Neuropsychologic testing versus visual contrast sensitivity: response. (Correspondence).

We appreciate the opportunity to respond to Swinker's letter regarding our response (Hudnell and Shoemaker 2002) to her previous letter (Swinker and Burke 2002). Her previous letter concerned our first EHP article (Shoemaker and Hudnell 2001) on possible estuary-associated syndrome (PEAS). Her current letter raises five issues: a) "nonspecificity" of visual contrast sensitivity (VCS) and neuropsychologic tests; b) memory loss being the most unique and significant effect in PEAS; c) validity of VCS as an indicator of neurologic deficits in PEAS cases; d) VCS deficits in Swinker's 10 hotline caller controls; and e) hydrogen sulfide exposure in North Carolina estuaries.

Concerning "nonspecific" tests, in their previous letter Swinker and Burke (2002) objected to our use of VCS tests in PEAS investigations because VCS deficits are "nonspecific." As noted in our EHP articles on PEAS (Shoemaker 2001; Shoemaker and Hudnell 2001) and in our response to her first letter (Hudnell and Shoemaker 2002), VCS deficits are "nonspecific" because they have multiple possible etiologies. In her current letter Swinker objects to our response that "neuropsychologic test deficits are nonspecific," reasoning that neuropsychologic tests identify "specific areas of functional deficits." We maintain that tests which detect functional deficits associated with impairment in specific neurologic pathways are still "nonspecific" tests if there is more than one possible etiologic agent. Our position is consistent with the definition of "nonspecific" in Dorland's Illustrated Medical Dictionary (Dorland 1988): "1. not due to any single known cause, as to a particular pathogen." We stand by our statement and maintain that both VCS and neuropsychologic tests a) are "nonspecific" because deficits have multiple possible causes; b) can reveal impairment in specific neurologic pathways; c) are useful objective indicators of neurologic impairment in a syndrome otherwise described only by "nonspecific" symptoms and; d) require investigation of alternative explanations of deficits because the tests are "nonspecific."

Swinker stated that

   Memory problems have been the most unique
   and significant symptoms reported following
   Pfiesteria exposure in both the laboratory setting
   (Glasgow et al. 1995) and in the 1997 Maryland
   environmental cohort (Grattan et al. 1998)

This statement is not supported by those reports or the experience of clinicians who have recognized PEAS cases. Memory problems are not unique to PEAS, and cases reported many symptoms, each of which can cause a significant decline in quality of life. The laboratory worker most severely affected by Pfiesteria exposure reported 13 multiple-system symptoms (Glasgow et al. 1995). He recovered memory function over many months, but developed unilateral blindness for which Pfiesteria exposure was considered the most likely cause (Schmechel and Koltai 2001). The Maryland study reported higher percentages of 10 symptoms in exposed participants than in control participants (Grattan et al. 1998). Memory loss was not a unique symptom category in that study, but was lumped with confusion, disorientation, and concentration difficulty (Grattan et al. 1998). Shoemaker's 37 PEAS cases reported 18 diverse symptoms, 13 of which were reported by more than one-third of the cases, and VCS was reduced by 60% in cases relative to controls (Shoemaker 2001). In her current letter, Swinker further states that the Maryland neuropsychologic results were specific for memory loss and that "deficits were not global." The Maryland study actually reported statistically significant neuropsychologic deficits in fine motor speed, dexterity, resistence to interference, and selective attention in addition to memory loss (Grattan et al. 1998). This evidence suggests that PEAS is a distinct syndrome characterized by multiple-system symptoms and a variety of neurologic effects, including vision and memory loss.

