BRITTA OSTERMEYER SHOAIB, MD, and BERNARD M. PATTEN, MD, Houston, Tex

Southern Medical Journal, February 1996, Vol. 89 No. 2, p179-188

SILICONE BREAST IMPLANTS have been associated with a number of local and systemic complications such as capsular contracture, implant rupture, gel migration, gel bleeding, granuloma formation, lymphadenopathy, infection, interference with tumor detection, and systemic autoimmune diseases.^{1 -10} Studies by Naim et al ¹¹and Dow Corning Corporation (P. C. Klykken, T. W. Galbraith, M. R. Woolhiser, et al, written communication, March 9, 1993) showed that silicone-gel is as adjuvant as complete Freund’s adjuvant in amplifying anti-bovine serum albumin (BSA) antibody response in rats injected with silicone and BSA. Dow Corning Wright Corporation, the largest implant manufacturer until it left the implant business in 1992, announced on March 19,1993, that the company’s silicone-gel had been found to be a strong stimulant of the immune system.¹² If silicone is an adjuvant, then there should be a group of patients with evidence of immune system activation and consequent adverse effects on multiple organ systems including brain, spinal cord, peripheral nerves, muscle, and connective tissues.

We report here the clinical and laboratory findings of 26 women referred to us in Houston, where breast implants were first introduced in 1963 by Cronin and Gerow.¹³ The patients were referred for evaluation of a nervous system disease resembling multiple sclerosis associated with silicone breast implants or direct injection of silicone fluid into the breasts as possible examples of human adjuvant disease.

Each patient had been seen by a board-certified neurologist prior to referral to us and had been diagnosed with possible or atypical multiple sclerosis (MS). Some patients were told that they had a disease that neurologists had not seen before and therefore would not be able to identify. Patients were then referred to us because of the atypical nature of their disease and a history of breast implants or silicone fluid injections into breasts.

Each patient gave a medical history and had a physical examination and laboratory testing consisting of urine analysis, SMA 15, serum protein electrophoresis, measurements of IgG, IgM, IgA, C3 and C4 by immune precipitation using rate-nephelometry, rheumatoid factor (RF) assessment by latex agglutination, detection of antinuclear antibodies (ANA), antimyelin antibodies, and anticardiolipin antibodies (ACA) by indirect immunofluorescence, and magnetic resonance imaging (MRI) of the brain. Nineteen patients had serum tested for antiganglioside M₁ antibodies (anti-GM₁), antisulfatide antibodies (ASA), and antimyelin associated glycoprotein antibodies (anti-MAG) by enzyme-linked immuno-asorbent assay (ELISA). Two patients had measurements of beta-tubulin antibodies, 2 patients had measurements of antismooth muscle antibodies (ASMA) by ELISA, and individual patients had measurements of anti-GM₁ asialo antibodies, antimitochondrial antibodies (AMA), antiadrenal antibodies, and antistriatal antibodies. Twenty-three patients had a spinal tap with analysis of cells, protein, glucose, electrophoresis, and IgG synthesis rate; 23 patients had visual evoked response measurements; 19 patients had an electromyelogram (EMG) with studies of nerve conduction velocity; 15 patients had a sural nerve biopsy and a biceps muscle biopsy. One patient had a brain biopsy.

Twenty-four patients underwent implant removal. Nineteen had a biopsy of the surrounding implant capsule, and 10 had a biopsy of the pectoralis major muscle. Frozen sections of muscle tissue were processed for staining using nicotinamide-adenine dinucleotide-tetrazolium reductase, myofibrillar ATPase at pH 9.4, and modified Gomori’s trichrome. Formalin sections of the capsule were stained using hematoxylin and eosin (H&E). Nerve biopsy tissue was stained with H&E, modified Gomori’s trichrome, and crystal violet.

In 1981, at age 41, patient 4 had double-lumen silicone-gel breast implants (left 175 cm³ gel/25 cm³ saline, right 200 cm³ gel/25 cm³ saline) for cosmetic augmentation. Four years later she developed joint stiffness and joint pain in hands, feet, and hips. Progressive weakness developed, and fatigue became so severe that she stopped working. Over the next 6 years, the joint pain and stiffness increased, especially in both hips. She developed an ataxic and spastic gait, loss of coordination and balance, loss of bladder control, and optic neuritis first on the left and later on the right side. She then began to notice weakness of the intrinsic muscles of her hands. She had delayed visual evoked responses bilaterally (average P value right eye 118.75 milliseconds, average P value left eye 114.8 milliseconds; normal to age 50 P <109 milliseconds), multiple white matter lesions on MRI scan of the brain, and 6 oligoclonal bands on cerebrospinal fluid electrophoresis. At the same time, she developed painful capsular contracture of the breasts.

