Medical Hypotheses 5: 1237-1249, 1979

THE NAEGLERIAL CAUSATION OF RHEUMATOID DISEASE AND MANY HUMAN

A NEW CONCEPT IN MEDICINE.

R. Wyburn-Mason, 2 Hillbrow, Richmond Hill, Richmond, Surrey,

ABSTRACT

CANCERS.

England.

Man and terrestrial animals live in an environment containing free- living amoebae on the surface soil, in pools, fresh water lakes, rivers and streams. They form cysts, which float in the air and which are continually inhaled and found in the nasopharynx and their trophozoites are present in human and animal faeces. Amoebae of the genus, Naegleria, have been demon- strated in all human tissues, both healthy and in larger numbers in those taken from cases of rheumatoid disease, in all human cancers and in the unaffected tissues of cancer patients. They can be killed in vitro by a series of different anti-amoebic substances and treatment of active cases of rheumatoid disease by any of these, either causes cessation of disease activity or a temporary exaggeration of symptoms followed by their lessening or disappearance (Herxheimer reaction), indicating the presence of an amoeba in the affected tissues as the causative organism of the inflammation in this disease in subjects genetically sensitive to the organism. Every internal organ may be involved in the inflammatory response in cases of rheumatoid disease and this also ceases with the above treatments. Many of these internal lesions are premalignant, so that infection with the organism either in sensitive subjects or with pathogenic species, appearsto be the primary cause of cancer in many cases. The presence in the body of Naegleria represents the source of the constant antigenic stimulation thought to be responsible both for rheumatoid disease and for the development of lymphomata and myelomatosis.

Key Words AMEBA AMEBIASIS ARTHRITIS, RHEUMATOID NEOPLASMS PRECANCEROUS CONDITIONS PROTOZOAN INFECTIONS SJOGREN'S SYNDROME

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INTRODUCTION -

The considerations which follow are a resume of the author's recently published monograph (1) and statements made can be confirmed by reference to this. The existence of free-living amoebae, not requiring a host for their conti‘nued existence, has been known at least since the last century. They are found on the surface soil in most parts of the world, preferring warm moist conditions, and they proliferate in warm stagnant pools, lakes and at the bottom of rivers, particularly in the regions where a warm effluent enters. Pathogenic free-living amoebae are readily isolated from chlorinated swi'mming pools, potable waters, sewage and nasal and throat cavities. They have been found in the domestic water supply in South Australia and recently in the warm water of the Roman Baths at Bath, England. There are probably about 300 different species known at present, and they have been divided into two main genera, the Acanthamoebae and Naegleria. The trophozoites of these differ in various details, such as shape, size, number of pseudopodia and vacuoles,rate of movement, mode of nuclear division and in antigenic content. spherical

In inimical conditions they form hollow cysts of 9-27 microns in diameter. The Naegleria cysts have a

smooth surface with fenestrations and readily form in vitro, but never in the tissues, while Acanthamoebae readily encyst both in vitro and in the tissues. Naegleria develop into biflagellate forms in distilled water and organisms of both genera are soluble in one per cent deoxycholate (bile salts). Cysts of free-living amoebae are found in the air in most parts of the world other than those covered by ice and can readily be observed on agar plates exposed to air for 10 minutes or more. These organisms often contaminate tissue cultures. Most free-living amoebae prefer warm surround- ings and they tend to migrate from cooler to warmer conditions, a property known as thermotropism possessed by many parasites of warm-blooded animals. Apart from their presence in the nose and throat, trophozoites of these organisms are often found in human faeces and that of most animals and in sewaye. It is obvious that all living terrestrial animals and plants and many in fresh water live in a world surrounded by many species of free- living amoebae, which certainly pass into the respiratory passages as cysts or trophozoites and which are also present as trophozoites in the bowel: since they are found in the faeces. As the organisms possess thermotropic properties, it would be unreasonable to suppose that once they had entered the orifices of the body, they would not migrate through the mucosae to the warmth of the body tissues and, if pathogenic, induce an inflammatory reaction in susceptible subjects.

Free-living amoebae as a cause of human disease

Pathogenic Naegleria have been recovered from the nasopharynx and bronchus in patients with or without fever and respiratory symptoms. Since 1970 one species of Naegleria (N. fowleri) has been shown to be the cause of primary amoebic meningo-encephalitis, an uniformally fatal condition. An amoebic infection of the eye with a free-living amoeba, probably of the Acanthamoeba genus, was described in 1974 and a case of multiple brain abscessescontaining a free-living amoeba, also probably Acanthamoeba, who suffered from long-standing Hodgkin's disease of the lung has also been reported. Apart from these cases free-living amoebae have been considered non-pathogenic in man. One of the features stressed by all workers on

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infection with all amoebae, either in man or induced by inoculation of cultures into experimental animals, is that the organisms usually cannot be identified in the tissues by ordinary staining techniques, although they are known to be there. They are usually mistaken for macrophages, polymorphs or lymphocytes. Their presence can be shown, however, by the use of immunofluorescent staining techniques using antisera prepared against various species of Naegleria and Acanthamoebae.

