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Digest Number 172

From: " Gofer " gofer@...

Date: 10 Jun 2000 07:39:49 -0000

From: SBI-Talkegroups

There are 21 messages in this issue.

Topics in this digest:

5. USSW: Silicone Breast Implants And The Risk Of Fibromyalgia And

Rheumatoid Arthritis.

6. USSW: Definitive Diagnosis Of Breast Implant Rupture By

Ultrasonography

7. USSW: Undated PS study

8. USSW: An Evaluation Of Silicone Breast Implant Patients For

Silicone Associated Disease

9. USSW: Scleroderma After Cosmetic Surgery: 4 Cases Of Human

Adjuvant Disease

10. USSW: Serum Antinuclear Antibodies In Women With Silicone Breast

Implants

11. 1996: Article by Dr. R. Shanklin

12. USSW: Experimental Evidence On The Carcinogenicity Of Silicone

Gel and Polyurethane Foam Implants

13. USSW: Abnormal SPECT Scans and Impaired Memory in Patients With

Adjuvant Breast Disease

14. USSW: Breast Diseases - A Year Book Quarterly Date

15. 1995 Medline A Clinical and Laboratory Profile of Symptomatic

Women With Silicone Breast Implants

16. USSW: Cutaneous T-cell lymphoma in association with silicone

breast implants

17. USSW: SYSTEMIC DISEASE IN WOMEN FOLLOWING THE INSERTION OF

SALINE BREAST IMPLANTS

18. USSW: Immunopathologic effects of silicone breast implants

19. USSW: Copenhagen Declaration-Fibromyalgia

20. USSW: Fibromyalgia

21. USSW: Breast Implant Chronology

22. USSW: Ethylene Oxide

23. USSW: Fibromyalgia/What it is and how ot manage it

24. USSW: Experimental Evidence On The Carcinogenicity Of Silicone

Gel and

25. USSW: Silica

__________________________________________________________________

Message: 5

Abstract: Silicone Breast Implants And The Risk Of Fibromyalgia And

Rheumatoid Arthritis.

Author: F.Wolfe Arthritis Center and Univ.of Kansas Wichita,Ks.

Source: American College of Rheumatology Sept.1995 Vol.38, No.9

Abstract: In the legal setting silicone breast implants (SBI) have

been alleged and sometimes adjudged to be causally associtated with

certain rheumatic diseases,including rheumatoid arthritis (RA),

systemic lupus erythematosus, and scleroderma. But scientific

studies have not supported any association. it has similarly been

claimed that fibromyalgia (FIB) may be caused by SBI. To investigate

these associations in women, we performed a case control study of

533 patients with 533 patients with FIB and 637 with RA. Controls

were 479 with OA and 655 randomly selected women in the general

population (COM). Patients were assessed by mailed questionnaires

and COMs by telephone interviews. mean ages in years at interview

and disease start with RA(64.4, 47.1), OA (67.4, 52.7), FIB (51.6,

38.5), and COM (55.3, NA). SBI were noted in 14 of 2304 subjects

yielding rates noted in Table 1. In 3 FIB patients and no others,

SBI occurred after disease onset, yielding a pre-diesease onset rate

of .75 (.20, 1.9). To assess the association between pre-disease SBI

and BIB and RA we computed odds ratios (OR) adjusted for age by

logistic regresion. Table 2 shows non-significan ORs for both FIB

and RA. When FIB was examined considering both pre and post-disease

exposures, statistically significant ORs (~4) were identified. In

summary, SBI was uncommon in our sample. No associations between SBI

and RA were identified. But FIB is associated with SBI when SBI both

before and after FIB are considered. It is likely that factors

common to both FIB and the decision to have SBI explain the linkage

rather than a causal relationship from SBI to FIB.

__________________________________________________________________

Message: 6

Abstract: Definitive Diagnosis Of Breast Implant Rupture By

Ultrasonography.

Author: Levine,

Source: Plast Reconstr Surg. Jun.1991 Vol.87-Pgs. 1126-1128

Abstract: Silicone breast implantation is entering its fourth

decade. Our ability to monitor the intergrity of " old " prostheses is

questioned. Clinical and mammographic examinations are reliable

indicators of implant rupture only if there has been gel migration

away from the implant pocket. Ultrasonography is presented as a

reliable, sensitive method of evaluation of implant integrity. It

should be considered the definitive study of prosthesis integrity.

When sonography is added to mammographic and clinical examination,

the preoperative evaluation of symptomatic augmented breasts is

complete. Ultrasonography may be considered with mammography in the

routine breast examination of all previously augmented patients.

__________________________________________________________________

Message: 7

Undated PS study

Abstract PLASTIC SURGEON STUDY

A recently released medical study conducted by some renowned plastic

surgeons gives further evidence of a link between silicone breast

implants and autoimmune disease. The study looked at women who

decided to have their silicone breast implants taken out

(Explantation Group) and compared them to women who decided to keep

their implants (Observation Group).

According to the study: " Systemic symptoms were eliminated or

improved in 79% of 39 women who underwent explantation plus

capsulectomy. In contrast, 88% of 16 Observation Group patients

remained unchanged or worsened. " " Our data suggest that explantation

may be more effective in relieving connective tissue disease-like

symptoms in women who are younger. Furthermore, a longer duration of

implantation may result in a poorer outcome after explantation. "

Summary follows:

The Effect of Explantation and Capsulectomy on Symptoms and Antibody

Levels in Women With Silicone Gel-filled Breast Implants.

V. Leroy Young, MD, D. Schwartz, MD, PhD, Donna Phelan, MT

(HEW), CHS(ABHI), Marla Schorr, MA

PURPOSE: This study was designed to determine the effect of

explantation on symptomatology and antibody levels in women with

silicone gel breast implants.

METHODS: Fifty-five women with breast implants were prospectively

evaluated for long-standing symptoms (of fatigue, breast pain,

myalgia/arthralgia, and/or generalized upper torso pain), capsular

contracture, implant integrity, autoantibodies to B cells,

antinuclear antibodies, and rheumatoid factor. Thirty-nine of these

women underwent explantation because of concerns about implant

safety, rheumatologic symptoms, implant rupture, or capsular

contracture. Sixteen other women elected not to have surgery but

wished to remain under observation. For the Explantation group, the

postsurgical follow-up period averaged 11.8 months. For the

Observation group, the follow-up period averaged 17.0 months.

RESULTS: Results were analyzed by comparing women who had undergone

explantation with those who chose observation. The two groups were

further categorized into subgroups: those who were

improved/asymptomatic and those who were unchanged/worse at the end

of follow-up. Results are shown in the table below. The study

demonstrates that explantation of silicone gel implants plus

complete capsulectomy resulted in symptomatic improvement in 79% of

the Explantation group. Symptom relief was comparable regardless of

whether a patient chose explantation only, reaugmentation with

saline-filled implants, or autologous tissue transfer. In contrast,

88% of women in the Observation group remained unchanged or became

worse during the follow-up period. As a whole, the Explantation

group had a mean age of 46, and the Observation group had a mean age

of 49. In the explantation group, those who improved after surgery

had a mean age of 44, while those who remained unchanged had a mean

age of 52. This may suggest that younger women have a more favorable

outcome after explantation; alternatively, it could mean that

patients who judged themselves to be unchanged were suffering from

symptoms associated with aging.

The mean duration of implantation was 10.8 years in the Explantation

group and 11.9 years in the Observation group. We found a disturbing

correlation between the duration of implantation and symptom

improvement. In the explantation group, women who improved after

surgery had implants for a mean time of 10.1 years, while those who

did not improve had implants for a mean of 13.7 years. In the

Observation group, the two patients who improved during the follow-

up period had implants for a mean of 7.0 years; those who remained

unchanged had implants for a mean of 12.6 years.

Patient % of Fatigue Breast pain Myal/Arth

Group group Pre/post Pre/Post Pre/Post

Pre/Post

Explantation(n=39)

Improved(31) 79% 97%/26% 68%/10% 94%/29%

Unchanged(8) 21% 100%/100% 63%/63% 100%/100%

Observation(n=16)

Improved(2) 12% 50%/0 50%/0 100%/0

Unchanged(14) 88% 71%/79% 71%/71% 88%/88%

Patient Gen Pain AutoX+ ANA>80 RF+

Group Pre/Post Pre/Post Pre/Post

Pre/Post

Explantation(n=39)

Improved(31) 26%/10% 53%/23% 31%/27% 13%/0

Unchanged(8) 50%/38% 13%/0 14%/29% 0/0

Observation(n=16)

Improved(2) 0/0 100%/50% 0/0 0/0

Unchanged(14) 43%/43% 38%/0 8%/8% 17%/8%

CONCLUSION: Systemic symptoms were eliminated or improved in 79% of

39 women who underwent explantation plus capsulectomy. In contrast,

88% of 16 Observation group patients remained unchanged or worsened.

Our data suggests that explantation may be more effective in

relieving connective tissue disease-like symptoms in women who are

younger. Furthermore, a longer duration of implantation may result

in a poorer outcome after explantation.

__________________________________________________________________

Message: 8

Abstract: An Evaluation Of Silicone Breast Implant Patients For

Silicone Associated Disease.

Author: Abeles, Waterman Univ.of Connecticut Health Center,

Farmington, CT.

Source: American College of Rheumatology Sept.1995 Vol.38-No.9

Abstract: " Siliconosis " is a term suggested for putative set of 14

key symptoms/signs (fatigue, cognitive dysfunction, arthralgia, dry

mount, alopecia, dry eye, photosensitive dermatitis, dysphagia,

chest wall erythema, telangiectasia, petechiae, carpal tunnel

syndrome, lacimal glad enlargement, and parotid enlargement) seen in

patients with breast implantations. We evaluated 105 consecutive

silicone breast patients in an attempt to assess

whether " Siliconosis " was a recognizable syndrome. All patients

underwent extensive history and physical examinations and laboratory

testing. Results indicate that only fatigue (62%), cognitive

dysfunction (60%) and arthralgia (52%) were common complaints. All

other siliconosis syndrome complaints were present in only 5-25% of

patients. However, depression (38%), breast/chest pain (37%),

headaches (35%), easy bruising (32%) and weakness (30%) were more

common problems than the proposed " siliconosis " set of

symptoms/signs. Physical findings failed to reveal chest wall

erythema, petechiae, telangiectasias, salivary or parotid gland

enlargement. 3 patient's had positive Tinel's sign. An elevated ESR

was seen in 3 patients and a positive ANA in 4 patients.14 patients

met criteria for fibromyalgia and 6 for chronic fatigue syndrome.

Overall, there was a mean score of 2.3 symptoms/signs of

proposed " siliconosis syndrome " . One patient with SLE had the

diagnosis made 10 yrs. before her breast implantation. No other

rheumatic inflammatory diseases including SS and PSS were present.

We conclude that " siliconosis " is not useful diagnostic concept in

the 105 patients evaluated by us.

__________________________________________________________________

Message: 9

Abstract: Scleroderma After Cosmetic Surgery: 4 Cases Of Human

Adjuvant Disease

Authors: Kumagai, Abe, Shiokawa

Source: Arthritis Rheum - 1979(May) 22(5):532-7

Abstract: In 9 cases of human adjuvant disease, 4 cases of

scleroderma (3 progressive systemic sclerosis and 1 localized

morphea) were observed. 7-19 years after injection of foreign

substances into the breasts or nose for cosmetic purposes, some

patients developed human adjuvant disease. In one case the foreign

substances were removed by bilateral mastectomy with no discernible

effects on the patient's clinical course. Histopathologic findings

of the removed breasts demonstrated foreign body granulomas with

calcification. The injected substance was identified as a mixture of

liquid and solid paraffin. Human adjuvant disease might be caused by

prolonged hypersensitization activated by the injected foreign

materials which act as an adjuvant.

__________________________________________________________________

Message: 10

Abstract: Serum Antinuclear Antibodies In Women With Silicone Breast

Implants.

Authors: Cuellar,Scopelitis,Tenenbaum,Garry,Silveira,

Cabrera,Espinoza. Department of Medicine, LSU Medical Center at New

Orleans.

Source: J Rheumatol Feb.1995 Journal- Vol.22, Pgs.236-240

Abstract:Objective.Recent evidence suggests that immunologic

abnormalities are not uncommon in individuals with silicone breast

implants.The purpose of our study was to evalutate in a consecutive

manner, the prevalence of autoimmunity as assessed by the presence

of antinuclear antibodies in a larger number of patients with

silicone breast implants.

Methods.Antinuclear antibody (ANA) testing using an indirect

immunofluorescence technique was performed on 813 individuals with

silicone breast implants.All subjects except for 3 transsexual

males, were female.The overwhelming majority, over 99 were white.

The average age of the subjects was 46.2, with a range of 17 to 72

yrs.

Results.ANA positivity was found in 244 of 813 individuals using a

mouse kidney substrate;and in 470 of 813 individuals using HEp-2

cell line. The most common immunofluorescent pattern found using HEp-

2 was speckled, present in 341 individuals, followed by homogeneous

pattern in 113 nucleolar in 63 and 5 were anticentromere. Anti-dsDNA

antibodies measured by ELISA assay were found in 6 of 71 patients

Figure Rheumatoid factor and C-reactive protein were found above

healthy controls in less than 10 of cases studied. The high

prevalence of ANA found in patients with silicone breast implants

agrees with similar observations by others.The finding of

anticentromere and nucleolar patterns has great interest and

relevance.These fairly distinct ANA patterns are most commonly seen

in the idiopathic form of scleroderma and related conditions.

Conclusion. These findings suggest that ANA positivity is relatively

common in individuals with silicone breast implants, and may support

the existence of autoimmune mechanisms in the pathogenesis of the

clinical manifestations seen in this

population.

