Another new name for polio - as it was defined earlier, is "Motor Neurone Disease" JR

A MOTOR NEURON DISEASE SYNDROME
IN SILICONE BREAST IMPLANT RECIPIENTS

BRITTA OSTERMEYER SHOAB
AND BERNARD M. PATTEN
Department of Neurology
Baylor College of Medicine

Houston, Texas

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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, Sjogren's syndrome, and Raynaud's phenomena.

Some had autoantibodies such as anti-GM, 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 implant 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 a 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 at., 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; 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 physicalexamination. 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 Coming silicone gel-silicone elastomer breast implants, 600cc 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 EMS 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 than right, and it became necessary for 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, Sojgren'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 lower 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 wheel- chair-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-GM1 antibodies, antimyelin antibodies, decreased IgG and IgA, and an abnormal D-xylose breath test indicating small bowel bacterial overgrowth. EMS 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 prostheses. 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 later, 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 gammaglobulin infusions over one and a half years, which stabilized her neurological symptoms, but pain, headache, Sjogren'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 he 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.

All patients showed widespread evidence of denervation on needle EMO. 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 at., 1966; Kossovsky et at., 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 at., 1987). Garrido et al. (1993) demonstrated in an animal model that silicone migrates from the implant to the liver and new silica compounds arc 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 at., 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 Ct 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 (nSA). 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 ( Kumagni et a., 1984; Sergott et al., 1984; Vojdani et al., 1992, 1994; Bridges et al., 1993; Freundlich et at., 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 (Kumagal 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 a!., 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 responses (Kossovsky eta!., 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 implants. 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.