Visual contrast sensitivity: response. (Correspondence).

We are pleased to respond to the letter from Swinker and Burke regarding our paper "Possible Estuary-Associated Syndrome: Symptoms, Vision, and Treatment" (1), which was published in EHP as a Grand Rounds in Environmental Medicine article. Swinker and Burke state that "the use of VCS as a diagnostic test for PEAS (and subsequent treatment of PEAS with cholestyramine) is not supported by a careful examination of the existing evidence." Their letter, however, does not discuss the data presented for the five Grand Rounds cases; they mention only our Case 1, and that is in reference to the patient's participation in the Maryland study on exposure to waterways containing toxin-producing Pfiesteria (2). We agree that previous publications only associated a VCS deficit with Pfiesteria-inhabited estuary contact, not with active PEAS. The North Carolina study, which associated the VCS deficit with estuarine contact (3, 4), was designed to investigate the potential for persistent, estuary-associated health effects (5). Unlike the Maryland study, which involved recent exposure to fish kills and active PEAS (2), members of the North Carolina estuary cohort had no recent fish-kill exposure and were not selected because of complaints of current health effects (5). The North Carolina study (5) attempted to use the Centers for Disease Control and Prevention (CDC) symptom-based case definition (6) to assess PEAS at remote times of fish kill or lesioned fish contact, times at which VCS data were unavailable (5). The Virginia study (7) verified the VCS deficit in people contacting estuaries inhabited by "Pfiesteria-like organisms," but reported no active PEAS cases. Neither the North Carolina nor the Virginia study reported the prevalence of current PEAS symptoms in the exposed or control populations (5, 7). The Grand Rounds cases, therefore, represent the first reports of VCS data measured before and during active PEAS diagnosis and after successful treatment (1). The dramatic and concurrent variations in VCS with the presence and absence of symptoms suggested that VCS measurements are a useful adjunct to the PEAS case definition.

In the Grand Rounds article, we carefully described the PEAS diagnostic criteria, involving exposure potential, symptoms, and the lack of alternative explanations. We measured VCS in Cases 2-5 to assess its usefulness in aiding PEAS diagnosis and recovery monitoring (1). All cases became ill shortly after exposure to estuaries in which Pfiesteria was identified and after dead or lesioned fish were observed. The cases initially had depressed VCS and multiple symptoms, including many of those listed by the CDC in the PEAS case definition, as well as the others reported (1). All cases had no history of illness involving neurologic dysfunction, allergy, asthma, eosinophilia, or neurotoxicant exposure. Complete blood count, comprehensive metabolic profile, and pulmonary function test results were within normal parameters. The pattern of VCS recovery and symptom resolution promptly following initiation of cholestyramine (CSM) therapy seen in all cases was documented prospectively in Case 2 (a researcher). His fall in VCS and symptom onset occurred within 36 hr of exposure to a site where a fish kill occurred 2 days later, and with very low probability of exposure to nonestuarine-associated neurotoxicants. Collectively, the cases demonstrated similar, large VCS deficits in acute, chronic, and repeated-acquisition illness, and subsequent rapid return to normal VCS coincident with CSM treatment.

The lack of significant exposure to known solvents in the Grand Rounds cases and the VCS recovery with treatment strongly argued that neither the symptoms nor VCS deficits were caused by solvent exposure. Solvent-induced symptoms and deficits in VCS and neurobehavioral performance are persistent or permanent, having been measured long after cessation of solvent exposure (8-10). We found no literature on recovery from solvent- or other toxicant-induced VCS deficits. Symptomatic patients with occupational solvent exposure and VCS deficits did not respond to CSM treatment (11). The concern of possible hydrogen sulfide exposure, mentioned by Swinker and Burke, is highly unlikely to be a causative factor for VCS deficits in watermen who work outdoors without occupational exposure to sources of [H.sub.2]S, such as submerged, decaying sediments of marshes.