__________________________________________________________________

Message: 11

Article by Dr. R. Shanklin

Widespread silicone sickness is very real in women with past and

continuing exposure to silicone breast implants. Pathological study

of tissues over the past 10 years shows that many of these women are

sicker today than a decade ago.

Latency of disease is characteristic of progressive autoimmune

disorders. Two widely quoted surveys in The New England Journal of

Medicine failed to pick up the latency of silicone disease because

of the short periods considered (averages of 7.8 and 9.9 years,

respectively). A third, much larger study, involving more than 6,000

women with implants, shows a 50 percent increase in rheumatoid

arthritis for women with implants placed prior to 1980, a clear

indication of the latency period required to develop these disorders.

Release of this study is apparently being held up by Dow Corning

Corp., largest former implant manufacturer. It should be published

immediately so it can receive full evaluation by the scientific

community.

It is evident from recent congressional testimony of physicians that

many have not kept up with basic science research on silicones and

silicone disease, which has grown remarkably since early 1992.

It has now been confirmed that:

(1) silicone induces atypical antibodies and peptides through

changes in native tissue proteins,

(2) there is clear-cut cellular immunity, lymphocytes and

macrophages, principal means by which the body responds to silicone

and silica, a major device component and silicone breakdown product,

(3) the lymphocyt stimulation involves interleukin-2, part of the

system of chemical signals between inflammatory cells, and

(4) there is growing evidence of progression into plasma cell

myeloma, an unusual malignancy of the immune system and certain

precursor disorders.

The changes are part of a new form of autoimmunity which, for lack

of a formal designation, can be called simply silicone disease.

The American College of Rheumatology has established a special

committee to study this and to recommend clinical diagnostic

criteria. Meanwhile, basic research has turned to these problems,

and 1995 has been a watershed year for these breakthroughs. In

addition, FDA recorded over 50 deaths of women with silicone breast

implants through early 1994. If physicians are to counsel women

toward informed consent on these issues, it is requisite for doctors

to be fully informed themselves about such findings. These aspects

and deficiencies notwithstanding, thousands of women have realized

their medical and personal troubles are due, in whole or in part, to

their implants, whether intact or ruptured. They are deciding to

have the implants removed. A recent study indicates an accumulative

rupture rate of 100 percent by about 20 years post implant, a

compelling justification for not waiting that long to do so. Many

women have gained relief of symptoms after removal. No surgery is

risk-free, so careful review of X-rays or MRI studies should precede

surgical removal.

Sadly, evidence has now begun to accumulate that children born after

a woman has these devices implanted are likely to be in poor health.

The children show lymphocyte sensitization indices at about half the

maternal levels. Children born before implants to the same women

have normal health and show normal growth and development.

These are the present features of silicone disease. As the much

larger number of women implanted between 1985 and 1992 pass 10 and

15 years post implant, there will be ever more adverse outcomes. It

is hoped that, before then, the basic science insight on the

mechanisms of injury to these women will also reveal a treatment or

at least a means to relieve their travail.

_____________________________________________________________

Shanklin, MD, is professor of pathology and of obstetrics

and gynecology at the University of Tennessee in Memphis

__________________________________________________________________

Message: 12

Experimental Evidence On The Carcinogenicity Of Silicone Gel and

Polyurethane Foam Implants:

Silicone Gel: In August of 1987,FDA was presented with the results

of a 2 yr.rat bioassay conducted by Dow Corning. Two gels used to

fill breast implants were tested to assess the long-term

biocompatibility of silicone. The dose used in the rat study was

adjusted to be equivalent per relative body weight to the amount of

gel used in humans who undergo augmentaion mammaplasty. The data

from the study indicated that the silicone gels implanted

subcutaneously in rats induced pronounced increases in the incidence

of fibrosarcoma at the implant site,compared to the control.Of

additonal concern was the fact that metastasis was recorded in a

number of those animals.

The 2 yr.rat carcinogenicity study which was done by Dow Corning to

see if silicone gel caused cancer involved 3 groups of animals,each

with 50 males and 50 females. The first group,the controls,developed

no malignant fibrosarcoma tumors similar to the ones seen in the

silicone-treated animals. The second group was implanted with a

silicone gel used before 1976 and 20% of the females and 22% of the

males developed fibrosarcomas at the injection site. More disturbin,

21% of the animals with these tumors had evidence of

metastases,including spread to lungs, kidney, adrenal, skin, thymus,

and liver. The third group was implanted with the silicone gel

currently in use, and in this group 23% of the females and 26% of

the males developed gel-associated fibrosarcomas,with 18% of those

animals with sarcomas having metastases to distant organs.

The induction of sarcomas in 25% of test animals is a very important

observation as it is lethal in 85% of the sarcomatous animals. This

should be viewed in the context that sufficient time has not elapsed

to record an epidemiologically significant increase in human

malignancies.

The sarcomas in the rat study are at variance with several classical

characteristics of solid-state tumor. They are highly metatastic,

lethal, and show no variation between sexes.

It was concluded that while there is no direct proof that silicone

causes cancers in humans, there is considerable reason to suspect

that it can do so. For these reasons, a senior staff scientist on

the FDA Task Force reviewing the carcinogenicity data urged that: " A

medical alert should be issued to warn the public of the possibility

of malignancy development in humans following long-term implant of

silicone breast prostheses "

Source: International Journal of Occupational Medicine and

Toxicology. 1995

Author: Dr. Epstein

__________________________________________________________________

Message: 13

Title: Abnormal SPECT Scans and Impaired Memory in Patients With

Adjuvant Breast Disease

Among the first - 100 patients with silicone breast implants that we

evaluated 81 patients reported memory problems. We therefore started

to investigate patients with breast implants and memory problems

with SPECT scans and psychological testing. We report here the

results of 15 implanted women with systemic autoimmune disease who

received a SPECT scan and psychological testing.

SPECT scans were digitalized at the midcerebellar transaxial plane

and that region compared to 8 regions of the cortex at the

midventricular transaxial slice. All patients underwent California

Verbal Learning Test, Wechsler Adult Intelligence Scale-Rovised,

Timed Sustained Attention Test and Verbal Fluency Test at the same

time. Occipital regions were normal (Ratio R-0.962, L=O.937), but

other regions including bilateral temporal showed decreases which

were statistically signlf icant using paired tests. Repeated scans

after removal of the implants showed signif icant improvement in

most patients. On the California Verbal Learning Test, performance

was below average for verbal learning,, short and long delayed free

recall and delayed recognition. In contrast, performance on tasks

requiring attention, language and intelligence was average. Women

with implants can develop impaired memory and abnormal SPECT scans.

Further studies are warrant.

COMPRECARE CLINICS: Britta Ostermeyer Shoaib, MD, Director of

Silicone Clinical Research.

__________________________________________________________________

Message: 14

From: Breast Diseases - A Year Book Quarterly Date: Jan-March 1995

Vol 5-#4

Title: Silicone Breast Implants and Immunogenic Dysfunction By:

Brautbar,

Several experimental animal studies, patient case reports, and

patient-controlled studies as well as in vivo and in vitro studies

indicate that silicone is associated with immunologic abnormalities.

These studies coupled with major public outcry let the FDA to ban

the use of silicone breast implants for cosmetic purposes effective

in 1992. Since that time, many clinical and experimental studies

have enlarged our base of knowledge and added further support to the

notion that silicone is a foreign body capable of causing

immunologic reactions and immune dysfunction. This editorial will

summarize the available data.

EVIDENCE FROM EXPERIMENTAL ANIMAL DATA:

SUBCUTANEOUS AND INTRAPERITONEAL INJECTIONS OF SILICONE INTO

EXPERIMENTAL ANIMALS CAUSED MIGRATION OF SILICONE FLUID AND DEPOSITS

SPLEEN, LIVER, ADRENALS, PANCREAS, OVARIES, ABDOMINAL LYMPH NODES,

AND KIDNEYS.

The mechanism suggested is phagocytosis by histiocytes and

generalized deposition in the reticuloendothelial system similar to

the distribution of carbon particles. Recently released documents

from Dow Corning describe a study conducted in mice utilizing linear

3,4-and cyclic 4,5-silicone.These researchers concluded that

silicone injected into experimental animals (1)causes an immunologic

reaction with production of inflammatory reaction phagocytosis,(2)is

transported by the lymphatic system into the reticuloendothelial

system, liver, spleen, kidney, and pancreatic lymph glands; and(3)

directly influences the function of the reticuloendothelial system.

EVIDENCE THAT IMPLANTS " BLEED " (LEAK)

Barker et al. showed that silicone implants " leak " even in the absence

of a rupture. Histologic studies and measurements of silicone in the

human breast showed an inflammatory response as a result of silicone

leakage through the membranes. Recent studies utilizing NMR

technology showed the presence of silicone in the livers of animals

with silicone implants. The NMR studies are in complete agreement

with the histologic studies showing that silicone gel leaks through

an intact membrane. These investigators also showed that silicones

are not metabolically inert. These studies show very clearly that(1)

there is degradation of silicone gel that can be detected with NMR

spectroscopy and atomic absorption,(2)silicone migrates to adjacent

organs, and(3)silicone is not metabolically inert. Futhermore, these

investigators showed that silicone that migrated from the implants

biodegraded to other silicones and silica. If this observation is

confirmed and free silica can be demonstrated adjacent to the

implants or in lymph nodes, one form of mechanism of injury will be

probable since silica is known to be an immunogenic and carcinogenic

agent.

EVIDENCE FROM HUMAN CASE REPORTS AND CONTROLLED STUDIES

Several investigators described autoimmune conditions in patients

either injected with silicone fluid or implanted with silicone

breast implants. Despite this large number of human case reports and

experimental animal studies, a recent review by -Guerro et

al. concluded that no definite association between silicone breast

implants and connective tissue disease exists. Recently, et

al., in a paper that was supposed to study risk assessment of

connective tissue diseases after breast implantation, interestingly

enough made conclusions about " association. " Unfortunately, this study

is a risk assessment study and does not address causation. Indeed,

Dr.Angell of the editorial board stated very clearly that " reaching

conclusions without evidence is impossible. The study of et

al is not perfect, but their data are the best we have. "

EVIDENCE THAT SILICONE IS IMMUNOGENIC

Naim and Lanzafame showed that silicone gel is a potent immunologic

adjuvant and concluded that silicone gel may mediate an autoimmune

reaction. Picha and Goldstein showed that silicone elastomer causes

a significant immunologic response that is absent if the silica is

removed from the silicone elastomer. These findings are in agreement

with other findings showing that silica induces selected toxic

effects on macrophages and that its adjuvant activity is prevented

by treatment of animals with macrophage-stabilizing material. These

observations suggest that silica may play a role in the

immunogenicity of the shell of saline implants. We have recently

studied 40 symptomatic women with silicone breast implants and a

control group of 40 normal women and found significant elevations of

myelin basic protein, together with significant T-helper/suppressor

ratio abnormalities. The lymphocytic mitogenic response was also

abnormal in silicone-exposed patients. These studies showed that

silicone triggers autoimmunity as well as a lymphocyte subcellular

response. The lymphocytes and macrophages needed for an immune

response are present in relatively high concentrations around the

silicone and fibrous material of the breast implant, while the

protein antigen is absorbed into the silicone droplets, which are

then phagocytized by the antigen-presenting cells with an enhanced

humoral immune response. This humoral immune response may end with

production of an antibody to silicone, native macromolecule, or

their combination and may trigger an immune disease in genetically

prone patients.

EVIDENCE OF A DIRECT EFFECT OF SILICONE ON NATURAL KILLER CELL

ACTIVITY.

We have recently shown that natural killer cell activity is

significantly suppressed in patients with silicone breast implants

and that this suppression of natural killer cell activity is

reversible upon removal of the silicone breast implant. Our studies

were recently confirmed by et al., who showed that silicone

gel from implants suppresses natural killer cell activity in

experimental animals and that this suppression is reversible upon

removal of silicone gel. Potter et al. have shown that the

administration of silicone gel taken from silicone breast implants

was associated with induction of lasmacytomas in genetically

susceptible strains of mice. These findings prompted the editorial

board to call for an epidemiologic study of women with silicone

breast implants to look for carcinogenicity and hematologic

malignancies. Our findings in humans along with the findings of

that silicone causes a reduction in natural killer cell

activity plus the recent findings of Potter support the notion that

silicone gel may be a carcinogenic agent and that the mechanism may

be partially mediated in genetically susceptible individuals via

suppression of natural killer cell activities. There is a great deal

of confusion in the minds of serval investigators in the field as

regards causation, association, and risk assessment. Almost all

studies addressing the issue of causation thus far have actually

addressed risk assessment and have not examined the issue of

causation in specific populations of symptomatic patients. Rather,

they reviewed medical records or charts from populations without

symptoms or with minimal symptoms. For medical causation, the

clinician need not look for 99%probability but rather look for the

criteria established by Hill in his famous manuscript establishing

criteria for medical causation. The following shows the application

of the Hill criteria to medical causation in general as well as to

silicone breast implants.

1.Strength of the association-Multiple case reports and population

studies show the strength of association.

2.Consistency-The association is consistent.

3.Specificity-The association is specific for silicone.

4.The relationship in time-Recovery of patients upon removal of the

implants clearly shows a temporal relationship.

5.Dose response-Dose response is shown.

6.Bilogical plausibility-Plausibility is shown in the vivo and in

vitro studies indicating that silicone is immunogenic.

These criteria clarify the difference between causation and risk

assessment and should be utilized in addressing causation for any

disease process, especially for the issue of silicone and

immunologic dysfunction.

Finally, it must be understood that silicone-associated syndromes

and diseases are the result of immune dysfunction and may be

manifested as a wide spectrum immunologic, rheumatologic, and

neurologic syndromes from atypical connective tissue disease through

systemic lupus erythematosus,scleroderma, peripheral neuropathy with

demyelination, and mixed connective tissue disease.

