Small fiber neuropathy or small fiber pathology?
It is likely that different mechanisms of nerve fiber degeneration are operating in small fiber pathology vs small fiber neuropathy. This distinction is, at present, necessarily based on different phenotypes, as our current knowledge does not allow a mechanistic classification. Small fiber neuropathy is clinically defined by the presence of characteristic manifestations, mostly painful, that are directly related to small fiber damage.4,8 This often occurs in the context of systemic diseases, such as diabetes mellitus, which presents with a typical clinical picture of small fiber neuropathy, associated or not with other manifestations of the disease.4,8 The same is true for Fabry disease which can manifest with symptoms and signs characteristic of small fiber neuropathy (and not simply small fiber pathology). This is appropriately shown by Üçeyler in Table 1,9 listing Fabry disease among potential etiologies of small fiber neuropathy, but contradictorily, Fabry disease is discussed under the heading “Small fiber pathology in other diseases.”
The term small fiber pathology is used to designate findings of abnormal small fiber tests in painful or painless disorders with distinct clinical presentation and disease pathophysiology. For instance, small fiber impairment has been clearly demonstrated in Parkinson disease5 and amyotrophic lateral sclerosis1 in the absence of a definite clinical correlate. Fibromyalgia syndrome is an intriguing example of small fiber pathology,10 in that (neuropathic?) pain, although often prominent, is only part of a constellation of symptoms, and there is no evidence that small fiber involvement plays a primary role in its pathophysiology. However, it should be further clarified whether the subgroup of patients with fibromyalgia with small fiber pathology may constitute a discrete phenotype. It could be, for instance, that in these patients, small fiber damage acts as a triggering factor or represents the hallmark of a transition form with non–length dependent small fiber neuropathy.3,6 However, classifying postherpetic neuralgia as small fiber pathology is questionable, as in this condition, small fiber damage, although topographically circumscribed, is directly responsible for typical painful symptoms and signs,2 consistent with the defining features of small fiber neuropathy.
I agree with Dr. Üçeyler that a clear-cut differentiation of small fiber pathology from small fiber neuropathy is essential for ensuring the most effective therapeutic strategy and may offer new clues to the pathophysiology of small fibers. Furthermore, peculiar mechanisms specific to the associated diseases could be identified, as exemplified in a mouse model of amyotrophic lateral sclerosis displaying small fiber pathology caused by accumulation of a peripherin splice variant, which precedes the onset of motor neuron disease.