Introduction of cultures of Acanthamoebae or Naegleria into experi- mental animals, such as monkeys and guinea pigs, produces a chronic wasting disease resembling carcinomatosis, lymphadenopathies, splenomegaly and infiltration of lymphocytes into various tissues and especially vascular lesions typified by formations like periarteritis nodosa, arteritis and thromboses and marked intimal proliferation and by pyelitis. The lymph node lesions eventually change to a granulomatous reaction with lymphocytes, plasma cells, intense reticul urn cell proliferation and multi-nucleated cell formation. The liver shows lesions in the portal triads.

Recently it has been shown by using indirect fluorescent antibody tests that the sera of all living humans, including the new-born, contain anti- bodies against free-living amoebae, This shows that every human,

either Naegleria or Acanthamoeba (2). and probably other animals also, have been or

are presently infected with free-living amoebae to produce such an antibody response, though the organisms may not have been observed in the tissues. The discovery that FREE-LIVING PROTOZOA ARE NOT PURELY NON-PATHOGENIC, BUT ARE ABLE TO INFECT MAN AND ANIMALS HAS REVOLUTIONIZED THE VERY CONCEPT OF PARASITOLOGY and shows that all humans contain foreign antigens in their plasma and tissues, in the case of the new-born evidently resulting from transplacental passage of either the organisms or their antibodies into the foetus in utero. In 1922 several groups of workers in California described the presence of an amoeba in the bone marrow in cases of rheumatoid disease. This could be grown in cultures, but subsequent work, though confirming its amoebic nature, failed to verify that this was E. Histolytica as postulated, though its nature was never elucidated. Furthermore, amoebae have been demonstrated in every soft tissue of the body (3), while Acanthamoebae have been cultured from a liver abscess in man.

A new method of recovery of Naegleria from human tissues and other sources. _.

In view of these observations the author attempted to induce an organism to migrate out of fresh, minced, unfixed human tissue obtained at autopsy, biopsy or operation using the property of thermotropism. The minced tissue was placed on a membrane filter with pores of 0.5-1.0

s-' m in diameter,

which itself rested on a zinc gauze diaphragm anchored half w y down a funnel. The tissue was cooled to O°C by placing a glass beaker containing ice on top of it. The lower half of the funnel and its stem were filled with Ringer's solution reaching to the level of the zinc gauze diaphragm and wetting the membrane filter. The spout of the funnel was closed with rubber tubing and a clip. To the Ringer's solution was added 20 units of penicillin and 40 units of streptomycin per ml. The temperature of the Ringer's solution was maintained at 37OC by a water-bath reaching to the level of the gauze diaphragm. The whole apparatus was sterilized before use

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and the introduction of the minced material and the experiment carried out in sterile conditions. In the above circumstances there existed a temperature differential between the minced tissue at O°C and the Ringer's solution at body temperature of 370C. If a contractile organism was present in the tissues, it might migrate through the filter under thermotropic influences into the Ringer's solution, which is, in fact, what occurred. The organism was found in the Ringer's solution when this was run off into a sterile centrifuge tube and centrifuged at 150 revolutions per minute. When placed on slides, the deposit showed an amoeba-like organism, usually brown stained from uptake of cell debris, about 30 /urn in diameter, showing no motility and being impossible to culture. It was when discovered that centrifuging killed the organism. If this was avoided and the Ringer's solution replaced by "amoeba saline" and later this was run off on to Noble agar plates carpeted with a live strain of E.coli, the organism could be cultured.

The isolation of the organism by the above method has been confirmed in the Biological Department of Vanderbilt University, USA, and the Bratislava Oncological Institute, Czechoslovakia. It has the characteristics of a Naegleria with limax features, 25-30 /urn in diameter with a single lobose or spike-like pseudopodium, l-12 contractile vacuoles and a rapid rate of movement up to 60 /urn per minute. The cysts are 9-30 /urn in diameter, in which no nuclei are visible and the walls of which are polygonal and fenestrated. Itreadily encysts in vitro, but not in the tissues and bi- flagellate forms occur in distilled water. The cysts are exactly similar to those of various species of Naegleria and Acanthamoebae, but the tropho- zoites are those of a Naegleria and their failure to form cysts in the tissues is also typical of this genus. It is possible that a number of different Naegleria species were recovered, though this has not yet been determined.

