International Journal of Occupational Medicine and Toxicology, Vol. 4, No. 1, 1995

A MOTOR NEURON DISEASE SYNDROME IN SILICONE BREAST IMPLANT RECIPIENTS   BRITTA OSTERMEYER SHOAIB AND BERNARD M. PATTEN

Six (n = 6) women developed motor neuron disease syndrome (MNDS) at a mean latency period of 11 years (range 2-23 years) after receiving silicone gel breast implants (n = 5) or saline breast implants (n = 1). In addition to MNDS, patients had myalgia, fatigue, arthralgia, joint swelling and stiffness, rash, headache, Sjögren's syndrome, and Raynaud's phenomena. Some had autoantibodies such as anti-GM 1, ANA, or antimyelin antibodies, and abnormal serum levels of immunoglobulins. Three patients died during the study. Five patients had sural nerve biopsy, all of which revealed loss of myelinated fibers. Five patients had a biceps muscle biopsy, all of which revealed neurogenic atrophy. Five patients underwent removal, all of which were found to have ruptured implants with silicone spilled into tissue. Foreign material such as silicone breast implants might cause a MNDS, probably indirectly through an autoimmune mechanism. Further investigations of the syndromic nature of MND associated with silicone breast implants are needed.

INTRODUCTION

A syndromic nature of motor neuron disease (MND) or amyotrophic lateral sclerosis has been proposed (Patten, 1987), indicating a syndrome of MND can be due to various causes such as hyperthyroidism, hexosamidase A deficiency, cervical spondylosis, lead poisoning, or exposure to insecticides and pesticides. An autoimmune pathogenesis in MND has been considered as well (Patten, 1987; Drachman and Kuncl, 1989). Basically, it has been concluded that disease or toxin that causes damage to the upper and lower motor neurons can cause the syndrome of MND(Patten, 1987).

Many clinicians have noted a causal relationship between silicone breast implant surgery and the onset of autoimmune disease (Kumagai et al., 1984; Sergott et al., 1984; Vojdani et al.,

1.        Address all correspondence to Britta Ostermeyer Shoaib, M.D., 6560 Fannin # 720, Houston,

2.        Key Words: ALS, disease, implants, MND, silicone

                International Journal of Occupational Medicine and

Toxicology, Vol. 4, No.1, pp. 155-163

Copyright 1995 Princeton Scientific Publishing Co., Inc.

ISSN: 1054-044X

1992, 1994; Bridges et al., 1993; Freundlich et al., 1994; Ostermeyer Shoaib and Patten, 1994; Ostermeyer Shoaib et al., 1994; Silverman et al., 1994; Solomon, 1994; and Vasey et al., 1994). We report here on six women who developed MND syndrome after receiving silicone breast implants.

PATIENTS AND METHODS

All patients were diagnosed with MND by at least two other Board Certified neurologists before they were referred to our service at Baylor College of Medicine. All patients had evidence of upper and lower motor neuron involvement with or without bulbar signs. Patients underwent history and physical examination, and laboratory testing as outlined previously (Patten, 1987).

ILLUSTRATIVE CASE REPORT

In 1983, patient 5 underwent a mastectomy at age 36 for fibrocystic disease. She received breast reconstruction using Dow Corning silicone gel-silicone elastomer breast implants, 600 cc on each side. In 1984, she developed weakness of her left leg, fatigue, severe myalgia and arthralgia, severe headache and memory problems. In 1985, she developed weakness and atrophy of the intrinsic hand muscles. Her myalgia and arthralgia became unbearable and she was referred to a pain clinic. Routine laboratory testing as well as an EMG were normal. She was referred to a psychiatric hospital for pain management, where she spent three months without any improvement in her symptoms. She then developed a bilateral foot drop, worse on the left that right, and it became necessary to her to use a cane. She started to have weakness in both arms and blurred vision. In 1986, her weakness grew progressively worse, necessitating the use of a wheelchair. She suffered from hair loss, Sjögren's syndrome, morning stiffness, Raynaud's phenomena, and erythematous rash on her face and under her left breast and left arm. She also experienced hot flushes, chills, low-grade fevers, recurrent fungal infections of fingers and toes, recurrent urinary tract infections, and constipation. She was diagnosed with ALS, and in 1987, was referred to a specialist for ALS, who confirmed the diagnosis. She was told she had half a year more to live. At that time, on examination, her tongue was normal. She had weakness of upper and lover extremities, and bilateral atrophy of intrinsic hand muscles. Her deep tendon reflexes and sensory examination were normal. Her gait could not be tested because she was wheelchair-bound. An EMG showed widespread denervation, fasciculations, and giant units, but her tongue was normal. Biceps muscle biopsy showed chronic neurogenic atrophy.

