence of diabetic neuropathy and painful diabetic neuropathy. Sci Rep. 2018; 8:3283. PMID: 29459766.

104. Wu T, Ahmed A, Bril V, Orszag A, Ng E, Nwe P, Perkins BA. Variables associated with corneal confocal microscopy parameters in healthy volunteers: implications for diabetic neuropathy screening. Diabet Med. 2012; 29:e297–e303. PMID: 22519850.

105. Sivaskandarajah GA, Halpern EM, Lovblom LE, Weisman A, Orlov S, Bril V, Perkins BA. Structure-function relationship between corneal nerves and conventional small-fiber tests in type 1 diabetes. Diabetes Care. 2013; 36:2748–2755. PMID: 23579181.

106. Petropoulos IN, Green P, Chan AW, Alam U, Fadavi H, Marshall A, Asghar O, Efron N, Tavakoli M, Malik RA. Corneal confocal microscopy detects neuropathy in patients with type 1 diabetes without retinopathy or microalbuminuria. PLoS One. 2015; 10:e0123517. PMID: 25853247.

107. Gotze A, von Keyserlingk S, Peschel S, Jacoby U, Schreiver C, Kohler B, Allgeier S, Winter K, Rohlig M, Junemann A, Guthoff R, Stachs O, Fischer DC. The corneal subbasal nerve plexus and thickness of the retinal layers in pediatric type 1 diabetes and matched controls. Sci Rep. 2018; 8:14. PMID: 29311586.

108. Tavakoli M, Kallinikos P, Iqbal A, Herbert A, Fadavi H, Efron N, Boulton AJ, Malik RA. Corneal confocal microscopy detects improvement in corneal nerve morphology with an improvement in risk factors for diabetic neuropathy. Diabet Med. 2011; 28:1261–1267. PMID: 21699561.

109. Azmi S, Ferdousi M, Petropoulos IN, Ponirakis G, Fadavi H, Tavakoli M, Alam U, Jones W, Marshall A, Jeziorska M, Boulton AJ, Efron N, Malik RA. Corneal confocal microscopy shows an improvement in small-fiber neuropathy in subjects with type 1 diabetes on continuous subcutaneous insulin infusion compared with multiple daily injection. Diabetes Care. 2015; 38:e3–e4. PMID: 25538321.

110. Tavakoli M, Mitu-Pretorian M, Petropoulos IN, Fadavi H, Asghar O, Alam U, Ponirakis G, Jeziorska M, Marshall A, Efron N, Boulton AJ, Augustine T, Malik RA. Corneal confocal microscopy detects early nerve regeneration in diabetic neuropathy after simultaneous pancreas and kidney transplantation. Diabetes. 2013; 62:254–260. PMID: 23002037.

111. van Velzen M, Heij L, Niesters M, Cerami A, Dunne A, Dahan A, Brines M. ARA 290 for treatment of small fiber neuropathy in sarcoidosis. Expert Opin Investig Drugs. 2014; 23:541–550.

112. Dahan A, Dunne A, Swartjes M, Proto PL, Heij L, Vogels O, van Velzen M, Sarton E, Niesters M, Tannemaat MR, Cerami A, Brines M. ARA 290 improves symptoms in patients with sarcoidosis-associated small nerve fiber loss and increases corneal nerve fiber density. Mol Med. 2013; 19:334–345. PMID: 24136731.

113. Culver DA, Dahan A, Bajorunas D, Jeziorska M, van Velzen M, Aarts LPHJ, Tavee J, Tannemaat MR, Dunne AN, Kirk RI, Petropoulos IN, Cerami A, Malik RA, Brines M. Cibinetide improves corneal nerve fiber abundance in patients with sarcoidosis-associated small nerve fiber loss and neuropathic pain. Invest Ophthalmol Vis Sci. 2017; 58:BIO52–BIO60. PMID: 28475703.

114. Brines M, Dunne AN, van Velzen M, Proto PL, Ostenson CG, Kirk RI, Petropoulos IN, Javed S, Malik RA, Cerami A, Dahan A. ARA 290, a nonerythropoietic peptide engineered from erythropoietin, improves metabolic control and neuropathic symptoms in patients with type 2 diabetes. Mol Med. 2015; 20:658–666. PMID: 25387363.

115. Lewis EJH, Perkins BA, Lovblom LE, Bazinet RP, Wolever TMS, Bril V. Effect of omega-3 supplementation on neuropathy in type 1 diabetes: a 12-month pilot trial. Neurology. 2017; 88:2294–2301. PMID: 28515269.

116. Davidson EP, Coppey LJ, Shevalye H, Obrosov A, Kardon RH, Yorek MA. Impaired corneal sensation and nerve loss in a type 2 rat model of chronic diabetes is reversible with combination therapy of menhaden oil, α-lipoic acid, and enalapril. Cornea. 2017; 36:725–731. PMID: 28476051.

117. Pritchard N, Edwards K, Russell AW, Perkins BA, Malik RA, Efron N. Corneal confocal microscopy predicts 4-year incident peripheral neuropathy in type 1 diabetes. Diabetes Care. 2015; 38:671–675. PMID: 25573881.

118. Lovblom LE, Halpern EM, Wu T, Kelly D, Ahmed A, Boulet G, Orszag A, Ng E, Ngo M, Bril V, Perkins BA. In vivo corneal confocal microscopy and prediction of future-incident neuropathy in type 1 diabetes: a preliminary longitudinal analysis. Can J Diabetes. 2015; 39:390–397. PMID: 25936902.

