Syndromes

Journal of Nutritional & Environmental Medicine; Abingdon; Mar 1998;

Arthur Dale Ericsson;

Abstract:

Silicone breast implants have been associated with a variety of medical conditions. This article is the first in an analysis of the data that have been accumulated in over 500 patients with medical conditions that appear coincident with implantation with several different silicone breast prosthetic devices.

Full Text:

Silicone breast implants have been associated with a variety of medical conditions. This article is the first in an analysis of the data that have been accumulated in over 500 patients with medical conditions that appear coincident with implantation with several different silicone breast prosthetic devices. The vast majority, over 87% of symptomatic patients, appear to have a neuropathy (demyelinating and axonal diagnosis made on nerve and muscle biopsy and ELISA analysis), while approximately 22-25% of symptomatic patients have evidence of autoimmune thyroid disease. A small percentage of patients (10-12%) have evidence of central demyelination (brain and spinal cord-diagnosis made by magnetic resonance imaging and ELISA testing). Silicone breast implant adjuvant syndrome is proposed as a diagnosis for these symptomatic patients. The significance of these findings is discussed in considerable detail and extensive references are offered for the reader. Keywords: silicone, silica, polyurethane, silicone breast implants, chronic inflammatory demyelinating polyneuropathy, fibromyalgia, Hashimoto's thyroiditis, multiple sclerosis-central demyelination, autoantibodies, polymyositis, dermatomyositis, lupus erythematosis, rheumatoid arthritis, scleroderma.

INTRODUCTION

Silicone breast implants have been associated with a number of local complications as well as a diffuse systemic inflammatory disease. It has been suggested that the systemic syndrome should be called `adjuvant breast disease' [1] although the name 'silicone breast implant adjuvant syndrome' is more precise and appropriate and will be used throughout this article. The silicone gel used in the silicone implants for the purpose of mammary prosthesis has been found to be an adjuvant to the immune system in experimental animals. After an overview of the chemistry of the various types of silicone breast implant, this article will present the clinical and laboratory features of 138 patients with the uniquely neuroimmunological 'silicone breast implant adjuvant syndrome'.

CHEMISTRY AND TYPES OF BREAST IMPLANT

Silicon is the basic element of all silicones which represent a family of synthetic polymers that all have a 'backbone' of repeated Si-O units. Silicon has the same electronic configuration as the carbon atom which presents four binding sites [2]. Silicones vary in their composition and this is dependent upon the length of the polymers as well as the organic grouping in the side chains. The longer the side chain and the more cross-links (usually vinyl groups) between the side chain groups the more solid is the resulting silicone. Therefore, silicone can have the consistency of fluid, oil, gel or rubber [3]. Polydimethylsiloxane is the pre-eminent medical grade silicone polymer used for mammary prosthetic devices [4, 5]. To make this compound,quartz is purified to silica (silicon dioxide: SiO2), which is then reduced to silicon, reacted with methylene chloride and hydrated to form a polydimethylsiloxane:

Since the polymer itself is never thick enough for the envelope, silica (SiO2), itself is added to the polymer to make up 30% of the envelope [6]. Moreover, platinum is used as the catalyst for the manufacturing process of silicone breast implants and this elemental metal is bound and remains behind in the prosthesis. On the other hand, the gel inside the silicone-gel implant can contain anywhere between 50 and 95% of the silicone fluids, which are low molecular weight silicones [7, 8]. Since the silicone envelope is a semi-permeable membrane, every commercially available silicone breast implant leaks and this phenomenon is called `gel bleeding' of the low molecular weight silicones in the case of silicone-gelfilled breast implants. Incidentally, since the capsule of a breast implant is a semi-permeable membrane, the lighter molecular weight saline of the saline-filled implants is particularly susceptible to inducing body fluids to leak into, rather than out of, the silicone-saline breast implant [2].

CLINICAL HISTORY OF SILICONE BREAST IMPLANTS

In 1962, Dr Thomas Cronin and Dr Frank Gerow, two plastic surgeons from Houston, Texas, were the first physicians to insert a silicone-gel breast implant in a patient [9]. Although breast implants have been on the market since the mid-1960s, most silicone breast prostheses were implanted in the 1980s and it is now estimated that between 304 000 and 815 700 women have received breast implants in the US [10, 11]. While approximately 20% of those implanted were for reconstruction of the breast(s) after mastectomy for either fibrocystic disease or cancer, approximately 80% have been implanted for cosmetic breast enlargement in otherwise healthy women.Until 1991, there were four types of implant available in the US [12].

(1) The silicone-gel-filled silicone elastomer envelope breast implant (the implant most commonly used and the one placed in the Federal Drug Administration (FDA) moratorium on 4 January 1992) [13-15].

(2) The saline-filled silicone elastomer envelope breast implant.

(3) The double lumen breast implant with silicone gel in the inner elastomer envelope and saline in the outer elastomer envelope.

(4) The silicone-gel-filled (with or without the silicone elastomer envelope) breast implant coated with polyurethane and withdrawn from the market by the manufacturer on 10 April 1991 [16]. Polyurethanes Polyurethanes are polymers that contain the urethane linkage:

The urethane linkage is formed from isocyanates and alcohols without the inclusion of any volatile by-product. The remainder of the polymer may contain a variety of other functional groups such as polyether, polyesters, ureas, epoxies, silicones, aromatic or aliphatic hydrocarbon groups and polyolefins [17].

Biological Potentials of Silicone, Silica and Polyurethane

It has become clear from the experimental evidence that silicone is neither biologically nor chemically inert. It has been demonstrated that silicone as well as silica is cytotoxic [4, 14, 18] and that they are active immunostimulatory agents when given in vivo [8, 13, 19-32]. Furthermore, they are efficiently taken up by macrophages from the implant surface and react with the membranes surrounding the implant containing secondary lysosomes.Lytic enzymes are released into the cytoplasm, causing death of the macrophage and damage to the surrounding tissue environment. Moreover, silicone has been found phagocytized in macrophages and lymphocytes in tissue and in monocytes and polymorphonuclear leukocytes in peripheral blood of implanted patients [33-35].

It has been demonstrated experimentally by Pfleiderer et al. [30] that implanted silicone in rats will degrade and migrate to the liver, spleen and pericapsular tissue and, furthermore, that silicone is not biologically inert. In fact, silicone biodegradation in tissue may be monitored within 9-12 months following experimental implantation in animals. These changes were observed by (Si, C and H) magnetic resonance spectroscopy and confirmed by atomic absorption spectroscopy. The implication of this research is that with time (12 months) the chemical composition of the silicone gel changes and there appears to be a rupture of the polymer chain which increases the molecular mobility of the silicone polymer. Moreover, the degradation provides valuable information about the metabolic intermediate products of silicone which include substitution of the methyl and vinyl groups of the silicone-gel backbone by hydroxyl groups which leads to hydrolyzed silica and silica. In this model, silicone has been shown to migrate from the implants to adjacent tissues as well as to remote sites.

