Visual contrast sensitivity as a diagnostic tool. (Correspondence).

In "Possible Estuary-Associated Syndrome: Symptoms, Vision, and Treatment," Shoemaker and Hudnell (1) advocated use of the visual contrast sensitivity (VCS) test as a biomarker to diagnose possible estuary-associated syndrome (PEAS) and to assess response to their proposed treatment regimen. However, 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. These points should be clarified.

Shoemaker and Hudnell (1) made indirect reference to my work (2) in citing Hudnell's publication that suggested a statistical association between VCS deficits in estuary watermen and hours spent at fish kills (3). In this paper Hudnell et al. (3) used our medical data and their vision data, but reached some conclusions that are not wholly supported by the original historical data. For example, Hudnell et al. (3) ruled out the possibility that observed VCS deficits could be due to known neurotoxicants such as solvents or metals, on the basis of our occupational and environmental history responses. These responses were qualitative only and were not sufficiently detailed to distinguish between gasoline poured into a fuel tank (reported by most fishermen) and that used as hand-cleaner (reported by some fishermen). The history elicited did not fully document exposure to other specific and potentially neurotoxic substances that might be found in estuaries, such as hydrogen sulfide from decaying" organic materials. [These omissions have been addressed in the current cohort studies in North Carolina (4).] Hudnell et al.'s alternative hypothesis (3), that the VCS deficits may be

   caused by unknown, non-exposure-related factor(s) or by some other, perhaps
   more continuous exposure factor(s) associated with the estuaries or
   geographical area (p. 590)

is more tenable, as is his comment that "given the multiple potential explanations and the study limitations, each of these possibilities should be viewed as tentative (p. 590). Hudnell does concede that in this work, "few study participants met the [Centers for Disease Control and Prevention] case definition for PEAS" (3; p. 590). Actually, no subjects met the case description for active PEAS; the prevalence of past symptoms consistent with PEAS was equal in the estuary (exposed) and offshore (unexposed) watermen and consisted of one individual in each group. This suggests that neither current active nor past history of PEAS is likely to be the reason for the intergroup differences in VCS in the estuary versus offshore watermen.

In addition, the (P)EAS description is an epidemiologic concept, meant primarily for surveillance and enumeration purposes. Epidemiologists frequently adopt these concepts to identify potential cases for further clinical evaluation. The description does not represent diagnostic criteria, but is an indication for further evaluation. These descriptions are used to "cast a wide net" and do not indicate that disease is present until further testing verifies a diagnosis. VCS is an indicator of a subclinical process and is not a diagnostic test.

In a study in Virginia, Turf et al. (5) did not identify any cases of EAS in the first year of their ongoing prospective cohort study. They observed VCS deficits, which correlated with age, exposure time to estuary waters where Pfiesteria organisms may be found more than 50% of the time, and smoking. However, these deficits were not correlated with active (P)EAS, "as no cases were identified during the study. No toxic Pfiesteria events nor changes in neurocognivive function were observed" (5). Data are accumulating that Pfiesteria is enzootic in Atlantic coastal waters, even where ichthyotoxic effects have never been observed. The presence of the organism is not equivalent to presence of its secreted biotoxin, which is produced under rare, and currently incompletely defined, environmental conditions (6).

Other studies in North Carolina have evaluated telephone hotline callers with self-reports of symptoms and exposures potentially related to PEAS. As a group, the self-identified "cases" had normal VCS and the control subjects (predominantly non-watermen) had VCS abnormalities (7). Hudnell (8) concluded that VCS data in this case-control series "do not indicate that visual function was affected by exposure to North Carolina estuaries" (p. 16).

Hudnell et al. (3) stated that VCS may be a useful indicator for the diagnosis of PEAS, citing the work of Shoemaker and Hudnell (1) as evidence, while Shoemaker and Hudnell (1) cited Hudnell et al. (3) to support the use of VCS as a diagnostic test, setting up a circular pattern of reasoning. VCS has never been validated as having any correlation to the neuropsychologic (NP) deficits seen in Maryland (9, 10). The Maryland cases represent the only documented, fully evaluated cluster of environmental PEAS cases to date. Shoemaker and Hudnell (1) did not obtain NP testing on their subjects, although this represents the current "gold standard" for verifying PEAS; thus, this is a major shortcoming in their work. [One subject described by Shoemaker and Hudnell (1) had been part of the Maryland cohort and was fully evaluated in that context (9). That his NP scores were normal on 3-month follow-up by the Maryland research team is not unique or attributable to a specific treatment regimen. Most affected persons in Maryland improved over 3-6 months without any treatment (11)]. Symptoms such as confusion and memory problems are seen in a wide variety of clinical situations, ranging from neurotoxin exposure to sick building syndrome to emotional distress. Such symptoms indicate the need for further evaluation and full characterization before the initiation of treatment. VCS is a nonspecific test for neurologic function, which happens to be sensitive to some neurotoxin exposures, such as polychlorinated biphenyls and styrene. It is also affected by common conditions such as alcohol and medication use, learning disabilities, Parkinsonism, Alzheimer's dementia, vitamin deficiencies, and multiple sclerosis (7).