__________________________________________________________________

Message: 15

Subject: 1995 Medline A Clinical and Laboratory Profile of

Symptomatic Women With Silicone Breast Implants

DATABASE: MEDLINE ® 1976-1985 (Copyright 1995)

SOURCE: National Library of Medicine

Periodical: SEMINARS IN ARTHRITIS AND RHEUMATISM

Title: A Clinical and Laboratory Profile of Symptomatic Women With

Silicone Breast Implants

Name: G

Subject(s): ADULT

Aged.

Breast Implants Adverse effects

Connective Tissue Diseases diagnosis.

Connective Tissue Diseases Etiology

Fatigue diagnosis.

Fatigue etiology.

FEMALE

HUMAN

Mammaplasty.

Middle age.

Postoperative Complications.

Prosthesis Failure.

Reoperation.

Retrospective Studies.

Rheumatic Diseases diagnosis.

Rheumatic Diseases etiology.

Silicones Adverse effects

Sjogren's Syndrome Diagnosis

Sjogren's Syndrome Etiology

SYNDROME

Imprint: Oklahoma City, Okla. : 1994 Aug

Note: CAS Registry 0 (Silicones)

JOURNAL ARTICLE

Abstract:

One hundred seventy-six patients with breast prosthetic implants

were evaluated. All women were symptomatic and were referred by

either attorneys (152) or physicians (24) for rheumatic evaluation.

The women ranged in age from 24 to 72 with a mean of 45 years.

Indications for surgery were cosmetic (128), cancer (34), and other

(14). Implants had been in place for 7 years or more in 120 patients

and 2 years in only 8. Eighty-three women required explantation of

their original prostheses, and 63 had new implants inserted of which

47 were silicone and 16 were saline. Capsular contractures were

present in 128 women, and documented implant rupture occurred in 67.

Sixty-four women underwent manual closed capsulotomies. Of the 63

revisions, 37 resulted in contractures of the new implant. The most

frequent symptoms seen in the women were chronic fatigue (77%)

cognitive dysfunction (65%), arthralgia (56%), dry mouth (53%), dry

eye (50%), alopecia (40%), and dysphagia (35%). The most common

findings on physical examination were telangiectasias (60%),

erythema of the chest wall (56%), carpal tunnel syndrome (47%),

petechiae (46%), lacrimal gland enlargement (26%), thyroid

tenderness (22%), thyroid enlargement (21%), and parotid enlargement

(18%). Laboratory findings included elevated cholesterol (59%),

elevated erythrocyte sedimentation rate (32%), elevated serum

immunoglobulin (28%), and positive autonuclear antibody (25%) seen

most often. Despite clinical features suggesting Sjogren's syndrome,

antibodies to Ro (SSA) were seen in only 2 patients, and antibodies

to La (SSB) were seen in only 4 patients. Siliconosis is a novel

systemic disease with symptoms of chronic fatigue, cognitive

dysfunction, sicca syndrome, and arthralgia.(ABSTRACT TRUNCATED AT

250 WORDS)

__________________________________________________________________

Message: 16

Cutaneous T-cell lymphoma in association with silicone breast

implants

ABSTRACT

Authors: Duvic, , Menter, Vonderheid

Institution: Department of Dermatology, University of Texas Medical

School Houston, USA.

Title: Cutaneous T-cell lymphoma in association with silicone breast

implants.

Source: Journal of the American Academy of Dermatology. 32(6):939-

42,1995 Jun.

BACKGROUND:Cutaneous T-cell lymphoma (CTCL) is a chronic malignancy

of helper T cells with the CD4 phenotype. It occurs less frequently

in young women but is increasing in incidence for unknown reasons.

Silicone breast implants have been associated with T-cell-mediated

autoimmune reactions .

OBJECTIVE: Our purpose was to suggest the hypothesis that CTCL may

arise after breast implants and that different patients with CTCL

may be stimulated by different antigens.METHODS:Investigators with

many patients with CTCL were queried regarding the occurrence of

CTCL in women after breast implants.

RESULTS:Three cases of confirmed CTCL after breast implants were

identified and are reported .In one patient with Sezary syndrome and

CTCL, the disease went into remission after removal of

implants ,resolution of chronic staphylococcal infection, and

initiation of photopheresis and interferon alfa therapy. Another

patient had progressive disease.

CONCLUSION: CTCL may occur in association with breast implants in

young female patients,but causality is unknown.If CTCL is antigen

driven,then it is likely to result from several different antigens

in different groups of patients.

__________________________________________________________________

Message: 17

SYSTEMIC DISEASE IN WOMEN FOLLOWING THE INSERTION OF SALINE BREAST

IMPLANTS.

Britta Ostermeyer Shoaib, M.D. and, Bernard M. Pattern, M.D., F.A.C.P

Implant manufacturers are now also asked to show safety and efficacy

data on saline filled silicone elastomer shell breast implants,

because they have been associated with the development of systemic

autoinmune diseases in a number of reports. We report 10

consecutively presenting women with saline filled silicone elastomer

shell breast implants, who developed a peripheral neuropathy (n=9)

or motor neuron disease syndrome (n=l) at an average latency period

of 7 years (range 6 months - 13 years) after implant surgery. Four,

of the patients with neuropathy had evidence of systemic vasculitis.

Raynaud's phenomena was seen in 8/10, gangrene in 1/10 and vasospasm

of major veins of lower extremities on phlebography was seen in

1/10. Implants were removed in 8 patients and 5/8 had ruptured

implants. Implant capsule biopsy showed foreign body giant cells and

free silicone in 4/5. Pectoralis muscle biopsy showed neurogenic

atrophy in 4/5 and myosins in 1/5. Sural nerve biopsy showed loss of

myelinated fibers in 3/5 and vasculitis in 1/5. Biceps muscle biopsy

showed type II atrophy in 2/6, neurogenic atrophy in 1/6, myositis

in 1/6, fasciitis in 1/6 and vasculitis in 1/6. Autodirected

antibodies were found in 10/10 (the commonest was ANA in 6/10). We

suggest saline breast implants might cause or Provoke a, " systemic

autoimmune disease with findings of systemic vasculitis in some

patients. Further investigations about saline breast implants and

associated diseases are needed.

__________________________________________________________________

Message: 18

Title: Immunopathologic effects of silicone breast implants.

Authors: Teuber, Suzanne S.; Yoshida, H.;

Gershwin, M.

Citation: The Western Journal of Medicine, May 1995 v162 n5 p418(8)

-----------------------------------------------------------------

Subjects:Breast implants_Physiological aspects Silicones in

surgery_Physiological aspects Transplantation of organs, tissues,

etc._Immunological aspects

Reference #: A16933127

============================================================

Author's Abstract: COPYRIGHT California Medical Association 1995

Silicone-gel breast implants have been associated with a myriad of

autoimmune and connective tissue disorders by anecdotal reports and

small observational series. To date, no prospective epidemiologic

studies have been done to substantiate these observations, but an

increasing body of literature is being developed and older studies

are being recognized that point to immunotoxic or inflammatory

effects of these breast implant components. The development of

disease due to implants would depend on the interaction of genetic

host factors so that only a few patients would potentially be at

risk. Based on the example of other chemically mediated disorders,

such as scleroderma in association with silica exposure, latency

periods of more than 30 years before disease develops may be

possible. Herein we review studies on silicone and immunity.

Full Text COPYRIGHT California Medical Association 1995

(Teuber SS, Yoshida SH, Gershwin ME: Immunopathologic effects of

silicone breast implants. West J Med 1995; 162:418-425)

Silicone-gel implants for breast augmentation and reconstruction

have been in use since 1962. [1] Local complications have long been

known to occur, primarily consisting of capsular contracture, [2-5]

which is a hardening of the implant to palpation due to contracture

of the fibrous capsule that normally forms (to varying degrees of

thickness) around the implanted foreign body. [2-7] In two series,

noticeable capsular contracture developed in as much as 40% to 50%

of patients.[3,4] Ruptures can occur either intracapsularly or with

extracapsular extension and spread of the gel to the chest wall or

axilla. The exact incidence is not known. Virtually all implants

have been shown to " bleed " silicone into the local microenvironment,

[6] which can be reflected in histologic findings of foreign-body

granulomas in the capsular tissues or regional lymph nodes.[7-9]

More recent observations using magnetic resonance spectroscopy have

demonstrated silicon compounds in the blood of some women with

silicone breast implants, as well as evidence of silicone migrating

to the liver. [10]

The controversy over the safety of silicone-gel implants has focused

not on local complications but rather on the postulated link between

the implanted gel and systemic illnesses or symptoms. Well-

publicized anecdotal reports have raised concerns, especially in

regard to scleroderma,but no prospective clinical series that

clearly supports a link between connective tissue disease and

implants as yet exists. Because of the lack of studies actually

proving the safety of implants, the United States Food and Drug

Administration, in its 1992 review of medical devices,decided that

the implants should be removed from the market except for use in

surgical reconstruction as part of clinical trials. [11] This has

spurred research on the bioreactivity of silicone and of clinical

observations of

patients with implants. Herein we review the chemical properties of

silicone implants and bench research studies pointing to adverse

immune effects.

Chemistry of Silicone

Silicon constitutes about 28% of the earth's crust by weight. [12]

It is an important trace mineral in bone formation and

mineralization. [12] Silicon is also associated with

glycosaminoglycans, unbranched polysaccharide chains that covalently

attach to core proteins to form proteoglycans, which are components

of the connective tissue matrix. [13] Silicones are a family of

synthetic polymers using silicon-oxygen chains with organic side-

groups. The silicones used in a multitude of medical products are

heterogeneous with respect to polymer lengths, side-chain

substitutions, and fillers used. Thus, great variation exists in the

biologic and physical properties of these chemicals.

Many persons have had exposure to silicones in some form such as in

simethicone (an antifoaming agent in antacids) or possibly in

microscopic amounts in injections where silicone oil is used to

lubricate the syringe (such as for insulin), but it must be

emphasized that the chemical properties of each product are unique.

Figure 1 illustrates the synthetic process. [14,15] First, elemental

silicon is produced by heating silica ([siO.sub.2] with carbon.

Silicon is then reacted with methyl chloride ([CH.sub.3]CI),followed

by hydrolysis, which results in the formation of linear or cyclic

low-molecular-weight siloxanes.

Silanoate catalysts are added that break open the most prevalent

siloxane, octamethylcyclotetrasiloxane, to form high molecular-

weight polydimethylsiloxane (PDMS)linear polymers,the silicone used

in silicone gel implants. The gel material is formed by controlling

chain lengths and cross-linking to produce a desired viscosity.

Platinum and hydride-containing polymers may also be added to the

gel. [16] Within the cross-linked PDMS polymer matrix, lower-chain-

length PDMS (less viscous oil) is still present.

The outer silicone rubber envelope is a dispersion of silicone

elastomer wherein fumed silica (amorphous or particulate, 10 to 15

[mu]m) is compounded with the PDMS polymer to act as a filler or a

strengthening agent. [14,15] Hexamethyldisilazane,

divinyltetramethyldisilazane, and cyclic or short linear siloxanes

are some of the materials that can be used to treat the silica to

favorably alter its chemical interactions with the PDMS polymers.

[15,16]

Exposure to Implant Components

Local Exposure

Implants were previously thought to be inert, and after an initial

mild, nonspecific foreign body reaction to " seal off " the implant

from the rest of the body by a thin collagenous layer, there would

be no further interaction such as biodegradation or adherence to

tissues. [17] In studies of implants removed because of capsular

contracture, it has been shown that the surface of an implant

becomes coated with albumin, fibfonectin, transferrin, and other

proteins, as well as with fibroblasts and macrophages. [18] The

affinity of fibronectin for the surface of an unused, sterile,

smooth silicone envelope was also investigated in which pieces were

incubated in normal human serum or saline solution, and, after

washing,a high amount of fibronectin was shown to be adhering to the

surface.

Fibronectin is an important component of the extracellular matrix

allowing cellular adherence and migration.

In 1978 Barker and colleagues conclusively showed that silicone-gel

implants do " bleed " silicone gel through the implant shell. [6]

Filter papers on which various brands and types of implants had been

sitting for a week were sent to Dow Corning (Midland, Michigan)

scientists for analysis. They reported that the " distribution, by

molecular weight, of the leaked material corresponded to relative

quantities of each gel species present inside the envelopes and was

not shifted to the lower molecular weights. " [6](p36) This finding

is of possible relevance because many of the initial studies in

animals showing minimal tissue reaction to silicones used low-

molecular-weight silicone oils, whereas later studies, to be

discussed, showed more reactivity to the higher-molecular-weight gel

species. Gel bleeding follows the principle that " like dissolves

like " --that is, the gel and the envelope are manufactured from the

same materials, and therefore the envelope is not impermeable to its

contents. In a similar manner, hydrophobic human constituents such

as triglycerides and other lipids can diffuse into prostheses.