In addition to the cytotoxic effects, both silicone and silica elicit a cellular immune and a humoral response, acting as hapten-like incomplete antigens. Thus, antigen trapping by macrophages has been demonstrated by investigators who have identified silicone in the antigen-processing rough endoplasmic reticulum of the macrophages [19]. In 1993, Heggers et aL [13] identified silicon at both ends of plasma bridges from macrophages to lymphocytes with silicone deposits in up to 30% of the Golgi apparatus, endoplasmic reticulum and exocytic vesicles.

Anti-silicone antibodies in symptomatic patients with silicone breast implants have been measured [33, 34]. Moreover, Goldblum et al. [25] demonstrated specific antibody production to elastomers of polydimethylsiloxane in two children with ventriculo-peritoneal shunts. Furthermore, in two animal studies by Nain et al. [35] and Black [36], Dow Coming inbred rats were injected with a homogenized gel form of silicone in the presence of bovine serum albumin (BSA). In this model, it was demonstrated that the silicone gel has a similar adjuvant activity compared to that of complete Freund's adjuvant in amplifying the anti-BSA antibody response. These studies, therefore, have demonstrated that silicone acts as an adjuvant, enhancing the ability of the immune system to produce antibodies to a foreign antigen.

In 1975 an experiment was conducted at Dow Coming on D4 (cyclotetradimethylsiloxane), a low molecular weight silicone compound used in breast implants, and it was found that there was a significant gel bleed through the elastomer envelope. Furthermore, this study demonstrated that D4 had both a very strong immunostimulatory and cytotoxic action.

Biochemically, the interaction of native macromolecules with silicone leads to conformational changes and denaturation [33, 37] and the denatured macromolecules may then present as an antigenic target to the immune system. Kossovsky et al. [37] found that antibodies were present against macromolecules, in particular fibronectin and laminin, which were denaturated by silicone in patients with silicone breast implants. The denatured macromolecules, moreover, present as an antigenic target to the immune system. A cross-reaction of antibodies to still intact macromolecules may then explain the subsequent often-delayed autoimmune response.

Many of the complexes of silicone, including pentamethylsiloxane, hexamethyldisiloxane,decamethyltetrasiloxane,pentamethylvinylsiloxane,tetravinyltetramethylsiloxane, trivinylmethyltrisiloxane,heptamethylvinyltrisiloxane and octapentamethyltrisiloxane, have been studied extensively for their ability to evoke a cytotoxic reaction. Many of these siloxane derivatives readily produce lethal effects on cells in very low concentrations of the 25-80 uM range. Furthermore, it has been demonstrated that each may penetrate the plasma membrane at a sublethal concentration in the 15 MM range or less. Once the cellular membranes have been bridged by these molecules, the various cellular interactions and degradation reactions of these cells are possible. Macrophages have demonstrated that three primary cellular reactions to silicone may take place. These are as follows [22, 23,38, 39].

(1) Hydrolysis: the polar siloxane bond is subject to hydrolysis by the addition of water molecules under a variety of conditions. In the conditions of the human body temperature, hydrolysis occurs in S8 years (37oC) and at this temperature approximately half of the surface silonals are converted by the addition of water.

(2) Oxidation: in the presence of water the alkyl group on siloxane is subject to hydrogen abstraction and this process has been shown to occur in the macrophage when exposed to siloxane.

(3) Conjugation: conjugates are formed by vinyl siloxanes in the presence of other silicone gels, in vitro and in vivo. By a process of silicone degradation, new species of silicone(s) may be introduced into the body and, thus, cause a variety of tissue reactions. The capsule of the periprosthetic tissue is organized and it is usually a multi-layered tissue in which the inner surface is composed of an amorphous proteinaceous material with an adjacent layer of vacuolated palisading pseudo-synovium containing a variable number of inflammatory cells, including lymphocytes, plasma cells and macrophages. On the other hand collagen and fibroblasts comprise the outermost surface of the capsular membrane. Later, multi-nucleated giant cells predominate the cell type of the capsule. Experimentally, the inflammatory silicone granuloma persists for many months and, at about the tenth month of the inflammatory process, the character changes, in which the granuloma is gradually replaced by a foamy conglomeration of silicone-like material with less inflammatory components. Later in this stage of inflammation, this mass breaks up into tiny shreds of stringy silicone material and remains in the localized tissue. In the experimental model, the genetically predisposed animals, these masses of inflammatory cells differentiate into plasma cells which persist and then proliferate, forming plasmacytomas and, possibly, through cytokine interaction, monoclonal gammopathy of undetermined significance. In certain animal models, in the presence of specific cytokines, normal B-cells and plasma cells may be transformed into myeloma cells.

Clinically, systemic scleroderma, systemic lupus erythematosis (SLE) and silicosis of the lungs have been reported in individuals with occupational silica exposure, as found in coal miners [35, 40, 45]. The development of rheumatological-type illness in coal miners has also been described as Caplan's Syndrome [42, 43]. Injections of silica into the body may cause a florid inflammatory reaction. Therefore, many laboratories use silica as a booster or adjuvant to provoke the most significant immunological response possible in animals and to enhance antibody production in order to manufacture sera for vaccinations [44]. Moreover, macrophages exposed to silica in vivo elaborate factors that cause increased fibroblast proliferation and stimulate collagen production [45, 46] and might even produce silica from phagocytized silicone [13], an important concept because silica itself is mutagenic. Furthermore, Garrido et al. [23, 24] showed that silicone migrates from the implant to the liver in an animal model and they further found that new silicon-containing compounds are formed after silicones are injected into rats. The interaction of silica and macrophages resulted in a derangement of the immune system and, irrespective of the anatomic source, silica was found to be equally lethal for macrophages from the blood, peritoneal cavity, liver and lung [6].

The polyurethane foam that has been used on the surface of some breast implants was found to be a polyester polyurethane which could be expected to be susceptible to hydrolysis and, furthermore, the diisocyanate was used for the manufacture of polyurethane; this was toluene diisocyanate (TDI) which upon hydrolysis releases toluenediamine (TDA) [17]. In 1991, the manufacturer withdrew polyurethane-covered breast implants from the market because of the degradation of polyurethane to 2,4 diaminotoluene (TDA) and 2,4 dinitrotoluene, both of which are known carcinogens [13, 25]. The FDA, the National Toxicology Program and the International Agency for Research on Cancer have all categorized TDA as an animal carcinogen and a potential human carcinogen [13]. Furthermore, the polyurethane of these silicone breast implants was manufactured and sold as Scott Industrial Foam, a product made for automobile air filters and carpet cleaning equipment, which was never tested for human implantation [13]. David Black, the Director of Aegis Analytical Laboratories, conducted studies on polyurethane for the breast implant manufacturer, Surgitek. Not surprisingly, he found the carcinogen (TDA) in the breast milk of women with polyurethane-coated silicone breast implants [12, 36] and Chan et al. [47] isolated toluenediamines in the urine of a woman with polyurethane-coated breast implants. Moreover, Picha et al. [32] showed that the foreign body reaction led to the degradation of polyurethane in long-term animal studies. Finally, by 1986, there appeared two reports of women whose polyurethane-coated breast implants had totally 'dissolved' on explantation [12].

