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.

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.

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.

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].

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

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