Small Fiber Neuropathy in Veterans With Gulf War Illness

Discussion

Biopsy-confirmed SFN was present in more than half of our sample of veterans with GWI, which is broadly consistent with what has been reported in the literature.^13,35-38 In this clinical observation study, SFN was similarly prevalent in veterans with and without GWI; although it should be noted that biopsies only were obtained when there was a strong clinical suspicion for SFN. Almost half of patients with GWI did not have SFN, so our study does not support SFN as the underlying explanation for all GWI. Although our data cannot provide clinical guidance as to when skin biopsy may be indicated in GWI, work done in fibromyalgia found symptoms of dysautonomia and paresthesias are more specific for SFN and may be useful to help guide medical decision making.³⁹

Veterans with GWI in our clinical sample reported a high burden of clinical symptoms conceivably attributable to ANS dysfunction. This symptom reporting is consistent with that seen in other GWI studies, as well as in other studies of SFN.^{4,5,7-9,14,15,34,38,40} Our clinical sample of veterans with GWI found no differences in the ANS symptom reporting between those with and without SFN. Therefore, our study cannot support SFN alone as accounting for ANS symptom burden in patients with GWI.

Two-thirds of biopsy-confirmed SFN in our clinical sample of veterans with GWI could potentially be explained by established medical conditions. As in other studies of SFN, prediabetes and diabetes represented a plurality (46%). Even after considering hyperlipidemia as a potential explanation, about 21% of SFN cases in veterans with GWI still were deemed idiopathic.

Evidence supports certain environmental agents as causal factors for GWI. Neurotoxicants reportedly related to GWI include pesticides (particularly organophosphates and carbamates), pyridostigmine bromide (used during the Gulf War as a prophylactic agent against the use of chemical weapons), and low levels of the nerve agent sarin from environmental contamination due to chemical weapons detonations.¹ Some of these agents have been implicated in neuropathy as well.^1,28-30 It is biologically plausible that deployment-related exposures could trigger SFN, though the traditional consensus has been that remote exposure to neurotoxic substances is unlikely to produce neuropathy that presents many years after the exposure.⁴¹ In the WRIISC clinical experience, however, veterans often report that their neuropathic symptoms predate the diagnosis of the associated medical conditions, sometimes by decades. It is conceivable that remote exposures may trigger the condition that is then potentiated by ongoing exposures, metabolic factors, and/or other medical conditions. These may perpetuate neuropathic symptoms and the illness experience of affected veterans. Our clinical observation study cannot clarify the extent to which this may be the case. Despite these findings and arguments, an environmental contribution to SFN cannot be discounted, and further research is needed to explore a potential relationship.

Limitations

This study’s conclusions are limited by its observational/retrospective design in a relatively small clinical sample of veterans evaluated at a tertiary referral center for postdeployment exposure-related health concerns. The WRIISC clinical sample is not representative of all GWVs or even of all veterans with GWI, as there is inherent selection bias as to who gets referred to and evaluated at the WRIISC. As with studies based on retrospective chart review, data are reliant on clinical documentation andaccuracy/consistency of the reviewer. Evaluation for SFN with skin biopsy is an invasive procedure and was performed when a high index of clinical suspicion for this condition existed, possibly representing confirmation bias. Therefore, the relatively high prevalence ofbiopsy-confirmed SFN seen in our clinical sample cannot be generalized to GWVs as a whole or even to veterans with GWI.