She then presented to us for a further opinion. We found a positive ANA, anti-GM ₁ antibodies, antimyelin antibodies, decreased IgG and IgA, and an abnormal D-xylose breath test indicating small bowel bacterial overgrowth. EMG showed widespread signs of denervation. Nerve conduction velocities were normal. Sural nerve biopsy showed demyelination with inflammation, and findings of vasculitis. We felt she had an autoimmune disease associated with silicone breast implants. Therefore, we recommended removal of the protheses. In 1987, she underwent implant removal, but not removal of the surrounding implant capsule. Her left implant was found to be ruptured with silicone spilled into tissue. Two weeks late, she had no more low-grade fevers, her pain lessened, and constipation and recurrent urinary tract infections resolved. She was also treated with prednisone and oral cyclophosphamide and was then able to raise her arms. Her condition began to fluctuate. She received plasma exchange and gamma globulin infusions over one and a half years, which stabilized her neurological symptoms, but pain, headache, Sjögren's syndrome, frequent rashes, and swelling of hands and feet persisted. In addition she had an abnormal sleep study, showing an arterial PO₂ of only 44%, indicating respiratory insufficiency.

In 1989, a repeat EMG showed absent sensory potentials throughout, except for the right radial which was borderline slowed and small. In an attempt to find out whether all silicone had been previously removed, she underwent an ultrasound and chest MRI. Marked residual silicone and the implant capsule were found. In 1992, she underwent more surgery to remove the implant capsule and residual silicone. After surgery, weakness decreased. She could raise both arms over her head, hold a cup of coffee, and dress herself. Swelling of hands and feet resolved, and she could wear rings on her fingers for the first time since 1985. Sexual intercourse, which previously had been impossible because of severe vaginal dryness and respiratory distress, now became possible. Whereas previously she used artificial tears throughout the day for dry eyes, she now only needed one drop in the morning. Her pain and headache improved to the point that she did not need any more pain killers and her rash disappeared. Morning stiffness that used to involve her entire body was now only present in her neck.

After a few months, her condition again worsened. She went into respiratory failure several times and had to be intubated. She underwent further treatment, including plasma exchange and oral and intravenous cyclophosphamide, and was weaned off the respirator. In December of 1993, she again fell into respiratory failure and died.

RESULTS

All six patients were Caucasian women. Five had received silicone gel breast implants (patients 1, 4, and  6 for augmentation, patients 3 and 5 for reconstruction after mastectomy for fibrocystic disease) and one (patient 2) had received saline-filled silicone breast implants for augmentation. The mean age of first implantation was 33 years (range 29-37). The mean age of onset of symptoms was 43 years (range 38-50). The mean latency period between implant surgery and onset of clinical symptoms was 11 years (range 2-23 years).

All patients had upper and lower motor neuron involvement without any significant sensory findings, except for patient 5. Patients 1 and 3 also had bulbar involvement. The patients' symptoms and laboratory and tissue biopsy findings are listed in Table 1.

TABLE 1

TABLE 1 continued

All patients showed widespread evidence of denervation on needle EMG. Nerve conduction studies were normal, except for those of patient 5. All five patients who had a sural nerve biopsy taken were found to have loss of myelinated fibers, and all five patients who had a biceps muscle biopsy were found to have neurogenic atrophy.

Patient 1 died of respiratory failure after seven years of disease. The findings at autopsy were compatible with progressed MND. The pathologist confirmed the loss of myelinated fibers on sural nerve biopsy. Patients 2 and 5 died after eight and nine years of disease, respectively.

DISCUSSION

Silicone is biologically and chemically active. It has been demonstrated that both silicone and silica (up to 30% of the elastomer shell and the gel of a breast implant) are cytotoxic (Kessel et al., 1963; Allison et al., 1966; Kossovsky et al., 1987) and immunostimulatory agents (Pernis and Paronetto, 1962; Heggers et al., 1983; Mancino et al., 1984; Kossovsky et al., 1987). They are efficiently taken up by macrophages from the implant surface and react with the membranes surrounding the secondary lysosomes, causing death of the macrophage and general damage to the adjacent tissue (Kossovsky et al., 1987).

Garrido et al. (1993) demonstrated in an animal model that silicone migrates from the implant to the liver and new silica compounds are formed. Silica itself is known to cause scleroderma-like illness and arthritis (Caplan's syndrome) in coal miners (Rodnan et al., 1966).

Denaturation of native macromolecules by interaction with silicone has also been reported (Kossovsky et al., 1987, 1993; Kossovsky and Petrovich, 1994; Vojdani et al., 1994). Denatured macromolecules then develop antigenic characteristics and become the target of an immune response. A cross-reaction of the immune response to normal tissue could thus explain an autoimmune reaction.