COMPLICATIONS OF SILICONE BREAST IMPLANTS

Local Complications

Local complications of silicone breast implants such as pain, swelling,redness, infections, capsular contracture (hardening of the surrounding implant scar tissue) [48], implant rupture [1, 46, 49, 50], silicone-gel bleeding through the intact capsule [8, 33, 50] and migration have all been well documented [19, 26, 31, 49]. In addition, we have found that approximately 75% of symptomatic patients, who presented to our clinic for evaluation for systemic disease, had local complications with their implants [51, 52]. The most common problem appeared to be capsular contracture which was seen in approximately 65% of our patients. A smaller group of our patients experienced severe angina-like chest pains but had normal cardiac evaluation. Further examination confirmed the presence of dense inflammatory capsule and spilled silicone in the surrounding capsule tissue and in the pectoralis major muscle [53].

Cocke [50] found intracellular silicone in the surrounding tissue of an intact doublelumen prosthesis 120 h after its placement. In 1979, Vargas [54] also reported silicone shedding from the envelope of saline-filled silicone breast implants. Thus, it is now generally accepted that all types of silicone-gel implant bleed silicone through the intact envelope, both in vivo [21, 32, 50] and in vitro, with resulting granulomas [7, 55], lymphadenopathy and migration of free silicone to remote areas of the body through lymphatic or hematogenic pathways.

General Complications

In 1964, Miyoshi et al. [56] reported on two patients who developed connective tissue-like disorders several years after augmentation mammoplasty by injection of paraffin and noted one complete resolution of the clinical symptoms after mastectomy to remove the foreign body. They were the first to name this disorder `human adjuvant disease', because it was considered the human counterpart of adjuvant arthritis found in rats after subcutaneous injection of Freund's complete adjuvant (dispersion of dried heat-killed tubercle bacilli in mineral oil). They defined six characteristics of the condition:

(1) Autoimmune disease-like symptoms which developed after the plastic surgery using foreign substances.

(2) Paraffin, silicone or related substances with possible adjuvant effects had been previously injected in the patient.

(3) Foreign body granulomata were observed histopathologically in the injected area.

(4) The presence of autoantibodies.

(5) There was no evidence of infection or malignancy in the operated area.

(6) Improvement occurred after the removal of the foreign substances. The first reports of an autoimmune connective tissue disease occurring in patients after augmentation mammoplasty with a silicone-gel-filled prosthesis came from van Nunen et al. [57] in Australia in 1982 and the following year from Baldwin et al. [20] from the US. However, it was Endo et al. [58] in 1984 and Varga et al. [59] and Varga and Jiminez [60] in 1989 who were the first to report human adjuvant disease in patients who had received saline breast implants. Since that time, a growing number of patients with diseases such as scleroderma SLE, Sjogren's syndrome, rheumatoid arthritis or atypical connective tissue disease have been described [10, 12, 26, 29, 37, 55-58,61-67]. Among those that have been described as atypical, there was one report of a life-threatening systemic illness that developed 24 h after implant removal [68] as well as an adult respiratory distress syndrome following augmentation by silicone injections [69].

It has been recognized that every normal individual makes autoantibodies, but only certain individuals produce pathogenic autoantibodies that may lead eventually to autoimmunity. Central to this process is the activation of self-reactive T-helper/inducer cells and it has been established that T-cells recognize a complex consisting of a major histocompatibility complex (MHC) restriction element and a peptide antigen fragment. After the processing of the antigen by the endosomes of the cell, some of these fragments become associated with class II molecules. Therefore, the ability of a specific antigen to bind with a MHC dictates an association between the immune response to a specific antigen [70, 71]. After the specific antigen is presented to the immune system, it binds with receptors on the surface of the B-lymphocyte. The antigen may also bind to an immunoglobulin-like globulin on the surface of the inducer T-lymphocyte and on the surface of a suppresser T-cell. The inducer T-lymphocyte may thus permit the B-lymphocyte to mature into a plasma cell and, thus, secrete antibody to the foreign antigen. A second T-lymphocyte carrying a specific receptor may then bind with the newly formed antibody [63]. This process will then permit the B-lymphocyte to become a plasma cell that will secrete an antigen and then bind the original B-lymphocyte. Therefore, B-lymphocyte activation is dependent on T-lymphocytes for subsequent autoantibody production [72, 73]. Peritoneal inflammatory granulonatosis, foamy conglomeration and, finally, plasmacytomagenesis in genetically susceptible mice (BALC/C.DBA/2-IHD1-PEP3) has been shown following intraperitoneal injection of silicone. In addition, experimental allergic encephalopathy (EAE) and experimental allergic neuropathy (EAN) have been extensively studied. Moreover, silicone gel and octamethylcyclotetrasiloxane (D4) have been shown to potentiate antibody production to bovine serum in A/J mice [74].

During the 1992-1995 American College of Rheumatology meetings, numerous studies were presented that reported patients who had developed atypical rheumatic disease after silicone breast implant surgery [2, 46, 62, 73, 75-78]. Interestingly, Bridges et al. [76] reported 156 women with silicone breast implants who had developed atypical rheumatic disease. In their study, only 9% had tested positive for the rheumatoid factor and only 22% had tested positive for antinuclear antibodies. They concluded that women with silicone breast implants might develop atypical rheumatic diseases, which differ from the classical idiopathic disease. Furthermore, Love et al. [79] reached the same conclusion after investigating 13 patients who had developed myositis after receiving breast implants; they found that their clinical and immunogenic features differed from the classical idiopathic myositis (polymyositis-dermatomyositis). Moreover, Freundlich et al. [80] reported 24 patients with breast implants who had developed atypical Sjogren's-like syndrome with dry eyes and dry mouth, adenopathy and glandular mononuclear cell infiltrates in the absence of serological findings. In addition, Morse and Spera [73] reported a significant increase in B- and DR-cells, a decrease in CD2- and CD8-cells and an increase in the CD4:CD8 (T4:TB) ratio in 30 patients with breast implants when compared to controls. Some investigators, however, have reported novel antibodies in patients with breast implants; among them Tenenbaum et al. [81] identified an antibody that bound to large molecular weight proteins appearing as a bobble in over 70% of their patients with breast implants and that serum antibodies from healthy individuals failed to react to this protein, suggesting an atypical immune response in symptomatic breast implant recipients. Ostermeyer and Patten [51, 52, 82, 83] were the first to report adjuvant breast neurological disease, multiple sclerosis (MS)-like syndrome and motor neuron disease-like syndrome in silicone breast implant recipients. Some investigators have reported antimicrosomal thyroid antibodies in 30% of patients with silicone breast implants [72].

