Federal Practitioner

Critical illness is commonly associated with interrelated conditions including pain, agitation, delirium, immobility, and sleep disruption (PADIS). Managing PADIS is often complex and includes pharmacologic and nonpharmacologic interventions.¹ Incorporating multifaceted practices to enhance PADIS management has been shown to improve several intensive care unit (ICU)-related outcomes.²

Many pharmacologic PADIS treatments are ineffective or associated with adverse effects. For example, antipsychotics used for treating ICU-related delirium have not shown improved outcomes.^3,4 Commonly used medications for agitation, such as benzodiazepines, increase delirium risk.^5,6 Because of these limitations, several nonpharmacologic interventions for PADIS have been evaluated.

Pet therapy has been implemented in some ICU settings, but is not widely adopted.⁷ Also referred to as animal-assisted activities, animal-assisted therapy, or animal-assisted interventions, pet therapy typically involves interaction between a patient and a live animal (most commonly a dog) under the direction of an animal handler, with the intention of providing therapeutic benefit. Interactions frequently include meet and greet activities such as petting, but also could include walking or other activities. Pet therapy has been reported to reduce pain, agitation, and stress among ICU patients.⁸ Introducing a pet therapy program with live animals in the ICU could be challenging because of factors such as identifying trained, accredited animals and handlers, and managing infection control and other risks.⁹ As an alternative to live pets, robotic pet therapy has been shown to be beneficial—mostly outside the ICU—in settings such as long-term care.^10,11 Although uncommon, robotic pets have been used in the ICU and hospital settings for therapeutic purposes.¹² Robotic pets reduce many concerns associated with live animals while mimicking the behaviors of live animals and potentially offering many of the same benefits.

OBSERVATIONS

The North Florida/South Georgia Veterans Health System (NF/SGVHS) implemented a novel robotic pet therapy program for patients requiring ICU care to improve the treatment of PADIS. Funding was provided through a Veterans Health Administration Innovation Grant procured by a clinical pharmacy specialist as the program’s champion. Goals of the robotic pet therapy program include reductions in: distressing symptoms associated with PADIS, use of psychoactive drugs and physical restraints, and ICU length of stay. The ICU team developed standard operating procedures and an order menu, which were integrated into the ICU prescriber ordering menu. Patients were selected for pet therapy based on PADIS scores and potential for positive response to pet therapy as assessed by the ICU team.Patients in medical and surgical ICU settings were eligible for the program. The robotic pets used in the program were Joy for All Companion Pets (Ageless Innovation LLC). Robotic cats and dogs were available and pets were “adopted’ by each patient (Figure). As an infection control measure, pets were not reissued or shared amongpatients and pets could be cleaned with a disinfectant solution. Nurses were primarily responsible for monitoring and documenting responses to robotic pet therapy.

It was necessary to secure buy-in from several services to successfully implement the program. The critical care clinical pharmacy specialists were responsible for ordering, storing, and dispensing the robotic pets. The NF/SGVHS innovation specialist helped secure funding, procure the robotic pet, and promote the program. The standard operating procedures for the program were developed by a multidisciplinary team with input from critical care nurses, intensivists, pharmacists, patient safety, and infection control (Table 1). Success of the program also required buy-in from ICU team members.

 

 

Program Impact

A retrospective cohort study was conducted to assess for improvements in PADIS symptoms and medication use post-intervention. Patients were included if they received robotic pet therapy in the ICU from July 10, 2019, to February 1, 2021. Individuals aged < 18 years or > 89 years, were pregnant, or were not receiving ICU-level care were excluded. Outcomes assessed included improvement in pain scores, agitation scores, sleep quality, resolution of delirium, and use of pain or psychoactive medications during patients’ ICU stay.

Thirty patients were included in the study (Table 2). After receiving a robotic pet, 9 (30%) patients recorded decreased pain scores, 15 (50%) recorded decreased agitation scores, 8 (27%) had resolution of delirium, and 2 (7%) described improvement in sleep. Pain medication use decreased in 12 (40%) patients and psychoactive medication use was reduced in 7 (23%) patients.

Limitations

The robotic pet therapy program has shown promising results; however, some aspects merit discussion. Evaluation of this program is limited by factors such as the observational study design, single-center patient sample, and lack of comparator group. Although no known adverse effects of robotic pet therapy were seen, it is possible that some patients may not have a favorable response. Challenges of implementing a robotic pet therapy program include cost and additional operational activities (storage, ordering, dispensing) necessary to maintain the program. Additional research is needed to evaluate the impact of robotic pet therapy on other outcomes including cost, ICU length of stay, and patient satisfaction.

CONCLUSIONS

Robotic pet therapy can be successfully implemented in the ICU and appears to provide a simple, safe, beneficial, nonpharmacologic intervention for PADIS. This study showed that many patients had favorable response to robotic pet therapy, indicating that it may be a viable alternative to traditional pet therapy. Other health systems could benefit from implementing programs similar to the robotic pet therapy program at NF/SGVHS.

Acknowledgments

The author would like to acknowledge Simran Panesar, PharmD, and Theresa Faison, PharmD, for their contributions to this project.

Critical illness is commonly associated with interrelated conditions including pain, agitation, delirium, immobility, and sleep disruption (PADIS). Managing PADIS is often complex and includes pharmacologic and nonpharmacologic interventions.¹ Incorporating multifaceted practices to enhance PADIS management has been shown to improve several intensive care unit (ICU)-related outcomes.²

Many pharmacologic PADIS treatments are ineffective or associated with adverse effects. For example, antipsychotics used for treating ICU-related delirium have not shown improved outcomes.^3,4 Commonly used medications for agitation, such as benzodiazepines, increase delirium risk.^5,6 Because of these limitations, several nonpharmacologic interventions for PADIS have been evaluated.

Pet therapy has been implemented in some ICU settings, but is not widely adopted.⁷ Also referred to as animal-assisted activities, animal-assisted therapy, or animal-assisted interventions, pet therapy typically involves interaction between a patient and a live animal (most commonly a dog) under the direction of an animal handler, with the intention of providing therapeutic benefit. Interactions frequently include meet and greet activities such as petting, but also could include walking or other activities. Pet therapy has been reported to reduce pain, agitation, and stress among ICU patients.⁸ Introducing a pet therapy program with live animals in the ICU could be challenging because of factors such as identifying trained, accredited animals and handlers, and managing infection control and other risks.⁹ As an alternative to live pets, robotic pet therapy has been shown to be beneficial—mostly outside the ICU—in settings such as long-term care.^10,11 Although uncommon, robotic pets have been used in the ICU and hospital settings for therapeutic purposes.¹² Robotic pets reduce many concerns associated with live animals while mimicking the behaviors of live animals and potentially offering many of the same benefits.