The organism was isolated from - 1. All the tissues of all cases of collagen and auto-immune diseases examined, including cases of rheumatoid disease, systemic lupus erythe- matosus (SLE), dermato(poly)myositis, diffuse sclerosis and polyarteritis modosa (almost 400 cases). When arthritis was present, they particularly occurred in the tissues of the joint capsules. They were also obtained from lymphocytic thyroid lesions and the salivary glands affected by Sjl)gren's syndrome and the spleen, lymph nodes and central nervous system in the above diseases, and, in fact, from all apparently normal tissues.

2. All body tissues in all cases of human leukaemia and lymphoma examined, including the affected lymph nodes.

3. All of more than 2,000 human and many mammalian malignant tumours examined, where it occurred in large numbers in the tumour itself, but in lesser numbers in all the unaffected tissues of the body.

4. All human aborted material exhibiting growth anomalies examined and from many placentae and still-born foetuses.

5. In small numbers from normal tissues of many previously healthy subjects killed in accidents.

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6.

7.

8.

9.

10.

Human and mammalian faecal material.

Uncooked beef, mutton and pork.

Unsterilized milk and eggs.

Some specimens of surface soil.

Geranium and tomato plant tumours growing at the site where the stem passes through the surface soil, where the organism was also present.

It was not found in laboratory mice and rat cancers. Though the organism could be isolated from the above tissues, no amoebae were visible in sections of these tissues stained by haematoxylin and eosin, but colleagues stained ordinary paraffin sections of tissues from which the organism had been obtained by an indirect immunofluorescent antibody tech- nique using rabbit antisera prepared against various species of amoebae and reported that the tissues showed immunofluorescence of some cells with the antiserum against Naegleria aerobia (Culbertsoni), HB-1 strain. Other colleagues in Germany, by slowly centrifuging fresh specimens of human tumours suspended in a centrifuge tube over Ringer's solution, found in the deposit at the bottom of the tube, not only dead tumour cells, but mobile cells with lo-14 vacuoles forming and reforming continuously and typical of the amoeba described above.

The effects of anti-amoebic substances on Naegleria derived from human and other sources.

Having cultured the organism, the inhibitory effect of various sub- stances on it was tested by adding them to the culture. It was found that minute traces of copper salts rapidly killed the organism in culture and, if copper gauze was substituted for the zinc gauze in the apparatus for recovery of these organisms, they failed to migrate into the Ringer's solution. Other substances which inhibited and killed the organism in culture were one per cent bile acids, 4-aminoquinolines, such as chloroquine, dehydrochloroquine and amodiaquin, pentamidine, emetine, dehydro-emetine clotrimazole, an imidazole compound (confirmed for N. fowleri in Adelaide), levamisole, another imidazole compound (confirmed by American colleagues), and especially by 5-nitro-imidazole compounds, such as metronidazole, tinidazole, ornidazole and nimorazole, all of which have a spectrum of potent antiprotozoal, including anti-amoebic, activity.

Rheumatoid and related diseases

While the term rheumatoid arthritis is in almost universal use, it is a misnomer, since the disease may involve every tissue of the body and is, in fact, a generalised condition. It may occur at any time in life and may even be present at birth or appear in childhood as Still's disease, though it is especially common in women about the time of the menopause. It is now generally agreed that rheumatoid arthritis, SLE, dermatomyositis (poly- myositis), primary systemic sclerosis and polyarteritis nodosa show every combination with and gradation one into another. A number of drugs, such