Vodjani et al. [34] reported abnormalities of the T-helper: T-suppresser ratio mechanism, increased autoimmunity and increased immune complexes in patients with breast implants when compared with healthy sex- and age-matched controls. Levine and Ilowite [84] reported 11 children with esophageal dysfunction who were breast-fed by mothers with breast implants. The same group also found increased nitrite and nitrate urinary excretion in those children breast-fed by mothers with implants which they thought was due to activated macrophages exposed to silicone [65].

The remission of some of the symptoms of silicone breast implant-associated disease after implant removal has also been reported. In fact, Brozema et al. [10] described a patient who presented with progressive scleroderma-like illness after silicone breast augmentation with dramatic recovery upon implant removal. Walsh et al. [68] reported on a patient with chylous effusions, peripheral edema and high antinuclear antibody titer whose symptoms resolved after implant removal. Gutierrez and Espinosa [85] also reported the reversal of progressive systemic sclerosis with severe hypertension in a woman after implant removal. Moreover, Kaiser et al. [16] reported on the remission of silicone-induced autoimmune disease after explantation, while Silver et al. [77] identified silicon in tissues involved by chronic inflammation and fibrosis such as implant capsules, synovium, skin and alveolar macrophages in three patients with connective tissue disease; all improved after implant removal.

There is convincing evidence that polyneuropathy (demyelinating) is associated with over 85% of our clinic patients complaining of symptoms after silicone gel implantation. This may be associated with a variety of autoimmune chemical phenomena. Less convincing, but an association of demyelination of the central nervous system and anti-thyroid antibodies may be found in approximately 30-35% of these patients with symptoms following implantation. Furthermore, local immune responses may be found in the capsule surrounding the silicone-gel implants and this includes activation of macrophages, B- and Tlymphocytes and selected T-cell receptor utilization and interleukin-2 antibodies. Moreover, lumen leukocyte antigen (HLA) typing has demonstrated that there is a significant HLA-DR53 positivity in those symptomatic patients with fibromyalgia associated with silicone-gel implants [86-89].

EAN and EAE have been extensively studied and each of the adjuvant-dependent antigens has been identified. In the EAN disease, which is produced in susceptible animals, Po glycoprotein, P2 lipid binding protein and myelin-associated globulin (MAG) have been etiologically associated with the development and progression of the disease which parallels that found in silicone breast implant adjuvant syndrome associated with peripheral neuropathy. The protein P1, also named myelin basic protein (MBP), is found only in the central nervous system and is responsible for the animal model of EAE. In the model of EAN, commonly produced in Lewis rats, a MHC II response regularly occurs which is mediated by T-cells and occurs in the following stages.

(1) Alteration of the blood-nerve barrier with the infiltration of T-cells within 72 h after the challenge.

(2) Migration of the inflammatory T-cells with the presence of edema, which it is associated with a decrease of nerve conduction. This occurs within 4-5 days following the induction of EAN.

(3) CD4 (T)-cells predominate with the production of cytokines, which in turn increase the cell adhesion molecules by endothelial cells.

(4) Finally, there is an accumulation of macrophages, T-cells and polymorphonuclear leukocytes which, when activated, release free oxygen, hydroxyl radicals, proteases and lipases. The damage appears to be oxidative damage, while the protein and lipid enzymes are produced in order to digest the damaged cell debris. These changes have been observed in patients with sural nerve biopsies.

In EAN the peripheral nerve myelin is a complex structure that is synthesized and maintained by Schwann cells. The chemical composition of peripheral nerve myelin is largely lipid with a small percentage of proteins. The major protein is Po glycoprotein (50%) and this protein is not detected in the central nervous system. Sequencing of the amino acids in mammals shows 219 amino acids organized into three structural domains: an extracellular domain containing a single glycosylation site, a hydrophobic transmembrane domain and a basic cytoplasmic domain. It is this protein that is thought to play a major role in stabilizing the compaction of the extracellular apposition of the myelin membrane in the peripheral nervous system. EAN is a cell-mediated process, induced passively in experimental animals by lymphocytes but not by serum, although there is recent evidence that serum may induce demyelination in peripheral nerves. The Po glycoprotein readily produces EAN; however, MBP and P2 protein may induce EAN as well. Po protein and P2 proteins of peripheral nerves may initiate a neurotogenic T-cell response in experimental animals and produce similar demyelinating neuropathy. There is a naturally occurring syndrome of demyelinating neuropathy in humans and this is known as Guillian-Barre-Strohl-Landry syndrome. There is considerable evidence that this syndrome, which follows prodromal infections, is associated with increased levels of complement-fixing, anti-peripheral, nerve myelin glycoprotein antibodies. Certain patients with demyelinating neuropathy develop an immunoglobulin (Ig) M monoclonal antibody response to peripheral nerve myelin antigens. In approximately 60-70% of these patients, these antibodies (M proteins) attach to a carbohydrate determinant shared by MAG, Po and three glycoprotein components of peripheral nerve myelin. The crucial event in the pathogenesis of demyelinating neuropathy is the peripheral activation and expansion of a neuritogenic T-cell response (possibly Po) which then induces blood-nerve barrier dysfunction. The antibody may then cross into the peripheral nervous system and act synergistically with the T-cell response to enhance clinical disease. The balance between the intensity of the initial inflammatory T-cell response and the antibody concentration may then determine the clinical course of the disease.

EAE is produced in experimental animals by inoculation of the brain, spinal cord extracts and MBP along with Freund's adjuvant. MBP represents approximately 30% of the protein in the central nervous system myelin and has a molecular weight of approximately 18 500 and is composed of 169 amino acid residues. Sequencing of the amino acids in MBP has been determined in many species. Moreover, MS appears to be the human counterpart to EAE and has been closely associated with HLA (B7 and Dw2). Demyelinating plaques develop around blood vessels and neuropathologically parallel the course of the human disease. The myelin proteins of peripheral nerve Po and P2 will not induce the demyelinating lesions in the central nervous system of experimental animals.

Neuroendocrine Immunity [71]

Immune responses alter neural and immune functions and, in turn, neural and endocrine functions alter immune function. Many regulatory peptides and their receptors are known to be expressed by both the brain and the immune system. The central nervous system itself can be involved in immune reactions, whether arising from within the brain or in response to peripheral immune stimuli. Activated immunocompetent lymphocytes and macrophages can penetrate the blood-brain barrier and take up residence in the brain, where they secrete their full repertoire of cytokines and other inflammatory mediators, such as leukotrienes and prostaglandins. Microglia, which are embryologically and functionally related to peripheral macrophages and astrocytes, are, like macrophages and monocytes, activated by toxins, antigens and products of cell injury arising within the brain or reaching the brain from the periphery. These cells, in turn, secrete cytokines and inflammatory mediators. Furthermore, the endothelial and smooth muscle cells of cerebral blood vessels secrete cytokines such as interleukin-1 and interleukin-6 in response to circulating antigens and toxins. Moreover, the activation of cytokines in the central nervous system can lead to profound changes in neural function, ranging from mild behavioral disturbances to anorexia, drowsiness, increased slow-wave sleep, dementia coma and the destruction of neurons. None of these changes may be detectable by routine medical technologies, including magnetic resonance imaging (MRI) of the brain.

