The National Institute for Occupational Safety and Health (NIOSH) has determined that survivors and responders at the World Trade Center (WTC) disaster are at a higher risk than the general population for a number of medical illnesses, including lung disorders such as asthma, reactive airway disease, and interstitial lung disease1–3 as well as certain cancers,4,5 including thyroid cancer, prostate cancer, and myeloma. Posttraumatic stress disorder,6 depression,7,8 and generalized anxiety disorder9 are also common in those exposed at the WTC. One important question is whether other illnesses might be associated with the WTC disaster. Many other illnesses have been suggested as being related to the exposure, but scientific evidence of causality is required before a condition can be added to the list of conditions covered under the Zadroga 9/11 Health and Compensation Act.
There is some empirical information supporting the idea that neuropathy may be associated with the WTC disaster. First, the dust from the WTC contains many potential neurotoxins,10 including heavy metals and complex hydrocarbons. Second, many responders have noted neuropathic symptoms during clinic visits. Third, an in vitro study11 demonstrated that exposure to a methanol extract of WTC dust reduced the conduction velocity in rat sciatic nerve. The purpose of this study was to investigate whether the prevalence of neuropathic symptoms, as measured by the Michigan Neuropathy Screening Instrument (MNSI), was greater in people exposed at the WTC than people who were not exposed.
This study was approved by the Winthrop University Hospital Institutional Review Board (#661099-3). The survey used in this study consisted of five parts. The first part was the MNSI Survey produced by the Michigan Diabetes Research and Training Center (http://www.med.umich.edu/borc/profs/survey.html),12 which has 15 questions related to various symptoms of neuropathy. The second part of the survey was a query about age and relevant medical comorbidities, including diabetes, heart failure, renal failure, gout, lung problems, eye problems, arthritis, skin rashes, stress, depression, anxiety, stroke, lupus, b12 deficiency, and back problems (either pinched nerve or previous surgery). The third part was a brief assessment of depression using the Patient Health Questionnaire-2 (PHQ-2) questions13 and a brief assessment of well-being using the WHO-5 well being index. One modification was made to the standard WHO-5 survey.14 The standard survey includes the responses (“all of the time,” “most of the time,” “more than half the time,” “less than half of the time,” “some of the time,” and “at no time”), but, in order to keep the survey as simple as possible, the choice “less than half of the time” was left out. The fourth part of the survey asked whether the patient ever had an Electromyography (EMG) or nerve conduction study and if they were told whether the study was normal. This presented the opportunity to confirm the results of the neuropathy questionnaire, as patients with true neuropathy would also be likely to have abnormal EMG studies. The results of the EMG or nerve conduction studies were not reviewed and this reflects purely the patients recollection of the results of the study performed. In the fifth part of the survey, the patient was asked whether they had any exposure to the WTC, whether they were caught in the dust cloud, and whether they worked on the “pile” and for how long.
The survey was distributed online with the help of John Feal from the FealGood Foundation to responders, survivors, and their families. It was also distributed to some faculty and staff at Queens College. Hard copies of the questionnaire were also distributed to WTC responders treated at Winthrop's Occupational/Environmental Medicine Division. The survey was also distributed to people visiting Winthrop's associated health facilities.
According to the instructions (http://www.med.umich.edu/borc/profs/survey.html) provided with the MNSI, a numerical score was assigned to each patient, which ranged from 0 to 13, with 0 indicating that the patient endorsed none of the neuropathy symptoms and 13 indicating that the patient endorsed many of the neuropathic symptoms. The PHQ-2 was scored on a scale of 0–6 with larger scores suggesting a higher risk of depression. A score of 3 or greater has 83% sensitivity and 90% specificity for major depression.13 The WHO-5 was scored on a scale of 0 to 20, with larger values indicating improved well being.