OBSERVATIONS

The North Florida/South Georgia Veterans Health System (NF/SGVHS) implemented a novel robotic pet therapy program for patients requiring ICU care to improve the treatment of PADIS. Funding was provided through a Veterans Health Administration Innovation Grant procured by a clinical pharmacy specialist as the program’s champion. Goals of the robotic pet therapy program include reductions in: distressing symptoms associated with PADIS, use of psychoactive drugs and physical restraints, and ICU length of stay. The ICU team developed standard operating procedures and an order menu, which were integrated into the ICU prescriber ordering menu. Patients were selected for pet therapy based on PADIS scores and potential for positive response to pet therapy as assessed by the ICU team.Patients in medical and surgical ICU settings were eligible for the program. The robotic pets used in the program were Joy for All Companion Pets (Ageless Innovation LLC). Robotic cats and dogs were available and pets were “adopted’ by each patient (Figure). As an infection control measure, pets were not reissued or shared amongpatients and pets could be cleaned with a disinfectant solution. Nurses were primarily responsible for monitoring and documenting responses to robotic pet therapy.

It was necessary to secure buy-in from several services to successfully implement the program. The critical care clinical pharmacy specialists were responsible for ordering, storing, and dispensing the robotic pets. The NF/SGVHS innovation specialist helped secure funding, procure the robotic pet, and promote the program. The standard operating procedures for the program were developed by a multidisciplinary team with input from critical care nurses, intensivists, pharmacists, patient safety, and infection control (Table 1). Success of the program also required buy-in from ICU team members.

 

 

Program Impact

A retrospective cohort study was conducted to assess for improvements in PADIS symptoms and medication use post-intervention. Patients were included if they received robotic pet therapy in the ICU from July 10, 2019, to February 1, 2021. Individuals aged < 18 years or > 89 years, were pregnant, or were not receiving ICU-level care were excluded. Outcomes assessed included improvement in pain scores, agitation scores, sleep quality, resolution of delirium, and use of pain or psychoactive medications during patients’ ICU stay.

Thirty patients were included in the study (Table 2). After receiving a robotic pet, 9 (30%) patients recorded decreased pain scores, 15 (50%) recorded decreased agitation scores, 8 (27%) had resolution of delirium, and 2 (7%) described improvement in sleep. Pain medication use decreased in 12 (40%) patients and psychoactive medication use was reduced in 7 (23%) patients.

Limitations

The robotic pet therapy program has shown promising results; however, some aspects merit discussion. Evaluation of this program is limited by factors such as the observational study design, single-center patient sample, and lack of comparator group. Although no known adverse effects of robotic pet therapy were seen, it is possible that some patients may not have a favorable response. Challenges of implementing a robotic pet therapy program include cost and additional operational activities (storage, ordering, dispensing) necessary to maintain the program. Additional research is needed to evaluate the impact of robotic pet therapy on other outcomes including cost, ICU length of stay, and patient satisfaction.

CONCLUSIONS

Robotic pet therapy can be successfully implemented in the ICU and appears to provide a simple, safe, beneficial, nonpharmacologic intervention for PADIS. This study showed that many patients had favorable response to robotic pet therapy, indicating that it may be a viable alternative to traditional pet therapy. Other health systems could benefit from implementing programs similar to the robotic pet therapy program at NF/SGVHS.

Acknowledgments

The author would like to acknowledge Simran Panesar, PharmD, and Theresa Faison, PharmD, for their contributions to this project.

Critical illness is commonly associated with interrelated conditions including pain, agitation, delirium, immobility, and sleep disruption (PADIS). Managing PADIS is often complex and includes pharmacologic and nonpharmacologic interventions.¹ Incorporating multifaceted practices to enhance PADIS management has been shown to improve several intensive care unit (ICU)-related outcomes.²

Many pharmacologic PADIS treatments are ineffective or associated with adverse effects. For example, antipsychotics used for treating ICU-related delirium have not shown improved outcomes.^3,4 Commonly used medications for agitation, such as benzodiazepines, increase delirium risk.^5,6 Because of these limitations, several nonpharmacologic interventions for PADIS have been evaluated.

Pet therapy has been implemented in some ICU settings, but is not widely adopted.⁷ Also referred to as animal-assisted activities, animal-assisted therapy, or animal-assisted interventions, pet therapy typically involves interaction between a patient and a live animal (most commonly a dog) under the direction of an animal handler, with the intention of providing therapeutic benefit. Interactions frequently include meet and greet activities such as petting, but also could include walking or other activities. Pet therapy has been reported to reduce pain, agitation, and stress among ICU patients.⁸ Introducing a pet therapy program with live animals in the ICU could be challenging because of factors such as identifying trained, accredited animals and handlers, and managing infection control and other risks.⁹ As an alternative to live pets, robotic pet therapy has been shown to be beneficial—mostly outside the ICU—in settings such as long-term care.^10,11 Although uncommon, robotic pets have been used in the ICU and hospital settings for therapeutic purposes.¹² Robotic pets reduce many concerns associated with live animals while mimicking the behaviors of live animals and potentially offering many of the same benefits.

OBSERVATIONS

The North Florida/South Georgia Veterans Health System (NF/SGVHS) implemented a novel robotic pet therapy program for patients requiring ICU care to improve the treatment of PADIS. Funding was provided through a Veterans Health Administration Innovation Grant procured by a clinical pharmacy specialist as the program’s champion. Goals of the robotic pet therapy program include reductions in: distressing symptoms associated with PADIS, use of psychoactive drugs and physical restraints, and ICU length of stay. The ICU team developed standard operating procedures and an order menu, which were integrated into the ICU prescriber ordering menu. Patients were selected for pet therapy based on PADIS scores and potential for positive response to pet therapy as assessed by the ICU team.Patients in medical and surgical ICU settings were eligible for the program. The robotic pets used in the program were Joy for All Companion Pets (Ageless Innovation LLC). Robotic cats and dogs were available and pets were “adopted’ by each patient (Figure). As an infection control measure, pets were not reissued or shared amongpatients and pets could be cleaned with a disinfectant solution. Nurses were primarily responsible for monitoring and documenting responses to robotic pet therapy.

It was necessary to secure buy-in from several services to successfully implement the program. The critical care clinical pharmacy specialists were responsible for ordering, storing, and dispensing the robotic pets. The NF/SGVHS innovation specialist helped secure funding, procure the robotic pet, and promote the program. The standard operating procedures for the program were developed by a multidisciplinary team with input from critical care nurses, intensivists, pharmacists, patient safety, and infection control (Table 1). Success of the program also required buy-in from ICU team members.

 

 

Program Impact

A retrospective cohort study was conducted to assess for improvements in PADIS symptoms and medication use post-intervention. Patients were included if they received robotic pet therapy in the ICU from July 10, 2019, to February 1, 2021. Individuals aged < 18 years or > 89 years, were pregnant, or were not receiving ICU-level care were excluded. Outcomes assessed included improvement in pain scores, agitation scores, sleep quality, resolution of delirium, and use of pain or psychoactive medications during patients’ ICU stay.