The glia, astroglia and microglia synthesize a number of cytokines in situ in the brain. These include interleukins 1, 2, 4 and 6, and tumor necrosis factor. Other neuroactive cytokines include thymosin (secreted by the thymus) and neuroleukin (a neurotrophic factor secreted by macrophages and neurons). The activation of cytokines in neural tissue by injury or toxins may not be entirely deleterious. For example interleukin-l stimulates the production of nerve growth factor, an important neurotrophic factor, thus enhancing the healing effect. Bromocriptine, a drug that inhibits prolactin secretion, ameliorates EAE and EAN, and trials in humans have produced improvement in many autoimmune diseases.

Human Diseases Expressing Autoimmune Phenomena

The known human diseases associated with autoimmunity are post-vaccinal and postinfectious encephalomyelitis, sympathetic ophthalmia, Hashimoto's and Graves' disease, aspermatogenesis, thrombocytopenia purpura, myasthenia gravis, rheumatic fever, SLE, glomerulonephritis, demyelinating neuropathies, MS, autoimmune hemolytic disease and rheumatoid arthritis.

SILICONE BREAST IMPLANT ADJUVANT SYNDROME

Systemic problems after implantation of silicone breast implants usually develop years after the initial surgery and tend to get progressively worse after repeated implantation. The mean latency period between initial implantation surgery and the development of symptoms in our observation was 56 years with a range of 2-26 years [1, 90].

We have investigated over 250 women who developed systemic illness after breast implant surgery. Whereas patients with classical rheumatological or neurological diseases report more circumscribed problems, the usual breast implant recipient with illness reported between 20 and 30 different symptoms. Table I summarizes the reported symptoms of our first 138 patients. The early symptoms include fatigue and tiredness, muscle weakness, body aches and pains, morning stiffness of the joints, joint pain and skin rashes. The initial symptoms are non-specific and may be tolerated by the patient until further progression of the illness occurs. Since a great number of our patients with systemic illness (60-70%) were found to have implant rupture, we believe that implant rupture may predispose to the development of a systemic inflammatory disease.

TABLE 1.

Careful evaluation revealed that over 138 of those cases had developed an underlying neurological problem. On the basis of neurological investigation and examination alone, the majority of our patients (80-90%) have findings of a polyneuropathy syndrome, approximately 10% have a syndrome that resembles MS (central white matter demyelination), approximately 12-15% have thyroid antibodies and are clinically hypothyroid, and approximately 2% have a motor neuron disease syndrome or a myasthenia gravis syndrome [l, 51, 52, 82, 83, 91-96]. This silicone neurological disease presentation differs from that expected of idiopathic neurological diseases. Furthermore, all patients present in this series have, in addition to their neurological disease, a variety of signs and symptoms, which are listed in Table 1.

Moreover, patients with a polyneuropathy syndrome associated with silicone breast implants usually have diminished vibration and/or pin-prick in a stocking and glove distribution, more in the lower than in the upper extremities. This is in contradiction to idiopathic polyneuropathy, however, in that it was associated with a proximal muscle weakness with preserved muscle bulk and preserved deep tendon reflexes. In fact, some patients had increased deep tendon reflexes, particularly at the knee and ankle. Furthermore, the symptoms (20-30) complained of by these patients cannot be attributed to the polyneuropathy. On the other hand, the patients who developed the MS-like syndrome usually had a chronic unremitting course of their illness, without any history of preceding attacks of retrobulbar neuritis. Dysarthria and bowel or bladder involvement seem to be less common than seen in patients with classic MS. While they develop multiple cerebral white matter demyelinating lesions, as seen on MRI of the brain, delayed visual evoked responses and oligoclonal band and inflammatory changes on spinal fluid examination, they also have a symmetrical peripheral neuropathy, a unique combination for classic MS. In addition to these differences, each of the breast implant patients with a MS-like syndrome has many other problems and symptoms that cannot be attributed to the neurological illness.

Laboratory investigations have demonstrated specific objective abnormalities (Tables 2 and 3) [1, 51, 52, 82, 831. Measurements of Igs and complement show an increase in some patients as well as a decrease in other patients.Fifty-eight per cent have autodirected antibodies, but only 36% tested positive for antinuclear antibody and only 11% tested positive for rheumatoid factor. Obviously, if these patients had classical lupus erythematosus or classical rheumatoid arthritis, the expected numbers (%) of positive antinuclear antibody or rheumatoid factor in the blood would be much higher than found in our series. On the other hand, our patients developed unique objective findings not found in classic rheumatological disease. For example, 80% had an abnormal sural nerve biopsy (79% had a loss of myelinated nerve fibers), 57% had an abnormal biceps muscle biopsy (27% had neurogenic atrophy) and 89% had an abnormal pectoralis muscle biopsy (55% had neurogenic atrophy). Since most of the patients had a loss of myelinated nerve fibers of 3545% with a depletion of the small, less rapidly conducting nerve fibers, the nerve conduction velocities studies, which measure the large rapidly conducting fibers, were usually normal. Inflammation and/or true vasculitis are other findings that could be observed in the sural nerve, biceps muscle and pectoralis major muscle biopsies. Moreover, additional studies have indicated that the presence of HLA DR genetic typing predisposes an individual to certain autoimmune diseases associated with silicone breast implants.

TABLE 2.

While specific activation of the immune system seems to occur in patients with classic rheumatological and neurological disease resulting in more specific and circumscribed signs and symptoms, continued diffuse activation of the immune system in breast implant patients who develop systemic illness seems a likely explanation for the host of problems and pathological abnormalities that are reported. The Cy/MAG and Cy/GM1 ratios are elevated in most of the patients, which indicates polyclonal antibody reactivity as seen in the global activation of the immune system. In addition, numerous autodirected antibodies, as many as 10 different ones, were found in this group of patients.

FIBROMYALGIA SYNDROME

Many rheumatologists have reported a fibromyalgia syndrome in patients with silicone breast implants owing to the fact that most women reported body pain and diffuse muscle aches and pain. In the same symptomatic patients, the rheumatological examination is often normal, including the absence of tender points. Most of these patients have moderate to severe muscle fatigue and weakness and usually numbness, tingling and burning and pain in their lower extremities. Based upon our data, the underlying neuropathy is the cause of these symptoms and the fibromyalgia muscle pain may be an early manifestation of the developing neuropathy. In most patients, however, the neuropathy has not been documented and, therefore, many patients might have been misdiagnosed with fibromyalgia. In fact, the high incidence of abnormal muscle and nerve biopsies attests to the neuropathic origin in this group of patients.