A crude index of exposure was taken as computed as in Table 1, ranging from 0 for no exposure to 1 for those exposed but not in the dust cloud or working on the “pile,” to 2 for those exposed to either and 3 for those exposed to both the dust cloud and the “pile.”
Descriptive statistics such as frequencies and means were generated and presented. WTC exposure was examined both as a binary variable (exposure vs. no exposure) and an ordinal variable (none, moderate, and high exposure) on the basis of whether participants were exposed to either the dust cloud or the “pile” (moderate) or both (higher exposure). The difference in frequencies of selected medical comorbidities between those with WTC exposure and not were assessed via Fisher's exact test. Differences in the average values of continuous variables such as age or neuropathy score were assessed via t test or analysis of variance (ANOVA). In order to examine the association between WTC exposure and neuropathy score in an adjusted regression model, an exhaustive model search was conducted using participant age, WTC exposure, and comorbidities as potential covariates; models of each size were ranked by their R2 value. The highest ranking models were examined, and a clinically relevant and parsimonious model was selected on the basis of all competing models as the final representative model and presented with its adjusted R2 value to summarize the proportion of variability accounted for by the model. Two-sided P values of 0.05 or less were considered statistically significant. All analyses were performed using SAS version 9.3 (The SAS Institute Inc, Cary, NC).
There were 368 total responses but many were incomplete in some aspect because of the large number of questions asked. When incomplete cases were removed, there were 255 complete surveys that were subjected to analysis.
Table 2 summarizes the presence of medical comorbidities in patients with and without WTC exposure. Using a highly conservative Bonferroni correction for multiple testing, the level of significance for a significant difference was taken as 0.05/18 = 0.0028. With this criterion, the WTC-exposed patients had a markedly increased risk of lung problems as well as rash, stress, depression, and anxiety, all of which are consistent with prior studies. Table 3 demonstrates that the exposed patients had lower WHO-5 well being scores as well as increased PHQ-2 scores. The MNSI neuropathy scores are higher in those exposed, indicating that they endorsed more neuropathic symptoms. The results of the questions regarding whether the respondent had an EMG/nerve conduction study and whether that study was normal or abnormal support this result (Table 4). In both patients who were exposed and not exposed to WTC, the neuropathy score was higher in patients with an abnormal EMG study, which helps to support the validity of the MNSI questionnaire results. In addition, among patients who had an EMG study at some point, patients exposed at the WTC had a higher rate of abnormal EMG studies than those who were not exposed. This result also supports the validity of the using the MNSI score as an objective measure of neuropathic symptoms in this group.
Table 5 summarizes that there is a strong relationship between lung disease and stress depression and anxiety with the result of the MNSI neuropathy score. Lung disease status accounted for over 20% of the total variation in neuropathy scores in univariate analysis. Severe stress, depression, and anxiety each accounted for 10% to 13% of the variation in scores, and as expected were highly correlated as a group. Table 6 summarizes the final representative multivariable model for neuropathy scores: diabetes mellitus (DM) and lung disease were independently associated with higher neuropathy scores, after adjustment for severe stress. Greater WTC exposure (included in the model as a categorical variable with reference group of no exposure) was significantly associated with higher average neuropathy scores. People with the highest levels of exposure are predicted to have average neuropathy scores that are 2.5 points higher than people without WTC exposure (P < 0.001). People with moderate WTC exposure had scores that were an average of 2.0 points higher than people without WTC exposure (P < 0.001). Thus, there was a linear dose effect observed, such that people with higher levels of exposure to the WTC were observed to have higher neuropathy scores; however, the increase in average score for the higher exposure group compared with moderate exposure group was not statistically significant (P = 0.19). The adjusted R2 value of this final model was 40%; WTC exposure was an important predictor in every competing model to the model presented. Participant age was not a statistically significant predictor in the final model or any of the competing models for neuropathy.