Thirty patients were included in the study (Table 2). After receiving a robotic pet, 9 (30%) patients recorded decreased pain scores, 15 (50%) recorded decreased agitation scores, 8 (27%) had resolution of delirium, and 2 (7%) described improvement in sleep. Pain medication use decreased in 12 (40%) patients and psychoactive medication use was reduced in 7 (23%) patients.

Limitations

The robotic pet therapy program has shown promising results; however, some aspects merit discussion. Evaluation of this program is limited by factors such as the observational study design, single-center patient sample, and lack of comparator group. Although no known adverse effects of robotic pet therapy were seen, it is possible that some patients may not have a favorable response. Challenges of implementing a robotic pet therapy program include cost and additional operational activities (storage, ordering, dispensing) necessary to maintain the program. Additional research is needed to evaluate the impact of robotic pet therapy on other outcomes including cost, ICU length of stay, and patient satisfaction.

CONCLUSIONS

Robotic pet therapy can be successfully implemented in the ICU and appears to provide a simple, safe, beneficial, nonpharmacologic intervention for PADIS. This study showed that many patients had favorable response to robotic pet therapy, indicating that it may be a viable alternative to traditional pet therapy. Other health systems could benefit from implementing programs similar to the robotic pet therapy program at NF/SGVHS.

Acknowledgments

The author would like to acknowledge Simran Panesar, PharmD, and Theresa Faison, PharmD, for their contributions to this project.

Following deployment to operations Desert Shield and Desert Storm (Gulf War) in 1990 and 1991, many Gulf War veterans (GWVs) developed chronic, complex symptoms, including pain, dyscognition, and fatigue, with gastrointestinal, skin, and respiratory manifestations. This Gulf War Illness (GWI) is reported to affect about 30% of those deployed. More than 30 years later, there is no consensus as to the etiology of GWI, although some deployment-related exposures have been implicated.¹

Accepted research definitions for GWI include the Centers for Disease Control and Prevention and Kansas definitions.² The US Department of Veterans Affairs (VA) uses the terminology chronic multisymptom illness (CMI), which is an overarching diagnosis under which GWI falls. Although there is no consensus case definition for CMI, there is overlap with conditions such as fibromyalgia, myalgic encephalomyelitis/chronic fatigue syndrome, and irritable bowel syndrome; the VA considers these as qualifying clinical diagnoses.³ The pathophysiology of GWI is also unknown, though a frequently reported unifying feature is that of autonomic nervous system (ANS) dysfunction. Studies have demonstrated differences between veterans with GWI and those without GWI in both the reporting of symptoms attributable to ANS dysfunction and in physiologic evaluations of the ANS.^4-10

Small fiber neuropathy (SFN), a condition with damage to the A-δ and C small nerve fibers, has been proposed as a potential mechanism for the pain and ANS dysfunction experienced in GWI.^11-13 Symptoms of SFN are similar to those of GWI, with pain and ANS symptoms commonly reported.^14,15 There are multiple diagnostic criteria for SFN, the most commonly used requiring the presence of appropriate symptoms in the absence of large fiber neuropathy and a skin biopsy demonstrating reduced intraepidermal nerve fiber density.^16-19 Several conditions reportedly cause SFN, most notably diabetes/prediabetes. Autoimmune disease, vitamin B12 deficiency, monoclonal gammopathies, celiac disease, paraneoplastic syndromes, and sodium channel gene mutations may also contribute to SFN.²⁰ Hyperlipidemia has been identified as a contributor, although it has been variably reported.^21,22

Idiopathic neuropathies, SFN included, may be secondary to neurotoxicant exposures. Agents whose exposure or consumption have been associated with SFN include alcohol most prominently, but also the organic solvent n-hexane, heavy metals, and excess vitamin B₆.^20,23-25 Agents associated with large fiber neuropathy may also have relevance for SFN, as small fibers have been likened to the “canary in the coal mine” in that they may be more susceptible to neurotoxicants and are affected earlier in the disease process.²⁶ In this way, SFN may be the harbinger of large fiber neuropathy in some cases. Of specific relevance for GWVs, organophosphates and carbamates are known to produce a delayed onset large fiber neuropathy.^27-30 Exposure to petrochemical solvents has also been associated with large fiber neuropathies.^31,32

The War Related Illness and Injury Study Center (WRIISC) is a clinical, research, and education center established by Congress in 2001. Its primary focus is on military exposures and postdeployment health of veterans. It is located at 3 sites: East Orange, New Jersey; Washington, DC; and Palo Alto, California. The New Jersey WRIISC began a program to evaluate GWVs with characteristic symptoms for possible SFN with use of a skin biopsy.

We hypothesize that SFN may underly much of GWI symptomatology and may not be accounted for by the putative etiologies detailed in review of the medical literature. This retrospective review of clinical evaluations for SFN in GWVs who sought care at the New Jersey WRIISC explored and addressed the following questions: (1) how common is biopsy-confirmed SFN in veterans with GWI; (2) do veterans with GWI and SFN report more symptoms attributable to ANS dysfunction when compared with veterans with GWI and no SFN; and (3) can SFN in veterans with GWI and SFN be explained by conditions and substances commonly associated with SFN? Institutional review board approval and waiver of consent was obtained from the Veterans Affairs New Jersey Health Care Center for the study.

Methods

A retrospective chart review was conducted on veterans evaluated at the WRIISC from March 1, 2015, to January 31, 2019. Inclusion criteria were: deployment to operations Desert Shield and Desert Storm between August 2, 1990, and February 28, 1991, and skin biopsy conducted at the WRIISC. Skin biopsies were obtained at the discretion of an examining clinician based on clinical indications, including neuropathic pain, ANS symptoms, and/or a fibromyalgia/chronic pain–type presentation.

Electronic health record review explicitly abstracted GWI status, results of the skin biopsy, and ANS symptom burden as determined by the Composite Autonomic Symptom Scale 31 (COMPASS 31) completed at the time of the WRIISC evaluation. Determination of GWI was established as per the clinical opinion of the WRIISC lead clinician or environmental exposure clinician as evidenced by a diagnosis of fibromyalgia or chronic fatigue syndrome, or explicit statement of CMI/GWI in the patient assessment. A diagnosis of SFN was established if clinical signs were present and an intraepidermal nerve fiber density below the lower limits, as compared to normative data from the clinical diagnostic laboratory (Therapath Neuropathology), was documented.

COMPASS 31 assesses symptoms across 6 domains (orthostatic, vasomotor, secretomotor, gastrointestinal, bladder, andpupillomotor). Patients are asked about symptom frequency (rarely to almost always), severity (mild to severe), and improvement (much worse to completely gone). Individual domain scores and a total weighted score (0-100) have demonstrated good validity, reliability, and consistency in SFN.^33,34

In veterans with GWI and documented SFN, a health record review was performed to identify potential etiologies for SFN (Appendix).