TREATMENT

Dow Corning recommends, in their package insert [64] from 1985, that: "if an immune response is suspected and the response persists, the prosthesis and the surrounding capsule should be removed. Such patients should not be re-implanted." We support this treatment recommendation. In addition, a ruptured implant itself is an absolute indication for implant removal because the free silicone that leaks into the surrounding tissue from a ruptured implant is considered as hazardous as the procedure of injecting silicone, a procedure now illegal in the US, because of the enormous clinical complications that it has caused in the many topless dancers in Nevada [79, 97, 98].

TABLE 3.

Every implant should be removed together with its surrounding implant capsule (closed capsulotomy) utilizing the en bloc technique, where the surgeon dissects down until the capsule is reached, then carefully cuts outside along the capsule and recovers both the implant and its capsule together as a single unit. With such an en bloc removal, silicone from a ruptured implant will not be spilled further in the patient's body by the surgery. In addition, in the case of a polyurethane-covered implant, the capsule tissue grows together with the foam and is strongly adhered to the surrounding tissue. If the surgeon attempts to pull the polyurethane implant out of the capsule during surgical removal, he/she might rupture the implant. Therefore, a complete capsulotomy is recommended as the surgical intervention for every patient because the capsule itself is composed of silicone and either gel bleeding or implant rupture, inflammatory cells and many denaturated proteins and destroyed cells occur over time [1, 13, 14]. Moreover, the implant capsule itself presents an antigenic entity to the immune system and continues to stimulate the immune system if not removed.

In addition to implant removal, there are other treatments that might be necessary, in particular in patients with polyurethane breast implants, implant rupture and patients with anti-GM1 antibodies and progressive muscular weakness and neuropathy. The use of a cytokine suppressant (bromocriptine) may be used for the symptomatic patient. Consideration should be given to intravenous infusions of gamma-globulin [99, 100]. Many patients, particularly those with a polyneuropathy, benefit from this therapy and usually the symptoms, such as fatigue, weakness, rashes, myalgia, arthralgia and joint stiffness, will improve faster than others, such as memory disturbances, cerebral vasculitis and central nervous system demyelinating disease. Treatment with plaquenil can also be considered, usually 400 mg daily at bedtime. Some patients may benefit from oral prednisone therapy; however, many patients do not accept it because of the Cushing-like side-effects. Methotrexate once a week may benefit some patients. Plasma exchange treatments or bolus therapy with intravenous steroids (methyl-prednisolone 500 mg daily for 5 days) should be considered in patients with a rapidly progressive neurological disease, in particular MS-like syndrome, who require immediate medical intervention. A minority of patients, particularly those with a high titer of anti-GMI progressive neurological disease (motor neuron disease type) and failure to respond to any other form of therapy, may need oral or intravenous cytoxan treatment in an effort to bring the rapidly progressing disease course under control and stabilization [101].

CONCLUSIONS

Silicone breast implantation appears to be associated, in some patients at least, with both local and systemic disease syndrome(s). By far the most common is the development of an autoimmune peripheral neuropathy (axonal and demyelinating) associated with a myriad of generalized symptoms. A discussion of the medical conditions that appear after a variable interval and progress to a debilitating illness has been made. In addition, several modes of therapy for this condition have been presented for the practitioner treating these conditions.

REFERENCES

[1] Ostenmeyer B, Patten BM, Calkins DS. Adjuvant breast disease: a clinical evaluation of 100 symptomatic women with silicone breast implants or silicone fluid injections into the breast. Keio Med J 1994; 43: 79-87. [2] Lappe, M. 'Nonreactive' Chemicals lack Adverse Effects in Chemical Deception. San Francisco: Sierra Club Books, 1991. [3] Kessler DA, Merkatz RB, Schapiro R. A call for higher standards for breasts implants. JAMA 1993; 270: 2607-8. [4] Kessler DA. The basis of the FDA's decision of breast implants. N Engl J Med 1992; 326: 1713-15. [5] Kumagai Y, Shiokawa Y, Medsger TA, et al. Clinical spectrum of connective tissue disease after cosmetic surgery. Arthrit Rheumat 1984; 27: 1-12. [6] Kossovsky N, Heggers JP, Robson MC. The bioreactivity of silicone. Crit Rev Biocompat 1987; 3: 53-85. [7] Hausner R, Schoen FJ, Pierson KK. Foreign body reaction of silicone-gel in axillary lymph nodes after augmentation mammoplasty. Plastic Reconstruct Surg 1978; 62: 381-3. [8] Hilts PJ. Maker of implants says silicone-gel poses health risks. Houston Chron 1993; 20 March: 1-2. [9] Cronin T, Gerow F. Augmentation mammoplasty, a new natural fell prosthesis. In: Transactions of the Third International Congress of Plastic and Reconstructive Surgery. Amsterdam: Excerpta Medica,1964; 41-2.

[Reference]

