Neurology -- Correspondence for Herrmann et al., 69 (23) 2121-2127

Correspondence published:

In vivo confocal microscopy of Meissner corpuscles as a measure of sensory neuropathy: Maria Nolano, Vincenzo Provitera and Lucio Santoro (5 March 2008)

Reply from the authors: David N. Herrmann, J Neil Boger, Cortney Jansen, Christi Alessi-Fox (5 March 2008)

In vivo confocal microscopy of Meissner corpuscles as a measure of sensory neuropathy 5 March 2008

Maria Nolano,
Neurology Division,
"S. Maugeri" Foundation I.R.C.C.S., Via Bagni Vecchi, 1 - 82037 Telese Terme (BN), Italy,
Vincenzo Provitera and Lucio Santoro
Send Correspondence to journal:
Re: In vivo confocal microscopy of Meissner corpuscles as a measure of sensory neuropathy

maria.nolano{at}fsm.it Maria Nolano, et al.

We read the interesting article by Herrmann et al. on the use of reflectance confocal microscopy (RCM) to measure sensory neuropathy. [1] Cutaneous innervation studies which evaluate the last endings of nerve fibers are useful in the early diagnosis of sensory neuropathies that share a "dying back" progression. We observed some conditions including small fiber neuropathies and Ross syndrome in which the neuropathic process seemed confined to cutaneous receptors. [2,3] The availability of a non-invasive method to evaluate the density of Meissner corpuscles (MC) could be a powerful tool in revealing a sensory defect.
As observed by the authors, the mean values of MC density (12±5.3/mm2) obtained using RCM are lower than values we obtained using immunohistochemistry (33±13.2/mm2). [4] But if we correct the absolute values for tissue shrinkage (correction factor =0.45), we obtain figures similar to those of Herrmann and colleagues. However, we evaluated the third fingertip where density is even lower than in the fifth fingertip. [4,5] Therefore the two methods provide different MC counts.
Part of this discrepancy can be attributed to the possibility that RCM misses some corpuscles. Authors observed zero, one, and occasionally two corpuscles per dermal papilla, while we often found two corpuscles in the same papilla. The possibility of finding three or more corpuscles in the same papilla is not uncommon. [4]
It is possible that RCM cannot discriminate two receptors in the same dermal papilla if they are very close. Moreover, sometimes two corpuscles are placed on the same vertical axis, one on top of the other. Due to the distance (30 micrometers) between subsequent optical cuts, RCM can miss the gap separating the corpuscles. In addition, as the authors stated, RCM cannot currently give information on MC abnormalities or on MC innervation and deafferented corpuscles cannot be excluded by their count.
We think that RCM may be a useful first-level diagnostic tool to screen and follow up sensory neuropathies. However, currently, it cannot replace skin biopsy in evaluating morphology or morphometry of MC and their myelinated endings.
References
1. Herrmann DN, Boger JN, Jansen C, Alessi-Fox C.In vivo confocal microscopy of Meissner corpuscles as a measure of sensory neuropathy. Neurology. 2007;69:2121-2127.
2. Nolano M, Provitera V, Stancanelli A, Saltalamacchia AM, Lanzillo B, Santoro L. Does small fiber neuropathy affect selectively small fibers? J Peripher Nerv Syst 2005;10:67–68.
3. Nolano M, Provitera V, Perretti A, et al. Ross syndrome: a rare or a misknown disorder of thermoregulation? A skin innervation study on 12 subjects. Brain. 2006;129:2119-2131.
4. Nolano M, Provitera V, Crisci C, et al. Quantification of myelinated endings and mechanoreceptors in human digital skin. Ann Neurol. 2003;54:197-205.
5. Bolton CF, Winkelmann RK, Dyck PJ. A quantitative study of Meissner's corpuscles in man. Neurology 1966;16:1-9.
Disclosure: The authors report no conflicts of interest.

Reply from the authors 5 March 2008

David N. Herrmann,
University of Rochester, Departments of Neurology and Pathology
601 Elmwood Avenue, Rochester, NY, 14642,
J Neil Boger, Cortney Jansen, Christi Alessi-Fox
Send Correspondence to journal:
Re: Reply from the authors

david_herrmann{at}urmc.rochester.edu David N. Herrmann, et al.

We thank Nolano et al. for their interest in our study. [1] Their elegant immunofluorescent confocal microscopy studies of MCs in skin biopsies, coupled with earlier work on MCs in peripheral neuropathies, stimulated our interest in this area. [2-5]
They pointed out that if a correction factor is used for tissue shrinkage, then the values they reported for fingertip MC density are not dissimilar to those observed in our RCM study. Ours was a pilot study with a small number of controls and additional studies will assess MC densities on RCM in a larger cohort to develop normative data for the technique.
Beyond “correction factors”, it is likely that different approaches will yield varying density estimates depending in part on counting conventions and visualization methods. For example, different normative ranges for epidermal nerve fiber density have been reported for an immunofluorescence confocal microscopy method, and a light microscopic approach. [6-8] This underscores the importance of referencing counts of MCs on RCM to normative data obtained using RCM, rather than from skin biopsies.
Nolano et al. suggest that RCM may not separate out MCs that are closely apposed. RCM has a horizontal axis resolution of 0.5-1 um. If there is a critical gap between adjacent MCs, separate counts should be possible. Regarding resolution of MCs that may occasionally be in the same vertical plane, we are in an ongoing study conducting RCM at smaller 20 um optical section intervals and comparing images at each of eight successive depths. Optical RCM sections can be obtained at 1um intervals in the Z-axis, so it should be feasible to determine optimal sampling for closely spaced MCs in this plane.
If detailed morphometry, morphology and molecular information are required to address a research question, then immunofluorescent confocal microscopy of MCs is a powerful, standard approach. [2-4] For screening, diagnosis and monitoring of SN clinically and potentially in therapeutic trials, a non-invasive approach such as in-vivo RCM is attractive. MC densities alone have shown promise as a measure in various chronic neuropathies. [2-5,9]
More experience is required with in-vivo RCM to see if it will yield useful information beyond MC density on the health of MCs. As has occurred with other imaging platforms such as MRI, with development of the technology and clinical and pathological correlations, further data will emerge about the imaging and signal characteristics of different pathologic states.
References
6. Kennedy WR, Wendelschafer Crabb G, Johnson T. Quantitation of epidermal nerves in diabetic neuropathy. Neurology 1996;47:1042 1048.
7. Periquet I, Novak V, Collins M, et al. Painful sensory neuropathy; prospective evaluation using skin biopsy. Neurology 1999; 53:1641-1647.
8. McArthur JC, Stocks EA, Hauer P, Cornblath DR, Griffin JW. Epidermal nerve fiber density: normative reference range and diagnostic efficiency. Arch Neurol 1998;55:1513-1520.
9. Nolano M, Provitera V, Lullo F, et al. Tactile stimulation and mechanoreceptors in sensory neuropathies. Neurol Sci 2001; 22:S31–S36.
Disclosure: The authors report no conflicts of interest.