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as amodiaquin and levamisole, may convert rheumatoid arthritis into SLE. These conditions have been grouped as the so-called collagen diseases and any of these may be associated with Hashimoto's thyroiditis. The typical lesion of all the diseases is at first a heavy lymphocytic infiltration, in the middle of which are found germinal centres. These are found not only in the joint capsules, but in all the tissues, including various viscera, which may be affected. The lesions usually thought typical of these diseases involve the locomotor system, including the joint capsules, spine, cryo-arytenoid joints, the big toe joints, often accompanied by varying degrees of over-riding of other toes, temporo-mandibular joints, fibrositis of various regions, tendinitis, tenosynovitis, bursitis and inflammatory changes in the muscles. Rheumatoid nodules may be found in any tissue, but especially at sites of pressure. The lymph nodes and spleen may be enlarged. Fatigue, anorexia, fever, weight loss and sweating, often profuse, oedemas of feet, hands or orbit, and amyloidosis may be found. In his monograph, the author reviews at much length the world literature and his own experience in over 3,000 cases where, accompanying the above lesions of the locomotor system, there are found lesions affecting every other organ, including the skin and its appendages, the viscera, the central nervous system, blood and bone marrow, which may form part of the various manifestations of the collagen disease complex. Thus, any of the collagen diseases may be associa- ted with Raynaud's phenomenon, various forms of vasculitis, necrotizing arteritis involving both medium sized and microscopic arteries, a subacute arteritis, an intimal cell hyperplasia (endarteritis obliterans) and thrsmbotic microangiopathy. The venules may be similarly affected. Any of the collagen diseases may be associated with SjBgren's syndrome (Mikulicz'z disease, if the salivary glands are enlarged), where the same lesions which affect the joint capsules involve the salivary and lacrimal glands, giving rise to fibrosis and cyst formation from dilatation of the ducts: with diffuse lymphocytic thyroiditis (Hashimoto's thyroiditis), the fundamental lesion of primary myxoedema; with primary thyrotoxicosis, "idiopathic" atrophy of the adrenal cortex, leading to Addison's disease, atrophic gastritis with or without pernicious anaemia, diabetes mellitus and intrinsic asthma developing into chronic bronchitis in some cases. Lymphocytic infiltration may occur in any endocrine gland, including the parathyroids and pituitary, or thymic lesions, either hypertrophy with lymphocytic infiltration and the appearance of germinal centres in the medulla comparable with that found in Hashimoto's thyroiditis or hypertrophy with the above changes and with tumour formation, either a lymphoma, lympho-epithelioma, spindle-cell tumour or teratoma. These changes may or may not be associated with myasthenia gravis. Any of the above lesions may be accompanied by pleuritis, cryptogenic fibrosing alveolitis or rheumatoid nodules in the lungs, granulomatous endocarditis, myocarditis or pericarditis or congenital heart block. There has also been a suggestion that collagen diseases pre- dispose to coronary occlusion. In addition, the liver may be involved in the form of active chronic hepatitis, so-called "lupoid hepatitis" or as biliary cirrhosis or post necrotic cirrhosis. Chronic cholecystitis, pro- gressive sclerosing cholangeitis or chronic lymphocytic pancreatitis (with changes identical with those in the salivary glands of Sjbgren's syndrome histologically) may be found. Renal tubular acidosis, focal glomerulo- nephritis, various diseases of the skin, such as psoriasis, ichthyosis acquisita, alopecia universalis and areata, vitiligo and melanoderma,

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pemphigus erythematosus and vulgar-is and pemphigoid, acanthosis nigricans and dermatitis herpetiformis and urticaria may also be found. Chronic inflammatory change, hay fever or atrophy of the nasal, pharyngeal, oral, tracheal and bronchial mucosa may coexist. Cystic mastitis with changes identical with those of Sjbgren's syndrome may be found. Lymphadenopathy and splenomegaly, atrophy of the gastric mucosa and gums, atrophy of the small intestinal mucosa with coeliac disease and ulcerative colitis may be present. The walls of the aorta and large arteries may exhibit typical lymphocytic perivascular changes, which may give rise to weakness of the vessel wall leading to abdominal aneurysm. Clubbing of fingers and toes may occur. Recurrent conjunctivitis, irido-cyclitis, episcleritis, chloroidal nodules and exudative detachment of the retina,endocrine exophthalmos, nerve deafness, involvement of the joints between the ossicles of the middle ear and chronic adhesive otitis and Eustachian salpingitis may be present, also leading to deafness. Relapsing polychondritis, peripheral neuropathy, migraine, rheumatoid nodules in the meninges or any form of mental disease may complicate collagen diseases. Various changes in the red corpuscles, which include hypochromic normocytic, microcytic, pernicious and auto- immune haemolytic anaemia may occur. Changes in the white blood cells may be found and consist of a neutrophil leucocytosis or leucopenia or a lymphocytosis or lymphopenia, a monocytosis or an eosinophilia (typical of a parasitic infection). There may be a thrombocytopenia, thrombo- cytosis, pancytopenia or polycythaemia Vera, myelofibrosis and myelo- sclerosis and allergic purpura. The bone marrow may exhibit infiltration with eosinophils, lymphoid follicles with germinal centres, a plasmocytosis as well as immature plasma cells accompanied by diffuse hypergammaglobulin- aemia or monoclonal gammopathy, as also occur in chronic infections, such as tuberculosis or syphilis, and Waldenstrom's macroglobulinaemia may also complicate rheumatoid disease. The blood may also exhibit cryoglobulinaemia, which likewise occurs in chronic diseases, such as syphilis, leprosy and kala azar, or it may exhibit an immunoparesis. The bones may show Paget's disease, the testis and epididymis may be swollen or atrophic and exhibit the typical histological changes or acute hydrocoele may occur. There may be atrophic volvovaginitis, resembling the atrophy of the oral, nasal, pharyngeal, bronchial, oesophageal and gastric mucosa. Cystic disease of ovaries and uterine myomata are common. Any organ and tissue of the body may exhibit typical rheumatoid nodules. It has long been recognised since the time of Pasteur and Koch that organisms present in the body settle down in areas of pressure or trauma. This phenomenon is seen in certain lesions mentioned above, such as joint inflammation, rheumatoid nodules, psoriasis and Paget's disease of bone. This coupled with the pyrexia, sweating, weight loss and anaemia suggests the above diseases are organismal in nature.