[19,20]

Numerous reports document the presence of periprosthetic silicone

particles [21] shed from intact implant surfaces or, more commonly,

amorphous refractile material (either intracellular or

extracellular) and foamy histiocytes with vacuoles--presumed to

represent silicone oils that were removed by xylene used in

histologic slide processing. [2,3,22,23] Studies have also

documented the high content of silicon in these tissues, affirming

that the materials seen are likely silicones. [23-26] Peri-implant

silicone has been found in both tissues with little or no visible

inflammation and those capsule tissues with extreme fibrosis,

mononuclear cell infiltrates, granulomas, and calcification. [26] It

is hypothesized that the uptake of silicone by macrophages results

in cellular activation and the secretion of inflammatory mediators,

[27-30] resulting in chronic inflammation, the proliferation of

fibroblasts, and collagen deposition around the implant. A recent

study showed immunoreactivity in implant capsules for tumor growth

factor [beta], insulin-like growth factors I and II, and some

reactivity for platelet derived growth factor [beta], nerve growth

factor, and tumor necrosis factor-[alpha]. Mature skin scar tissue

did not show any immunoreactivity for these growth factors. [31] It

has also been proposed that low-grade bacterial contamination of the

implant surface, rather than the body's reaction to silicone, may

account for chronic inflammation in some cases. [32]

Silicone gel-filled implants account for the vast majority of

implants that have been used. Saline implants pose the same exposure

to the body of the components of the outer silicone rubber envelope.

Polyurethane-coated gel-filled implants pose another exposure

variable that will not be addressed in this review. These implants

were removed from the market in 1991 when concern arose that the

polyurethane foam can be degraded to constituents that include

toluene 2,4-diisocyanate, a carcinogen in rats. [33] The

polyurethane foam coating has been noted to separate from the

implant and slowly degrade, provoking a foreign-body inflammatory

response much like the response to silicone alone. [34]

Distant Exposure to Implant Components

Studies in animals done in the 1960s with small volumes of liquid

silicone administered either subcutaneously or intraperitoneally in

mice resulted in mild inflammation and fibrosis at the site of many

of the subcutaneous injections and occasional collections of

silicone-laden cells in the zona reticularis of the adrenal glands.

Massive doses resulted in widespread visceral collections of

vacuolated cells in lymph nodes, liver, kidneys, spleen, pancreas,

adrenal glands, and ovaries. [35,36] Vacuoles, presumed to represent

silicone fluid. Were seen for several weeks in the peripheral blood

neutrophils and some monocytes of mice and baboons after the

subcutaneous or intraperitoneal administration of silicone fluid.

[37]

It is evident also from human case reports that silicone droplets

that bleed from an implant or shed elastomer particles from the

outer implant shell do indeed undergo phagocytosis by macrophages

and transport to distant organs. The most commonly reported

involvement is of the axillary lymph nodes. [8,9] Silver and co-

workers recently demonstrated silicon-containing material by

electron-probe microanalysis in the skin, alveolar macrophages, and

synovia of three patients with implants and connective tissue

disorders. [38] Experience with migrated liquid silicone

administered in humans--in which silicone has been found in alveolar

macrophages associated with pneumonitis and in liver parenchyma with

granulomatous changes--can be extrapolated to gel implants, but

inadvertent intravenous or intra-arterial administration remains a

possibility. [39,40] Shed silicone particles from dialysis tubing

were reported to be the cause of granulomatous splenomegaly (with

foreign-body reaction) in one patient suffering from splenomegaly-

associated pancytopenia. [41]

Gel bleeding can explain the exposure of virtually all patients to

at least microscopic quantities of silicone, but it should be kept

in mind that implants do have a finite life span, and rupture, which

may be contained by the capsular tissue or which may also involve

the capsule, is probably inevitable. The actual incidence of implant

rupture is not known.

Silicone could migrate away from the site of the breasts by several

mechanisms: migration of silicone collections along fascial planes,

probably influenced by gravity and muscle action [42]; uptake by

macrophages that may enter lymphatic channels or the bloodstream

[8,9]; release from dying macrophages with possible uptake by

macrophages or other phagocytic cells, depending on site [37,43];

transfer from macrophage to lymphocyte by cytoplasmic bridging:

[44]; and the formation of emulsions with host molecules and

subsequent dispersal. [45]

Biodegradation of Implant Materials

A point to keep in mind is that biodegradation products of silicone

implants, or even chemical contaminants, may be more mobile and more

important than an implant's original and primary constituents in any

eventual manifestation of disease. Hydrolytic degradation may slowly

affect lightly cross-linked polymers. [46] Silicones may be degraded

by oxidants such as hydroxyl radicals that can cleave silicon

carbide bonds. When exposed to water, silanol bonds could form that

could result in new siloxane chain linkages. In addition, although

silicones were reported to be resistant tubsids and bases, under

certain conditions, they may be susceptible to cleavage (C. W.

Lenzt, " It's Safe to Use Silicone Products in the Environment, " Dow

Coming Chemical Corporation, Industrial Research Development, April

1980). A study on silicone bag-gel implants in dogs showed changes

in mechanical properties after a year. [44] Anecdotally, in the

operative report of one of our patients seen in the University of

California, , Rheumatology Clinic, the surgeon reported that

the implant shell was no longer present at the time of explantation.

An internal Dow Corning report provides some of the first data on

the biodegradation of organosilicones in humans. In 1980 a male

volunteer inhaled about 20 mg of the DC-344 fluid; measurements

suggested that nearly 20% of the estimated quantity of DC-344 fluid

was excreted in the urine in the eight hours following exposure. The

presence of monomethyl as well as dimethyl silicon in the urine

implicated demethylation of the cyclic dimethyl species during human

metabolism. Of greater concern is the presence of metabolites in the

breast milk of a lactating woman who was exposed by inhalation (R.

B. Annelin, " Trace Analysis of Organosilicon in Human Urine and Milk

by the ASFT Technique, " Dow Corning Toxicology Department File No.

3135-1, Series No. 1-0005-0752, 1980; and the Jefferson Group,

Inc, " A Review of the Toxicological Information on

Octamethylcyclotetrasiloxane and Related government Action, " Dow

Corning Corp, 1992, pp 28402115-28402143).

The strongest data in the literature for biodegradation in vivo come

from a series of articles detailing findings in a rat model by

nuclear magnetic resonance spectroscopy. [10,47-50] These studies

demonstrate the migration of silicones from both subcutaneous

administration of a polysiloxane emulsion and from bag-gel implants

to the lymph nodes and liver at 12 months. An interesting point is

that there were shifts in the resonance peaks to those corresponding

with hydrolyzed silicone and with silica. Neither of these

resonances was present in the silicones before implantation,

suggesting in vivo degradation.

Inflammatory and Immune Responses to Implants and Components

Local Tissue Response

In the most thorough investigation on tissue responses to various

implant components, [16] rats were implanted subcutaneously with

fumed silica, silicone gel, silicone fluid, silica-free implant

shell, implant shell ( " as manufactured " ), xylene-extracted implant

shell ( " implant-ready " ), and the evaporated xylene extract possibly

containing residual macrocyclics or platinum catalyst, but unknown).

Rats were sampled at days 7, 14, 30, 60, and 90. All components

showed inflammation to varying degrees, but the most intense

inflammatory response was towards the fumed silica, with

fibroblasts, lymphocytes, macrophages, plasma cells, and

multinucleated giant cells. Cellular destruction was also evident

with the fumed silica, reminiscent of what is seen with crystalline

silica. [51-52] The silica-free shell was somewhat less reactive

than the " implant-ready " extracted shell and showed less collagen

capsule formation, which could possibly be attributed to mechanical

factors (increased compliance). Although the authors of these

studies do not propose that silica is released from implant shells,

nuclear magnetic resonance studies done later make this a tenable

hypothesis and may account for the differences seen. [47-50] The

implant shell extract, which would not be expected to contain

silica, had the greatest number of multinucleated giant cell.

Amorphous silica has not been associated with pulmonary silicosis or

scleroderma, unlike crystalline silica, [53,54] but it has not been

as extensively studied. [55,56]

Tissue response to accidentally introduced siliceous material in the

skin from concrete or rock can induce local silica granulomas that

can mimic sarcoidosis. It has been proposed that many cases of

sarcoid arising in scars are actually silica granulomas. [57,58] A

series of 41 patients was recently published wherein the

periprosthetic tissues were examined for magnesium silicate, which

was hypothesized to be talc ([MgSi.sub.4] [O.sub.10] [OH].sub.2])

[59] Of these 41 patients, 29 (71%) did have birefringent crystals

in granulomas or in perivascular histiocytes. Silicone aggregates

were not birefringent. Of the capsules, 70% showed free silicone,

but 100% of the tissues did have empty cysts and vacuoles after

xylene processing, suggesting dissolution of silicone before

scanning electron microscopy. The presence of magnesium silicate and

silicone was confirmed by scanning electron microscopy with energy-

dispersive x-ray microanalysis. This is the first report of possible

talc granulomas associated with breast implants. Talc is a known

sclerosing agent [60] and is associated with granulomatous

inflammation. [61,62] It also may have adjuvant properties in animal

models. [60,63] The source of magnesium silicate in these patients

is unknown; it may have been introduced on surgeons' gloves, on the

implants, bled from the implant,or formed de novo as a degradation

product. This is an area sure to receive more attention as further

histologic studies are done.

Cellular Immune Response

In another internal Dow Coming report, the endotoxin-induced

interferon type I production in mice was examined after pretreatment

with various silicones. Dow Corning 360 fluid (DC 360, medical-grade

silicone fluid used for administration in humans), mixed 1:1 with

octamethylcyclotetrasiloxane (D4) in a volume of 0.3 ml administered

intraperitoneally, substantially augmented the interferon production

to endotoxin over that in the controls, and the production was twice

as great as the response to D4 alone. The response lasted several

days and was hypothesized to be due to transient effects on splenic

macrophages (laden with oil droplets), with decreased endotoxin

clearance (R. S. Lake and M. F. Radonovich, " Action of

Polydimethylsiloxanes on the Reticuloendothelial System of Mice:

Basic Cellular Interactions and Structure-Activity Relationships, "

Dow Corning Corporation Research Department Report No. 5409, 1975).

This study reported a dramatic addjuvant action as well as local

cellular response to various silicones.

Direct responses of lymphocytes to silicone were not demonstrable by

lymphocyte transformation, [64] but delayed-type hypersensitivity to

PDMS fluid incubated with syngeneic pooled guinea pig serum

(presumed silicone-protein complexes formed) was shown in inbred

guinea pigs inoculated intraperitoneally with the silicone-serum

plus complete Freund's adjuvant (CFA) before intradermal challenge.

[65] Challenges with saline solution, serum alone, and silicone

alone did not produce notable responses. Histologic examination

revealed a moderate to pronounced lymphocytic infiltrate only at the

silicone-serum site and a positive response to purified-protein

derivative testing at the control site. The results suggest that

silicone-protein complexes are immunogenic. The ability of silicone

gel to act as an adjuvant in a delayed-type hypersensitivity system

was examined recently by inoculating gel with bovine serum albumin

(BSA), saline solution and BSA, or CFA and BSA. Subsequent BSA

intradermal challenge showed that silicone gel produced a cellular

response to BSA equivalent to that of CFA. [66]

Another recent study examined the polyclonal human T-cell activation

that resulted from incubating T cells with inorganic silicate (not

silicone). The results suggested that silicate may act as a

superantigen. The suggestion was made that this may play a role in

scleroderma associated with occupational silica dust exposure. [67]

Humoral Immune Response

Silicone gel and amorphous silica have been shown in studies of

animals to have adjuvant effects on the humoral immune response, and

the presence of siliconegel implants in humans has been associated

with a variety of autoantibodies and antisilicone antibodies. The

earliest study on humoral adjuvancy of medical-grade PDMS was done

by Dow Coming in an unpublished report in 1974 (W. F. Boley and R.

R. Levier, " Immunological Enhancing Activity of Organosilicon

Compounds and Non-Functional Fluids, " Dow Corning File No. 1063-19

[report reference 63]). An adjuvant is a substance that enhances the

immune response to an antigen. Adjuvants have not been known to

cause disease in humans; rather, they have been used to increase

antibody responses to various antigens in immunizations. Some

adjuvants, however, particularly CFA and pristane, can produce

notable disease, including autoimmunity, in animals. Dow Corning

compared the ability of various silicon-containing compounds to

stimulate anti-BSA antibody responses in guinea pigs immunized with

BSA-saline solution or BSA-organosilicone compounds; CFA was the

standard positive control. DC-360, or medical-grade silicone fluid

used for administration, caused a 5.0 log, increase in titer,

compared with 1.3 for saline solution and 8.1 for CFA. Not all the

silicone fluids exhibited adjuvancy using this specific assay.

The ability of silicone gel from a mammary implant mixed in a 1:1

ratio with DC-360 fluid to enhance the antibody response to BSA in

rats was tested in 1993. [68] DC-360 fluid alone enhanced the

antibody response only slightly compared with saline solution, but

the response to the gel-fluid mixture was as great as that to the

CFA. Dow Coming, in another internal report, repeated this research

and came to similar conclusions--the gel potentiated the immune

response considerably, whereas the DC-360 fluid response was only

marginally notable, if at all (P. C. Klykken, T. W. Galbraith, M. R.

Woolhiser, et al: " A Humoral Adjuvancy Study of Dow Corning Silicone

Fluids Alone [360 fluid, 20cs; 7-2317, 1000cs! and Dow Corning 360

Fluid, 20cs, Mixed With Dow Corning Mammary Gel [Q7-2159a] or McGhan

Mammary Gel in the Rat, " Dow Corning Corporation Report 1993-10000-

37981, 1993).

