Neuropathy Secondary to Inflammation

The prevailing theory is that VVS is a neuropathic disorder involving abnormal pain perception, postulated to result from sensitization of the vestibular nerve fibers and the establishment of a sympathetically maintained pain loop. In this theory, unidentified trigger events (presumably some form of chronic inflammation) activate and cause prolonged firing of the sympathetic Type C nerve fibers responsible for transmitting noxious chemical or thermal stimuli to the brain; this, in turn, causes the wide dynamic range neurons in the brain to respond abnormally, such that mild stimuli are perceived as pain. The process has been suggested first to result in the localized pain of VVS, then to progress to the chronic, generalized vulvar pain of dysesthetic vulvodynia (21).

Several lines of investigation support a neuropathic etiology for VVS. Consistent with other neuropathic pain syndromes, thresholds to thermal and mechanical stimuli are lowered in VVS patients (4,5,22). The affected tissue is hyperalgesic to thermal, tactile, and pressure stimuli, sometimes involving a hyperpathic "after pain" that lasts for minutes after removal of the stimulus (5). Neuronal hyperplasia is observed in the most afflicted areas of the vestibular tissue (20,23,24). Neurochemical characterization of these free nerve endings indicates that they are nociceptors responsible for transmitting noxious stimuli to the brain (25). Doppler perfusion imaging has revealed heightened erythema and increased superficial blood flow in the posterior vestibule of VVS patients, which suggests either the presence of classic inflammation or neurogenically induced vasodilation (26).

Recent evidence highlights a potential genetic predisposition to chronic inflammation among VVS-afflicted women. Proinflammatory variants of the polymorphic interleukin-1 receptor antagonist gene and the melanocortin-1 receptor gene are substantially more prevalent in VVS patients (27,28). The risk of VVS rises additively in women who carry proinflammatory variants of both genes (28). Homozygosity for allele 2 of the interleukin-1 receptor antagonist gene leads to a reduced capacity to terminate an inflammatory response. Notably, markedly reduced induction of interleukin-1 receptor antagonist was observed in the blood of VVS patients compared to controls (29).

Separately, a deficiency in interferon-« production, unrelated to these genotypes, may contribute to the chronic vestibular inflammation in a subset of VVS patients by reducing their ability to combat intracellular infection (30). Some VVS patients have impaired natural killer cell function, which is involved in tumor surveillance and antiviral immune activity (31). Studies have also demonstrated significantly reduced estrogen receptor expression in localized regions of the vestibular mucosa from VVS patients (32). Because estrogen both stimulates the antibody response and inhibits T-cell mediated inflammation, localized insensitivity to circulating estrogen may increase vulvar susceptibility to inflammation caused by infectious agents.

Although these lines of evidence support a pathogenic role for inflammation, they do not establish a causative relationship to nociceptor sensitization and hyperproliferation. Associations between an altered pattern of innervation of the posterior vestibule and local tissue inflammation (33) and between hyperin-nervation of the vestibular epithelium and the number of degranulated mast cells around the vestibular glands are suggestive (20). Conversely, other researchers have found no evidence for active tissue inflammation in VVS patients, as assessed by inflammatory markers (cyclo-oxygenase-2 and inducible nitric oxide synthase) that are usually upregulated during the inflammatory process. A complicating factor in identifying possible inflammatory triggers is the delay between first onset of symptoms and first diagnosis; inflammation associated with an initiating event either may subside by the time patients are evaluated or may persist only in the most severe cases.

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