To summarise, every tissue in the body may be involved either singly or in every conceivable combination in this disease and, in fact, r_he joints may not be obviously affected. Many of the lesions of internal organs associated or unassociated with arthritis have been termed auto-immune diseases and it has been suggested that they are the result of the action of auto-antibodies in the blood against specific organs. However, the source of such auto-antibodies is unknown and they have been suggested to be the result of an infection. In cases of rheumatoid disease with the

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emphasis on joint changes and also with other "collagen diseases" the serum often, but not always, contains an antibody known as the rheumatoid factor (RF) and also frequently auto-antibodies against internal organs. These abnormalities, however, may be found in a proportion of apparently normal subjects. These factors may also occur in the serum in many infections in low concentration, but only in such high concentration as occurs in rheuma- toid disease in infections with protozoa, that is malaria, kala azar, leishmaniasis, trypanosomiasis and giardiasis, successful treatment of which causes their disappearance from the serum. In some cases of gheumatoid disease the onset is fulminating with a severe pyrexia of 105 F or more and drenching sweats, especially in sleep. In three of the author's cases this occurred in identical circumstances. All were farmers, one in Ontario, one in Ohio and one in Rhodesia. Each was ploughing very dry earth, sitting on a tractor and breathing in large amounts of the dust of the surface soil, where free-living amoebae abound. This was followed next morning by the above symptoms and intense acute arthritis of every joint in the body last- ing three months or more, the disease persisting permanently. Such a history and the frequent pyrexia and sweating of many cases strongly suggests the infective nature of the disease, which has been suspected for a century or more. The amyloidosis not uncommonly found in rheumatoid disease is indicative of a chronic antigenic stimulation, possibly by an infective organism. Most striking is the close resemblance of rheumatoid disease in general to syphilis, not only in its protean manifestations, but in its vascular, bone marrow and histological appearances, the occurrence of Paget's osteitis (as Paget himself remarked, closely resembling syphilitic osteitis) and the tendency to aneurysmal formation and the occurrence of acute arthritis in both diseases. In syphilis also various auto-immune anti- bodies and even RF are found in the serum. It has been suggested that a chronic antigenic stimulation exists to cause the changes in rheumatoid diseases, but the nature of this is quite unknown. There is no evidence that bacteria are involved in rheumatoid disease, since antibiotics have no effect on it, or that a virus is causally related. In the author's monograph a great deal of evidence is adduced to suggest a priori that rheumatoid disease is probably a protozoa1 infection and, since Naegleria have been found in large numbers in the tissues in the disease, these might be causally related. An argument against this is the failure to note amoebae in the tissues in ordinary stained sections of rheumatoid disease, but mention has already been made of failure to detect such organisms in the tissues in experimental and clinical infections with free-living amoebae. However, it will be recalled that years after the establishment of the science of histology no obvious organismal cause for syphilis was seen in ordinary sections of syphilitic lesions and the treponema pallidum was not discovered until special silver staining techniques were used. As noted above similar immunofluorescent antibody staining techniques against Naegleria species demonstrate their presence in the lesions of rheumatoid disease. None other thank'aldenstrdm himself stated "that if the treponema had not been discovered, syphilis would be the ideal model for auto-immune disease".

The action of substances which kill Naegleria on active rheumatoid disease

In view of the above experimental and clinical findings it was necess- ary to try the effect of various anti-Naeglerial substances discovered in