In 1987, she was diagnosed with atypical MS. In 1991 she received Solu-Medrol intravenously (IV) 1 g/day for 5 days, followed by oral prednisone starting at 60 mg/day and tapering to 0 mg over the ensuing 16 days. After this, she noticed some temporary improvement in her condition. Because of atrophy of the intrinsic hand muscles, the diagnosis of motor neuron disease was considered; however, EMG and nerve conduction velocity studies were normal.

In 1991, she developed septic arthritis of the hips with effusions, trochanteric bursitis, and osteoarthritis with synovial thickening of the metacarpophalangeal joints. In addition, she was given a diagnosis of fibromyalgia. She tested positive for IgM GM1 at a titer of 1,716 (normal <350), IgG GM₁ at a titer of 1,124 (normal < 500), IgM asialo GM₁, at a titer of 1,765 (normal <600), and IgG asialo GM₁ at a titer of 1,166 (normal <600). Serum IgG was increased to 1,880 mg/dL (normal 650 to 1,500 mg/dL), and serum IgA was decreased to 67.9 mg/dL (normal 76 to 390 mg/dL). RF and ANA test results were negative.

In 1991, two ruptured implants were removed. Implant capsules had foreign body giant cell granulomas with free silicone spilled into tissue and chronic inflammation. Her condition continued to deteriorate. She became wheelchair bound and was unable to dress herself. Examination revealed a left internuclear ophthalmoplegia, atrophy of intrinsic muscles of both hands (Fig 1), atrophy of forearm and calf muscles, diplopia, positive Babinski’s sign on the right, generalized hyperrefiexia, absent superficial abdominal reflexes, loss of vibration and pin-prick in a glove-and-stocking distribution, and a positive Lhermitte’s sign. Another MRI showed multiple foci of increased signal abnormality in white matter, basal ganglia, and brain stem (Fig 2). She had a positive anti-GM1 antibody test and decreased IgA, IgM, and complement 3 in serum. Sural nerve biopsy results showed loss of myelinated fibers (Figs 3 and 4). Biceps muscle biopsy results showed type II atrophy. She received IV cyclophosphamide 500 mg/day for 10 days, followed by an infusion of 12.5 g of IV gammaglobulin over 2 hours. She responded to the treatment and became able to walk with a cane, drive a car, and dress herself.

In 1988 at age 39, patient 25 had silicone-gel breast implants for cosmetic breast augmentation. In 1990, she developed dry eyes and dry vagina. Her basic tear secretion (Schirmer’s tear test) was found to be 0 mm over 3 minutes in both eyes (normal 10 mm in 5 minutes). She also had capsular contracture of the surrounding implant capsule with chest pain. Her implants were replaced with a pair of silicone-gel breast implants covered with polyurethane (290 cm³ of gel each side, brand name Replicon).

In 1993, she woke up one morning with pins and needles sensation in both hands. She developed slurred speech, numbness over the left side of her face, severe ataxia to the point that she could not walk and became bedridden. She also had recurrent superficial skin infections with crusting and drainage of clear fluid on her hands and feet, a livedo reticularis in the upper and lower extremities, a papular rash along the eyebrows, as well as skin tightness. Her proximal interphalangeal joints were swollen and tender, and she had enlarged parotid glands. She also had myalgia, fatigability, morning stiffness in her joints, headache, memory and concentration problems, episodes of delusions, upper respiratory tract infections, dry eyes, dry mouth, and dry vagina, diplopia, numbness in the feet and hands, clumsiness, swollen lymph nodes, shortness of breath, severe facial pain, hair loss, dysphagia, nausea, vomiting, dizziness, Raynaud’s phenomena, and diarrhea with weight loss of 35 lb. She was hospitalized with acute encephalomyelitis in April 1993. MRI of the brain revealed multiple white matter lesions, most in periventricular distribution enhancing with contrast, and surrounding edema (Fig 5). One lesion was present in the left cerebellar peduncle. MRI of the cervical spine revealed a demyelinating plaque at the C2 level. Cerebrospinal fluid analysis showed two oligoclonal bands. She had a right parietal stereotactic biopsy of the meninges and brain. The biopsy showed perivascular lymphocytic infiltrates with occasional macrophages and myelin loss with marked fibrous gliosis compatible with demyelinating disease. Seiver Munger stain to mark axons and Luxol fast blue stain for myelin confirmed marked loss of myelin with relative axonal preservation. She received a course of Solu-Medrol IV 500 mg/day for 5 days and showed remarkable improvement. Another MRI of the brain and cervical spine in December 1993 showed improvement in the lesions.