[10] Brozema SJ. Fenske NA, Cruse CW et al. Human adjuvant disease following augmentation mammoplasty. Arch Dermatol 1988; 124: 1383-6. [11] Cuellar M, et al. Silicone breast implants associated with musculo-skeletal manifestations. Clin Rheumat 1995; 14: 667-72. [12] Human Resources and Intergovernmental Relations Subcommittee of the Committee on Government Operations. The FDA's Regulation of Silicone Breast Implants. Washington, DC: US Government Printing Office, 1992. [13] Heggers JP. Kossovsky N, Parsons RW, et al. Biocompatability of silicone implants. Ann Plastic Surg 1983; 11: 3845. [14] Jenny H, Smahe L. Clinicopathological correlation in pseudocapsule formation after breast augmentation. Aesth Plastic Surg 1981; 5: 63-8. [15] Kessel RWI, Monaco L, Marchisio MA. The specificity of the cytotoxic action of silica. A study in vitro. Br J Exp Pathol 1963; 44: 351-64. [16] Kaiser W, Beisenback W, Stuby U, et al. Human adjuvant disease: remission of silicone-induced autoimmune disease after explantation of breast augmentation. Ann Rheumat Dis 1990; 49: 937-8. [17] Batich C, DePalma D. Materials used in breast implants: silicones and polyurethanes. J Long-Term Effects Med Implants 1992; 1: 25568. [18] Allison AC, Harrington JS, Birbeck M. An examination of the cytotoxic effects of silica on macrophages. J Exp Med 1966; 124: 141-53. [19] Argenta LC. Migration of silicone gel into breast parenchyma following mammary prosthesis rupture. Aesth Plastic Surg 1983; 7: 2534. [20] Baldwin CM, Kaplan EN. Silicone induced human adjuvant disease. Ann Plastic Surg 1983; 10: 270-3. [21] Barker DE, Retsky MI, Schultz S. Bleeding of silicone from bag-gel breast implants and its clinical relation to fibrous capsule reaction. Plastic Reconstruct Surg 1978; 61: 836-41. [22] Batich C. Silicone degradation products. In: NIH Immunology of Silicones Workshop, 13-14 March 1995. [23] Garrido L, Detection of Silicone Migration with NMR. In: NIH Immunology of Silicones Workshop, 13-14 March 1995. [24] Garrido L, Pfleiderer B, Papisow M. et al. In vivo degradation of silicones. NRM 1993; 29: 839-43. [25] Goldblum RM, Pelley RP, O'Donell AA, et al. Antibodies to silicone elastomers and reactions to ventriculoperitoneal shunts. Lancet 1992; 340: 51013. [26] Guthrie JL, McKinney RW. Determination of 2,4 and 2,6 diaminotoluene in flexible urethane foam. Anal Chem 1977; 49: 1676-80. [27] Harrison M. Adjuvancy and breast implants. Dow Corning Commun 1993; 4 March: 1-2. [28] Pernis B, Pametto F. Adjuvant effect of silica (tridymite) on antibody production. Proc Soc Exp Biol Med 1962; 110: 3902. [29] Lake RS, Radonovich H. Action of Polydimethylsiloxanes on the Reticuloendothelial System of Mice: Basic Cellular Interactions and Structure-Activity Relationship. Midland, MI: Dow Corning Corporation, Research Department, 1975. [30] Pfleiderer B, et al. Migration and biodegradation of free silicone from silicone gel-filled implants after long-term implantation. Magnet Res Med 1993; 30: 534-43. [31] Uber CL, McReynold RA. Immunotoxicology of silica. CRC Crit Rev Toxicol 1982; 10: 303-19. [32] Picha GJ, Goldstein JA, Stohr E. Natural-Y meme polyurethane versus smooth silicone: analysis of the soft-time interaction from 3 days to year in the rat animal model. Plastic Reconstruct Surg 1990; 85: 903-16. [33] Kossovsky N, Freiman S. Silicone breast implant pathology: clinical data and immunologic consequences. Arch Pathol Lab Med 1994; 118: 686-93. [34] Vodjani A, Campbell A, Brautbar N. Immune functional abnormalities in patients with clinical abnormalities and silicone breast implants. Toxicol Ind Health 1992; 8: 415-29. [35] Nain JO, Lanzafame RJ, van Oss CJ. The adjuvant effect of silicone gel on antibody formation in rats. Immunol Invest 1991; 22: 151-61. [36] Black DL. 2,4-TDA analysis with regards to PUF breast implants. Aegis Anal Lab Commun 1991; 4 June: 1-2 and 1993; August II: 3-4. [37] Kossovsky N, Heggers JP, Robson MC. Experimental demonstration of the immunogenecity of silicone-protein complexes. J Biomed Mater Res 1987; 21: 1125-33. [38] Wolf C, et al. Chemical analysis of explanted breast implants. In: NIH Immunology of Silicones Workshop. 1995. [39] Bergman RB, van der Ende AE. Exudation of silicone through the envelope of gel filled breast prostheses: an in-vitro study. Br J Plastic Surg 1979; 32: 314. [40] Lust JA. The role of cytokines in the pathogenesis of monoclonal gammopathies. Mayo Clin Bull 1994; 69: 691-7. [41] Rodnan GP, Bendek TG, Medsger TA, et al. The association of progressive systemic sclerosis (scleroderma) with coal miners' pneumoconiosis and other forms of silicosis. Ann Intern Med 1966; 66: 323-8.

[Reference]

[42] Swan S. Epidemiology of silicone-related disease. Sem Arthrit Rheumat 1994; 24 (Suppl 1): 38-43. [43] Tasher A, Broughton A. An ELISA method for detecting serum antibodies. Clin Chem 1993; 39: 1247-9. [44] Sergott TJ, Limoli JP, Baldwin CM et al. Human adjuvant disease; possible autoimmune disease after silicone implantation: a review of the literature, case studies and speculation for the future. Plastic Reconstruct Surg 1984; 78: 104-14. [45] Sahn EE, Garen PD, Silver RM et al. Scleroderma following augmentation mammoplasty. Arch Dermatol 1990; 126: 1198-202. [46] Schmidt GH. Mammary implant shell failure. Ann Plastic Surg 1980; 5: 369-71. [47] Chan SC, Birdsell DC, Gradeen CY. Detection of toluenediamines in the urine of a patient with polyurethane-covered breast implants. Clin Chem 1991; 37: 7568. [48] Gayou R, Rudolph R. Capsular contraction around silicone mammary prostheses. Ann Plastic Surg 1979; 2: 62-71. [49] Capozzi A, Du Bou R, Pennisi VR. Distant migration of silicone-gel from a ruptured breast implant. Plastic Reconstuct Surg 1978; 62: 302-3. [50] Cocke WM Jr, Sampsom HW. Silicone bleed associated with double-lumen breast prostheses. Ann Surg 1979; 18: 524-6. [51] Ostermeyer B, Patten BM. Abnormal laboratory and histopathological findings in women with systemic disease and saline breast implants. Brain Pathol 1994; 15: 376-9. [52] Ostermeyer B, Patten BM. An atypical motor neuron disease syndrome in patients with breast implants. Can J Neurol Sci 1994; 1 (Suppl 2): 64-9. [53] Lee L, Ostermeyer B, Patten BM. An atypical chest pain syndrome in silicone breast implant patients. S Med J 1994; 87: 978-84. [54] Vargas A. Shedding of silicone particles form inflated breast implants. Plastic Reconstruct Surg 1979; 64: 252-3. [55] Travis WD, Balogh K, Abraham JJ. Silicone granulomas: report of three cases and review of the literature. Human Pathol 1985; 16: 19-26. [56] Miyoshi K, Miyamura T. Kobayashi Y. et al. Hypergammaglobulinemia by prolonged adjuvanticity in man. Disorders developed after augmentation mammoplasty. Jpn Med J 1964; 2122: 9-14. [57] Van Nunen SA, Gatenby PA, Basten A. Post-mammoplasty connective tissue disease. Arthfit Rheumat 1982; 25: 694-7. [58] Endo LP, Edwards NL, Longley G, et al. Silicone and rheumatic diseases. Sem Arthrit Rheumat 1987; 47: 112-18. [59] Varga J, Schumacher HR, Jimenez SA. Systemic sclerosis after augmentation mammoplasty with silicone implants. Ann Intern Med 1989; 149: 1194-6. [60] Varga J, Jimenez SA. Augmentation mammoplasty and scleroderma. Arch Dermatol 1990; 126: 1220-2. [61] Ericsson AD, DeGeorge J. The story of silicone. Explore 1996; 6: 13-16. [62] Fock KM, Feng PH, Tey BH. Autoimmune disease developing after augmentation mammoplasty: report of 3 cases. J Rheumat 1984; 11: 98-100. [63] Gelfand EW. Intervention in autoimmune disorders. Clin Immunol Immunopathol 1989; 53: S1-6. [64] Package Insert. Arlington, TX: Dow Corning Wright 1991. [65] Trachman H. Ilowite N, Levine J. Increased urinary NO and NO excretion in children breast fed by mothers with silicone implants (SI). Arthrit Rheumatol 1994; 37: s422 (1-8). [66] Truong LD, Cartwright J, Goodman D, et al. Silicone lymphadenopathy associated with augmentation mammoplasty. Morphologic features of nine cases. Am J Surg Pathol 1988; 12: 484-91. [67] Uretsky BF, O'Brien JJ, Courtiss EH, et al. Augmentation mammoplasty associated with a severe systemic illness. Ann Plastic Surg 1979; 3: 445-7. [68] Walsh FW, Solomon DA, Espinosa LR, et al. Human adjuvant disease. A cause of chylous effusions. Arch Intern Med 1989; 149: 1194-6. [69] Celli B, Texter S, Kovnat DM. Case report: adult respiratory distress syndrome following mammary augmentation. Am J Med Sci 1978; 275: 81-5. [70] Washington University Neuromuscular Clinical Laboratory Evaluation Publication, 1996. [71] Rechlin S. Neuroendocrine-Immune interactions. N Eng J Med 1993; 329: 124652. [72] Broughton A, Trasher JD. Auto-antibodies associated with silicone breast implants. Clin Chem 1993; 39: 113940. [73] Morse JH, Spiera H. Autoimmune disease immunoglobulin isotypes and lymphocyte subsets in 30 females with breast augmentation mammoplasty Arthrit Rheumat 1992; 35: 65-7. [74] Mancino D, Vuotto ML, Minucci M. Effects of a crystalline silica on antibody production to t-dependent and t-independent antigens in bald/c mice, Int Arch Allergy Appl Immunol 1984; 73: 10-13. [75] Bar-Meir E, Teuber SS, Lin HC, et al. Autoantibody profile of women with silicone breast implants. breast implants and symptoms of rh Rheumatic disease. Ann Intenn Med 1994; 37: s422 (9-12). [76] Bridges AJ, Conley C, Wang G, et al. A clinical immunological evaluation of women with silicone breast implants and symptoms of rheumatic disease. Ann Intern Med 1993; 118: 929-36.