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vitro on active generalised rheumatoid disease or on the disease ar; affect- ing single organs which may form part of the general complex. These in- clude rheumatoid disease with or without early SjBgren's syndrome,Hashimoto's thyroiditis with or without hypothyroidism, cystic mastitis, myasthenia gravis, endocrine exophthalmos, cervical spondylitis, lumbago and sciatica in the absence of radiological changes, ulcerative colitis,ichthyosis acquis- ita, dermatomyositis (polynU/ositis), SLE, "idiopathic" Addison's disease, Paget's disease of bone, leucoderma and melanoderma, migraine, many cases of intrinsic asthma, hyperkeratoses,chrvnic rheumatoid liver disease, diabetes mellitus, etc. These are all described in the monograph and the effects of copper salts, bile acids, pentamidine, emetine and dehydro- emetine, the imidazole-containing clotrimazole and in particular anti- amoebic 5-nitro-imidazole compounds on cases of active rheumatoid di:,ease studied. It was found in general that any of these substances administered in appropriate doses would cause either a fairly rapid disappe.lran~.t~ of active inflammation in the affected joints or alternatively a slight or violent temporary increase in the inflammatory changes in affected joints or inflammation in previously unaffected joints. The increased joint involve- ment was often accompanied by pyrexia, sweating, headache and general malaise. The lymph nodes may enlarge and the breasts may become hot, tender an+ swollen, especially if areas of cystic mastitis are present. The back c)f the neck may be painful and there may be generalised stiffness, lumbago or sciatica. The ESR and RF content of the blood rises. (In healthy subjects the drugs produce no effect). This inflammation gradually disappears with marked improvement in the patient's condition and often after several doses of the drug, a complete disappearance of disease activity, fall to normal in ESR and disappearance of the RF from the serum. Any bony and cartilaginous changes present before treatment persist, however, but in early cases the disease can be cured providing reinfection can be prevented. These findings have been confirmed by colleagues in various parts of the world, including the United States. In subjects of coeliac disease 5-nitro-imidazoles cause central abdominal pain lasting a few hours after each dose, gradually lessen- ing with successive doses, till it does not occur. Temporary arthropathy may develop with early doses. Jejunal biopsy at the end of the course now shows normal appearances. This exaggeration of the symptoms of rheumatoid disease by anti-Naeglerial drugs constitutes an Herxheimer reaction, which is a temporary exaggeration of symptoms of a disease when drugs which kill the causative organism are administered.

SUCH OBSERVATIONS IN RHEUMATOID DISEASE WITH DRUGS OF A WIDELY DIFFERENT NATURE, HAVING IN COMMON ONLY THEIR ABILITY TO KILL NAEGLERIA, PROVE CONCLUSIVELY THAT SUCH AN ORGANISM CAUSES THE INFLAMMATION AND IS PRESENT IN THE AFFECTED TISSUES IN THIS DISEASE. This is further proved by the finding that intra-articular injections of metronidazole into an inflamed swollen rheumatoid joint causes rapid disappearance of the inflamma- tion. Various of these drugs will in EARLY cases cause the disappearance of Sjtlgren's syndrome, of Hashimoto's thyroiditis with return of thyroid function to normal, of "idiopathic" Addison's disease, of myasthenia gravis; a fall in the blood ESR and alkaline phosphatase content and pain in Paget's disease; a disappearance of migraine, intrinsic asthma and hay fever in many subjects; clearing of ichthyosis, the gradual fading of melanoderma and leucoderma and disappearance of the lesions of cystic mastitis. They usually abolish temporarily the hyperglycaemia and qlycosuria in many

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late-onset diabetics for a period after a short course of, for example, bile acids or copper sulphate. Endocrine exophthalmos, polymyositis and dermatomyositis rapidly subside after administration of a number of these anti-amoebic substances. The same results were obtained in dogs and horses with rheumatoid disease. Such observations on cases in which single organs are affected are in accord with the effect of these anti-Naeglerial drugs on the generalised disease. They show that this disease in its various forms is a result of the universal infection of man (and also of animals) by free- living amoebae derived from his surroundings.

Myasthenia appears to result from the effects of substances liberated from the organisms on neuro-transmitters liberated at the myoneural junctions from the motor nerves. Finally, mental disturbances, such as schizophrenia or manic depression, which may occur in cases of rheumatoid disease, like- wise disappeared after administration of anti-amoebic drugs in the treat- ment of the joint lesions. Moreover, accompanying the Herxheimer reaction in the treatment of rheumatoid disease occasionally temporary confusion or affective disorders may occur, while in early cases of presenile dementia anti-Naeglerial substances may abolish the symptoms. Such findings suggest that substances liberated from the organism may be responsible for various forms of mental disease by interfering with the neurohormones in the basal regions of the brain.

Since Naegleria in the tissues only cause inflammatory change in a pro- portion of subjects and rheumatoid disease is often present in a number of members of a family, this indicates that the body tissues inflammatory response to the organism is genetically controlled, probably by HLA antigens and also that many Naegleria species are non-pathogenic. As a corollary to the conclusion that rheumatoid disease is an infection, the treatment of the disease with cortico-steroids, which though anti-inflammatory, depress bodily resistance to infectionsis the worst possible practice and prevents the disease ever being cured. Likewise the standard treatment of the affected regions by heat, massage and exercise merely spread the organism and inflammatory changes and prevent healing. In addition, these observations show that many cases of diabetes mellitus are due to secretion from the organism interfering with the action of insulin on the target organs or its carriage in the blood and that this disease is not one of the pancreas.