In February 1994, her symptoms worsened. White blood cell (WBC) count was low at 4,400/dL (normal, 4,800/dL to 10,800/dL), red blood cell (RBC) count was low at 3,860,000 (normal, 4,200,000 to 8,400,000), hematocrit was low at 36.7% (normal, 37% to 47%), and mean cell hemoglobin (MCH) was high at 34 pg (normal, 27 to 33 pg). Visual and auditory evoked potentials were normal. Somatosensory evoked potentials showed a more than 50% decrease in amplitude of the right ulnar to cortex stimulation evoked potential in the upper extremities and a decrease in amplitude of the right P-37 and a latency delay of the left P-37 from the lower extremities. The right N-13 cervical response showed a decrease in conduction time. An 18-channel electroencephalogram (EEG) showed sharp activity in the frontal and temporal poles bilaterally and an alpha frequency burst of about 20 µV lasting for up to a second and a burst of polymorphic delta and theta activity. In addition, the EEG showed prominent wicket rhythms in the frontal and temporal poles. Quantitative EEG showed large amounts of wicket rhythm in the temporal and frontal poles. Transcranial doppler ultrasonography showed increased mean flow velocities through the anterior, middle and posterior cerebral arteries bilaterally, as well as through the vertebrobasilar system, consistent with intracranial vasospasm. After Imitrex Injection (Cerenex Pharmaceuticals, Research Triangle Park, NC), the mean flow velocities dropped from a clearly abnormal range to essentially the normal range.

She again had developed capsular contracture and because of her systemic illness, in May 1994, her breast implants were removed. The implants were intact, but the polyurethane coating had dissolved. Biopsy of the implant capsule showed foamy macrophages, foreign body giant cells, and free silicone in tissue.

In August 1994, she was referred to us. She had a livedo reticularis more in the lower than upper extremities and eczema over the shin area of her legs. She had a stiff, ataxic, and broad-based gait, pale optic discs bilaterally, loss of pinprick and vibration in a glove-and-stocking distribution, proximal and distal muscle weakness, atrophy of her calves, and increased deep tendon reflexes. Rapid alternating movements were normal. Babinski’s sign was negative.

In our series, the mean age at first implantation or injection was 33.5 years (range, 21 to 50 years). The mean age of onset of clinical symptoms was 39.2 years (range, 23 to 64 years). The median latency period between implantation or injection and development of symptoms was 5.71 years (range, 3 months to 15 years). Of our patients, 25 had received breast implants (Table 1) and 1 (patient 2) had received free silicone fluid injections into breast (Fig 6). Twenty-three patients had undergone the surgery for cosmetic breast enlargement. Three patients had undergone surgery for reconstructive purposes after mastectomy for fibrocystic disease (patients 19 and 22) or breast cancer (patient 21).

All patients had evidence of disseminated lesions in the central nervous system. All patients had several additional rheumatologic symptoms. Twenty patients also had evidence for peripheral neuropathy (Tables 1 and 2).

Autodirected antibodies were detected in 16 of 26 patients (Table 3). MRI showed white matter lesions in 21 of 26 patients. Four patients had, in addition, cerebral atrophy, and 1 patient had ischemic lesions in the white and grey matter. Four patients had a normal MRI. Visual evoked responses were delayed in 14 of 23 patients. CSF analysis was abnormal in 20 of 23 patients: 18 had oligoclonal bands, 10 had an increased IgG synthesis rate, and 8 had increased gammaglobulin (Table 3). EMG and nerve conduction velocity studies were abnormal in 9 of 19 patients: 4 had findings of carpal tunnel syndrome, 3 had myopathic units, and 1 had signs of denervation. Sural nerve biopsy results were abnormal in all 15 patients who had the biopsy. Biceps muscle biopsy results were abnormal in 10 of 15 patients (Table 3).

