Download Report

Pretibial myxedema (elephantiasic
form): treatment with cytotoxic therapy
C. William H a n k e , M.D. 1 2
Wilma F. Bergfeld, M.D. 1
Marcelle N. Guirguis, M.D. 1
L . J a m e s Lewis, Ph.D. 3
progressive and is refractory to treatment. Patients are uncomfortable with their thickened,
weighty legs and feet a n d have trouble walking.
T h e wearing of shoes, stockings, a n d slacks may
become nearly impossible. W e describe o u r experience in treating a patient with a particularly
advanced case of elephantiasic P T M .
O n e of the f o u r major components of Graves' disease, pretibial m y x e d e m a (PTM), occurs in approximately 0.5% to 4.3% o f patients with ophthalmic goiter
and is o f t e n s e e n f o l l o w i n g treatment of the goiter. A n
advanced case o f elephantiasic P T M is reported.
Index terms: Elephantiasis • Goiter • Graves' disease
Cleve Clin Q 5 0 : 1 8 3 - 1 8 8 , S u m m e r 1983
Case report
Pretibial myxedema (PTM) is one of the f o u r
major components of Graves' disease. 1 T h e o t h e r
three components are ophthalmopathy, hyperthyroidism caused by diffuse goiter, and the presence of a b n o r m a l serum levels of long-acting
thyroid stimulator (LATS). Lynch et al 1 believed
that a diagnosis of Graves' disease could be m a d e
when at least two of the f o u r components were
present.
T h e incidence of P T M in Graves' disease is
0 . 5 % - 4 . 3 % . 2 - 4 T h e clinical lesions of P T M usually appear as skin-colored or erythematous
plaques or nodules on t h e lower legs. Mild cases
may resolve spontaneously, and little if any treatment is indicated. 4 , 3 More severe elephantiasic
forms of P T M have occasionally been reported. 4 , 6 , 7 T h e s e cases usually are associated
with ophthalmic goiter a n d often occur following
treatment of t h e goiter. 5
T h e severe elephantiasic f o r m of P T M is o f t e n
A 44-year-old man with malignant exophthalmos, thyrotoxic goiter, a n d P T M was seen in N o v e m b e r 1973. H e was
treated with radioactive iodine in N o v e m b e r 1974 a n d
F e b r u a r y 1975. Multiple ocular decompression p r o c e d u r e s
were p e r f o r m e d in 1974 a n d 1975. T h e patient was r e f e r r e d
to t h e Cleveland Clinic in O c t o b e r 1 9 7 5 f o r progressive
elephantiasic e n l a r g e m e n t of both lower extremities. Examination at that time revealed severe e x o p h t h a l m o s o f
both eyes (Fig. 1) and m a r k e d e n l a r g e m e n t of b o t h legs (Fig.
2), t h e dorsal aspect of the feet, a n d toes (Fig. 3). T h e skin
on the legs h a d a verrucous a p p e a r a n c e with multiple b r o w n ish r e d nodules s u r r o u n d e d by d e e p fissures. T h e skin
a r o u n d the ankles was thickly folded. Skin biopsy specimens
were o b t a i n e d f r o m the v e r r u c o u s pretibial areas as well as
the normal-appearing skin o n the e x t e n s o r f o r e a r m a n d
u p p e r eyelid. T h e biopsy sites on the f o r e a r m left shiny
pinkish brown nodules a f t e r healing (Fig. 4).
Laboratory studies. Most laboratory values were n o r m a l .
Results of a liver biopsy w e r e also n o r m a l . T h e effective
thyroxine ratio was 1.02, which indicated a n o r m a l thyroid.
H o w e v e r , an abnormal 7S g a m m a globulin was identified
on serum protein electrophoresis. An assay f o r L A T S by
the m o u s e bioassay m e t h o d revealed a 1750% increase
(normal, 8 0 % - 1 2 0 % ) .