These findings appear to complement the histologic reports that the

higher-molecular weight silicone gel produces more inflammation than

the fluids. [16]

Studies on the adjuvancy of crystalline and amorphous silica suggest

that effects on macrophages, which are the target of cytotoxicity by

crystalline silica, [51,52] are primarily responsible. Crystalline

silica was able in one system to stimulate antibody production to a

Tcell-dependent antigen, but not a T cell-independent antigen. [69]

Another study suggested that nonspecific stimulation and expansion

of the reticuloendothelial system were responsible for adjuvancy to

crystalline silica. [70] Amorphous silica treated with various

antigens was able to substantially enhance antibody response to the

antigens except for BSA. [71] Patients with silicosis have had high

titers of anticollagen type I antibodies and elevated levels of

immunoglobulins--perhaps reflecting nonspecific B- and T-cell

activation due to silica, postulated, as noted earlier, to be a

superantigen [67]--and other autoantibodies including antinuclear

antibodies (ANAs) and rheumatoid factors. It is not known whether

the anticollagen autoantibodies are pathogenic or merely reflect the

adjuvancy action of silica on a self-protein found in high

quantities in the lungs of patients with silicosis. [72]

In our own studies, we looked at the anticollagen antibodies in

women with silicone-gel breast implants and found that 26% of

patients were positive for antibodies (>3 standard deviations above

the enzyme-linked immunosorbent assay mean optical density of normal

controls) against either native or denatured type I collagen. Only

2% of normal women had such autoantibodies. We hypothesized that if

silicone induces an autoimmune response, reactivity would be

expected against components of the peri-implant milieu, such as type

I collagen.[73] We also examined reactivity to type II collagen; 20%

of patients had antibodies against either native or denatured type

II collagen.

Western immunoblotting has subsequently been done on an expanded

series of patients with anticollagen antibodies, with the results

showing that the epitopes involved are different from those seen in

the autoimmune diseases systemic lupus erythematosus and rhetimatoid

arthritis. Thus, it does not appear that these patients are in a

prodromal phase of either of these autoimmune diseases, which some

have associated with silicone implants. [74] Antibody responses

against connective tissue proteins were also examined in women with

implants. Results suggest that some patients produce antibodies

against matrix molecules that have been altered from native

conformation due to interaction with silicone, thus rendering them

possibly more immunogenic. [75]

It also appears that antibodies can develop specifically against the

silicone polymer itself, not just against associated connective

tissue proteins. Two patients with inflammatory reactions to

silicone ventriculoperitoneal shunts exhibited immunoglobulin (1g) G

binding to silicone tubing in vitro.[76] A large study in women with

implants showed substantial levels of IgG by enzyme-linked

immunosorbent assay compared with normal controls, especially those

women with ruptured implants. Most control patients did have

background antisilicone antibodies. [77]

A higher-than-expected incidence of antinuclear antibodies was

recently reported in women with implants. [78] Women with implants

who were asymptomatic had an 18% incidence of positivity for ANAs

(titers of at least 1:256) compared with 0% in the controls. Of

women with various symptoms, but without a defined autoimmune

disease, 26% were also positive for ANAs. In a series

of patients with silicone-gel implants, 11 with autoimmune diseases

and 13 with complaints such as myalgias or fatigue, the patients

with autoimmune diseases had positive ANA tests, as expected (except

one) but, in addition, 7 of 13 of the others were positive for ANAs

with several bands of unknown specificity on immunoblotting. [79]

The importance of antibodies to silicone or connective tissue

components as they relate to possible disease is unknown at this

time, but it is an issue of concern. Although no prospective

epidemiologic studies that prove a relationship between silicone-gel

implants and systemic disease have been done, two retrospective

studies were recently published that could not establish a link, but

lacked sufficient power to be considered definitive. [80,81] One was

done in Sydney, Australia, and looked specifically at scleroderma; 4

of 251 women with scleroderma had implants, and 5 of 289 controls

had implants. [80] At 90% power, this study has a minimum detectable

relative risk of 5.3, and yet, with a disease like scleroderma, even

a relative risk of 2.0 would be considered of great importance and

could have been missed (S. H. Swan, PhD,School of Public Health,

University of California, Berkeley, written communication, fall,

1994). Another study looked at all major connective tissue diseases,

including, for unclear reasons, ankylosing spondylifis, which

affected 3 women in the control group. [81] The minimum detectable

relative risk for scleroderma based on the incidence in this study

was 19.2 (with 90% power) (S. H. Swan, Phd).

It is possible that we will never be able to prove that a particular

connective tissue disease, such as scleroderma, is associated with

implants because of its overall rarity. However, researchers cannot

assume that the patients with scleroderma reported to date in the

literature are the only scleroderma patients with implants. In our

own experience, we have examined eight patients with progressive

systemic sclerosis who have not been reported in the literature. It

is therefore misleading to take the number reported to date and

divide it into 1 to 2.2 million--the putative number of women in the

United States and Canada who have had implants in the past 30 years--

to obtain a prevalence rate. [82] In addition, the denominator may

be highly inaccurate because it is based on the number of implants

sold and not on the actual number of women with implants. For

example, in a series of 70 patients with implants in our clinic,

more than 200 actual breast implants have been Itaced--many women

required two or more surgical procedures to correct problems of

capsular contracture or rupture. Also, the latency period for a

disease such as scleroderma could be as long as 30 years if

parallels can be drawn with scleroderma due to occupational silica

exposure.

__________________________________________________________________

Message: 19

Copenhagen Declaration-Fibromyalgia

COPYRIGHT Lancet Ltd. 1992

Last week the " Copenhagen Declaration " established fibromyalgia as a

distinctive diagnosis. The document 1 stems from the 2nd World

Congress on Myofascial Pain and Fibromyalgia, held in Copenhagen

from August 17 to 20. The diagnosis has been incorporated in WHO's

tenth revision (1992) of the International Statistical

classification of Diseases and Related Health Problems (ICD-10),

which comes into force on Jan 1, 1993.

Fibromyalgia (with fibrositis) appears in ICD-10 as " M79.0

Rheumatism, unspecified " , one of many soft-tissue disorders not

specified elsewhere. The new document defined fibromyalgia as a

painful, non-articular condition predominantly involving muscles,

and as the commonest cause of chronic, widespread musculoskeletal

pain. onset of symptoms occurs usually between the ages of 20 and 40

years, mainly in women.

Diagnostic criteria were defined by the American College of

Rheumatology (ACR) in 1990. 2 The ACR conducted a blinded study with

558 patients (of which 265 were control patients) in 16 centers in

the United States and Canada, and concluded that fibromyalgia could

be diagnosed clinically by a history of widespread pain in

combination with pain in 11 or more out of 18 specified tender

points in muscular tissue. The 18 tender points are nine bilateral

pairs from occiput (at the suboccipital muscle insertions) to knee

(at the medial fat pad proximal to the joint line).

The Copenhagen Declaration recommends the adoption of the two

criteria established by ACR for research purposes, since they work

as a standardizing protocol. However, it enhances ACR's definition

into a pragmatic and clinical perspective: " the diagnosis is

commonly entertained in the presence of unexplained widespread pain

or aching, persistent fatigue, generalized morning stiffness, non-

refreshing sleep, and multiple tender points. Most patients with

these symptoms have 11 or more tender points. But a variable

proportion of otherwise typical patients may have less than 11

tender points at the time of the examination " . Besides, says the

document, fibromyalgia is often " part of a wider syndrome

encompassing headaches, irritable bladder, dysmenorrhoea, cold

sensitivity, Raynaud's phenomenon, restless legs, atypical patterns

of numbness and tingling, exercise intolerance, and complaints of

weakness " . " I believe this is a strong document " , says Bente

Danneskiold-Samsoe, president of the congress. " Many patients will

not have to be considered as hypochondriacs any more. " Fibromyalgia,

which has a prevalence of 0.6% in Denmark, is often accompanied by

symptoms of depression and anxiety. 3 Although the aetiology is

unknown, members of the consensus panel tended to rule out

psychological distress as a cause of the muscular pain and

tenderness in fibromyalgia. It could be the other way round,

suggests the declaration: psychological state could be mainly an

effect of the pain patients suffer.

Muscle biopsy has revealed important morphological changes but no

characteristic ones, and other tests (e.g., serum levels of muscle

enzymes, electromyography, exercise testing, and nuclear magnetic

resonance spectroscopy) have not been helpful. Laboratory tests can

be important to rule out conditions that mimic fibromyalgia, such as

hypothyroidism, polymyalgia rheumatica, or generalized

osteoarthritis. Regional myofascial pain syndrome can be excluded

clinically because it is associated with limited pain distribution.

" With the Copenhagen Declaration, these people will now have better

chances that governments and insurance companies accept their

condition as a cause for invalidity pensions and early retirement " ,

says Finn Kamper-nsen, of the Danish Institute for Clinical

Epidemiology, chairman of the consensus panel.(*I) (*I)Other members

were: Liv Anne ssen (Norway), M. Bennet (USA), Dag

Bruusgaard (Norway), Bente Danneskiold-Samsoe (Denmark), Alfonse T.

Masi (USA), and Janine Morgall (Denmark). The expert panel

contributing to the declaration was: Ann Bengtsson (Sweden),

M. (chairman, USA), Anders Bjelle (Sweden), C. S. Burckhardt

(USA), Don L. Goldenberg (USA), K. G. Henrikason (Sweden), Soren

sen (Denmark), Marijke van Santen-Hoeufft (the Netherlands),

Henning Vaeroy (Norway), and Frederick Wolfe (USA). 1. The

Copenhagen Declaration. Available from Bente Danneskiold-Samsoe,

Department of Rheumatology, Frederiksberg Hospital, Ndr Fasanvej 57,

DK-2000 Frederiksberg, Denmark. 2. Wolfe F, Smythe HA, Yunus MB, et

al. The American College of Rheumatology 1990 criteria for the

classification of fibromyalgia. Arth and Rheum 1990; 33 (no 2): 160-

72. 3. Prescott E, sen S, Kjoller N, et al. Prevalence of

fibromyalgia in the adult Danish population. Scand J Rheumatol 1992;

supplement 94.

__________________________________________________________________

Message: 20

Fibromyalgia

AUTHOR(s): Clauw, J.

TITLE(s): Fibromyalgia: more than just a musculoskeletal disease.

(includes patient information sheet) by J. Clauw ill. (table,

diagram) Fibromyalgia is a common condition characterized diffuse

musculoskeletal pain and fatigue. The syndrome is defined by the

presence of musculoskeletal tender points on physical examination.

Additionally, persons with this syndrome have a high incidence of

headaches, ocular and vestibular complaints, paresthesias,

esophageal dysmotility, " allergic " symptoms, irritable bowel

syndrome, genitourinary symptoms and affective disorders. Recent

research has revealed a number of objective biochemical,hormonal and

neurotransmitter abnormalities associated with fibromyalgia, making

it a clearly identifiable condition. These abnormalities may clarify

our understanding of the pathogenesis and

treatment of fibromyalgia.

COPYRIGHT American Academy of Family Physicians 1995

DESCRIPTORS: Fibromyalgia__Care and treatment

American Family Physician 0002-838X Sept 1 1995, v52, n3, p843(11)

COPYRIGHT American Academy of Family Physicians 1995 characterized

by diffuse musculoskeletal pain and fatigue. The syndrome is defined

by the presence of musculoskeletal tender points on physical

examination. Additionally, persons with this syndrome have a high

incidence of headaches, ocular and vestibular complaints,

paresthesias, esophageal dysmotility, " allergic " symptoms, irritable

bowel syndrome, genitourinary symptoms and affective disorders.

Recent research has revealed a number of objective biochemical,

hormonal and neurotransmitter abnormalities associated with

fibromyalgia, making it a clearly identifiable condition. These

abnormalities may clarify our understanding of the pathogenesis and

treatment of fibromyalgia.

Fibromyalgia is a common musculoskeletal syndrome characterized by

generalized pain, fatigue and a variety of associated symptoms.

Although the term " fibromyalgia " was not introduced until 1976, this

symptom complex was described as muscular rheumatism, fibrositis,

fibromyositis and psychogenic rheumatism as early as the 17th

century.

(1) Further complicating the diagnosis of fibromyalgia is the

considerable overlap with conditions such as myofascial pain

syndrome and chronic fatigue syndrome,

(2) since some persons meet criteria for more than one of these

diagnoses. The confusion surrounding the diagnosis of fibromyalgia

was reduced considerably by a multicenter study sponsored by the

American College of Rheumatology (ACR) that developed criteria for

the diagnosis of fibromyalgia. These criteria, generally referred to

as the 1990 ACR criteria,

(3) are listed in Table 1. These criteria are particularly useful

for the standardization of patient groups in studies examining the

epidemiology or pathogenesis of fibromyalgia but, as with most

diagnostic criteria, they should not be too rigidly applied when

making a diagnosis.

TABLE 1 1990 American College of Rheumatology Diagnostic Criteria

for Fibromyalgia

History of widespread pain of at least 3 months' duration Pain must

be present in the axial skeleton as well as all four quadrants of

the body

2. Pain in at least 11 of 18 of the following paired tender points

on digital palpation (approximately 4 kg of pressure should be

applied with digit, and the patient

must state that the palpation was painful):

Occiput: at the suboccipital muscle insertions

Cervical: at the anterior aspects of the intertransverse spaces

at C5-C7

Trapezius: at the midpoint of the upper border

Supraspinatus: at origins above the scapular spine near the medial

border

Second rib: at the second costochondral junctions

Lateral epicondyle: 2 cm distal to epicondyles

Gluteal: in upper outer quadrants of buttocks in anterior fold of

muscle

Greater trochanter: posterior to trochanteric prominences

Knees: at the medial fat pad proximal to joint line

Adapted from Wolfe F, Smythe HA, Yunus MB, RM, Bombardier C,

Goldenberg DL, et al. The American College of Rheumatology 1990

Criteria for the Classification of Fibromyalgia.

Report of the Multicenter Criteria Committee. Arthritis Rheum 1990;

33:160-72. Used with permission.

Epidemiology

Several breakthroughs in our understanding of fibromyalgia have been

made in the past few years. Recent studies have examined the

prevalence of fibromyalgia in the general population. All of these

studies used the 1990 ACR criteria for diagnosis but used disparate

methods for subject selection, and all reached similar conclusions.