Statistical Analysis

Microsoft Excel and IBM SPSS 12.0.1 for Windows were used for data collection and statistical analysis. Fisher exact test was used for comparing the prevalence of SFN in veterans with GWI vs without GWI. The independent samples t test was used for comparing COMPASS 31 scores for veterans with GWI by SFN status. α < .05 was used for determining statistical significance. For those GWVs documented with SFN and GWI, potential explanations were documented in total and by condition.

Results

From March 1, 2015, to January 31, 2019, 141 GWVs received a comprehensive in person clinical evaluation at the WRIISC and 51 veterans (36%) received a skin biopsy and were included in this retrospective observational study (Figure). The mean age was 48.6 years, and the majority were male and served in the US Army. Skin biopsies met clinical criteria for GWI for 42 (82%) and 24 of 42 (57%) were determined to have SFN. Four of 9 (44%) veterans without GWI had positive SFN biopsies, though this difference was not statistically significant (Table 1). Veterans with SFN but no GWI were not included in the further analysis.

Thirty-five veterans with GWI—18 with SFN and 17 without SFN—completed the COMPASS 31 (Table 2). COMPASS 31 data were not analyzed for veterans without GWI. Individual domain scores and the difference in COMPASS 31 scores for veterans with GWI and SFN vs GWI and no SFN (38.3 vs 37.8, respectively) were not statistically significant.

Sixteen of 24 veterans with GWI and SFN (67%) had ≥ 1 conditions that could potentially be responsible for SFN (Table 3), including 11 veterans (46%) with prediabetes/diabetes. Hyperlipidemia is only variably reported as a cause of SFN; when included, 19 of 24 (79%) SFN cases were accounted for. We could not identify a medical explanation for SFN in 5 of 24 veterans (21%) with GWI, which were deemed to be idiopathic.

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.

Assessment of autonomic dysfunction was based on COMPASS 31 symptom reporting by an small subset of the clinical cohort. Symptom reporting may not be reflective of true abnormality in ANS function. Physiologic tests of the ANS were not performed; such studies could more objectively establish whether ANS dysfunction is more prevalent in GWI veterans with SFN.

Evaluation for all potential etiologic/contributory conditions to SFN was not exhaustive. For example, sodium channel gene mutations have been documented to account for up to one-third of all cases of idiopathic SFN.⁴² For those cases in which no compelling etiology was identified, it is plausible that medical explanations for SFN may be found on further investigation.

Clinical assessments at the WRIISC were performed on GWVs ≥ 26 years after their deployment-related exposures. Other conditions/exposures may have occurred in the interim. What is not clear is whether the SFN predated the onset of any of these medical conditions or other putative contributors. This observational study is not able to tease out a temporal association to make a cause-and-effect assessment.

Conclusions

Retrospective analysis of clinical data of veterans evaluated at a specialized center for postdeployment health demonstrated that skin biopsy–confirmed SFN was prevalent, but not ubiquitous, in veterans with GWI. Symptom that may be attributed to ANS dysfunction in this clinical sample was consistent with literature on SFN and with GWI, but we could not definitively attribute ANS symptoms to SFN. Our study does not support the hypothesis that GWI symptoms are solely due to SFN, though it may still be relevant in a subset of veterans with GWI with strongly suggestive clinical features. We were able to identify a potential etiology for SFN in most veterans with GWI. Further investigations are recommended to explore any potential relationship between Gulf War exposures and SFN.

Following deployment to operations Desert Shield and Desert Storm (Gulf War) in 1990 and 1991, many Gulf War veterans (GWVs) developed chronic, complex symptoms, including pain, dyscognition, and fatigue, with gastrointestinal, skin, and respiratory manifestations. This Gulf War Illness (GWI) is reported to affect about 30% of those deployed. More than 30 years later, there is no consensus as to the etiology of GWI, although some deployment-related exposures have been implicated.¹

Accepted research definitions for GWI include the Centers for Disease Control and Prevention and Kansas definitions.² The US Department of Veterans Affairs (VA) uses the terminology chronic multisymptom illness (CMI), which is an overarching diagnosis under which GWI falls. Although there is no consensus case definition for CMI, there is overlap with conditions such as fibromyalgia, myalgic encephalomyelitis/chronic fatigue syndrome, and irritable bowel syndrome; the VA considers these as qualifying clinical diagnoses.³ The pathophysiology of GWI is also unknown, though a frequently reported unifying feature is that of autonomic nervous system (ANS) dysfunction. Studies have demonstrated differences between veterans with GWI and those without GWI in both the reporting of symptoms attributable to ANS dysfunction and in physiologic evaluations of the ANS.^4-10

Small fiber neuropathy (SFN), a condition with damage to the A-δ and C small nerve fibers, has been proposed as a potential mechanism for the pain and ANS dysfunction experienced in GWI.^11-13 Symptoms of SFN are similar to those of GWI, with pain and ANS symptoms commonly reported.^14,15 There are multiple diagnostic criteria for SFN, the most commonly used requiring the presence of appropriate symptoms in the absence of large fiber neuropathy and a skin biopsy demonstrating reduced intraepidermal nerve fiber density.^16-19 Several conditions reportedly cause SFN, most notably diabetes/prediabetes. Autoimmune disease, vitamin B12 deficiency, monoclonal gammopathies, celiac disease, paraneoplastic syndromes, and sodium channel gene mutations may also contribute to SFN.²⁰ Hyperlipidemia has been identified as a contributor, although it has been variably reported.^21,22

Idiopathic neuropathies, SFN included, may be secondary to neurotoxicant exposures. Agents whose exposure or consumption have been associated with SFN include alcohol most prominently, but also the organic solvent n-hexane, heavy metals, and excess vitamin B₆.^20,23-25 Agents associated with large fiber neuropathy may also have relevance for SFN, as small fibers have been likened to the “canary in the coal mine” in that they may be more susceptible to neurotoxicants and are affected earlier in the disease process.²⁶ In this way, SFN may be the harbinger of large fiber neuropathy in some cases. Of specific relevance for GWVs, organophosphates and carbamates are known to produce a delayed onset large fiber neuropathy.^27-30 Exposure to petrochemical solvents has also been associated with large fiber neuropathies.^31,32

The War Related Illness and Injury Study Center (WRIISC) is a clinical, research, and education center established by Congress in 2001. Its primary focus is on military exposures and postdeployment health of veterans. It is located at 3 sites: East Orange, New Jersey; Washington, DC; and Palo Alto, California. The New Jersey WRIISC began a program to evaluate GWVs with characteristic symptoms for possible SFN with use of a skin biopsy.

