Neurology -- Correspondence for Cox and Sacks, 58 (6) 956-959

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Correspondence published:

Reply to Letter to the Editor: Paul Alan Cox, Oliver W Sacks (27 June 2002)

Cycad neurotoxins, consumption of flying foxes, and ALS-PDC disease in Guam: Kwang-Ming Chen, Ulla K Craig, Chin-Tian Lee, and Robert Haddock (27 June 2002)

Reply to Letter to the Editor 27 June 2002

Paul Alan Cox
National Tropical Botanical Garden Kalaheo Kauai,
Oliver W Sacks
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Re: Reply to Letter to the Editor

mkasay{at}ntbg.org Paul Alan Cox, et al.

According to the most recent monograph (which excludes [1] C. circinalis from Guam), we are correct in referring the Guam species of cycad (which appears in our photograph) to Cycas rumphii sensu latissimo. The Cycas rumphii species complex has been placed in the subsection Rumphiae of the genus Cycas. Referring to the Guam cycad species, Hill notes that "nomenclature of this taxon has been unstable" (Hill 1994: 556) and proposes the new binomial C. micronesica as part of the Cycas rumphii species complex. Our ethnobotanical research focused on this indigenous cycad species which the Chamorro people call "fadang".
The fleshy sarcotesta of the seed, as opposed to the hard gametophyte, is easily ingested by flying foxes, and is rich in BMAA as confirmed by HPLC analysis [2] as distinguished from the other 54 species of plants [3, 10] they consume. The fleshy seeds are among the ten favorite food items [4] of P. mariannus as confirmed in field observations. [5] We confirmed the attractiveness of fleshy cycad seeds to P. mariannus during five weeks of field work in Guam [5] which did not occur during a drought.
Spencer's papers on cycad neurotoxins are classics, have never been withdrawn, and may now be of even greater interest since the biomagnification mechanism that we propose could account for high doses of cycad neurotoxins in those who consume cycad-fed flying foxes.
As we reported in our article, Lujan claimed that flying foxes were so numerous in the early twentieth century that farmers fed them to their hogs when plant resources were scarce. Details of our estimates of P. mariannus densities in Guam prior to militarization are in press, [5] and are consistent with previous estimates of 93 flying foxes per km2 in the northern
Marianna Islands [6[ and 195 flying foxes per km2 in Rota [7] An estimated 230,000 flying foxes representing at least 10 species were imported to Guam from 1975 to 1990 from other islands [8] where cycads are not native or do not play a prominent role in the vegetation, and thus would have no effect on the incidence of ALS-PDC. Sources for data on ALS incidence in Guam are noted in our paper.
Chen et al. facetiously suggest that snake densities or number of automobiles correlate with ALS-PDC incidence, but such factors do not have a rise and subsequent decline as does the human consumption of cycad-eating flying foxes, and are not consistent with epidemiological data which indicate that the only variable significantly associated with an increased incidence of ALS-PDC in Guam is a preference for traditional Chamorro food. [9] Such an epidemiological pattern suggests that any and all unique items in the Chamorro diet should be considered. A finding of elevated levels of cycad neurotoxins in museum specimens of flying foxes and cycad-fed live animals, or discovery of ALS-PDC lesions in their brains, would give further weight to our hypothesis.
References:
1. Hill KD. The Cycas rumphii complex (Cycadaceae) in New Guinea and the Western Pacific. Australian Systematic Botany 1994;7:543-567.
2. Banack SA, Douglass J, Cox PA, in preparation.
3. Wiles GJ. The status of fruit bats on Guam. Pacific Science 1987a;41:148-157.
4. Wiles GJ. Current research and future management of Mariana fruit bats on Guam. Australian Mammalogy 1987b;10:93-95.
5. Monson CS, Banack SA, Cox PA. ALS-PDC and flying fox declines in Guam: Linkage of a human health crisis to wildlife extinction. Conservation Biology 1989;3:66.75.
6. Wiles GJ, Lemke TO, Payne, NH. Population estimates of fruit bats, pteropus mariannus in the Mariana Island. Conservation Biology 1989;3:66.75.
7. Stinson DW, Glass PO, Taisacan EM. 1992. Declines and trade in fruit bats on Saipan,Tinian, Anguijan, and Rota. In: Wilson DE, Graham GL, Eds. Pacific Island flying foxes; Proceedings of an International Conference. Biological Report. Fish and Wildlife Service,Washinton D.C. 1992;90(23):61-67.
8. Wiles GJ. The pacific flying fox trade: A new dilemma. Bats 1994;12(3):15-18.
9. Reed D, Labarthe D, Chen, KM, Stallones R. A cohort study of amyotrophic lateral sclerosis and parkinsonism-dementia on Guam and Rota. American Journal of Epidemilogy 1987;125:92-100.
10. Wiles GJ, Fujita MS. Food plants and economic importance of flying foxes on Pacific Islands. In: Wilson DE and Graham GL. Pacific Islands flying foxes. Proceedings of an International Conservation Conference. US Fish and Wildlife Service. Biological Report 1992;90

