Fw: PT2....Ethics, epidemiology, and law

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From: " Kathi " <pureheart@...>

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Subject: PT2....Ethics, epidemiology, and law

> 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 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 (see Fig. 1).

>

> 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.

>

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>

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>

> FIG. 1.

>

> --------------------------------------------------------------------------

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>

> Subj: Part 3-Syndromes Associated with Silicone Breast Implants: A

> Clinical Study and Review 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.

>

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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.

>

> 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].

>

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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].

>

> 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.

>

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> 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. sson. Tel: 713 790 9590; Fax:

>

> 713 7901763.

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