We hypothesize that SFN may underly much of GWI symptomatology and may not be accounted for by the putative etiologies detailed in review of the medical literature. This retrospective review of clinical evaluations for SFN in GWVs who sought care at the New Jersey WRIISC explored and addressed the following questions: (1) how common is biopsy-confirmed SFN in veterans with GWI; (2) do veterans with GWI and SFN report more symptoms attributable to ANS dysfunction when compared with veterans with GWI and no SFN; and (3) can SFN in veterans with GWI and SFN be explained by conditions and substances commonly associated with SFN? Institutional review board approval and waiver of consent was obtained from the Veterans Affairs New Jersey Health Care Center for the study.

Methods

A retrospective chart review was conducted on veterans evaluated at the WRIISC from March 1, 2015, to January 31, 2019. Inclusion criteria were: deployment to operations Desert Shield and Desert Storm between August 2, 1990, and February 28, 1991, and skin biopsy conducted at the WRIISC. Skin biopsies were obtained at the discretion of an examining clinician based on clinical indications, including neuropathic pain, ANS symptoms, and/or a fibromyalgia/chronic pain–type presentation.

Electronic health record review explicitly abstracted GWI status, results of the skin biopsy, and ANS symptom burden as determined by the Composite Autonomic Symptom Scale 31 (COMPASS 31) completed at the time of the WRIISC evaluation. Determination of GWI was established as per the clinical opinion of the WRIISC lead clinician or environmental exposure clinician as evidenced by a diagnosis of fibromyalgia or chronic fatigue syndrome, or explicit statement of CMI/GWI in the patient assessment. A diagnosis of SFN was established if clinical signs were present and an intraepidermal nerve fiber density below the lower limits, as compared to normative data from the clinical diagnostic laboratory (Therapath Neuropathology), was documented.

COMPASS 31 assesses symptoms across 6 domains (orthostatic, vasomotor, secretomotor, gastrointestinal, bladder, andpupillomotor). Patients are asked about symptom frequency (rarely to almost always), severity (mild to severe), and improvement (much worse to completely gone). Individual domain scores and a total weighted score (0-100) have demonstrated good validity, reliability, and consistency in SFN.^33,34

In veterans with GWI and documented SFN, a health record review was performed to identify potential etiologies for SFN (Appendix).

Statistical Analysis

Microsoft Excel and IBM SPSS 12.0.1 for Windows were used for data collection and statistical analysis. Fisher exact test was used for comparing the prevalence of SFN in veterans with GWI vs without GWI. The independent samples t test was used for comparing COMPASS 31 scores for veterans with GWI by SFN status. α < .05 was used for determining statistical significance. For those GWVs documented with SFN and GWI, potential explanations were documented in total and by condition.

Results

From March 1, 2015, to January 31, 2019, 141 GWVs received a comprehensive in person clinical evaluation at the WRIISC and 51 veterans (36%) received a skin biopsy and were included in this retrospective observational study (Figure). The mean age was 48.6 years, and the majority were male and served in the US Army. Skin biopsies met clinical criteria for GWI for 42 (82%) and 24 of 42 (57%) were determined to have SFN. Four of 9 (44%) veterans without GWI had positive SFN biopsies, though this difference was not statistically significant (Table 1). Veterans with SFN but no GWI were not included in the further analysis.

Thirty-five veterans with GWI—18 with SFN and 17 without SFN—completed the COMPASS 31 (Table 2). COMPASS 31 data were not analyzed for veterans without GWI. Individual domain scores and the difference in COMPASS 31 scores for veterans with GWI and SFN vs GWI and no SFN (38.3 vs 37.8, respectively) were not statistically significant.

Sixteen of 24 veterans with GWI and SFN (67%) had ≥ 1 conditions that could potentially be responsible for SFN (Table 3), including 11 veterans (46%) with prediabetes/diabetes. Hyperlipidemia is only variably reported as a cause of SFN; when included, 19 of 24 (79%) SFN cases were accounted for. We could not identify a medical explanation for SFN in 5 of 24 veterans (21%) with GWI, which were deemed to be idiopathic.

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.

Assessment of autonomic dysfunction was based on COMPASS 31 symptom reporting by an small subset of the clinical cohort. Symptom reporting may not be reflective of true abnormality in ANS function. Physiologic tests of the ANS were not performed; such studies could more objectively establish whether ANS dysfunction is more prevalent in GWI veterans with SFN.

Evaluation for all potential etiologic/contributory conditions to SFN was not exhaustive. For example, sodium channel gene mutations have been documented to account for up to one-third of all cases of idiopathic SFN.⁴² For those cases in which no compelling etiology was identified, it is plausible that medical explanations for SFN may be found on further investigation.

Clinical assessments at the WRIISC were performed on GWVs ≥ 26 years after their deployment-related exposures. Other conditions/exposures may have occurred in the interim. What is not clear is whether the SFN predated the onset of any of these medical conditions or other putative contributors. This observational study is not able to tease out a temporal association to make a cause-and-effect assessment.

Conclusions

Retrospective analysis of clinical data of veterans evaluated at a specialized center for postdeployment health demonstrated that skin biopsy–confirmed SFN was prevalent, but not ubiquitous, in veterans with GWI. Symptom that may be attributed to ANS dysfunction in this clinical sample was consistent with literature on SFN and with GWI, but we could not definitively attribute ANS symptoms to SFN. Our study does not support the hypothesis that GWI symptoms are solely due to SFN, though it may still be relevant in a subset of veterans with GWI with strongly suggestive clinical features. We were able to identify a potential etiology for SFN in most veterans with GWI. Further investigations are recommended to explore any potential relationship between Gulf War exposures and SFN.

Following deployment to operations Desert Shield and Desert Storm (Gulf War) in 1990 and 1991, many Gulf War veterans (GWVs) developed chronic, complex symptoms, including pain, dyscognition, and fatigue, with gastrointestinal, skin, and respiratory manifestations. This Gulf War Illness (GWI) is reported to affect about 30% of those deployed. More than 30 years later, there is no consensus as to the etiology of GWI, although some deployment-related exposures have been implicated.¹

Accepted research definitions for GWI include the Centers for Disease Control and Prevention and Kansas definitions.² The US Department of Veterans Affairs (VA) uses the terminology chronic multisymptom illness (CMI), which is an overarching diagnosis under which GWI falls. Although there is no consensus case definition for CMI, there is overlap with conditions such as fibromyalgia, myalgic encephalomyelitis/chronic fatigue syndrome, and irritable bowel syndrome; the VA considers these as qualifying clinical diagnoses.³ The pathophysiology of GWI is also unknown, though a frequently reported unifying feature is that of autonomic nervous system (ANS) dysfunction. Studies have demonstrated differences between veterans with GWI and those without GWI in both the reporting of symptoms attributable to ANS dysfunction and in physiologic evaluations of the ANS.^4-10

