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I read with interest the Letter to the Editor by Dr Gemignani on my recent review article about small fiber pathology.13 Dr Gemignani agrees that the distinction between small fiber neuropathy (SFN) and small fiber pathology is increasingly important in view of the rising number of entities such as fibromyalgia syndrome (FMS),1,4,8–10,17 Fabry disease,5,11,12,15,16 amyotrophic lateral sclerosis,18 Friedreich ataxia,6 or Parkinson disease7 showing pathological findings in small nerve fiber tests. The review article13 has, however, also raised several questions that I am happy to comment on.
One question relates to the classification of Fabry-associated neuropathy and pain as SFN or small fiber pathology. Fabry-associated pain is of a very distinct phenotype consisting of episodic and permanent, mostly acral and triggerable, pain.14 It is frequently classified as an SFN because of the key finding of acral burning pain and additional findings in small fiber tests such as elevated thermal perception thresholds, reduced intraepidermal and corneal innervation, and impaired electrical small nerve fiber conductivity.11,14–16 However, new insights from research show that Fabry-associated pain also includes pain that cannot easily be classified as neuropathic at all (eg, pain crises) and mostly responds to treatment that is normally ineffective in neuropathic pain such as nonsteroidal antirheumatics. Thus, the pathophysiological mechanisms underlying pain and small nerve fiber pathology in Fabry disease are yet unclear and go beyond an SFN.
Another question referred to the classification of small fiber impairment in subgroups of patients with FMS and its phenotypic reflection. Small fiber neuropathy particularly needs to be distinguished from small fiber pathology present in FMS subgroups. After the first publication on this topic,17 further analogous8 and complementary10 data have been reported, and a controversial discussion has started on whether or not small fiber impairment contributes to FMS pain. Unfortunately, FMS is often equated with SFN, which is misleading and inadequate because the mechanisms underlying small fiber pathology in FMS are not known so far and because the clinical phenotype of FMS is completely distinct from SFN. An important first step in this area, suggested by Dr Gemignani, would be to thoroughly characterize patients with FMS with and without small fiber pathology to better understand potential mechanistic links. Such a characterisation is not possible with the data published so far because of the limited number of patients investigated in each study; thus, large scale studies are needed to answer this crucial question.
Finally, pain in postherpetic neuralgia (PHN) has elements of an SFN in terms of severe burning often accompanied by allodynia. However, the PHN pain phenotype with its very localized presentation is distinct from SFN that typically affects distal extremities symmetrically—with known variations.2 The viral basis of disease pathophysiology per se is known in herpes zoster. However, it is still unclear why some of these patients develop pain and PHN, while others do not. This, together with the clinical phenotype, allows the categorization as small fiber pathology.
The review article13 also underscores two points. First, those pathological findings on additional small fiber tests such as quantitative sensory testing or skin punch biopsy do not prove SFN or small fiber pathology. Second, the absence of pathological findings in such tests does not disprove small fiber impairment or diagnoses such as FMS. In particular, the strategy of investigating patients without obvious pathological findings with additional tests does teach us to consider the immense importance of clinical phenotypes and patients' pain description when diagnosing SFN or small fiber pathology.3 Further research is needed to better understand the underlying mechanisms of small fiber degeneration and regeneration and dysfunction and to allow pathophysiological rather than clinical classification of damage to the small nerve fibers.
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