Our most recent data, presented at the CDC National Conference on Pfiesteria (12) and published in EHP (13), confirmed the observations reported in the Grand Rounds article (1) in a population of 77 patients with residential and/or recreational exposure to Pfiesteria-inhabited estuaries in Maryland (13). Relative to two control populations totaling 87 patients, one with residential and/or recreational exposure to marine waters and one with no exposure to any bodies of water, the estuary cohort showed significantly depressed VCS. Thirty-seven members of the estuary cohort met the CDC case definition for PEAS (6). The 60% loss of VCS in the PEAS cases accounted for the entire VCS difference between the estuary and combined-control cohorts. VCS recovered to control levels as symptoms resolved within 2 weeks of CSM treatment. Shoemaker (13) also presented results from an earlier small, double-blinded, placebo-controlled, crossover clinical trial that showed the efficacy of CSM treatment in PEAS and the lack of a placebo effect. He also presented data indicating that repeated testing does not alter VCS scores and that CSM has no effect on VCS in non-PEAS patients treated for hypercholesterolemia (13).

Swinker and Burke refer to neuropsychologic tests as the "`gold standard' for verifying PEAS." This is curious because neuropsychologic test deficits are nonspecific, and Swinker and Burke object to the use of VCS testing in PEAS diagnosis because VCS deficits are nonspecific. We think that all tests which objectively describe neurologic deficits in symptom-described illness may assist in diagnosis, particularly when preexposure data are available. Issues of neuropsychologic testing availability in rural areas, patients' willingness to spend 3-4 hr in testing, and individual diagnosis criteria must be confronted, however, before neuropsychologic tests can become a gold standard for practicing physicians. The VCS data presented in the Grand Rounds article (1) showed 40-90% fluctuations between wellness and illness that occurred within days in individual cases. The VCS test provided a rapid, inexpensive, and readily available objective indicator that was strongly associated with corresponding changes in symptoms. All VCS deficits were outside the range of our (unpublished) age-adjusted, normative data.

Neither the Maryland study (2), our Grand Rounds article (1), nor our recent paper (13) definitively attributed illness to Pfiesteria-toxin(s) exposure. Definitive attribution of PEAS causation to Pfiesteria toxin(s), if that is the case, must await the identification of the toxin or toxins produced by Pfiesteria, detection of the toxin(s) in ill patients, and the absence of the toxin(s) in recovered patients. Recent research by Kimm-Brinson et al. (14) reported that a partially isolated toxin from Pfiesteria is an agonist for the adenosine-5'-triphosphate P2X7 receptors found in the membranes of microglia and peripheral macrophages. Activation of P2X7 receptors triggers a proinflammatory cytokine response that could potentially account for the Pfiesteria-related effects observed in humans and wildlife. The hypothesis that direct Pfiesteria-toxin(s) effects, combined with downstream cytokine effects (in the absence of abnormalities in standard immunologic system test results), are the sources of symptoms in PEAS cases should be pursued.

We wish to address several other issues raised by Swinker and Burke. They are correct in quoting Hudnell (3) on the hotline-caller data from the North Carolina study. The VCS data "do not indicate that visual function was affected by exposure to North Carolina estuaries" (p. 19). Swinker and Burke did not mention, however, the potentially confounding factors concerning characteristics of the hotline callers and their control group that may be responsible for the lack of association. First, of the 11 hotline callers assessed, Swinker et al. (15) subsequently reported that only 6 were found to have "relevant fish or water exposure," that only 6 had "actual" exposure (pp. 129-130). Second, analyses done at Swinker's request suggested VCS "abnormality" in the six cases with "relevant" or "actual" exposure (Figure 1). In fact, their VCS was at or below the level of the occupational estuary cohort (3,4) at all spatial frequencies. Swinker et al. (15) reported that only these six cases with actual exposure met the CDC criteria for estuary-associated syndrome, and that four had neuropsychologic impairment. They dismissed the diagnoses of estuary-associated syndrome, saying that "All six exposed cases had underlying or pre-existing medical condition(s) that could explain at least some of their symptoms" (15).

[FIGURE 1 OMITTED]

We submit that the description "could explain at least some of their symptoms" is insufficient for dismissing the diagnosis in situations where the VCS deficit is present and CSM treatment would clarify the issue. Third, the four callers without actual exposure, for whom VCS could be assessed, showed "normal" values (Figure 1)--values similar to those of the control offshore cohort (3, 4). Fourth, VCS appeared to be "abnormal" in the hotline-caller control cohort (Figure 1). Of the 10 controls for whom VCS could be assessed, all reported exposures to North Carolina estuaries (recreational, n = 10; occupational, n = 3; living by the estuaries, n = 2), and 8 reported solvent exposure (occupational, n = 5; avocational, n = 4). Comparison of the VCS data for the entire hotline-caller cohort with that of the hotline-caller control cohort (3), therefore, did not give evidence of an estuary-associated VCS deficit in the callers, perhaps due to a confounding of relevant exposures between groups.