Small fiber neuropathy (SFN), a condition with damage to the A-δ and C small nerve fibers, has been proposed as a potential mechanism for the pain and ANS dysfunction experienced in GWI.^11-13 Symptoms of SFN are similar to those of GWI, with pain and ANS symptoms commonly reported.^14,15 There are multiple diagnostic criteria for SFN, the most commonly used requiring the presence of appropriate symptoms in the absence of large fiber neuropathy and a skin biopsy demonstrating reduced intraepidermal nerve fiber density.^16-19 Several conditions reportedly cause SFN, most notably diabetes/prediabetes. Autoimmune disease, vitamin B12 deficiency, monoclonal gammopathies, celiac disease, paraneoplastic syndromes, and sodium channel gene mutations may also contribute to SFN.²⁰ Hyperlipidemia has been identified as a contributor, although it has been variably reported.^21,22

Idiopathic neuropathies, SFN included, may be secondary to neurotoxicant exposures. Agents whose exposure or consumption have been associated with SFN include alcohol most prominently, but also the organic solvent n-hexane, heavy metals, and excess vitamin B₆.^20,23-25 Agents associated with large fiber neuropathy may also have relevance for SFN, as small fibers have been likened to the “canary in the coal mine” in that they may be more susceptible to neurotoxicants and are affected earlier in the disease process.²⁶ In this way, SFN may be the harbinger of large fiber neuropathy in some cases. Of specific relevance for GWVs, organophosphates and carbamates are known to produce a delayed onset large fiber neuropathy.^27-30 Exposure to petrochemical solvents has also been associated with large fiber neuropathies.^31,32

The War Related Illness and Injury Study Center (WRIISC) is a clinical, research, and education center established by Congress in 2001. Its primary focus is on military exposures and postdeployment health of veterans. It is located at 3 sites: East Orange, New Jersey; Washington, DC; and Palo Alto, California. The New Jersey WRIISC began a program to evaluate GWVs with characteristic symptoms for possible SFN with use of a skin biopsy.

We hypothesize that SFN may underly much of GWI symptomatology and may not be accounted for by the putative etiologies detailed in review of the medical literature. This retrospective review of clinical evaluations for SFN in GWVs who sought care at the New Jersey WRIISC explored and addressed the following questions: (1) how common is biopsy-confirmed SFN in veterans with GWI; (2) do veterans with GWI and SFN report more symptoms attributable to ANS dysfunction when compared with veterans with GWI and no SFN; and (3) can SFN in veterans with GWI and SFN be explained by conditions and substances commonly associated with SFN? Institutional review board approval and waiver of consent was obtained from the Veterans Affairs New Jersey Health Care Center for the study.

Methods

A retrospective chart review was conducted on veterans evaluated at the WRIISC from March 1, 2015, to January 31, 2019. Inclusion criteria were: deployment to operations Desert Shield and Desert Storm between August 2, 1990, and February 28, 1991, and skin biopsy conducted at the WRIISC. Skin biopsies were obtained at the discretion of an examining clinician based on clinical indications, including neuropathic pain, ANS symptoms, and/or a fibromyalgia/chronic pain–type presentation.

Electronic health record review explicitly abstracted GWI status, results of the skin biopsy, and ANS symptom burden as determined by the Composite Autonomic Symptom Scale 31 (COMPASS 31) completed at the time of the WRIISC evaluation. Determination of GWI was established as per the clinical opinion of the WRIISC lead clinician or environmental exposure clinician as evidenced by a diagnosis of fibromyalgia or chronic fatigue syndrome, or explicit statement of CMI/GWI in the patient assessment. A diagnosis of SFN was established if clinical signs were present and an intraepidermal nerve fiber density below the lower limits, as compared to normative data from the clinical diagnostic laboratory (Therapath Neuropathology), was documented.

COMPASS 31 assesses symptoms across 6 domains (orthostatic, vasomotor, secretomotor, gastrointestinal, bladder, andpupillomotor). Patients are asked about symptom frequency (rarely to almost always), severity (mild to severe), and improvement (much worse to completely gone). Individual domain scores and a total weighted score (0-100) have demonstrated good validity, reliability, and consistency in SFN.^33,34

In veterans with GWI and documented SFN, a health record review was performed to identify potential etiologies for SFN (Appendix).

Statistical Analysis

Microsoft Excel and IBM SPSS 12.0.1 for Windows were used for data collection and statistical analysis. Fisher exact test was used for comparing the prevalence of SFN in veterans with GWI vs without GWI. The independent samples t test was used for comparing COMPASS 31 scores for veterans with GWI by SFN status. α < .05 was used for determining statistical significance. For those GWVs documented with SFN and GWI, potential explanations were documented in total and by condition.

Results

From March 1, 2015, to January 31, 2019, 141 GWVs received a comprehensive in person clinical evaluation at the WRIISC and 51 veterans (36%) received a skin biopsy and were included in this retrospective observational study (Figure). The mean age was 48.6 years, and the majority were male and served in the US Army. Skin biopsies met clinical criteria for GWI for 42 (82%) and 24 of 42 (57%) were determined to have SFN. Four of 9 (44%) veterans without GWI had positive SFN biopsies, though this difference was not statistically significant (Table 1). Veterans with SFN but no GWI were not included in the further analysis.

Thirty-five veterans with GWI—18 with SFN and 17 without SFN—completed the COMPASS 31 (Table 2). COMPASS 31 data were not analyzed for veterans without GWI. Individual domain scores and the difference in COMPASS 31 scores for veterans with GWI and SFN vs GWI and no SFN (38.3 vs 37.8, respectively) were not statistically significant.

Sixteen of 24 veterans with GWI and SFN (67%) had ≥ 1 conditions that could potentially be responsible for SFN (Table 3), including 11 veterans (46%) with prediabetes/diabetes. Hyperlipidemia is only variably reported as a cause of SFN; when included, 19 of 24 (79%) SFN cases were accounted for. We could not identify a medical explanation for SFN in 5 of 24 veterans (21%) with GWI, which were deemed to be idiopathic.

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.

Assessment of autonomic dysfunction was based on COMPASS 31 symptom reporting by an small subset of the clinical cohort. Symptom reporting may not be reflective of true abnormality in ANS function. Physiologic tests of the ANS were not performed; such studies could more objectively establish whether ANS dysfunction is more prevalent in GWI veterans with SFN.

Evaluation for all potential etiologic/contributory conditions to SFN was not exhaustive. For example, sodium channel gene mutations have been documented to account for up to one-third of all cases of idiopathic SFN.⁴² For those cases in which no compelling etiology was identified, it is plausible that medical explanations for SFN may be found on further investigation.

Clinical assessments at the WRIISC were performed on GWVs ≥ 26 years after their deployment-related exposures. Other conditions/exposures may have occurred in the interim. What is not clear is whether the SFN predated the onset of any of these medical conditions or other putative contributors. This observational study is not able to tease out a temporal association to make a cause-and-effect assessment.