Cycad neurotoxins, consumption of flying foxes, and ALS-PDC disease in Guam 27 June 2002

Kwang-Ming Chen
Lytico and Bodig Research Project Magilao Guam,
Ulla K Craig, Chin-Tian Lee, and Robert Haddock
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Re: Cycad neurotoxins, consumption of flying foxes, and ALS-PDC disease in Guam

sandi_moriarity{at}urmc.rochester.edu Kwang-Ming Chen, et al.

The Cox and Sacks' hypothesis on the century old mysterious neurodegenerative disease of Guam was quite interesting. [1] Vigorous epidemiological and etiological investigations by NINDS for the past 50 years were mainly research by exclusion. Many hypotheses were postulated and then discarded due to negative results. These included genetic [2, 3. 4] (before the age of molecular genetics), as well as environmental risk factors such as zoonoses, viral and prion infections. [5, 6, 7] Whiting and Kurland at NIH extensively investigated food practices of the native Chamorros. They launched six International Conferences of Cycad Toxicity from 1962-1974. [8] Amazingly the cycad neurotoxin is still haunting those phytotoxin investigators over the past four decades, even though cycad was proved beyond doubt to be epileptogenic, carcinogenic and hepatotoxic, but not neurotoxic. [8]
Some 15 years later in 1987, Spencer's BMAA experiment on the monkey surprised the neuroscience world. [9] The July 31 issue of Science editorialized: "a combination of dogged determination and inspired science appeared to have solved the mystery of a brain disease in Guam�". It was an instant sensation of hope and fervor in the history of ALS research. In fact it was the old cycad story revisited with monkey experiment using mega-dose of synthetic BMAA. Had Spencer used BMAA extracted from C. cirinalis seeds from Guam, the monkey would have had to consume 40 kg of seeds a day, which is impossible. The neuropathology was that of subacute chemical encephalitis, not formation of pathognomonic NFTs. No lab throughout the world could reproduce his experiment [10, 11, 12] and Spencer had to retract his paper from Science in 1990. [13]
The authors' hypothesis needs clarification:
1. C. circinalis grows exclusively in the Marianas but not C. rumphuii. The latter is found in small numbers in Guam but grows mainly in Australia and Malay archipelagoes. It may contain negligible amount of BMAA. [12] The cycad seeds in Figure 2 are C. rumphii, not circinalis. It lost its green color and its leaflets, showing that they were ripe and dry.
2. The bats' main source of food is fruits and flowers, hence called one of "major jungle pollinators." P. marianas eats fruits or flowers of 39 species of plants [14, 15] that grow in Guam limestone forests. They eat only cycad seed skin when forests are devoid of fruits and wild flowers in time of extreme dry season. The bats' teeth cannot crack open an extremely hard husk of the cycad seed and eat the juicy pulp, which contains cycasin and BMAA. If the bat could consume the toxic pulp in large quantity, accumulations of "biomagnified" toxins, as authors claimed, could have killed them all.
3. Guam Department of Agriculture Aquatics and Wild Life Division banned the hunting of P. marianas on February 21, 1973. It was federally listed as endangered species on August 27, 1984. The bats smuggled into Guam from Northern Marianas were the same species, but from the Carolinian Islands and Samoa. They were different and do not eat cycad. There has been no single case report of ALS from these islands. The authors also did not report per capita consumption of bats on Guam.
4. Figure 4 plotting of bat population from 1920-1940 is highly questionable. Coultas made the earliest report available in 1930, which considered "uncommon" over most of the island. [15] The Federal concern for Guam flora and fauna began in the 1970's. In addition, the number of bats consumed in Guam after the 1970's did not actually decrease due to massive importation from the outer islands. It peaked in the late 1970's when 20,000-29,000 bats were imported annually. [16] The annual incidence of AlS is also inaccurate. The real incidence published in 1964 was 70/100,000 and by 1990 it was 7/100,000. [17] The sex ratio had been 2:1 at most, while PDC had been steady at 3:1 over the years.