Silicone and silica elicit both cellular and humoral immune responses (Heggers et al., 1983; Kossovsky et al., 1987, 1993). Vojdani et al. (1992) actually measured antisilicone antibodies in women with silicone breast implants. Other investigators found novel antibodies and proteins in sera of silicone breast implant recipients when compared to normal controls. In studies by Naim et al. (1993) and Dow Corning Corporation, ¹ rats were injected with a homogenized gel form of silicone in the presence of bovine serum albumin (BSA). In this

¹ Klykken, P.C. Galbraith, T.W., Woolhiser, M.R., Duwe, R.L., Mudgett, S.L., Nash, G.E., and Malczewski, R.M. (1993). A humoral adjuvancy study of Dow Corning silicone fluids alone 360 fluid, 20 cs.; 7-2317, 1000 cs) and Dow Corning 360 fluid, 20 cs., mixed with Dow Corning mammary gel (Q7-2159A) or McGhan mammary gel in the rat. March 9, 1993, Dow Corning Corporation, Midland, MI 48640.

model, it was demonstrated that silicone gel has adjuvant activity similar to that of complete Freund's adjuvant in amplifying the anti-BSA antibody response. These studies have shown that silicone can act as an adjuvant, enhancing the ability of the immune system to produce antibodies to a foreign antigen.

A growing number of patients have been reported who developed an atypical autoimmune disease with rheumatological and neurological symptoms (Kumagai et al., 1984; Sergott et al., 1984; Vojdani et al., 1992, 1994; Bridges et al., 1993; Freundlich et al., 1994; Ostermeyer Shoaib and Patten, 1994; Ostermeyer Shoaib et al., 1994; Silverman et al., 1994; Solomon, 1994; Vasey et al., 1994). The clinical symptoms and laboratory features of this autoimmune disease from the silicone breast implants are clearly distinguishable from the known classical rheumatological and neurological diseases. Therefore, it has been concluded that women with breast implants tend to develop a new syndrome that we call "Adjuvant Breast Disease" (Ostermeyer Shoaib et al., 1994; Patten and Ostermeyer Shoaib, 1995).

We recently reported one hundred women who developed adjuvant breast disease with nervous system involvement at a mean latency period of six years after silicone breast implant surgery or silicone fluid injections (Ostermeyer Shoaib et al., 1994). A high number of the patients (60%) had ruptured implants. Therefore, we believe patients with implant rupture and spills of silicone into tissue are at higher risk for developing a systemic disease. In this study, the mean latency period was longer (11 years), and all patients who underwent implant removal were found to have ruptured implants. Our patients with MNDS also had the rheumatic and neuromuscular symptoms, as well as laboratory findings (Table 1) that were described in other women with adjuvant breast disease (Kumagai et al., 1984; Sergott et al., 1984; Vojdani et al., 1992, 1994; Bridges et al., 1993; Freundlich et al., 1994; Ostermeyer Shoaib et al., 1994; Silverman et al., 1994; Solomon, 1994; Vasey et al., 1994). Thus, it appears that our patients developed adjuvant breast disease with symptoms of an MNDS due to an underlying autoimmune response to siloxane, a foreign material that has been shown to act as an adjuvant to immune system response (Kossovsky et al., 1993; Naim et al., 1993).

We conclude that attention should be paid to those patients who develop an MNDS after receiving foreign material. Patients with such a condition might benefit from removal of the foreign body, e.g., silicone breast implant. The surrounding capsule tissue must be removed together with the implants since it presents antigenic character, being full of leaked silicone, inflammatory reactions, and damaged tissue. Additional immunosuppressive therapy should be considered for each individual patient.

ACKNOWLEDGMENT

We thank Ms. Linda Culligan and Mr. George Lindler for their generous support of this study.

REFERENCES

ALLISON, A.C., HARINGTON, J.S. and BIRBECK, M. (1966). "An examination of the cytotoxic effects of silica on macrophages." J. Exp. Med. 124(2): 141-154

BRIDGES, A.J., CONLEY, C., WANG, G., BURNS, D.E., and VASEY, F.B. (1993). "A clinical and immunologic evaluation of women with silicone breast implants and symptoms of rheumatic disease." Ann. Int. Med. 118(12): 929-936.

DRACHMAN, D.B. and KUNCL, R.W. (1989). "Amyotrophic lateral sclerosis: an unconventional autoimmune disease?" Ann. Neurol. 26(2): 269-274.

FREUNDLICH, B., ALTMANN, C., SANDORFI, N., GREENBERG, M., and TOMASZEWSKI, J. (1994). "A profile of symptomatic patients with silicone breast implants: a Sjögren's-like syndrome." Sem. Arthr. Rheum. 24(1 Suppl. 1): 44-53.

GARRIDO, L., PFLEIDERER, B., PAPISOV, M., and ACKERMAN, J.L. (1993). "In vivo degradation of silicones." Mag. Res. Med. 29(6): 839-843.

