DN4 Is Not a Screening Tool for Small Fiber Neuropathy: An Expected Result

To the Editor,

In their remarkable study, Frachet and colleagues demonstrate the inaccuracy of the I‐DN4 questionnaire for diagnosing small fiber neuropathy (SFN) in a large cohort of 872 patients [1]. This result fully confirms the limitations of the DN4 questionnaire and was expected for several reasons.

Frachet et al. correctly defined the presence of SFN as a loss of small nerve fibers on skin biopsy with a reduced intraepidermal nerve fiber density (IEFND) and pinprick hypoesthesia on clinical examination. The reduction of IENFD is causally associated with negative sensory symptoms, whereas pain descriptors, as listed in the I‐DN4 questionnaire, are positive sensory symptoms. The lack of correlation between IENFD values and I‐DN4 scores is therefore not surprising, since there is no direct causal link between small fiber loss and the presence of pain [2]. This is why objective tests of small fiber lesion, such as the IENFD, cannot be used to diagnose neuropathic pain [2]. Furthermore, even for this diagnosis, the DN4 questionnaire is inaccurate, mainly because it was designed to distinguish neuropathic pain from nociceptive pain and does not distinguish between neuropathic pain and nociplastic pain [3].

In their definition of SFN, Frachet and colleagues included allodynia in addition to signs of loss of nerve fibers or sensation. It is important to emphasize that, unlike hyperalgesia, not all types of allodynia are due to small fiber dysfunction, and that large‐diameter A‐beta fibers are responsible for most forms of mechanical allodynia.

Finally, it is important to note that lesion‐based SFN with fiber loss, as evidenced by a reduced IEFND, can be accompanied by pain, but not systematically, and that, on the other hand, pain involving small nerve fibers may also occur in the absence of fiber loss with a normal IEFND. These cases, which can be described as “small fibre neuralgia” [4], are related to small fiber hyperexcitability/hyperactivity linked to various pathophysiological mechanisms. This can manifest as sensory symptoms specific to small fiber involvement, such as burning sensations. In this regard, Frachet et al. [1] found that “only the burning sensation was a moderate predictor of the risk of SFN” based on a decrease in the IEFND. In contrast, in a study of patients with familial amyloid polyneuropathy [5], we found that the intensity of persistent burning sensations was inversely correlated with the severity of SFN lesions, as assessed by quantitative thermal sensory testing and laser evoked potentials. These conflicting results clearly illustrate the complex relationship between the loss of small fibers and the concomitant hyperexcitability/hyperactivity of the remaining small fibers that cause burning sensations. In any case, for screening SFN and even to assess the pain components of SFN, the current neuropathic pain questionnaires, such as DN4, lack specificity and new tools are needed to identify the involvement of small fibers according to clinical aspects.

Author Contributions

Jean‐Pascal Lefaucheur: conceptualization, writing – original draft, writing – review and editing, validation.

Conflicts of Interest

The author declares no conflicts of interest.

Linked Articles

This article is linked to https://doi.org/10.1111/ene.70499.

Lefaucheur J.‐P., “ DN4 Is Not a Screening Tool for Small Fiber Neuropathy: An Expected Result,” European Journal of Neurology 33, no. 6 (2026): e70666, 10.1111/ene.70666.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.