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.

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                    Copyright Carfax Publishing Company Mar 1998  [Headnote]

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.

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'.

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:

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.

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].

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.

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

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.

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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.

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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.

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.

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].

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                    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].

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.

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                    [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 7901763.