An advertisement for Shoemaker's latest book, Desperation Medicine (12), in the Carnrick (Pharmaceuticals) Quarterly newspaper (13) describes

   how a family practice doctor discovered the neurotoxin basis of chronic
   Lyme disease, sick building syndrome, Pfiesteria, ciguatera and other
   chronic illnesses (p. 20),

and that

   ... a physiologic test of contrast sensitivity pinpoints the true
   neurotoxic cause of symptoms which are often incorrectly passed off as
   depression, fibromyalgia, stress and IBS [irritable bowel syndrome] (p.
   20).

A successful treatment regimen is promised to readers (13). Shoemaker also advocates the use of VCS to screen all patients "who want [the] Lymerix" vaccination for Lyme disease at his chronic fatigue center (14); he has written that "many asymptomatic patients with a history of Lyme ... have the VCS deficit" (14). On his Web site, "Visual Contrast Sensitivity Test Center" (15), Shoemaker stated that

   Neurotoxin forming algae are being identified nearly monthly. If you do not
   have the VCS deficit, response to binding therapy is less [than] 66%. If
   you have the VCS deficit, response to therapy is over 90%.

He also stated that "unexplainable recurring joint pains of hands, wrists and/or feet" is another symptom of neurotoxin poisoning. Also on this Web site (15), Shoemaker discussed the use of the VCS exam to diagnose

   pfiesteria, ciguatera, cylindrospermosis (blue green algae in central
   Florida), sick building syndrome, Lyme disease, and soon chronic fatigue
   syndrome and chronic soft tissue pathways when our clinical data reach
   statistical certainty.

He stated that papers on ciguatera, sick building syndrome, and Lyme disease were being prepared, but we have not found these reports in a publications database to date.

On the basis of this evidence, it can only be concluded that a) VCS abnormalities are so widespread and nonspecific as to have limited usefulness as a biomarker for any particular condition (especially in the absence of industrial hygiene or environmental documentation regarding the source of exposure); and b) there is no evidence that VCS deficits have been observed in persons with current active PEAS verified by accepted, objective NP tests. Of note, passive surveillance efforts to detect PEAS have not recorded any verified cases (16) through 2000. Health-care providers have been asked to report suspected PEAS cases to their county health departments in Delaware, Florida, Maryland, North Carolina, South Carolina, and Virginia. The health departments can facilitate the full evaluation of these cases, including NP testing through state health agencies. We hope that the readers of EHP will recognize the anecdotal and unsubstantiated nature of the reports in the paper by Shoemaker and Hudnell (1), as well as the tremendous amount of medical research yet to be done before either VCS as a biomarker or cholestyramine as a treatment can be appropriately advocated.

REFERENCES

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

(2.) 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).

(3.) Hudnell HK, Rouse 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 62:575-594 (2001).

(4.) Moe CL, Turf E, Oldach D, Bell P, Hutton S, Savitz D, Koltai D, Turf M, Ingsrisawang L, Hart R, et al. Cohort studies of health effects among people exposed to estuarine waters: North Carolina, Virginia, and Maryland. Environ Health Perspect. 109(suppl 5):781-786 (2001)

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

(6.) Rublee PA, Kempton J, Schaefer E, Burkholder JM, Glasgow HB, Oldach D. PCR and FISH detection extends the range of Pfiesteria piscicida in estuarine waters. VA J Sci 50:323-335 (1999).

(7.) 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 12:126-132 (2001).

(8.) 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.

(9.) Grattan LM, Oldach D, Perl 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).

(10.) Grattan LM, Oldach D, Tracy K, Greenberg DR. Neurobehavioral complaints of symptomatic persons exposed to Pfiesteria piscicida or morphologically related organisms. MD Med J 47:127-129 (1998).

(11.) Grattan LM. Current status and future directions for the investigation and management of the human health effects of exposure to Pfiesteria piscicida or Pfiesteria-like dinoflagellates. MD Med J 47:146-150 (1998).

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

(13.) Books/journals available. The Carnrick (Pharmaceuticals) Quarterly (March):20 (2001).

(14.) Shoemaker R. [OEM] Fw. Lymerix questions. Available: http://mailman.mc.duke.edu/pipermail/occ-env-med-l/2001-March/016418.html [cited 22, January 2002].

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

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

Marian Swinker
William A. Burke
East Carolina University School of Medicine
Greenville, North Carolina
E-mail: [e-mail]