Various cutoffs for making the diagnosis of clinical neuropathy based on the MNSI survey scale have been proposed. Herman et al12 studied the sensitivity and specificity of the score in patients with type 1 diabetes. Although older studies suggested a cutoff of 7,15 this more recent study proposed that a cutoff value of 4 may yield a better sensitivity and specificity. Roughly, 66% of those exposed and only 11% of those not exposed met the criterion of MNSI at least 4, while 21% of the WTC exposed met the criterion of MNSI at least 7, while only 1% of those unexposed did (Table 7). Participants with WTC exposure had over 15 times the odds of a MNSI score of at least 4 (P < 0.0001) and 30 times the odds of a MNSI score of at least 7 compared with controls (P < 0.0001).
The results of this survey indicate that people exposed to the WTC endorse neuropathic symptoms more frequently than patients who were not exposed. Moreover, the neuropathic symptoms were more severe (as noted by the MSNI neuropathy score) in people with a greater exposure. One possible limitation of this result is that patients with anxiety and depression16 may endorse more somatic symptoms than other patients and people with exposure to the WTC do have higher levels of anxiety and depression than those not exposed. This effect alone is an unlikely explanation for the effect of WTC exposure on the neuropathy scores because we included measures of depression and well being in the survey and independent effects of depression/stress and WTC exposure were demonstrated in the multivariable models. In addition, the EMG studies, which are an objective measure of peripheral nerve function, confirm that in both those exposed and unexposed, patients with an abnormal EMG had a higher neuropathy symptom score. In addition, the WTC patients who had EMGs were more likely to have an abnormal EMG than the unexposed patients. In the current study, we did not obtain the original EMG or nerve conduction study results. It will be important in future studies to obtain EMG/nerve conduction studies as well as standardized neurological examinations on this group of patients as objective measures of the neuropathic symptoms and to learn more about the pathophysiology of the neuropathic symptoms.
The next question is whether the difference in neuropathy scores is clinically significant. Previous studies12,15 have suggested that MNSI neuropathy scores of at least 4 or at least 7 are strongly correlated with the presence of clinical neuropathy in diabetic individuals. In the current study, 68% of those exposed had MNSI neuropathy scores of at least 4 and 21% had scores of at least 7. This compares to 18% and 5%, respectively, in patients with type 1 diabetes.12 This suggests that neuropathic symptoms occur at a higher rate in the WTC-exposed people than in patients with diabetes.
The mechanism by which exposure results in neuropathy will require additional investigations. Our prior study of the effects of WTC dust on rat sciatic nerves11 provides a model for biologic plausibility of a causative effect between WTC dust exposure and increased risk of neuropathy. It also suggests that this effect may be mediated by a methanol-soluble element in the dust. Although there is a strong correlation between lung disease and neuropathy scores suggesting that the exposure pathways may be the same, alternate pathways may be operative. Dermal absorption is also likely to have occurred in those covered by the toxic dust cloud released by the WTC collapse. In addition, responders often toiled on the “pile” without gloves or other protective equipment. Digging with hands and small tools would have exposed the skin of the extremities of these heroes to neurotoxic materials. Finally, responders and survivors often had to trudge through piles of toxic “sludge” that resulted from the collapse, which represents an additional route of exposure. In conclusion, this study suggests that WTC dust exposure dose results in an increased risk of neuropathy in responders and survivors of the WTC. This risk is independent of any medical or psychiatric comorbidity and is more severe in patients with a higher degree of exposure. As neuropathy treatment in responders is currently not covered under the WTC program, our findings have strong policy implications and suggest that neuropathy should be added to the list of conditions covered. Additional research may clarify the mechanism of injury as well as the specific types of peripheral nerve injury associated with the WTC.
The authors thank Mr John Feal and The FealGood Foundation for their assistance in disseminating the questionnaire to responders. We also thank Dr Paul Lioy for his help in beginning these investigations. We also thank Dr Francis Faustino, chairman of the family medicine department at Winthrop University Hospital, and Dan Marciano for assistance in distributing the survey.
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