Swinker and Burke note that the CDC (16) did not receive reports of any verified cases of PEAS through 2000 but that "the health departments can facilitate the full evaluation of cases." The State of Maryland Pfiesteria Surveillance Team announced that it had identified five patients meeting the CDC PEAS criteria from 1997 to 2000 (17). We commend the Maryland team and hope that our publications on PEAS will assist other health-care professionals in identifying PEAS cases.

Swinker and Burke omitted the quotation marks around "asymptomatic" in an e-mail message written by Shoemaker (18), which referred to patients with arthritic and biotoxic symptoms following dosages of the Lyme vaccine. The point Shoemaker made was that among patients who wanted the Lymerix vaccine following treatment with antibiotics for Lyme disease, there were many who had persistent symptoms attributed, perhaps inappropriately, to other illnesses. Shoemaker's data suggest that the persistent symptoms may represent another biotoxin-induced illness, post-Lyme syndrome. The patients' history of Lyme disease, the persistence of symptoms following substantial antibiotic treatment, the continued presence of a VCS deficit, and VCS recovery concurrent with symptom resolution after CSM treatment suggest that the bacteria may have released toxins before and/or during cell lysis. Patients inappropriately labeled as "cured" or "asymptomatic" are at a significant risk, in Shoemaker's opinion, of possible adverse effects from the Lymerix vaccine due to potentiation of a proinflammatory cytokine response. An accurate quote of the full sentence does not suggest that truly asymptomatic patients have a VCS deficit (18), as Swinker and Burke imply. If VCS deficits were as common as. they imply, then it is unlikely that VCS testing would have been so successful in distinguishing toxin-affected or clinical groups from normal [see references in Shoemaker (13)].

Swinker and Burke indirectly criticize Shoemaker's Web site (19), which is still under construction. We thank them for pointing out typographical errors and regret that we have not yet had the time to complete manuscripts that will present data suggesting that the paradigm of chronic biotoxin-mediated illness may generalize to a number of conditions involving toxin-forming organisms. These organisms are increasingly being viewed as potential human health risks following direct contact or through contamination of food, water, and/or air. Because the Grand Rounds article (1) is early in the course of presentations on the basic concepts on biotoxin-mediated illnesses, there must be discussion and scientific debate regarding our observations. We agree with Swinker and Burke that our results must be confirmed in peer-reviewed publications. The purpose of the Grand Rounds article (1), our recent article (13), and the Web site was to introduce a series of new concepts to the academic community, primary-care physicians, and patients as part of a teaching and research-promoting process. Corrections and modifications will be made to the Web site as time and resources allow.

In their letter, Swinker and Burke refer to an advertisement for Shoemaker's book, Desperation Medicine (20). Cases supporting the hypothesis of generalization of a PEAS-like illness to patients with exposure to a variety of other biotoxin-producing organisms are described in Desperation Medicine (20). The book describes how symptoms in biotoxin-exposed patients stem from multiple system involvement, with day-to-day variation; there are no days in which affected patients are free from all symptoms. Taken alone, each symptom is nondiagnostic. Taken as a whole, however, as presented in the Grand Rounds article (1), the symptom complexes in patients who have particular environmental exposures and a distinct deficit in VCS are an important component in developing standard-of-care guidelines for the treating physician who must attempt diagnosis. The physician must take complete medical and potential biotoxin exposure histories and thoroughly characterize the patient's symptom profile, not relying on volunteered self-reports or a simple check-list. The physician may then identify the environmental exposure(s) associated with the illness, as well as those that are not, document the presence or absence of confounding neurotoxin exposures, administer clinical and laboratory tests of potentially confounding factors, and properly measure VCS to determine whether there is a deficit that is greatest at the mid-spatial frequencies. When clinical criteria for the likely presence of a biotoxin-mediated illness are met, prompt and predictable resolution of the symptom complex and VCS recovery, coincident with initiation of CSM treatment according to protocol, supports the diagnosis of chronic biotoxin-mediated illness. The usefulness of our case definition is particularly well demonstrated in patients with chronic illness that is unresponsive to previous treatments. We hope that acutely and chronically ill patients of all physicians will benefit from our new approach to diagnosing and treating the emerging health risk of biotoxin-induced illness.