Swinker states that VCS has not been validated for use in helping to diagnose PEAS. We submit that many steps have been taken toward validation. Impetus for investigating the validity of VCS in PEAS diagnosis came from earlier observations of VCS deficits in populations contacting Pfiesteria-inhabited estuaries, relative to populations without exposure potential (Hudnell 1998; Hudnell et al. 2001; Turf et al. 1999). The group differences in VCS were independent of age, smoking, and bright sunlight exposure, and the groups did not appear to differ in exposures to solvents, pesticides, metals, or fumes. The absence of group differences in visual acuity suggested that neurologic, rather than optical, factors likely caused the VCS deficits. The data further indicated that the VCS deficits were related to total time spent at fish kills in the past. These results suggested that the VCS deficit might be a persistent sign of a neurologic effect from Pfiesteria toxin(s) or other factors associated with estuarine contact (Hudnell 1998; Hudnell et al. 2001; Swinker et al. 2001 a). Our subsequent EHP articles reported the initial data on validity of VCS as an indicator of neurologic impairment in cases meeting the Centers for Disease Control and Prevention (CDC) criteria for PEAS (Shoemaker 2001; Shoemaker and Hudnell 2001). The Grand Rounds cases (Shoemaker and Hudnell 2001) showed large VCS deficits during illness, and VCS recovery coincident with symptom resolution after cholestyramine treatment during acute, chronic, and repeated-acquisition of PEAS. These associations between VCS, symptoms, and treatment were verified in Shoemaker's subsequent cohort study and double-blinded, placebo-controlled crossover trial (Shoemaker 2001). Control conditions ruled out several possible causes of VCS fluctuations; VCS remained stable over time in healthy individuals, VCS was not altered by cholestyramine therapy in hypercholesterolemia patients who did not have PEAS, and PEAS cases showed VCS recovery and symptom resolution with cholestyramine, but not placebo, therapy (Shoemaker 2001). The VCS deficits in PEAS cases did not appear to be caused by solvent exposures. The group average VCS spatial-frequency profile in the PEAS cases (Shoemaker 2001) showed greatest reduction at midspatial frequency, similar to that seen following chronic solvent exposure (Hudnell 1998). Solvent exposure cases, however, did not respond to cholestyramine therapy (Shoemaker RC. Unpublished data), and review of the literature revealed no reports of therapy that were effective at resolving solvent-induced VCS deficits. Ocular abnormalities and diseases involving neurologic function also were probably not the cause of VCS deficits in the PEAS cases. None of Shoemaker's active PEAS cases received treatment for these conditions during the time of cholestyramine therapy and VCS recovery (Shoemaker 2001; Shoemaker and Hudnell 2001). Each of these observations is an important step in the process of validating VCS for use in PEAS diagnosis. Further validation may come from the demonstration of correlations between VCS and neuropsychologic data during illness and recovery with treatment in 17 of Shoemaker's PEAS cases who submitted to neuropsychologic testing (Shoemaker RC. Unpublished data).

In her letter, Swinker claims that VCS deficits in the hotline controls suggest "that VCS deficits may be highly prevalent and so nonspecific as to be of limited value as a diagnostic test." Her 10 local government-employee controls all reported exposure to Pfiesteria-inhabited estuaries and/or organic solvents, risk factors for VCS deficits (Hudnell and Shoemaker 2002). Although Swinker claims that the controls were "asymptomatic" in her current letter, neither her report (Swinker et al. 2001b) nor our review of the original data (Hudnell HK. Unpublished data) indicated that symptoms were assessed in the control group. Swinker's speculation on the prevalence of VCS deficits based on a small sample with confounding factors and incomplete assessment is unfounded. The consistent ability of studies to show VCS differences between exposed and control cohorts suggests that VCS deficits are not common in control populations screened for risk factors such as neurotoxic exposure and neurologic disease (Hudnell et al. 1996).

Finally, Swinker proposed that hydrogen sulfide exposure in estuarine waters may cause VCS deficits (Swinker and Burke 2002) and implied that this hypothesis would be assessed in the North Carolina longitudinal cohort study. The North Carolina study did not include measurements of hydrogen sulfide or any other potentially neurotoxic compound (Moe et al. 2001). Questions on odor detection were included but are not sufficient to address the hypothesis. Hydrogen sulfide exposures at concentrations and durations that may impact VCS are unlikely to be encountered in the open estuaries frequented by watermen.

We look forward to additional clarification of these issues in peer-reviewed research articles.

This letter was reviewed by the National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the agency, nor does mention of trade names or commercial products constitute endorsement or recommendation.

H. Kenneth Hudnell
U.S. Environmental Protection Agency
ORD/NHEERL/NTD/NPBT
Research Triangle Park, North Carolina
E-mail: [e-mail]

Ritchie C. Shoemaker
Center for Research on Biotoxin-Associated
Illness, Inc.
Pocomoke City, Maryland

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