Widespread effects of clinically unilateral focal nerve injuries.

Letter To Editor: We admired the recent article by Younis et al. in which they performedbilateral quantitative sensory testing on both sides of the face and on 1 hand of patients with unilateral presurgical trigeminal neuralgia (TN). Their goal was to evaluate the long-standing impression that neurological deficits in TN are restricted to the classical receptive field of the damaged trigeminal division(s). They meticulously studied 36 patients with concealed endophenotype and compared results between those with or without persistent pain between TN attacks. Comparing participants’ quantitative sensory testing data to external normative references revealed that participants had mechanical and thermal sensory abnormalities not only in the TN-affected face but also in their contralesional mirror-image asymptomatic face and in their hands. These widespread subclinical abnormalities were attributed to undefined central nervous system abnormalities (“central sensitization”). 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. 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. Focal trigeminal lesions and systemic “small-fiber” polyneuropathies both cause clearly detectable damage. 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. 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 6 989.0 mm/frame, HSV—595.8 6 358.1, HZO—595.8 6 358.1; both P , 0.001), but also in the contralesional clinically unaffected corneas of patients with HSV (992.76 465.0;P, 0.01) and thosewith HZO (1053.16 441.4; P , 0.01). This pathology correlated with deficits in corneal nociceptive function. The contralesional losses were not merely due to spreading infection, because unilateral axotomyof the ciliary ophthalmic branches of V1 in mice causes similar contralesional changes by day 1 after surgery. The anatomical pathway may involve the small number of fibers that each eye (and other trigeminally innervated tissues) sends to the contralateral peripheral Gasserian ganglion. Plus, some central axons of peripheral trigeminal afferents project to both the contralateral and ipsilateral central trigeminal nuclei. This contralesional corneal denervation may involve the leukocyte infiltration we saw in the contralateral asymptomatic eyesof 28patientswith acute unilateral bacterial keratitis. Others have reported similar findings. The contralesional effects of unilateral nerve injuries are not restricted to the face. Protein gene product (PGP) 9.5immunolabeled 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. These findings were reproduced in a surgical-injury rat model, confirming that they did not merely reflect infectious spread. Unilateral nerve damage can cause mirror-image altered function of nociceptive terminals, pain-related behaviors, and changes in peripheral sensory ganglia and in the dorsal horn, presumably involving the dorsal commissure connecting the left and right dorsal horns. And what of the findings of Younis et al. of thermal and mechanical changes in their subjects’ hands? The contralesional changes above are generally restricted to the mirror-image receptive fields. But one does not necessarily need to invoke the catch-all “central sensitization”. Evidence going back to the increased prevalence of carpal tunnel syndrome in diabetics