Twenty-four patients underwent implant removal, and 17 of those (71%) were found to have one or both implants ruptured with silicone spills in tissue (Table 1). Implant capsule biopsy results were abnormal in 19 of 20 patients. Pectoralis major muscle biopsy results were abnormal in all 11 who had the biopsy (Table 3).

The name multiple sclerosis originated with the great 19th century neurologist Charcot ^l4 who found multiple glial scars in the white matter of patients who died of this disease. Usually, the clinical course experienced by his patients included exacerbations and remissions of nervous system signs and symptoms, but a fair number of patients with identical autopsy findings had only progressive nervous system dysfunction without remission. Thus, two clinical forms of multiple sclerosis, the exacerbating and remitting and the chronic progressive, probably constitute different aspects of the same condition. They certainly share the same pathologic findings at autopsy and both have, on MRI and evoked response measurements, evidence for multifocal scarring in the central nervous system.

Although the cause and the pathogenesis of multiple sclerosis are unknown, the most commonly held view is that it is an autoimmune disease related in some way to a viral infection. ¹⁵ Pathologically, there is an inflammatory response in the central nervous system consisting predominantly of activated T- lymphocytes and macrophages,¹⁶ accompanied by a local immune reaction with the secretion of oligoclonal immunoglobulins by plasma cells.¹⁷ In the peripheral blood, the hallmark finding remains the loss of suppresser function¹⁸ and the presence of activated T-cells.^19-21 Current thinking claims that the loss of suppression or imbalance in the immune system plays a crucial role in the disease pathophysiology. In fact, even minor activation of the immune system, as seen in banal infectious (usually viral) illnesses, acts as potent triggers of multiple sclerosis attacks.²² On the other hand, treatment with immune suppression such as adrenocorticotropic hormone, corticosteroids, or cyclophosphamide prevents the nervous system dysfunction that may occur.^15,23,24

Since the end of the 18th century, it has been known that foreign materials installed in the human body characteristically produce an immune response that usually consists of a dense accumulation of rnacrophages associated with lymphocytes, plasma cells, and foreign body giant cells. Breast implants constitute no exception ^2,3 and encapsulation and immune reaction to siloxane (the major compound of breast implants) occurs in the majority of cases. Severe persistent local inflammatory reaction to the siloxane explains the local pain, contracture, tenderness, heat, and other well-known local complications of implants that occur in some patients. ^1,2 Systemic symptoms, particularly of a rheumatic nature, occur as well in patients with breast implants. ^2,10

Although medical literature on the subject of foreign materials introduced into the human body dates far back, Miyoshi et al ²⁵ in 1964 first formulated the concept that such reactions could cause a human disease that was specifically related to the immune reaction to foreign materials. They called the resulting condition ‘human adjuvant disease’ because the disease resembled the illness produced in animals by injection of Freund’s adjuvant into tissue. Miyoshi et al ²⁵ also formulated a genus and a divisional definition of the condition. The genus definition states that human adjuvant disease is that autoimmune condition of humans caused by the presence of a foreign material in contact with human body. The divisional definition encompasses six criteria (Table 4). Of great interest, all of the cases Miyoshi et al ²⁵ reported were due to foreign materials introduced for cosmetic augmentation into the human female breast.

We report here the cases of 26 women who received silicone breast implants or silicone fluid injections into the breast and then developed a systemic inflammatory disease ("human adjuvant disease"). Within the human adjuvant disease, they also developed central nervous system involvement resembling multiple sclerosis. There was a median latency period of 5.71 years between the breast surgery and the onset of symptoms. All patients had evidence of disseminated nervous system disease, but none had typical relapsing-remitting courses. MRI scans showed periventricular white matter hyperintense lesions similar to those seen in patients with typical multiple sclerosis. Likewise, the evoked response abnormalities and the spinal fluid evidence of abnormal immune system activation appear similar, if not identical, to those found in multiple sclerosis, suggesting that these patients do have multiple scars throughout their central nervous systems and that those scars are produced by immunologic attack. Even cases of multiple sclerosis associated with peripheral neuropathy, similar to the neuropathy found in our patients, have been recorded.²⁶ Those cases are rare but do exist. Presumably, their existence reflects a cross-reaction of the immune system attack on peripheral nerve myelin producing the peripheral nerve disease in addition to the more usual immune attack against central nervous system myelin producing the multiple central nervous system scars.