119. Azmi S, Ferdousi M, Petropoulos IN, Ponirakis G, Alam U, Fadavi H, Asghar O, Marshall A, Atkinson AJ, Jones W, Boulton AJ, Tavakoli M, Jeziorska M, Malik RA. Corneal confocal microscopy identifies small-fiber neuropathy in subjects with impaired glucose tolerance who develop type 2 diabetes. Diabetes Care. 2015; 38:1502–1508. PMID: 25877814.

120. Perkins BA, Lovblom LE, Bril V, Edwards K, Pritchard N, Russell A, Pacaud D, Romanchuk K, Mah J, Boulton A, Jeziorska M, Marshall A, Shtein RM, Pop-Busui R, Feldman EL, Lentz SI, Tavakoli M, Efron N, Malik RA. Results of an International Corneal Confocal Microscopy (CCM) Consortium: a pooled multicentre analysis of the concurrent diagnostic validity of CCM to identify diabetic polyneuropathy in type 1 diabetes mellitus. Can J Diabetes. 2016; 40(5 Suppl):S20.

121. Tavakoli M, Marshall A, Banka S, Petropoulos IN, Fadavi H, Kingston H, Malik RA. Corneal confocal microscopy detects small-fiber neuropathy in Charcot-Marie-Tooth disease type 1A patients. Muscle Nerve. 2012; 46:698–704. PMID: 22996176.

122. Kemp HI, Petropoulos IN, Rice ASC, Vollert J, Maier C, Sturm D, Schargus M, Peto T, Hau S, Chopra R, Malik RA. Use of corneal confocal microscopy to evaluate small nerve fibers in patients with human immunodeficiency virus. JAMA Ophthalmol. 2017; 135:795–800. PMID: 28594979.

123. Tavakoli M, Marshall A, Pitceathly R, Fadavi H, Gow D, Roberts ME, Efron N, Boulton AJ, Malik RA. Corneal confocal microscopy: a novel means to detect nerve fibre damage in idiopathic small fibre neuropathy. Exp Neurol. 2010; 223:245–250. PMID: 19748505.

124. Tavakoli M, Marshall A, Thompson L, Kenny M, Waldek S, Efron N, Malik RA. Corneal confocal microscopy: a novel noninvasive means to diagnose neuropathy in patients with Fabry disease. Muscle Nerve. 2009; 40:976–984. PMID: 19902546.

125. Schneider C, Bucher F, Cursiefen C, Fink GR, Heindl LM, Lehmann HC. Corneal confocal microscopy detects small fiber damage in chronic inflammatory demyelinating polyneuropathy (CIDP). J Peripher Nerv Syst. 2014; 19:322–327. PMID: 25582791.

126. Ferdousi M, Azmi S, Petropoulos IN, Fadavi H, Ponirakis G, Marshall A, Tavakoli M, Malik I, Mansoor W, Malik RA. Corneal confocal microscopy detects small fibre neuropathy in patients with upper gastrointestinal cancer and nerve regeneration in chemotherapy induced peripheral neuropathy. PLoS One. 2015; 10:e0139394. PMID: 26430773.

127. Shetty R, Deshmukh R, Shroff R, Dedhiya C, Jayadev C. Subbasal nerve plexus changes in chronic migraine. Cornea. 2018; 37:72–75. PMID: 28990996.

128. Kass-Iliyya L, Javed S, Gosal D, Kobylecki C, Marshall A, Petropoulos IN, Ponirakis G, Tavakoli M, Ferdousi M, Chaudhuri KR, Jeziorska M, Malik RA, Silverdale MA. Small fiber neuropathy in Parkinson's disease: a clinical, pathological and corneal confocal microscopy study. Parkinsonism Relat Disord. 2015; 21:1454–1460. PMID: 26578039.

129. Ferrari G, Grisan E, Scarpa F, Fazio R, Comola M, Quattrini A, Comi G, Rama P, Riva N. Corneal confocal microscopy reveals trigeminal small sensory fiber neuropathy in amyotrophic lateral sclerosis. Front Aging Neurosci. 2014; 6:278. PMID: 25360111.

130. Khan A, Akhtar N, Kamran S, Ponirakis G, Petropoulos IN, Tunio NA, Dargham SR, Imam Y, Sartaj F, Parray A, Bourke P, Khan R, Santos M, Joseph S, Shuaib A, Malik RA. Corneal confocal microscopy detects corneal nerve damage in patients admitted with acute ischemic stroke. Stroke. 2017; 48:3012–3018. PMID: 29018135.

131. Petropoulos IN, Kamran S, Li Y, Khan A, Ponirakis G, Akhtar N, Deleu D, Shuaib A, Malik RA. Corneal confocal microscopy: an imaging endpoint for axonal degeneration in multiple sclerosis. Invest Ophthalmol Vis Sci. 2017; 58:3677–3681. PMID: 28727882.

132. Bitirgen G, Akpinar Z, Malik RA, Ozkagnici A. Use of corneal confocal microscopy to detect corneal nerve loss and increased dendritic cells in patients with multiple sclerosis. JAMA Ophthalmol. 2017; 135:777–782. PMID: 28570722.

133. Mikolajczak J, Zimmermann H, Kheirkhah A, Kadas EM, Oberwahrenbrock T, Muller R, Ren A, Kuchling J, Dietze H, Pruss H, Paul F, Hamrah P, Brandt AU. Patients with multiple sclerosis demonstrate reduced subbasal corneal nerve fibre density. Mult Scler. 2017; 23:1847–1853. PMID: 27811337.