(4)(5)(6)(7) The data suggest that at a given point in time, 3 to 6

percent of the population(including children) meet criteria for this

diagnosis. Since the ACR criteria indicate that pain must be present

in all four quadrants of the body and that 11 of 18 tender points

must be found at the time of examination, this figure probably

represents a conservative estimate of the prevalence of fibromyalgia

in the population.

These studies also demonstrated that women are more likely to have

fibromyalgia than men. However, studies show that at any given age

women have a lower pain threshold than men, even if those with

fibromyalgia are excluded from analysis.(4)(5) The other primary

determinant of tenderness is age. Tenderness increases linearly with

ages in both men and women.(4)(5) Persons with fibromyalgia who are

identified through epidemiologic studies are older (mean age: 55 to

60 years) and generally have fewer concurrent symptoms (irritable

bowel syndrome, sleep disturbance, affective disorders) than those

who seek medical attention.(4)(8)(9)

Clinical Features

PAIN AND TENDER POINTS

Widespread pain and tenderness are the cardinal features of

fibromyalgia. Although to meet the 1990 ACR criteria pain must be

present in all four quadrants of the body, many persons with

unilateral pain or pain that only affects the upper or lower half of

the body clearly have fibromyalgia. The pain in fibromyalgia tends

to be migratory and to wax and wane. Stiffness in the morning or

after remaining in one position for a prolonged period is common,

and patients will frequently note that the pain is worsened by

weather changes, physical activity, stress or menses. Although

patients often report swelling in the regions of pain (a common

report is that rings no longer fit), no objective evidence of

swelling or synovitis is apparent on examination.

A tender point is defined as an anatomic site where pain is elicited

when 4 kg (approximately 9 lb) of pressure is applied (Figure 1).

Although the presence of tender points on physical examination is

the hallmark of fibromyalgia, it is not the entire clinical

presentation(Figure 2). Several studies have suggested that persons

with fibromyalgia are more sensitive to pain throughout the body,

not simply in areas recognized as tender points.(10) In fact,

visceral as well as peripheral pain sensitivity may be increased in

fibromyalgia, as has been noted in related conditions such as

irritable bowel syndrome.(11)(12) Also, it is normal to have some

tenderness in these anatomic regions of the body, with a mean of

3.7 " positive " tender points in persons reporting no pain.(5)

Finally, nociception is probably influenced by a number of factors

besides the patient's age and sex, with aerobic fitness, poor sleep

and depression probably having significant effects.(5)(13) Since so

many variables influence nociception, diagnostic criteria that use

tenderness as the principal determinant have limited specificity and

sensitivity.

FATIGUE

Most patients with fibromyalgia complain of fatigue, but this

symptom is not universal and is not required for diagnosis. In some

persons, fatigue may be severe and debilitating, but in others it is

either not present or it has been accepted because of its chronic

nature. A careful sleep history should be obtained in patients who

are suspected of having fibromyalgia, especially men, since some

data suggest that a significant number of men with fibromyalgia may

have underlying sleep apnea.(14) Early work by Moldofsky and

colleagues(15) indicated that the fatigue associated

with fibromyalgia, as well some of the other clinical symptoms, was

thought to be due to a disruption of deep sleep. However, many

persons with this condition have normal sleep patterns, and the

sleep anomalies seen in some patients with fibromyalgia are also

seen in some persons without fibromyalgia as well as in patients

with other conditions.(16) In addition, only a small percentage of

persons with primary sleep disorders (e.g., sleep apnea) have

fibromyalgia, and improvement in fibromyalgia symptoms with

pharmacologic treatment does not correlate with improvement in sleep.

(17)(18) At present, the role of sleep disturbances in the

pathogenesis of fibromyalgia is unclear.

NEUROLOGIC SYMPTOMS

Patients with fibromyalgia have a higher incidence of both tension

and migraine headaches than normal persons. A number of other

neurologic symptoms in this group of patients, however, are not as

well recognized. Numbness or tingling is common and may occur

anywhere in the body; it is typically fleeting in nature and does

not follow a dermatomal distribution. In one series, 84 percent of

persons with fibromyalgia complained of these paresthesias.(19)

Hearing, ocular and vestibular abnormalities have also been noted,

including a lowered tolerance for painful sound, exaggerated

nystagmus and ocular dysmotility, and asymptomatic low-frequency

sensorineural hearing loss.(20)(21) Cognitive complaints, especially

difficulty with concentration and short-term memory, are also

common. Results of standard neurologic examinations, nerve

conduction tests and imaging studies are normal in these persons,

but results of more subtle testing (including evoked responses and

functional assessment) may be abnormal. Because of the variety of

neurologic symptoms seen in patients with fibromyalgia, once a

person is diagnosed it is prudent to use neurodiagnostic tests only

when objective abnormalities are apparent on physical examination.

ALLERGIC SYMPTOMS

Patients with fibromyalgia display a wide array of " allergic "

symptoms. These symptoms range from adverse reactions to drugs and

environmental stimuli (many patients meet criteria for " multiple

chemical hypersensitivity syndrome " ) to a higher-than-

expectedincidence of rhinitis, nasal congestion and lower

respiratory symptoms.(22) It is unlikely that all of these symptoms

have a true allergic basis; instead, these symptoms may be the

result of the central nervous system activation seen in fibromyalgia.

CARDIAC, PULMONARY AND GASTROINTESTINAL SYMPTOMS

For many years it has been believed that patients with fibromyalgia

have a number of symptoms of " functional " disorders of visceral

organs, including a high incidence of recurrent noncardiac chest

pain, heartburn, heart palpitations and irritable

bowel syndrome. However, prospective studies of randomly selected

patients with fibromyalgia have detected evidence of objective

abnormalities of visceral organs, including a 75 percent incidence

of echocardiographic evidence of mitral valve prolapse, a 40 to 70

percent incidence of esophageal dysmotility, and diminished static

inspiratory and expiratory pressures on pulmonary function testing.

(12)(23)(24) These studies suggest that the symptoms have a

physiologic mechanism that is likely to be centrally mediated.

GENITOURINARY SYMPTOMS

Patients with fibromyalgia have a higher incidence of dysmenorrhea,

urinary frequency and urgency than normal persons.(25) Fibromyalgia

may also be associated with other genitourinary conditions such as

interstitial cystitis, vulvar vestibulitis or vulvodynia (which are

characterized by dyspareunia and sensitivity of the vulvar region).

(26)(27)

AFFECTIVE DISORDERS

Patients with fibromyalgia have a higher incidence of psychiatric

disorders, including current and lifetime major depression (20

percent and 50 percent, respectively).

Considerable controversy surrounds the relationship between these

psychiatric conditions and the concurrent physical symptoms. Some

believe that fibromyalgia is primarily a psychiatric condition and

that the related symptoms are the result of somatization, whereas

others believe that psychiatric problems largely occur as a

consequence of the chronic pain, fatigue and disability that these

patients have. This debate becomes less relevant if the psychiatric

disturbances are considered in the same light as physical symptoms

in that there is a common neurotransmitter or hormonal imbalance

responsible, and thus both occur in increased frequency in patients

with fibromyalgia.

Diagnosis

Fibromyalgia can occur either in an isolated form (formerly

termed " primary " fibromyalgia) or in association with other diseases

(formerly termed " secondary " fibromyalgia). Table 2 lists conditions

that may mimic fibromyalgia or that may occur in association with

the syndrome. In many cases a triggering event can be identified,

such as physical or emotional trauma or infection. Even in cases in

which the full-blown syndrome develops after a triggering event, a

premorbid history frequently suggests a high lifetime incidence of

related conditions. This fact, in addition to studies suggesting

familial aggregation of fibromyalgia and associated syndromes,(28)

suggests that there may be a genetic tendency toward the development

of this disorder, which may express itself following an inciting

event either in childhood or later.

TABLE 2 Conditions Simulating or Associated with Fibromyalgia

Rheumatic

Early rheumatoid arthritis(*) Lymphoma

Polymyalgia rheumatica(*) Multiple Myeloma

Systemic lupus erythematosus Carcinomatosis

Sjogren's syndrome Neoplastic

Polymyositis/dermatomyositis Paget's disease

Scleroderma Osteomalacia

Endocrine/metabolic Hypokalemia

Hypothyroidism(*) Alcoholic or matabolic myopathy

Hyperparathyroidism Hyperpcalcemia

Hypoparathyroidism

Infectious Viral Hepatitis

Human immunodeficiency virus infection

Parasitic infections

Subacute bacterial endocarditis

(*)--This disorder should always be excluded because of similarity

of clinical features.

The conditions listed in Table 2 should be considered in the

differential diagnosis when a patient presents with symptoms

suggestive of fibromyalgia. In general, a supportive history and a

physical examination that is normal except for the presence of

tender points are strongly suggestive of the diagnosis.

Initial screening laboratory tests should include a complete blood

count with differential, a chemistry and thyroid panel, and an

erythrocyte sedimentation rate. Further testing (tests for

antinuclear antibody and rheumatoid factor, or imaging studies such

as magnetic resonance imaging MRI ) should be avoided initially

unless specifically indicated, not only because of the associated

expense but because these tests are associated with false-positive

results.

It must be emphasized that it is common for fibromyalgia to coexist

with other disorders. However, caution is urged before attributing

the patient's symptoms to another coexisting disorder. For example,

even if a patient is found to have abnormalities on skeletal MRI or

plain radiographs, or if evidence of an inflammatory disorder

(systemic lupus erythematosus, rheumatoid arthritis, Lyme disease)

is found, fibromyalgia may be responsible for the majority of the

symptoms.

Pathophysiology

Although the pathogenesis of fibromyalgia remains elusive, a review

of the current knowledge may facilitate a better understanding of

this disorder. Table 3 outlines the most pertinent neurotransmitter,

hormonal and biochemical abnormalities in fibromyalgia. Insulin-like

growth factor I (IGF I/somatomedin C) is a hormone produced in the

liver, primarily in response to growth hormone. Most patients with

fibromyalgia have low serum levels of IGF I, and this test has good

specificity and sensitivity in detecting fibromyalgia.(29)

TABLE 3 Hormonal, Neurotransmitter, and Biochemical Abnormalities in

Fibromyalgia

Test Abnormality Sensitivity Specificity

Serum insulin-like growth

factor I Low High Moderate

Cerebrospinal fluid substance

P High High ?

Serum serotonin Low Moderate Low

Serum tryptophan Low Moderate Low

Tissue magnesium Low High ?

Hypothalamic-pituitary-adrenal

axis Deranged Low Low

Substance P is a neuropeptide stored in the secretory granules of

sensory nerves and is released by axonal stimulation. Cerebrospinal

fluid levels of substance P are quite high in patients with

fibromyalgia, with little overlap between the levels seen in these

patients and levels seen in normal control subjects. Serum levels of

serotonin and its precursor, tryptophan, are low in persons with

fibromyalgia.(30)(31)

The hypothesis that low levels of serotonin may be responsible for

fibromyalgia is intriguing because many of the associated

conditions, including affective disorders, migraine headaches and

irritable bowel syndrome, are known or thought to be due to low

levels of serotonin. Low tissue levels of magnesium in fibromyalgia

(despite normal serum levels) have been demonstrated,(32) and the

efficacy of magnesium repletion is currently being tested.

Abnormalities of the hypothalamic-pituitary-adrenal axis are seen in

fibromyalgia and are likely responsible for the low IGF I noted, but

these abnormalities are also seen in a number of other disorders,

making the significance of this finding uncertain.(33)

The data suggest that objective hormonal, biochemical and

neurotransmitter abnormalities can be identified in patients with

fibromyalgia. Which of these abnormalities are causal and which

are " epiphenomena " is not clear at present. Although these tests

should not be used for screening purposes, many of them compare

favorably with commonly ordered tests such as rheumatoid factor,

which has a sensitivity of 80 percent and a comparable specificity

for the diagnosis of rheumatoid arthritis.

Management

Without an effective management plan, care for patients with

fibromyalgia can be frustrating and time-consuming. With an

effective management plan, clinicians can have a considerable

positive impact on patients with fibromyalgia.

EDUCATION

At initial diagnosis the physician and patient must discuss the

symptoms of fibromyalgia in depth. The physician should explain to

the patient that death or organ or tissue damage will not occur as a

result of this condition, but that there is no known cure and that

the condition is likely to be chronic with a fluctuating course.

Patients should be encouraged to take an active role in management

of their condition. A passive approach by the patient is rarely

successful in this disorder. A number of excellent pamphlets are

available for patient education, including one from the Arthritis

Foundation, 1314 Spring St. NW, Atlanta, GA 30309, or call 404-872-

7100.

BEHAVIOR MODIFICATION

Some simple suggestions may make a tremendous difference for

patients with fibromyalgia. The physician should emphasize the

importance of sleep. Some patients chronically attempt to subsist on

less sleep than their body requires, and pointing this out can be

helpful. Patients should be informed that consumption of caffeinated

or alcoholic beverages near bedtime may aggravate fibromyalgia

because deep sleep is impaired.

Emotional stress should be minimized. More formal behavioral

modification such as pain programs may also be helpful, especially

programs focusing on time-based pacing skills (many patients will do

so much on a " good " day that they hurt for several days thereafter),

scheduling pleasant activities that can act as distractors from

chronic pain, or cognitive therapy to decrease victimization

or " learned-helplessness " behavior.

PHARMACOLOGIC THERAPY

Drugs for the treatment of fibromyalgia that have been studied most

are low nighttime doses of the tricyclic compounds amitriptyline

(Elavil, Endep) and cyclobenzaprine (Flexeril). Although it is

sometimes helpful to explain to patients that the clinical benefit

from these drugs occurs as a result of improved deep sleep, this is

not likely the reason that they are effective, since improvement in

sleep status with these medications does not correlate with clinical

improvement. With either of these medications, the starting dose

should be 10 mg one to two hours before bedtime (or in patients who

have had adverse reactions to many medications, perhaps half of a 10-

mg tablet). This dose should be continued for at least one week

before it is increased by 10 mg.