Conclusions

Retrospective analysis of clinical data of veterans evaluated at a specialized center for postdeployment health demonstrated that skin biopsy–confirmed SFN was prevalent, but not ubiquitous, in veterans with GWI. Symptom that may be attributed to ANS dysfunction in this clinical sample was consistent with literature on SFN and with GWI, but we could not definitively attribute ANS symptoms to SFN. Our study does not support the hypothesis that GWI symptoms are solely due to SFN, though it may still be relevant in a subset of veterans with GWI with strongly suggestive clinical features. We were able to identify a potential etiology for SFN in most veterans with GWI. Further investigations are recommended to explore any potential relationship between Gulf War exposures and SFN.

Soldiers’ graves are the greatest preachers of peace.

Albert Schweitzer ¹

From the window of my room in the house where I grew up, I could see the American flag flying over Fort Sam Houston National Cemetery. I would ride my bicycle around the paths that divided the grassy sections of graves to the blocks where my father and grandfather were buried. I would stand before the gravesites in a state combining prayer, processing, and remembrance. Carved into my grandfather’s headstone were the 2 world wars he fought in and on my father’s, the 3 conflicts in which he served. I would walk up to their headstones and trace the emblems of belief: the engraved Star of David that marked my grandfather’s grave and the simple cross for my father.

My visits and writing about them may strike some readers as morbid. However, for me, the experience and memories are calming and peaceful, like the cemetery. There was something incredibly comforting about the uniformity of the headstones standing out for miles, mirroring the ranks of soldiers in the wars they commemorated. Yet, as with the men and women who fought each conflict, every grave told a succinct Hemingway-like story of their military career etched in stone. I know now that discrimination in the military segregated even the burial of service members.² It appeared to my younger self that at least compared to civilian cemeteries with their massive monuments to the wealthy and powerful, there was an egalitarian effect: my master sergeant grandfather’s plot was indistinguishable from that of my colonel father.

Memorial Day and military cemeteries have a shared history. While Veterans Day honors all who have worn the uniform, living and dead, Memorial Day, as its name suggests, remembers those who have died in a broadly conceived line of duty. To emphasize the more solemn character of the holiday, the original name, Decoration Day, was changed to emphasize the reverence of remembrance.³ The first widespread observance of Memorial Day was to commemorate those who perished in the Civil War, which remains the conflict with the highest number of casualties in American history. The first national commemoration occurred at Arlington National Cemetery when 5000 volunteers decorated 20,000 Union and Confederate graves in an act of solidarity and reconciliation. The practice struck a chord in a country beleaguered by war and division.²

National cemeteries also emerged from the grief and gratitude that marked the Civil War. President Abraham Lincoln, who gave us the famous US Department of Veterans Affairs (VA) mission motto, also inaugurated national cemeteries. At the beginning of the Civil War, only Union soldiers who sacrificed their lives to end slavery were entitled to burial. Reflective of the rift that divided the country, Confederate soldiers contended that such divisiveness should not continue unto death and were granted the right to be buried beside those they fought against, united in death and memory.⁴

Today, the country is more divided than ever: more than a few observers of American culture, including the new popular film Civil War, believe we are on the brink of another civil war.⁵ While we take their warning seriously, there are still signs of unity amongst the people, like those who followed the war between the states. Recently, in that same national cemetery where I first contemplated these themes, justice, delayed too long, was not entirely denied. A ceremony was held to dedicate 17 headstones to honor the memories of Black World War I Army soldiers who were court-martialed and hanged in the wake of the Houston riots of 1917. As a sign of their dishonor, their headstones listed only their dates and names—nothing of their military service. At the urging of their descendants, the US Army reopened the files and found the verdict to have been racially motivated. They set aside their convictions, gave them honorable discharges for their service in life, and replaced their gravesites with ones that enshrined that respect in death.⁶

Some reading this column may, like me, have had the profound privilege of participating in a burial at a national cemetery. We recall the stirring mix of pride and loss when the honor guard hands the perfectly folded flag to the bereaved family member and bids farewell to their comrade with a salute. Yet, not all families have this privilege. One of the saddest experiences I recall is when I was in a leadership position at a VA facility and unable to help impoverished families who were denied VA burial benefits or payments to transport their deceased veteran closer to home. That sorrow often turned to thankful relief when a veterans service organization or other community group offered to pay the funerary expenses. Fortunately, like eligibility for VA health care, the criteria for burial benefits have steadily expanded to encompass spouses, adult children, and others who served.⁷

In a similar display of altruism this Memorial Day, veterans service organizations, Boy Scouts, and volunteers will place a flag on every grave to show that some memories are stronger than death. If you have never seen it, I encourage you to visit a VA or a national cemetery this holiday or, even better, volunteer to place flags. Either way, spend a few moments thankfully remembering that we can all engage in those uniquely American Memorial Day pastimes of barbecues and baseball games because so many served and died to protect our way of life. The epigraph at the beginning of this column is attributed to Albert Schweitzer, the physician-theologian of reverence for life. The news today is full of war and rumors of war.⁸ Let us all hope that the message is heard around the world so there is no need to build more national cemeteries to remember our veterans.

Soldiers’ graves are the greatest preachers of peace.

Albert Schweitzer ¹

From the window of my room in the house where I grew up, I could see the American flag flying over Fort Sam Houston National Cemetery. I would ride my bicycle around the paths that divided the grassy sections of graves to the blocks where my father and grandfather were buried. I would stand before the gravesites in a state combining prayer, processing, and remembrance. Carved into my grandfather’s headstone were the 2 world wars he fought in and on my father’s, the 3 conflicts in which he served. I would walk up to their headstones and trace the emblems of belief: the engraved Star of David that marked my grandfather’s grave and the simple cross for my father.

My visits and writing about them may strike some readers as morbid. However, for me, the experience and memories are calming and peaceful, like the cemetery. There was something incredibly comforting about the uniformity of the headstones standing out for miles, mirroring the ranks of soldiers in the wars they commemorated. Yet, as with the men and women who fought each conflict, every grave told a succinct Hemingway-like story of their military career etched in stone. I know now that discrimination in the military segregated even the burial of service members.² It appeared to my younger self that at least compared to civilian cemeteries with their massive monuments to the wealthy and powerful, there was an egalitarian effect: my master sergeant grandfather’s plot was indistinguishable from that of my colonel father.