5. One can plot the epidemic of the brown tree snakes from 1978-1993 against the decline in ALS incidence. They wiped out most rodents and birds including bats during that period [18] or the rapid increase in numbers of civil automobiles form a handful in 1960 to 130,000 in 2000, coinciding with the decline in ALS but not PDC.
The human experiment of chronic exposure to Guam's environment in regards to food practice was best exemplified by Sergeant Shoichi Yokoyi, the Japanese Emperor's last soldier, who survived 28 years in the Guam jungle, eating cycads, grasses, taro, yam, wild boar and rodents, including fruit bats. Chen personally examined him when he was captured on January 26, 1972. He was 57;mentally sound but physically had B1 deficiency and chronic eczematous dermatitis from mosquito bites. He was given an honorary citizenship of Guam before he was repatriated to Japan. He married and spent his "golden age" in Nagoya near Toyota town. He quietly died on September 21, 1997 at age 82 from heart failure, but not ALS or PDC. Autopsy demonstrated classical Parkinson's disease with some Lewy bodies in the brainstem and hippocampus. No NFT or senile plaques were found. [19]
Any hypothesis, no matter how far-fetched, is welcome in the field of neurodegenerative disease research, but there should be pertinent data that are reliable enough to be reproduced and to satisfy Robert Koch's principle.
References:
1. Cox PA, Sacks OW. Cycad neurotoxin, consumption of flying foxes, and ALS/PDC disease in Guam. Neurology 2002;58:956.
2. Kurland IT, Mulder DW. Epidemiological investigations of ALS. II. Familial aggregations indictive of dominant inheritance. Neurology Part 1. 1955;5:182-193. Neurology Part 2. 1955;5:249-268.
3. Plato CC, Reed DM, Elizan TS, Kurland IT. ALS/PDC on Guam. IV. Familial and genetic investigations. Am J Hum Genet 1667;19:617-632.
4. Plato CC, Galasco D, Garruto RM, Plato M, et al. ALS and PDC on Guam: Forty-year follow-up Neurology 2002;58:765-773.
5. Gibbs CJ Jr, Gajdusek DC. ALS, PD, and A:S/PDC on Guam: A review and summary of attempts to determine infection as etiology. J Clin Path 1972;25(Suppl 6):132-140.
6. White I, Nemo GI, Gibbs CJ Jr, Gajdusek DC, Brody JA. Guamanian ALS: Search for a virus. Neurology 1976;26:396.
7. Gibbs CJ Jr, Dajdusek DC. An update on long-term in vivo studies designed to identify a virus as the cause of ALS, PDC and Parkinson's disease. Adv Neurol 1882:56:343-353.
8. Kurland LT. Ed. Six International Conferences on Cycd toxicity. Fed Proc 1962-1974. Vol. 21, 23, 25, 27, 29, 31.
9. Spencer PS, Nunn P, Hugon J, et al. Guam ALS/PDC linked to a plant excitant toxin. Science 1987;237:517-522.
10. Duncan MW, Kopin IJ, Garruto RM, et al. 2-Amino-3-methylamino-propionic acid in Cycad-derived food is an unlikely cause of ALS/parkinsonism. Lancet 1988;11:631-632.
11. Duncan W. Role of the Cycad Neurotoxin BMAA in the ALS-PDC of the Western Pacific. Adv Neurol 1991;56:301-310.
12. Gajdusek DC, Cycad toxicity not the cause of high incidence ALS/PDC on Guam, Kii peninsula of Japan or in the West New Guinea. In: Hudson AJ, ED. ALS: Concepts in pathogenesis and etiology. Toronto. Univ Toronto Press 1989:317-325.
13. Spencer PS, Allen R, Kisby GE, Ludolph AC. Excitotoxic disorder. Science 1990;248:144.
14. Wiles GJ, Fujita MS. Food plants and economic importance of flying foxes on Pacific Islands. IN: Wilsom DE and Graham GL. Eds. Pacific Islands flying foxes: Proceedings of an International Conservation Conference. US Fish and Wildlife Service. Biological Report 1992;90(23)24- 35.
15. Wiles Gj. Personal communication. Formerly Chief of Guam's Division of Aquatic and Wildlife Resources.
16. Wiles GJ. Recent trends in the fruit bat trade on Guam. In: Wilson DE and Graham GL. Eds. Pacific Islands flying foxes: Proceedings of an International Concervation Conference. US Fish and Wildlife Service. Biological Report 1992;0(23):53-60.
17. Chen KM. Disappearance of ALS from Guam: Implications for exogenous causes. Clin Neurol (Tokyo) 1995;35:1549-1553. (In Japanese)
18. Carlton J. It's man vs. tree snakes in Guam: For now snake is winning. Wall Street Journal December 12,1991.
19. Konagawa Y, Yoshida M. Hashizume Y. et al. An autopsy report on a Japanese soldier living soldierly in Guam for 28 years. Brain Nerve 2000;52:167-171.