The physician should explain that the first several nights that this

medication is taken, or whenever the dose is increased, the patient

is likely to have vivid dreams or nightmares, will need more than

the usual amount of sleep and may feel " hungover " the following day

(it is sometimes useful to suggest that medication be initiated on a

Friday evening for this reason). It should also be explained that

the improvement as a result of these medications may not occur for

four to six weeks.

Titration to the optimal dose is difficult. It is sometimes useful

to use the sleep cycle to make this determination, with the goal

being to identify the dose of either medication that is necessary to

keep the patient sleeping soundly throughout the night but

not " hungover. " This dose may be increased up to a maximum of 70 to

80 mg of amitriptyline or up to 40 mg of cyclobenzaprine.

Anticholinergic side effects occur with either of these medications

and, if one medication is not well tolerated, the patient may

respond to the other. Nonsteroidal anti-inflammatory drugs may be

useful in this condition. However, if an empiric trial of a few

drugs from this class is ineffective, then they probably should be

discontinued.

The selective serotonin reuptake inhibitors fluoxetine (Prozac),

sertraline (Zoloft) and paroxetine (Paxil), as well as venlafaxine

(Effexor), may also be of benefit in selected patients. It is

possible that patients with concurrent depression may respond best

to this class of drugs. Also, in patients who cannot tolerate

therapeutic doses of a tricyclic compound, occasionally the addition

of a selective serotonin reuptake inhibitor in a low dose may be of

benefit.

Benzodiazepines and narcotics should be avoided if possible in

patients with fibromyalgia, not only because of the associated

addictive potential but also because of the detrimental effect on

deep sleep. If a hypnotic agent must be used, zolpidem (Ambien) may

be a reasonable choice since it does not appear to impair deep sleep.

EXERCISE

It is helpful to explain that exercise is vital to improvement of

symptoms of fibromyalgia, since it is rare for patients to have a

lasting improvement unless they become involved in an aggressive

program of low-impact aerobic and stretching exercises. Although

exercise can be done with the help of a physical therapist,

psychologically it may be useful to avoid using a therapist and

encourage independence. Low impact aerobic exercises such as water

exercise classes, stationary bicycling, rowing machines or cross-

country skiing machines can be used. The patient should be

instructed to begin at the level of exercise that results in mild

tenderness on the following day, but no more. This level should be

slowly and gradually increased, and the patient should be instructed

that it may take several months until a benefit is seen.

OTHER MODALITIES

Injections of tender points with a topical anesthetic, either alone

or in combination with corticosteroids, may be of benefit,

especially when one region is particularly bothersome. Biofeedback,

acupuncture, massage therapy and spinal manipulation may all be of

benefit in selected patients.

Final Comment

Fibromyalgia is a common condition. Although the syndrome is defined

by its musculoskeletal features, virtually any area of the body may

be affected. If the conventional paradigm for the clinical

expression of fibromyalgia is represented in Figure 1, Figure 2

represents a new paradigm. This disease causes decreased pain

tolerance throughout the body, rather than only at tender points,

and patients with fibromyalgia display a higher incidence of a

number of other symptoms and syndromes than normal persons. Most of

these allied conditions are characterized by dysmotility or abnormal

tone in skeletal or smooth muscle and by increased peripheral or

visceral nociception. A number of objective biochemical, hormonal

and other abnormalities have been identified in patients with

fibromyalgia, and it is likely that this syndrome and associated

conditions, including affective disorders, have common centrally

mediated causes. Although this condition has no cure, prompt

recognition and proper management often lead to substantial

symptomatic improvement.

REFERENCES

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BMJ 1989; 298:474-5.

(2.)Goldenberg DL. Fibromyalgia, chronic fatigue syndrome, and

myofascial pain syndrome. Curr Opin Rheumatol 1993; 5:199-208.

(3.)Wolfe F, Smythe HA, Yunus MB, RM, Bombardier C,

Goldenberg DL, et al. The American College of Rheumatology 1990

Criteria for the Classification of Fibromyalgia. Report of the

Multicenter Criteria Committee. Arthritis Rheum 1990; 33:160-72.

(4.)Wolfe F, Ross K, J, IJ. The prevalence

andcharacteristics of fibromyalgia in the general population

Abstract. Arthritis Rheum 1993; 36(Suppl):48.

(5.)Silman A, Schollum J, Croft P. The epidemiology of tender point

counts in the general population Abstract . Arthritis Rheum 1993; 36

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(6.)Forseth KO, Gran JT. The prevalence of fibromyalgia among women

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(7.)Buskila D, Press J, Gedalia A, Klein M, Neumann L, Boehm R, et

al. Assessment of nonarticular tenderness and prevalence of

fibromyalgia in children. J Rheumatol 1993; 20:368-70.

(8.)Prescott E, sen S, Kjoller M, Bulow PM, Danneskiold-Samsoe

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(9.)Raspe H, Baumgartner C, Wolfe F. The prevalence of fibromyalgia

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(10.)Granges G, Littlejohn G. Pressure pain threshold in pain-free

subjects, in patients with chronic regional pain syndromes, and in

patients with fibromyalgia syndrome. Arthritis Rheum 1993; 36:642-6.

(11.)Whitehead WE, Holtkotter B, Enck P. Tolerance for rectosigmoid

distension in irritable bowel syndrome. Gastroenterology 1990;

98:1187-92.

(12.)Hiltz RE, Gupta PK, Maher KA, Blank CA, SB, Katz P, et

al. Low threshold of visceral nociception and significant objective

upper gastrointestinal pathology in patients with fibromyalgia

syndrome. Arthritis Rheum 1993; 36(Suppl):203.

(13.)Granges G, Littlejohn GO. A comparative study of clinical signs

in fibromyalgia/fibrositis syndrome, healthy and exercising

subjects. J Rheumatol 1993; 20:344-51.

(14.)May KP, West SG, Baker MR, Everett DW. Sleep apnea in male

patients with the fibromyalgia syndrome. Am J Med 1993; 94:505-8.

(15.)Moldofsky H, Scarisbrick P. Induction of neurasthenic

musculoskeletal pain syndrome by selective sleep stage deprivation.

Psychosom Med 1976; 38:35-44.

(16.)Doherty M, J. Elusive 'alpha-delta' sleep in fibromyalgia

and osteoarthritis Letter . Ann Rheum Dis 1993; 52:245.

(17.)Reynolds WJ, Moldofsky H, Saskin P, Lue FA. The effects of

cyclobenzaprine on sleep physiology and symptoms in patients with

fibromyalgia. J Rheumatol 1991; 18:452-4.

(18.)Alvarez Lario B, Teran J, Alonso JL, Alegre J, Arroyo I, Viejo

JL. Lack of association between fibromyalgia and sleep apnoea

syndrome. Ann Rheum Dis 1992; 51:108-11.

(19.) Simms RW, Goldenberg DL. Symptoms mimicking neurologic

disorders in fibromyalgia syndrome. J Rheumatol 1988; 15:1271-3.

(20.)Rosenhall U, Johansson G, Orndahl G. Eye motility dysfunction

in chronic primary fibromyalgia with dysesthesia. Scand J Rehabil

Med 1987; 19:139-45.

(21.)Gerster JC, Hadj-Djilani A. Hearing and vestibular

abnormalities in primary fibrositis syndrome. J Rheumatol 1984;

11:678-80.

(22.)Cleveland CH Jr, Fisher RH, Brestel EP, Esinhart JD, Metzger

WJ. Chronic rhinitis: an underrecognized association with

fibromyalgia. Allergy Proc 1992; 13:263-7.

(23.)Lurie M, Caidahl K, Johansson G, Bake B. Respiratory function

in chronic primary fibromyalgia. Scand J Rehabil Med 1990; 22:151-5.

(24.)Pellegrino MJ, Van Fossen D, Gordon C, JM, Waylonis GW.

Prevalence of mitral valve prolapse in primary fibromyalgia: a pilot

investigation. Arch Phys Med Rehabil 1989; 70:541-3.

(25.)Wallace DJ. Genitourinary manifestations of fibrositis: an

increased association with the female urethral syndrome. J Rheumatol

1990; 17:238-9.

(26.)Koziol JA, DC, Gittes RF, Tan EM. The natural history of

interstitial cystitis: a survey of 374 patients. J Urology 1993;

149:465-9.

(27.)Friedrich EG Jr. Vulvar vestibulitis syndrome. J Reprod Med

1987; 32:110-4. (28.)Stormorken H, Brosstad F. Fibromyalgia: family

clustering and sensory urgency with early onset indicate genetic

predisposition and thus a " true " disease Letter . Scand J Rheumatol

1992; 21:2 Published erratum appears in Scand J Rheumatol 1992;

21:264].

(29.) RM, SR, SM, Burckhardt CS. Low levels of

somatomedin C in patients with the fibromyalgia syndrome. A possible

link between sleep and muscle pain. Arthritis Rheum 1992; 35:1113-6.

(30.)Yunus MB, Dailey JW, Aldag JC, Masi AT, Jobe PC. Plasm

tryptophan and other amino acids in primary fibromyalgia: a

controlled study. J Rheumatol 1992; 19:90-4.

(31.) IJ, Michalek JE, Vipraio GA, Fletcher EM, Javors MA,

Bowden CA. Platelet 3H-imipramine uptake receptor density and serum

serotonin levels in patients with fibromyalgia/fibrositis syndrome.

J Rheumatol 1992; 19:104-9.

(32.)Clauw D, Blank CA, Hewett-Meulman J, Katz P. Low tissue levels

of magnesium in fibromyalgia Abstract . Arthritis Rheum 1993; 36

(Suppl):161.

(33.)Griep EN, Boersma JW, de Kloet ER. Altered reactivity of the

hypothalamic-pituitary-adrenal axis in the primary fibromyalgi

syndrome. J Rheumatol 1993; 20:469-74.

__________________________________________________________________

Message: 21

Breast Implant Chronology

Chronology of Silicone Breast Implants

Japanese prostitutes have their breasts injected with substances

such as paraffin, sponges and non-medical grade silicone to enlarge

their breasts, believing that American servicemen favor women with

large breasts. The first silicone breast implants are developed by

two plastic surgeons from Texas: Gerow and Cronin.

Timmie Lindsey becomes the first woman to receive silicone

breast implants.

The Food and Drug Administration enacts the Medical Devices

Amendment to the Federal Food, Drug and Cosmetic Act. FDA now has

the authority to review and approve the safety and effectiveness

data of new medical devices. But since silicone breast implants have

been on the market for almost 15 years, they are " grandfathered " .

Manufacturers of the implants, when called to do so by the FDA, will

be required to provide safety and effectiveness data.

Mithoff, a Houston attorney, wins the first lawsuit for a

Cleveland woman who claims that her ruptured implants and subsequent

operations had caused pain and suffering. She receives a $170,000

settlement from Dow Corning. Case receives little publicity.

Ralph Nader's Public Citizen Health Research Group, Washington, D.C.

sends out warning signals that silicone breast implants cause cancer.

January 1982

FDA proposes to classify silicone breast implants into a Class III

category which would require manufacturers to prove their safety in

order to keep them on the market.

Stern vs Dow Corning, San Francisco. Case wins on many internal Dow

Corning documents that had been discovered in a Dow storage area by

attorney Dan Bolton . Stern's systemic autoimmune disease is

found by a jury to be caused by her silicone breast implants. Bolton

introduces the silicone-induced problems for the first time in

court, with " experts " that theorize the silicone-immune system

connection. After a month long trial, the jury awards Stern

$211,000 in compensatory damages and $1.5 million in punitive

damages. The evidence is sealed by a court order.

June 1988

Six years after the 1982 proposal, FDA classifies the implants into

Class III. Premarket Approval Applications from silicone breast

implant manufacturers are due by July 1991. The PMA's must prove

affirmatively, with valid scientific data evaluated by

the FDA, that their devices are safe and effective. After the PMA's

are submitted by the manufacturers, the FDA has 180 days to evaluate

the safety data.

Dec 1990

Program on the dangers of silicone breast implants airs on " Face to

Face with Connie Chung " .

Dec 1990

Congressional hearing headed by Representative Ted Weiss deals with

the safety of silicone breast implants. This hearing also discusses

the fact that not all the information that the manufacturers have

are available for public scrutiny due to a court order from the

Stern verdict.

July 1991

Dow Corning releases 329 studies to FDA.

July 1991

Toole vs Baxter, Alabama. Jury decides against Baxter/Heyer-Shulte

and awards the largest settlement so far, $5.4 million, to

Toole. Toole, who shows only preliminary symptoms of systemic

autoimmune problems, nevertheless had silicone in her lymphatic

system according to plaintiffs' witnesses and thus an increased risk

of developing an autoimmune disease.

Sep 1991

FDA concludes that the silicone breast implant manufacturers' safety

data does not prove the devices are safe--or harmful. Manufacturers

are told to submit further data.

Nov 1991

The FDA brings together its General and Plastic Surgery Devices

Panel to review all of the safety data from the manufacturers'

PMA's. The purpose of the panel is to advise FDA as to what they

could tell the public about the safety and effectiveness of the

silicone breast implants based on the PMA's. The panel is composed

of a broad range of experts, including representatives from the

fields of plastic surgery, oncology, epidemiology, internal

medicine, immunology, radiology, pathology, gynecology, toxicology,

sociology, biomaterials and psychology, as well as industry and

consumer groups. The panel hearing rejects the data from Dow

Corning, Mentor, McGhan, and Bioplasty, concluding there is not

sufficient data about the risks and benefits of the devices. The

panel recommends the devices stay on the market temporarily and with

limited access. The need for more safety data is stressed.