Memorial Day and military cemeteries have a shared history. While Veterans Day honors all who have worn the uniform, living and dead, Memorial Day, as its name suggests, remembers those who have died in a broadly conceived line of duty. To emphasize the more solemn character of the holiday, the original name, Decoration Day, was changed to emphasize the reverence of remembrance.³ The first widespread observance of Memorial Day was to commemorate those who perished in the Civil War, which remains the conflict with the highest number of casualties in American history. The first national commemoration occurred at Arlington National Cemetery when 5000 volunteers decorated 20,000 Union and Confederate graves in an act of solidarity and reconciliation. The practice struck a chord in a country beleaguered by war and division.²

National cemeteries also emerged from the grief and gratitude that marked the Civil War. President Abraham Lincoln, who gave us the famous US Department of Veterans Affairs (VA) mission motto, also inaugurated national cemeteries. At the beginning of the Civil War, only Union soldiers who sacrificed their lives to end slavery were entitled to burial. Reflective of the rift that divided the country, Confederate soldiers contended that such divisiveness should not continue unto death and were granted the right to be buried beside those they fought against, united in death and memory.⁴

Today, the country is more divided than ever: more than a few observers of American culture, including the new popular film Civil War, believe we are on the brink of another civil war.⁵ While we take their warning seriously, there are still signs of unity amongst the people, like those who followed the war between the states. Recently, in that same national cemetery where I first contemplated these themes, justice, delayed too long, was not entirely denied. A ceremony was held to dedicate 17 headstones to honor the memories of Black World War I Army soldiers who were court-martialed and hanged in the wake of the Houston riots of 1917. As a sign of their dishonor, their headstones listed only their dates and names—nothing of their military service. At the urging of their descendants, the US Army reopened the files and found the verdict to have been racially motivated. They set aside their convictions, gave them honorable discharges for their service in life, and replaced their gravesites with ones that enshrined that respect in death.⁶

Some reading this column may, like me, have had the profound privilege of participating in a burial at a national cemetery. We recall the stirring mix of pride and loss when the honor guard hands the perfectly folded flag to the bereaved family member and bids farewell to their comrade with a salute. Yet, not all families have this privilege. One of the saddest experiences I recall is when I was in a leadership position at a VA facility and unable to help impoverished families who were denied VA burial benefits or payments to transport their deceased veteran closer to home. That sorrow often turned to thankful relief when a veterans service organization or other community group offered to pay the funerary expenses. Fortunately, like eligibility for VA health care, the criteria for burial benefits have steadily expanded to encompass spouses, adult children, and others who served.⁷

In a similar display of altruism this Memorial Day, veterans service organizations, Boy Scouts, and volunteers will place a flag on every grave to show that some memories are stronger than death. If you have never seen it, I encourage you to visit a VA or a national cemetery this holiday or, even better, volunteer to place flags. Either way, spend a few moments thankfully remembering that we can all engage in those uniquely American Memorial Day pastimes of barbecues and baseball games because so many served and died to protect our way of life. The epigraph at the beginning of this column is attributed to Albert Schweitzer, the physician-theologian of reverence for life. The news today is full of war and rumors of war.⁸ Let us all hope that the message is heard around the world so there is no need to build more national cemeteries to remember our veterans.

Soldiers’ graves are the greatest preachers of peace.

Albert Schweitzer ¹

From the window of my room in the house where I grew up, I could see the American flag flying over Fort Sam Houston National Cemetery. I would ride my bicycle around the paths that divided the grassy sections of graves to the blocks where my father and grandfather were buried. I would stand before the gravesites in a state combining prayer, processing, and remembrance. Carved into my grandfather’s headstone were the 2 world wars he fought in and on my father’s, the 3 conflicts in which he served. I would walk up to their headstones and trace the emblems of belief: the engraved Star of David that marked my grandfather’s grave and the simple cross for my father.

My visits and writing about them may strike some readers as morbid. However, for me, the experience and memories are calming and peaceful, like the cemetery. There was something incredibly comforting about the uniformity of the headstones standing out for miles, mirroring the ranks of soldiers in the wars they commemorated. Yet, as with the men and women who fought each conflict, every grave told a succinct Hemingway-like story of their military career etched in stone. I know now that discrimination in the military segregated even the burial of service members.² It appeared to my younger self that at least compared to civilian cemeteries with their massive monuments to the wealthy and powerful, there was an egalitarian effect: my master sergeant grandfather’s plot was indistinguishable from that of my colonel father.

Memorial Day and military cemeteries have a shared history. While Veterans Day honors all who have worn the uniform, living and dead, Memorial Day, as its name suggests, remembers those who have died in a broadly conceived line of duty. To emphasize the more solemn character of the holiday, the original name, Decoration Day, was changed to emphasize the reverence of remembrance.³ The first widespread observance of Memorial Day was to commemorate those who perished in the Civil War, which remains the conflict with the highest number of casualties in American history. The first national commemoration occurred at Arlington National Cemetery when 5000 volunteers decorated 20,000 Union and Confederate graves in an act of solidarity and reconciliation. The practice struck a chord in a country beleaguered by war and division.²

National cemeteries also emerged from the grief and gratitude that marked the Civil War. President Abraham Lincoln, who gave us the famous US Department of Veterans Affairs (VA) mission motto, also inaugurated national cemeteries. At the beginning of the Civil War, only Union soldiers who sacrificed their lives to end slavery were entitled to burial. Reflective of the rift that divided the country, Confederate soldiers contended that such divisiveness should not continue unto death and were granted the right to be buried beside those they fought against, united in death and memory.⁴

Today, the country is more divided than ever: more than a few observers of American culture, including the new popular film Civil War, believe we are on the brink of another civil war.⁵ While we take their warning seriously, there are still signs of unity amongst the people, like those who followed the war between the states. Recently, in that same national cemetery where I first contemplated these themes, justice, delayed too long, was not entirely denied. A ceremony was held to dedicate 17 headstones to honor the memories of Black World War I Army soldiers who were court-martialed and hanged in the wake of the Houston riots of 1917. As a sign of their dishonor, their headstones listed only their dates and names—nothing of their military service. At the urging of their descendants, the US Army reopened the files and found the verdict to have been racially motivated. They set aside their convictions, gave them honorable discharges for their service in life, and replaced their gravesites with ones that enshrined that respect in death.⁶

Some reading this column may, like me, have had the profound privilege of participating in a burial at a national cemetery. We recall the stirring mix of pride and loss when the honor guard hands the perfectly folded flag to the bereaved family member and bids farewell to their comrade with a salute. Yet, not all families have this privilege. One of the saddest experiences I recall is when I was in a leadership position at a VA facility and unable to help impoverished families who were denied VA burial benefits or payments to transport their deceased veteran closer to home. That sorrow often turned to thankful relief when a veterans service organization or other community group offered to pay the funerary expenses. Fortunately, like eligibility for VA health care, the criteria for burial benefits have steadily expanded to encompass spouses, adult children, and others who served.⁷

In a similar display of altruism this Memorial Day, veterans service organizations, Boy Scouts, and volunteers will place a flag on every grave to show that some memories are stronger than death. If you have never seen it, I encourage you to visit a VA or a national cemetery this holiday or, even better, volunteer to place flags. Either way, spend a few moments thankfully remembering that we can all engage in those uniquely American Memorial Day pastimes of barbecues and baseball games because so many served and died to protect our way of life. The epigraph at the beginning of this column is attributed to Albert Schweitzer, the physician-theologian of reverence for life. The news today is full of war and rumors of war.⁸ Let us all hope that the message is heard around the world so there is no need to build more national cemeteries to remember our veterans.