Amoebic infection of the foetus and new-born

Many of the "collagen" and "auto-immune" diseases may be present at birth, including rheumatoid arthritis, SLE, ichthyosis (identical with ichthyosis acquisita) intrinsic asthma, lymphocytic thyroiditis with or without thyrotoxicosis or hypothyroidism, acanthosis nigricans, congenital myasthenia in infants born of apparently normal mothers, diabetes mellitus and eczema. All of these are identical with the same diseases occurring in adults. They may be foundin offspring born of healthy mothers or in those already suffering from manifestations of rheumatoid and related diseases. Many of these disturbances are associated with developmental anomalies and/or congenital turnours. As mentioned above the sera of all new-born infants contains antibodies against Acanthamoeba or Naegleria and the author found that all foetuses or aborted material contained free-

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living amoebae which evidently cross the placenta like other infections, such as syphilis, tuberculosis, malaria, toxoplasmosis, leishmaniasis and trypanosomiasis. The author's monograph shows how such infection of the embryo must be responsible for many cases of developmental anomalies of previously unknown origin.

Naegleria infection and the ageing process -____

The various conditions, both generalised and affecting single or several internal organs, tend to appear in all humans with increasing age, though many may be present at birth. This applies to all forms of collagen disease affecting the locomotor apparatus, but also to various manifesta- tions of these diseases as affecting internal organs, as for example lympho- cytic thyroiditis, atrophic gastritis, Paget's disease of bone, abdominal aortitis, cystic mastitis, lymphocytic pancreatitis, ichthyosis, atrophic stomatitis or oesophagitis, vitiligo,,melanoderma, biliary cirrhosis, diabetes mellitus, presenile dementia and affective mental disorders. In addition, with increasing age RF and auto-antibodies tend to appear in the plasma. This indeed shows that the ageing process is to a large extent governed by the appearance of more and more manifestations of Naegleria infection, which begins at or before birth.

Naegleria infection and malignant disease ----_

It is generally agreed that in only about 10 per cent of human cancer is the cause known. In the other 90 per cent it is thought that some environ mental factor and often a genetic factor is concerned. Certain human lesions are known to be premalignant, but their causation has remained unknown. It has been shown above that rheumatoid disease, SLE, dermatomyositis, systemic sclerosis and polyarteritis nodosa, all of which may overlap or show grada- tion one to another, appear to be the result of Naeglerial infection in subjects genetically sensitive to the presence of these organisms in the tissues. Any of these conditions may involve the viscera, which exhibit so- called auto-immune diseases which appear to arise from a similar causation. Such involved organs contain numerous Naegleria. Many of these lesions are well recognised as being premalignant, for example atrophic gastritis and oesophagitis, coeliac disease, ulcerative colitis, Hashimoto's thyroiditis, chronic lymphocytic pancreatitis (without stone formation), the parotid lesions of Sjogren's syndrome and the thymic lesions which may complicate any of the above manifestations of Naeglerial infection. In the author's mono- graph his own experience and a combing of the World literature is brought together and reviewed. This shows that there are large numbers of cases described in which chronic rheumatoid disease with its chronic antigenic stimulation of the body defences, including those of the plasma cells and lymphocytes, results initially in a proliferation of the plasma cells in the bone mhrrow and of the lymphocytes in the lymph nodes and lymphatic tissue in the spleen and thymus and eventually in the development of lymphomatous tumours, myelomata or Waldenstrdm's macroglobulinaemia commonly considered a form of lymphosarcoma. Any of these conditions, especially myeloma, may be associated with the presence of paraproteinaemia. In such cases the bod.y may exhibit not only tumours of the lymphatic system and myeloma2 but also multiple cancers of other organs. The lesions in the thymus, while initially