Dec 1991

Hopkins vs Dow Corning, San Francisco. The largest award yet, $7.3

million, is given to nn Hopkins whose mixed connective-tissue

disease is linked to her ruptured silicone breast implants. The

lawyer for the case, Dan Bolton, wins the suit with the help of

internal memos and studies from the Stern lawsuit,in addition to new

studies he recently obtained from Dow. Mr. Bolton gives several of

the internal documents to the FDA which has never seen the documents

before.

Dec 1991

To date, 137 individual lawsuits have been filed against Dow Corning.

January 1992

FDA Commissioner, Kessler, calls for a voluntary

http://www.fda.gov//bbs/topics/NEWS/NEW00263.html

moratorium on the distribution or implantation of silicone breast

implants until the FDA and the advisory panel have an opportunity to

consider newly-available information. The manufacturers agree.

Feb 1992

The class action lawsuit is filed in Cincinnati

by " legal/lawyersbios.html#1 " Stan Chesley. The hope is to

compensate women at a faster rate than filing individual lawsuits.

Feb 1992

Dow Corning CEO, Lawrence , is replaced by McKennon.

Feb 1992

The General and Plastic Surgery Devices Panel reconvenes to review

the new information regarding the safety of silicone breast

implants. The panel recommends that the further use of implants be

limited for reconstruction only and that women receiving the

implants participate in scientific protocols and that epidemiologic

studies be conducted to assess the risk of autoimmune disease. The

panel concludes that no causal link has been established between

autoimmune disease and silicone breast implants.

Feb 1992

Many of the Dow Corning internal memos are released to the public.

March 1992

Dow Corning leaves the silicone breast implant business as do

Bristol-Myers Squibb and Bioplasty. McGhan and Mentor will still

manufacture breast implants. Dow sets up a fund for further research

into the safety of breast implants.

April 1992

Dr. Kessler lifts the moratorium on silicone breast implants. The

only women allowed to receive implant surgery are those undergoing

breast reconstruction. All of the implant recipients must become

part of a scientific protocol.

May 1992

First woman gets implants under new rules.

Dec 1992

vs Bristol-Myers Squibb, Houston. Pamela wins

$25 million, $5 million actual damages and $20 million punitive

damages in a case argued by Texas

attorney " legal/lawyersbios.html#2 " O'Quinn. A jury finds Ms.

's ruptured silicone implants were linked to her mixed

connective tissue disease, auto-immune responses, chronic fatigue,

muscle pain, joint pain, headaches, and dizziness. Expert witnesses

and lawyers admit her symptoms amount to " a bad flu. "

Dec 1992

To date 3,558 individual lawsuits have been filed against Dow

Corning.

June 1993

Dick Hazleton becomes CEO of Dow Corning.

Dec 1993

By year's end 12,359 individual lawsuits have been filed against Dow

Corning.

March 1994

A Houston jury awards three women a total of $27.9 million against

3M, $15 million in punitive, $12 million in compensatory damages for

illness. The lawyer arguing the case against 3M is O'Quinn. The

three women suffered from either atypical lupus, neurological

impairment, and a " silicone induced " autoimmune problem.

March 1994

The class action suit is finalized by manufacturers with Dow Corning

being the largest contributor. The other contributors include

Baxter, Bristol-Myers Squibb/MEC, 3M. It is the largest class action

settlement in history. Manufacturers laim there is no scientific

evidence linking silicone breast implants with autoimmune diseases.

There are set monetary amounts that will be awarded to women with

specific medical conditions. No requirements are needed to prove

implants are the cause of their ailments. Women will be allowed to

drop out of the settlement. Companies can also opt out if too few

women register claims.

April 1994

Preliminary approval to class action by Judge Pointer. Clears the

way for women to start applying for claims in the settlement.

June 1994

The Mayo Clinic epidemiologic study is published in the New England

Journal of Medicine, which finds no increased risk of connective-

tissue disease and other disorders that were studied in women with

silicone implants.

Sep 1994

Final approval of class action/global settlement from Judge Pointer.

Dec 1994

By this date 19,092 individual lawsuits have been filed against Dow

Corning.

Feb 1995

Gladys Laas vs Dow Corning.

May 1995

Dow Corning files for Chapter 11 bankruptcy. Dow is facing 20,000

lawsuits, some with multiple plaintiffs and about 410,000 potential

claims that have been filed in the global settlement. The bankruptcy

essentially halts all litigation.

June 1995

About 440,000 women have registered in the global settlement. About

70,000 can be immediately compensated.

June 1995

The Harvard Nurses Epidemiologic Study is published in the New

England Journal of Medicine. This finds no increased risk of

connective-tissue disease or certain signs and symptoms of

connective-tissue disease in women with silicone implants.

Oct 1995

Mahlum vs Dow Chemical, Reno. This is the first case where Dow

Chemical, the parent company of Dow Corning, is the sole defendant.

Charlotte Mahlum is awarded $3.9 million in compensatory damages and

$10 million in punitive damages. About 13,000 breast implant

lawsuits are pending against Dow Chemical.

Nov 1995

New global settlement is devised minus Dow Corning. Bristol-Myers

Squibb, Baxter and 3M are the participants. The monetary awards are

less than the previous settlement.

Dec 1995

By now 15 individual lawsuits against Dow Corning have gone to trial

involving some 19 plaintiffs. Of these, Dow Corning have had 8

trial " wins " and 6 trial " losses " , with one split decision.

Dec 1995

By now more than 20 (non-case report) studies and abstracts have

come out in the U.S. and internationally, all failing to support a

causal relationship between silicone implants and a variety of auto-

immune related illnesses.

WGBH Educational Foundation

http://www.wgbh.org

__________________________________________________________________

Message: 22

Ethylene Oxide

Ethylene oxide (ETO) has been used routinely to sterilize silicone

gel and PUF (polyurethane foam) implants. A 1988 FDA audit of

Surgical revealed a wide range of deficiencies in control procedures

particularly relating to ETO residues. These included the absence of

validated and formalized procedures for methods for sterilization

and aeration, the absence of established residue limits,and failure

to test for residues of ETO. Such concerns are particularly

significant because these residues-ranging up to 443 mg/kg are known

to persist on medical products,including plastics, even after 7 days

aeration. FDA tolerances for implants are 250 ppm. Other products

are also known to retain measurable levels of ETO several months

after fumigation.

Source: Internation Journal of Occupational Medicine and Toxicology

Vol.4, No.3, 1995

Author: Dr. Epstein

__________________________________________________________________

Message: 23

RELATED ARTICLE: Fibromyalgia: What It Is and How to Manage It What

is fibromyalgia?

Fibromyalgia is a common condition that causes pain in the muscles,

joints, ligaments and tendons. The pain occurs in certain parts of

the body, and these painful areas are called tender points. The

drawing below shows areas where tender points are common.

Fibromyalgia affects 2% to 6% of the population, including children.

This disorder might be hereditary, so you may have family members

with similar symptoms.

How can my doctor tell that I have fibromyalgia? Increased

sensitivity to pain is the main symptom of fibromyalgia. Many other

symptoms also occur in patients with this disorder. Symptoms may

come and go. You may have some degree of constant pain, but the

severity ofpain may vary in response to activity, stress, weather

changes and other factors. You may have a deep ache or a burning

pain. You may have muscle tightening or spasms. Many patients have

migratory pain (pain that moves around the body).

Most people with fibromyalgia feel tired or out of energy. This

fatigue may be mild or very severe. You may also have trouble

sleeping, and this may add to the fatigue. You may have feelings of

numbness or tingling in parts of your body, or a sensation of poor

blood flow in some areas. Many patients are very sensitive to odors,

bright lights, loud noises and even medicines. Headaches and jaw

pain are also common. In addition, you may have dry eyes or

difficulty focusing on nearby objects. Problems with dizziness and

balance may also occur. Some patients have chest pain, heart

palpitations, or shortness of breath.

Digestive symptoms are also common in fibromyalgia and include

difficulty swallowing, heartburn, gas, cramping, abdominal pain, and

alternating diarrhea and constipation. Some patients have urinary

complaints, including frequent urination, a strong urge to urinate

and pain in the bladder area. Women with fibromyalgia often have

pelvic symptoms, including pelvic pain, painful menstrual periods,

and painful sexual intercourse.

Depression or anxiety may occur as a result of the chronic pain and

fatigue, or the frustration you feel with the condition. It is also

possible that the same chemical imbalances in the brain that are

responsible for fibromyalgia might also cause depression and anxiety.

Although fibromyalgia causes symptoms that can be veryuncomfortable,

your muscles and organs are not being damaged. This condition is not

life-threatening, but it is chronic, or ongoing. There is no cure,

but you can do many things to help you feel better. Is there any

medicine I can take to help my symptoms?

Several medicines can help relieve symptoms of fibromyalgia. Many of

these medicines (such as amitriptyline Elavil, Endep or

cyclobenzaprine Flexeril ) are taken before bedtime and improve your

sleep. They also help the pain and other symptoms. When you begin

taking these medicines, it is common to feel very groggy the

following morning. Other possible side effects include dry eyes and

mouth, nightmares, constipation and increased appetite. These side

effects are worse when you first begin taking the medicine and

improve with time. You will probably begin to notice the benefits of

these medicines in about six to eight weeks.

What else can I do to relieve my symptoms?

One of the most effective treatments for fibromyalgia is low-impact

aerobic exercise. Examples of this type of exercise include swimming

or water exercise, stationary bicycling and exercising on ski-type

machines. You may need to begin at a very low level of exercise

(five minutes every other day is helpful at first). Continue to

increase the length and frequency of exercise until you are

exercising at least 20 to 30 minutes on at least four occasions per

week. Once you reach this point, you can consider switching to high-

impact exercises, like walking, jogging and tennis.

The symptoms of fibromyalgia are made worse by stress and poor

sleep. It is important to cut stress out of your life whenever

possible and to get as much sleep as your body needs. Since alcohol

and caffeine cause poor sleep quality, try to avoid these substances

near bedtime.

Other simple lifestyle changes may be helpful. Many people with

fibromyalgia try to do as much as possible on " good " days, which

leads them to have several " bad " days. If you keep your activity

level even, you may not have as many bad days. In many cities, there

are fibromyalgia patient groups that can provide both information

and support. The Arthritis Foundation also has some information you

may be interested in reading. In addition, a national fibromyalgia

support group publishes a newsletter on this disorder. For more

information, contact the Fibromyalgia Network Newsletter, P.O. Box

31750, Tucson, AZ 85751, or call 602-290-5508.

This information provides a general overview on fibromyalgia and may

not apply to everyone. Talk to your family doctor to find out if

this information applies to you and to get more information on this

subject.

1 Helliwell P S in ls of the Rheum 11/95 The semeiology of

arthritis:

2 Clauw J in American Family Phy 09/01/95 Fibromyalgia: more

than just a musculoskeletal disease

3 Wallace J in The New England Jou 08/31/95 The Fibromyalgia

Syndrome: Current Research

4 Brown Randy in Physical Therapy 08/95 Myofascial Pain and

Fibromyalgia: Trigger Point

5 Ehrlich E in JAMA, The Journal of 07/26/95 Myofascial Pain

and Fibromyalgia: Trigger Point

6 Lorin in Patient Care 07/15/95 Bad back and poor vision:

what's the connection

7 Alarcon Graciela S in JAMA, The Journal o 06/07/95 Rheumatology.

(Contempo 1995)

__________________________________________________________________

Message: 24

Experimental Evidence On The Carcinogenicity Of Silicone Gel and

Polyurethane Foam Implants:

Silicone Gel:

In August of 1987, FDA was presented with the results of a 2 yr.rat

bioassay conducted by Dow Corning. Two gels used to fill breast

implants were tested to assess the long-term biocompatibility of

silicone. The dose used in the rat study was adjusted to be

equivalent per relative body weight to the amount of gel used in

humans who undergo augmentaion mammaplasty. The data from the study

indicated that the silicone gels implanted subcutaneously in rats

induced pronounced increases in the incidence of fibrosarcoma at the

implant site, compared to the control. Of additonal concern was the

fact that metastasis was recorded in a number of those animals.

The 2 yr.rat carcinogenicity study which was done by Dow Corning to

see if silicone gel caused cancer involved 3 groups of animals, each

with 50 males and 50 females. The first group,the controls,developed

no malignant fibrosarcoma tumors similar to the ones seen in the

silicone-treated animals. The second group was implanted with a

silicone gel used before 1976 and 20% of the females and 22% of the

males developed fibrosarcomas at the injection site. More

disturbing, 21% of the animals with these tumors had evidence of

metastases, including spread to lungs, kidney, adrenal, skin,

thymus, and liver. The third group was implanted with the silicone

gel currently in use, and in this group 23% of the females and 26%

of the males developed gel-associated fibrosarcomas, with 18% of

those animals with sarcomas having metastases to distant organs.

The induction of sarcomas in 25% of test animals is a very important

observation as it is lethal in 85% of the sarcomatous animals. This

should be viewed in the context that sufficient time has not elapsed

to record an epidemiologically significant increase in human

malignancies.

The sarcomas in the rat study are at variance with several classical

characteristics of solid-state tumor. They are highly metatastic,

lethal, and show no variation between sexes.

It was concluded that while there is no direct proof that silicone

causes cancers in humans, there is considerable reason to suspect

that it can do so. For these reasons, a senior staff scientist on

the FDA Task Force reviewing the carcinogenicity data urged that: " A

medical alert should be issued to warn the public of the possibility

of malignancy development in humans following long-term implant of

silicone breast prostheses "

Source: International Journal of Occupational Medicine and

Toxicology. 1995 Author: Dr. Epstein