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. 2019 Sep;6(9):1718-1727.
doi: 10.1002/acn3.50865. Epub 2019 Aug 15.

Measuring peripheral nerve involvement in Friedreich's ataxia

Peter D Creigh  1 , Joan Mountain  1 , Janet E Sowden  1 , Katy Eichinger  1 , Bernard Ravina  1   2 , Jane Larkindale  3 , David N Herrmann  1
Affiliations

Measuring peripheral nerve involvement in Friedreich's ataxia

Peter D Creigh et al. Ann Clin Transl Neurol. 2019 Sep.

Abstract

Objective: Experimental therapies under development for Friedreich's Ataxia (FRDA) require validated biomarkers. In-vivo reflectance confocal microscopy (RCM) of skin is a noninvasive way to quantify Meissner's corpuscle (MC) density and has emerged as a sensitive measure of sensory polyneuropathies. We conducted a prospective, cross-sectional study evaluating RCM of MCs and conventional peripheral nerve measures as candidate peripheral nerve markers in FRDA.

Methods: Sixteen individuals with FRDA and 16 age- and gender-matched controls underwent RCM of MC density and morphology, skin biopsies for epidermal nerve fiber density (ENFD), nerve conduction studies (NCS), and quantitative sensory testing (QST) including touch, vibration, and cooling thresholds.

Results: MC densities were measurable in all participants with FRDA, and were lower at digit V (hand), thenar eminence, and arch (foot) compared to controls. By contrast, sensory NCS showed floor effects and were obtainable in only 13% of FRDA participants. QST thresholds for touch, vibration, and cooling were higher at the hand and foot in FRDA than controls. Reductions in ENFDs were present in more severely affected individuals with FRDA (Friedreich's Ataxia Rating Scale (FARS) >60) compared to matched controls, although skin biopsies were not well tolerated in children. MC densities, ENFDs, and touch and vibration thresholds were associated with clinical disease severity (FARS and modified FARS) and duration since symptom onset.

Interpretation: MC density, ENFD, and QST thresholds provide structural and physiologic markers of sensory involvement in FRDA. Longitudinal evaluation is needed to determine whether these measures can identify changes associated with disease progression or treatment.

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Conflict of interest statement

P.D.C., J.M., J.E.S., K.E., and D.N.H. received grant support from Friedreich's Ataxia Research Alliance and Voyager Pharmaceuticals for this work. P.D.C., J.M., and J.E.S. report no other disclosures. K.E. has done consulting for Acceleron Pharma and Ionis Pharmaceuticals and is on the scientific advisory board for Biogen. D.N.H. has done consulting for Acceleron Pharma, Flex Pharma, Narrow River Management, Guidepoint Global, GLG, Slingshot Insights, LAM Therapeutics, Inc., Voyager Therapeutics, ClearView Health Partners, MedPace, DDB Health NY, Cydan, Trinity Partners, Schlesinger, Human First Therapeutics and is on the scientific advisory board for Regenancy Pharmaceuticals. J.L. is an employee of the Critical Path Institute and the Friedreich's Ataxia Research Alliance. B.R. was an employee at Voyager Therapeutics during the conduct of this study and is now an employee at Praxis Precision Medicines. The University of Rochester co‐holds a use patent for in‐vivo reflectance confocal microscopy of Meissner’s corpuscles in peripheral neuropathy. D.N.H. is listed as a coinventor on this patent.

Figures

Figure 1
Figure 1
In‐vivo reflectance confocal microscopy images of Meissner’s corpuscles. Representative 0.75 mm × 0.75 mm images obtained from the palmar surface of the distal phalanx of digit V using in‐vivo reflectance confocal microscopy illustrating progressively lower Meissner’s corpuscle density between (A) a control subject, (B) a subject with Friedreich’s Ataxia with less severe clinical manifestations (FARS < 60), and (C) a subject with Friedreich’s Ataxia with more severe clinical manifestations (FARS > 60). White arrows highlight Meissner’s corpuscles.
Figure 2
Figure 2
Correlations between Meissner’s corpuscle (MC) densities (at the fingertip (Digit V), thenar eminence (TE), and arch of the foot) and Friedreich’s Ataxia Rating Scale (FARS), modified FARS, and duration since symptom onset in participants with Friedreich’s Ataxia. R values represent Spearman’s rank correlation coefficients.
See this image and copyright information in PMC

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