Widespread effects of clinically unilateral focal nerve injuries
Aside from the one mention that “peripheral sensitization” could not be excluded, the authors did not reference the robust evidence that unilateral nerve injuries routinely cause functional and anatomical changes in contralesional sensory neurons, as reviewed by Koltzenburg et al.13 The best evidence for the face comes from animal studies of the cornea, and from corneal imaging studies of living patients with laser in vivo confocal microscopy. Its rapid, objective, high-resolution, noninvasive optical sectioning provides a window into the morphology and pathology of the first trigeminal division (V1) nociceptive C-fibers that comprise virtually all corneal innervations.4–6,8,9,28 Focal trigeminal lesions and systemic “small-fiber” polyneuropathies both cause clearly detectable damage.7,21,24 For instance, we used in vivo confocal microscopy to analyze corneal innervation in both eyes of 27 patients with unilateral V1 herpes zoster ophthalmicus (HZO) and 31 patients with unilateral V1 herpes simplex virus (HSV) keratitis, and healthy controls.8,9 Both diseases caused reductions in the number and density of corneal neurites (depicted in Fig. 1). These occurred not only in patients' infected corneas (controls—2258.4 ± 989.0 μm/frame, HSV—595.8 ± 358.1, HZO—595.8 ± 358.1; both P < 0.001), but also in the contralesional clinically unaffected corneas of patients with HSV (992.7 ± 465.0; P < 0.01) and those with HZO (1053.1 ± 441.4; P < 0.01).8,9 This pathology correlated with deficits in corneal nociceptive function. The contralesional losses were not merely due to spreading infection, because unilateral axotomy of the ciliary ophthalmic branches of V1 in mice causes similar contralesional changes by day 1 after surgery.28 The anatomical pathway may involve the small number of fibers that each eye (and other trigeminally innervated tissues)23 sends to the contralateral peripheral Gasserian ganglion.11,20 Plus, some central axons of peripheral trigeminal afferents project to both the contralateral and ipsilateral central trigeminal nuclei.3 This contralesional corneal denervation may involve the leukocyte infiltration we saw in the contralateral asymptomatic eyes of 28 patients with acute unilateral bacterial keratitis.6 Others have reported similar findings.26
The contralesional effects of unilateral nerve injuries are not restricted to the face. Protein gene product (PGP) 9.5-immunolabeled skin biopsies from the torsos of 34 adults with or without postherpetic neuralgia after 1-sided thoracic shingles demonstrated that unilateral postherpetic neuralgia is also associated with bilateral damage to epidermal nociceptors.19 These findings were reproduced in a surgical-injury rat model, confirming that they did not merely reflect infectious spread.18 Unilateral nerve damage can cause mirror-image altered function of nociceptive terminals,1 pain-related behaviors,2 and changes in peripheral sensory ganglia16,17 and in the dorsal horn,15 presumably involving the dorsal commissure connecting the left and right dorsal horns.22,27
And what of the findings of Younis et al.29 of thermal and mechanical changes in their subjects' hands? The contralesional changes above are generally restricted to the mirror-image receptive fields.19 But one does not necessarily need to invoke the catch-all “central sensitization”.