HEGGERS, J.P., KOSSOVSKY, N., PARSONS, R.W., ROBSON, M.C., PELLY, R.P., and RAINE, T.J. (1983). "Biocompatibility of silicone implants." Ann. Plast. Surg. 11(1): 38-45.

KESSEL, R.W.I., MONACO, L., and MARCHISIO, M.A. (1963). "The specificity of the cytotoxic action of silica. A study in vitro." Br. J. Exp. Path. 44: 351-364.

KOSSOVSKY, R. and PETROVICH, D. (1994). "Novel antibodies to native macromolecules (anti-SSAA) in patients with SBI." Arth. Rheum. 37(9): S421.

KOSSOVSKY, N., ZEIDLER, M., CHUN, G., PAPASIAN, N., NGUYEN,A., RAJGURU, S., STASSI, J., GELMAN, A., and SPONSLER, (1993). "Surface dependent antigens identified by high binding avidity of serum antibodies in a subpopulation of patients with breast prostheses." J. Appl. Biomat. 4: 281-288.

KOSSOVSKY, N., HEGGERS, J.P., and ROBSON, M.C. (1987). "The bioreactivity of silicone." Crit. Rev. Biocompat. 3(1): 53-85.

KUMAGAI, Y., SHIOKAWA, Y., MEDSGER, T.A., and RODNAN, G.P. (1984). "Clinical spectrum of connective tissue disease after cosmetic surgery." Arth. Rheum. 27:1-12.

MANCINO, D., VUOTTO, M.L., and MINUCCI, M. (1984). "Effects of a crystalline silica on antibody production to t-dependent and t-independent antigens in balb/c mice." Int. Arch. Allergy Appl. Immun. 73:10-13.

NAIM, J.O., LANZAFAME, R.J., and VAN OSS, C.J. (1993). "The adjuvant effect of silicone gel on antibody formation in rats." Immunol. Invest. 22(2): 151-161.

OSTERMEYER SHOAIB, B. and PATTEN, B.M. (1994). "An MS-like syndrome in women with silicone breast implants or silicone fluid injections into breast." Neurology 44(2): A158.

OSTERMEYER SHOAIB, B., PATTEN, B.M., and CALKINS, D.S. (1994). "Adjuvant breast disease: a clinical evaluation of 100 symptomatic women with silicone breast implants or silicone fluid injection into breast." Keio Med. J. 43(2): 79-87.

PATTEN, B.M. (1987). "The syndromic nature of amyotrophic lateral sclerosis." Adv. Exper. Med. Biol. 209:99-107.

PATTEN, B.M. and OSTERMEYER SHOAIB, B. (1995)."Disquisition on human adjuvant disease." Perspect. Biol. Med. 38(2): 274-290.

PERNIS, B. and PARONETTO, F. (1962). "Adjuvant effect of silica (tridymite) on antibody production." Proc. Soc. Exp. Biol. Med. 110:390-392.

RODNAN, G.P., BENEDEK, T.G., MEDSGER, T.A., and CAMMARTA, R.J. (1966). "The association of progressive systemic sclerosis (Scleroderma) with coal miners pneumoconiosis and other forms of silicosis." Ann. Int. Med. 66:323-328.

SERGOTT, T.J., LIMOLI, J.P., BALDWIN, C.M., and LAUB, D.R. (1984). "Human adjuvant disease, possible autoimmune disease after silicone implantation: a review of the literature, case studies, and speculation for the future." Plast. Reconstr. Surg. 78:104-114.

SILVERMAN, S., MENDOSA, M., SILVER, D., and BELZA, B. (1994). "Measurement of fatigue in patients with silicone breast implant (SBI) as compared to fibromyalgia (FM) and rheumatoid arthritis (RA)." Arth. Rheum. 37(9): 271.

SOLOMON, G. (1994). "A clinical and laboratory profile of symptomatic women with silicone breast implants." Sem. Arthr. Rheum. 24(1)suppl 1:29-37.

VASEY, F. B., HAVICE, D.L., BOCANEGRAN, T.S., SELEZNICK, M.J., BRIDGEFORD, MARTINEZ-OSUNA, and ESPINOZA, L.R. (1994). "Clinical findings in symptomatic women with silicone breast implants." Arthr. Rheum. 1(1): 22-28.

VOJDANI, A., CAMPBELL, A., and BRAUTBAR, N. (1992). "Immune functional abnormalities in patients with clinical abnormalities and silicone breast implants." Toxicol. Ind. Health 8(6):415-429.

VOJDANI, A., BRAUTBAR, N., and CAMPBELL, A.W. (1994). "Antibody to silicone and native macromolecules in women with silicone breast implants." Immunopharm. Immunotoxicol. 16(4): 497-523.