REFERENCES AND NOTES

(1.) Shoemaker RC, Hudnell HK. Possible estuary-associated syndrome: symptoms, vision, and treatment. Environ Health Perspect 109:539-545 (2001).

(2.) Grattan LM, 0ldach D, Peri TM, Lowitt MH, Matuszak DL, Dickson C, Parrott C, Shoemaker RC, Kauffman CL, Wasserman MP, et al. Learning and memory difficulties after environmental exposure to waterways containing toxin-producing Pfiesteria or Pfiesteria-like dinoflagellates. Lancet 352:532-539 (1998).

(3.) Hudnell HK. Human Visual Function in the North Carolina Clinical Study on Pfiesteria piscicida. EPA 600-R-98-132. Research Triangle Park, NC:U.S. Environmental Protection Agency, 1998.

(4.) Hudnell HK, House D, Schmid J, Koltai D, Stopford W, Wilkins J, Savitz DA, Swinker M, Music S. Human visual function in the North Carolina clinical study on possible estuary-associated syndrome. J Toxicol Environ Health A 62:575-594 (2001).

(5.) Swinker M, Koltai D, Wilkins J, Hudnell K, Hall C, Darcey D, Robertson K, Schmechel D, Stopford W, Music S. Estuary-associated syndrome in North Carolina: an occupational prevalence study. Environ Health Perspect 109:21-26 (2001).

(6.) Possible estuary-associated syndrome. MMWR Morb Mortal Wkly Rep 48:381-382 (1999).

(7.) Turf E, Ingsrisawang L, Turf M, Ball JD, Stutts M, Taylor J, Jenkins S. A cohort study to determine the epidemiology of estuary-associated syndrome. VA J Sci 50:299-310 (1999).

(8.) Mergler D, Huel G, Bowler R, Frenette B, Cone J. Visual dysfunction among former microelectronics assembly workers. Arch Environ Health 46:326-334 (1991).

(9.) Broadwell DK, Darcey DJ, Hudnell HK, Otto DA, Boyes WK. Work-site clinical and neurobehavioral assessment of solvent-exposed microelectronics workers. Am J Ind Mad 27:677-698 (1995).

(10.) Donoghue AM, Dryson EW, Wynn-Williams G. Contrast sensitivity in organic-solvent-induced chronic toxic encephalopathy. J Occup Environ Mad 37:1357-1363 (1995).

(11.) Shoemaker RC. Unpublished data.

(12.) Hudnell HK. Residential and recreational acquisition of possible estuary associated syndrome: a new approach to successful diagnosis and treatment. Presented at the CDC National Conference on Pfiesteria: From Biology to Public Health, 18-20 October 2000, Stone Mountain, Georgia.

(13.) Shoemaker RC. Residential and recreational acquisition of possible estuary-associated syndrome: a new approach to successful diagnosis and treatment. Environ Health Perspect 109(suppl 5):791-796 (2001).

(14.) Kimm-Brinson KL, Moeller PDR, Barbier M, Glasgow H Jr, Burkholder JM, Ramsdell JS. Identification of a P2X7 receptor in G[H.sub.4][C.sub.1] rat pituitary cells: a potential target for a bioactive substance produced by Pfiesteria piscicida. Environ Health Perspect 109:457-462 (2001).

(15.) Swinker M, Koltai D, Wilkins J, Stopford W. Is there an estuary associated syndrome in North Carolina? Findings in a series of hotline callers. NC Med J 62:126-132 (2001).

(16.) CDC. Surveillance for possible estuary-associated syndrome--six states, 1998-1999. MMWR Morb Mortal Wkly Rep 49:372-274 (2000).

(17.) Dewar H. Pfiesteria may have sickened 5 people: Maryland medical officials document cases from past 3 years. Baltimore Sun (Maryland) 4 April 2001: B1.

(18.) Shoemaker RC. [OEM] Fw. Lymerix questions. Available: http://mailman.mc.duke.edu/pipermail/occ-env-med-l/[cited 22 January 2002]. Select 2001-March Subject, then [OEM] Fw: Lymerix questions Ritchie Shoemaker.

(19.) Visual Contrast Sensitivity Test Center. Available: www.chronicneurotoxins.com [cited 23 January 2002].

(20.) Shoemaker RC. Desperation Medicine. Baltimore, MD:Gateway Press, 2001.

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

Ritchie C. Shoemaker
McCready Outpatient Service Center
Pocomoke City, Maryland