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exhibiting the typical histology of rheumatoid disease, are frequently complicated by the development of malignant tumours of the organ of various types, such as lymphoma, thymoma, lympho-epithelioma, spindle-cell tumour or teratoma. Such thymic tumours may be accompanied by extra-thymic tumours of different types of almost any other organ, including leukaemias. Again the affected salivary glands in Sjdgren's syndrome frequently develop benign lympho-epithel ial lesions within them or lymphoma or plasmocytoma beginning locally and becoming generalised, leukaemias or Waldenstrbm's macroglobulin- aemia. The lesions of Hashimoto's thyroiditis are well recognised as pre- disposing to the development in the organ of either lymphoma or malignant tumours, including Hbrthle cell tumours, of the gland. Involvement of the parathyroid gland often associated with lymphocytic thyroiditis in rheuma- toid disease has frequently been reported as ending in parathyroid adenoma or carcinoma. Again dermatomyositis or polymyositis, which form part of the generalised rheumatoid (collagen) disease complex are well recognised as often preceding the development of malignant disease or benign tumours of almost any organ by upwards of 20 or more years. Scleroderma, bearing a similar relationship to rheumatoid disease as polymyositis, also frequently precedes malignant disease of any organ, as also may polyarteritis, another manifestation of the collagen diseases. Again there are hundreds of cases reported in which SLE or "rheumatoid arthritis" have been followed by the development of malignant disease of every conceivable nature, including lymphoma and leukaemias and often solid tumours of multiple organs (up to 9 different cancers have developed in such cases). Paget's disease of bone is well recognised in predisposing to osteogenic sarcoma, fibrosarcoma, chondro sarcoma, giant cell sarcoma or reticulosarcoma of bone, but also to multiple myelomatosis. In addition the disease may precede the development of malig- nant tumours of almost any kind in other parts of the body. Furthermore, cryptogenic fibrosing alveolitis is seen to be a precursor of cancer of the lung or bronchus or lymphoma, usually developing locally. Acanthosis nigri- cans, a manifestation of rheumatoid disease, frequently precedes by a long period the development of malignancy in any internal organ. Auto-immune haernolytic anaemias are well recognised as predating the onset of almost any malignancy. Atrophy of the buccal, pharyngeal, oesophageal and gastric mucosa, all features of rheumatoid infection, are well recognised as pre- malignant conditions as also is subtotal or total villus atrophy of the small intestine,which predisposes to the development of lymphoma or of carcinoma of any other organ. Ulcerative colitis is a well recognised pre- malignant condition, as is chronic pancreatitis and cystic mastitis, the lesions of which are identical in nature with those of the salivary glands in Sjdgren's syndrome. Again, like other organisms Naegleria collect at sites of trauma, where in certain circumstances cancer develops. It thus appears that the presence in a tissue of Naegleria, producing its typical lymphocytic infiltration with germinal centres,predisposes to the develop- ment of malignant change and the chronic antigenic stimulation produced by the presence of the organism results in the development of lymphoma and plasmocytoma. The change in climate of the normal cells of a tissue which results from the presence of the organism and the tissue reaction it produces appears to induce cell mutation to adapt to this in subjects with an unstable genetic content. This represents malignant change and is a slow adaptation process of the tissue cells to their new surroundings, a Darwinian concept. Regular treatment with anti-amoebic drugs may destroy the causative organism in a tissue and avoid reinfection and prevent the

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development of premalignant and malignant change, but, once the cell muta- tion has occurred, it seems unlikely that any treatment for disseminated cancer will ever be discovered. The same arguments apply to cancer of the new-born, which may exhibit all the features of Naeglerial infection. THIS MAY BE ONE OF THE MISSING ENVIRONMENTAL FACTORS RESPONSIBLE FOR MANY OF THE 90 PER CENT OF HUMAN CANCERS OF UNKNOWN AETIOLOGY.

Paraneoplastic lesions and Naegleria

It was found that all malignant tumours contained large numbers of Naegleria. This is probably an example of the phenomenon mentioned above that any infective agent in the body tends to collect in areas of trauma, wounds and cancers. The presence of large numbers of Naegleria in the tumours has a curious effect in that the first indication of the develop- ment of this tumour may be the appearance of an arthropathy (carcinomatous arthropathy) or dermatomyositis, systemic sclerosis and periarteritis and of various skin lesions, normally manifestations of rheumatoid disease. In such cases successful removal of may result in disappearance which are essentially those

the tumour containing large numbers of Naegleria or amelioration of these paraneoplastic conditions, of rheumatoid infection.

CONCLUSION

The author has pointed out that every gradation into and associ ation together of rheumatoid arthritis, SLE, dermato(poly-)myositis, scleroderma andperiarteritis nodosa exists and that all appear to have a single causa- tion. Any of the internal organs may be affected by the same histological lesions as those found around the joints, in the muscles, tendons and tendon sheaths and bursae in this disease or such lesions of internal organs may occur in the absence of external evidence of the disease. The work has shown that all these lesions are probably the result of infection with a free- living amoeba of the Naegleria genus in subjects who react by an inflammatory change to their present by virtue of their genetic make-up, probably as reflected by their HLA antigens. It is shown that the internal lesions of this disease are premalignant and that the chronic antigenic stimulation produced by the Naegleria is responsible for most cases of lymphoma and plasmocytoma, as has been suggested by others. The regular administration of anti-Naeglerial substances should prevent the development of malignant lesions and thus cancer, lymphoma or plasmocytoma.

References

1. Wyburn-Mason R, The Causation of Rheumatoid Disease and Many Human Cancers. A New Concept in Medicine. 131 Publishing Co., Tokyo, Japan, 1978.

2. Leading Article. Pathogenic Free-living Amoebae, Lancet, 2, 1165, 1977.

3. Craig and Faust's Clinic Parasitology, Sixth Edition, Edited by Faust EC Russell PC and Linicombe DR. Chapter XII, Henry Kimpton, London, 1957.