However, patients with classical multiple sclerosis usually do not have the additional difficulties that our patients had, including myalgia, joint stiffness, arthralgia, sicca complex, Raynaud’s phenomena, skin rash, headache, hair loss, fever, multiple allergies, sensitivity to sunlight, and lymphadenopathy. The aforementioned additional symptoms usually seen in breast implant recipients, together with the central nervous system involvement, suggest a diffuse activation of the immune system compared with a more limited activation of the immune system in patients with classical multiple sclerosis. Patients with multiple sclerosis usually do not have foreign materials installed in their chests, nor do they have rupture of implants with spill of foreign material producing significant severe chronic inflammation in the breast region.^1,2 We also wish to mention that even intact silicone-gel breast implants leak silicone through the envelope (so called "silicone bleeding").²⁷

We therefore suggest the patients we report here are unique and may constitute examples of a new presentation of human adjuvant disease in which foreign materials installed in the human body are associated with clinical and laboratory features of a multiple sclerosis-like syndrome.

In view of our experience, we would like to make the following predictions: (1) A large number of patients currently diagnosed as having atypical or possible multiple sclerosis may have breast implants; (2) most of those patients will have been diagnosed as having chronic progressive multiple sclerosis and not the exacerbation and remitting type because they will have been under continuous, not intermittent immune stimulation from the implant; (3) most of the patients with implants and a multiple sclerosis-like syndrome will have evidence of local reaction to the implants, and the majority of those with local reactions will have ruptured implants with spill of free silicone into tissue; (4) most of the patients so described will have other signs and symptoms suggesting diffuse activation of the immune system, including the presence of a systemic rheumatic illness; and (5) removal of foreign materials will be followed, probably within 2 years, in most patients by clinical and laboratory evidence of improvement.

Time will tell if these predictions hold true. Meanwhile, physicians should be alert about a multiple sclerosis-like syndrome in patients with breast implants or silicone fluid injections. If such a connection is established, we believe the recommendations of the manufacturer as stated in the package insert ²⁸ should be followed: If an immunologic response is suspected and the response persists, removal of the prosthesis is recommended, along with removal of the surrounding capsule-tissue. Such patients should not be re-implanted. In our opinion, the entire capsule has to be removed in the en-bloc technique as a single unit with the implant, because it contains bled or spilled silicone from the implant and inflammatory reactions.¹ A major component of the low-molecular silicones that bleed out is D₄ (octamethylcyclotetrasiloxane), the siloxane known to have adjuvant and cytotoxic effects (R. S. Lake and M. F. Radonovich. Dow Corning Corporation, Research Department, written communication, October 30, 1975).

Supported by a donation from Mr. George Lindler and Ms. Claudette Liner.

Reprint requests to Britta Ostermeyer Shoaib MD, CompreCare Clinics, 6560 Fannin, Suite 720, Houston, TX 77030

TABLE 1. Implant History and Neurologic Examination

TABLE 2. Clinical Symptoms

TABLE 3. Laboratory and Histopathologic Findings

TABLE 4. Miyoshi’s Criteria of Human Adjuvant Disease

PHOTO: FIGURE 1. Intrinsic hand muscle atrophy in patient 4. This patient’s condition was previously diagnosed as a combination of multiple sclerosis, motor neuron disease, and rheumatic disease.

PHOTO: FIGURE 2. Two-spin echo modified T2-weighted magnetic resonance image of brain of patient 4 shows multiple foci of increased signal abnormality in cerebral white matter and basal ganglia (1.5 Tesla, TR 2,500 msec, TE 30 msec.)

PHOTO: FIGURE 3. Cross section of patient 4’s sural nerve shows large myelinated fibers with central clearer areas that are axons. Instead of filling fascicle, myelinated fibers are depleted. (Hematoxylin and eosin stain, original magnification x 69).

PHOTO: FIGURE 4. Longitudinal section of patient 4’s sural nerve shows large myelinated fibers. Instead of filling fascicle, myelinated fibers are depleted. Note shortened internodal distances, partial demyelination of some fibers, and paranodal enlargement in center of field. (Congo red stain, original magnification x 69)

PHOTO: FIGURE 5. Two-spin echo modified T2-weighted magnetic resonance image of brain of patient 25 shows white matter lesions (arrows). (1.5 Tesla, TR 2,500 msec, TE 17 msec)

PHOTO: FIGURE 6. Two-spin echo T2-weighted magnetic resonance image of chest of patient 2 shows free silicone fluid (arrows) in breasts and pectoralis major muscles (1.5 Tesla, TR 2,200 msec, TE 90 sec)

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