[Reference]

[77] Silver R Sahn EE, Allen JA. et al. Demonstration of silicon in slides of connective-tissue disease in patients with silicone-gel breast implants. Arch Dermatol 1993; 129: 63-8. [78] Silverman S, Mendoza M, Silver D, et al. Measurement of fatigue in patients with silicone breast implants (SBI) as compared to fibromyalgia (FM) and rheumatoid arthritis (RA). Arthrit Rheumat 1994; 37: S271, 4-6. [79] Love LA, Weiner SR, Vasey FB, et al. Clinical and immunogenetic features of women who developed myositis after silicone implants. Arthrit Rheumat 1992; 35: 46-8. [80] Freundlich B, Tomaszewski J, Callegari P. A Sjogren's-like syndrome in women with silicone-gel breast implants. Arthrit Rheumat 1992; 35: 67-9. [81] Tenenbaum SA, Silveira LH, Martinez-Osuma P, et al. Identification of a novel auto-antigen recognized in silicone associated connective tissue disease. Arthrit Rheumat 1992; 35: 73-5. [82] Ostermeyer B, Patten BM. An MS-like syndrome in women with silicone breast implants or silicone fluid injections in breast. Neurology 1994; 44: A158: 37-4. [83] Ostermeyer B, and Patten BM. Human adjuvant disease presenting as multiple sclerosis-like syndrome. S Med J 1996; 89: 179-88. [84] Levine J, Ilowite N. Scleroderma-like esophageal disease in children breast-fed by mothers with silicone breast implants. JAMA 1994; 271: 213-16. [85] Gutierrez FJ, Espinosa LR. Progressive systemic sclerosis complicated by severe hypertension; reversal after silicone implant removal. Am J Med 1990; 89: 390-2. [86] Young, V. et al. HLA typing in women with breast implants. Plastic Reconstruct Surg 1995; 96: 1497-519. [87] Jekel J, et al, Epidemiology biostatistics and preventive medicine. Philadelphia, PA: W. B. Saunders, 1996. [88] Rosenberg N. The neuromythology of silicone breast implants. Neurology 1996; 310: 308-14. [89] Weisman MH, Vecchione TR, Albert D, et al. Connective tissue disease following breast augmentation: a preliminary test of the human adjuvant hypothesis. Plast Reconstr Surg 1988; 82: 626-30. [90] Bright RA, Jeng LL, Moore RM. National survey of self-reported breast implants; 1988 estimates. J Long-Term Effects Med Implants 1993; 3: 81-9. [91] Okano V, Nishikai M, Sato A. Scleroderma, primary biliary cirrhosis and Sjogren's syndrome after cosmetic breast augmentation with silicone injection: a case report of possible human adjuvant disease. Ann Rheumat Dis 1984; 43: 520-1. [92] Oxelius V. Immunoglobulin G subclasses and human disease. Am J Med 1984; 4: 7-18. [93Kumagai Y, Abe C, and Shiokawa Y. Scleroderma after cosmetic surgery. Arthrit Rheumat 1979; 22: 532-7. [94] Spiera H. Scleroderma after silicone augmentation mammoplasty. JAMA 1988; 260: 2368. [95] DeCamara DL, Sheridan JM, Kammer BA. Rupture and aging of silicone gel breast implants. Plastic Reconstruct Surg 1993; 91: 828-34. [96] Cook RR, Delongchamp RR, Woodbury M. et al. Breast implant prevalence. Dow Corning Commun 1993; 17 March: 2-3. [97] Spiera H, Kerr L. Scleroderma following silicone implantation: a cumulative experience of twelve cases. Arch Rheumat 1992; 35: 68-72. [98] Koeger C, Alxaix D. Rozenberg S, et al. Silica-induced connective tissue diseases do still occur. Arthrit Rheumat 1993; 35: 34-7. [99] Jordan S. Intravenous gamma globulin therapy in systemic lupus erythematosis and immune complex disease. Clin Immunol Immunopathol 1989; 53: 164-9. [100] Dwyer JM. Intravenous therapy with gamma globulin. Adv Intern Med 1987; 32: 111-36. [101] Barrett J. Textbook of Immunology. St Louis: Mosby Company, 1988.

[Author note]

ARTHUR DALE ERICSSON MD Institute of Biologic Research, 6560 Fannin, Suite 720, Houston, TX 77030, USA

[Author note]

Correspondence to: A. D. Ericsson. Tel: 713 790 9590; Fax: 713 790-1763.