Histopalhology. Skin biopsy specimens f r o m the pretibial
areas showed hyperkeratosis, irregular acanthosis, a n d a
white material replacing m u c h of the reticular d e r m i s in a
band-like fashion (Fig. 5). A colloidal iron stain identified
t h e substance as acid mucopolysaccharide (Fig. 6). T h e
' D e p a r t m e n t of D e r m a t o l o g y , T h e C l e v e l a n d Clinic F o u n d a tion. S u b m i t t e d f o r p u b l i c a t i o n F e b 1983; a c c e p t e d M a r c h 1983.
2
Associate P r o f e s s o r , D e p a r t m e n t of D e r m a t o l o g y , I n d i a n a
School of Medicine, I n d i a n a p o l i s .
3
Deceased.
183
Downloaded from www.ccjm.org on September 9, 2014. For personal use only. All other uses require permission.
'184
Cleveland Clinic Q u a r t e r l y
Vol. 50, N o . 2
F i g u r e 3. N o d u l a r h y a l u r o n i c acid deposits on t h e dorsal aspect
of t h e toes associated with pretibial m y x e d e m a .
F i g u r e 4. H e a l e d skin biopsy sites on t h e f o r e a r m of a patient
with elephantiasic pretibial m y x e d e m a . T h e biopsy sites have h e a l e d
with scars t h a t a r e heavilv laden with hyaluronic acid.
Tissue culture studies
F i g u r e 1. Malignant e x o p h t h a l m o s with m a r k e d e d e m a of t h e
u p p e r eyelids.
F i g u r e 2. Elephantiasic e n l a r g e m e n t of legs in a patient with
pretibial m y x e d e m a .
material was digestible with hyaluronidase. Colloidal iron
stains on the biopsy specimens from normal-appearing skin
on the forearm and upper eyelid also showed moderate
mucin deposition between the collagen bundles. T h e mucin
was also digestible with hyaluronidase. A colloidal iron stain
on the liver biopsy specimen showed no mucin deposition.
Methods. Fibroblasts from the verrucous pretibial areas
were studied in tissue culture. Skin biopsy specimens were
dissected into small pieces with sterile scalpel blades and
implanted as explants into 25-ml flasks. PTM fibroblasts
were isolated and grown in conjunction with fibroblasts
from the pretibial area of normal control patients. T h e
fibroblasts were grown on modified LJL media enriched
with 10% fetal calf serum, which was changed every three
days. T h e fibroblasts were cultured for two weeks, trypsinized, and then deposited in 75-ml flasks. Fibroblasts from
the sixth to the tenth passage were used for the study.
T h e studies were conducted in 100-ml Petri dishes with
inoculum densities of 400,000 cells. T h e rates of growth of
the fibroblasts were compared. On the tenth day, the fibroblasts were extracted with 0.3N potassium hydroxide to
measure the deoxyribonucleic acid (DNA) and protein in
both PTM and the normal control fibroblasts. T h e effect of
antimitotic drugs on the growth rate of the fibroblasts was
studied by comparing the DNA and protein content of an
untreated group of PTM fibroblasts and a group treated
with the following cytotoxic drugs: melphalan (0.08 m g / L
of media), cyclophosphamide (20 m g / L of media), nitrogen
mustard (10 m g / L of media), and methotrexate (1 m g / L
of media). T h e concentrations were calculated according to
Downloaded from www.ccjm.org on September 9, 2014. For personal use only. All other uses require permission.
Summer 1983
Pretibial m y x e d e m a
185
F i g u r e 5. Skin biopsy f r o m ihe leg of a patient with pretibial m y x e d e m a , showing a gray-white material r e p l a c i n g t h e reticular d e r m i s .
T h e material was digestible with h y a l u r o n i d a s e (hematoxylin a n d eosin stain, XlO).
F i g u r e 6. Skin biopsy from t h e leg of a patient with pretibial m y x e d e m a . T h e blue material is hyaluronic acid (colloidal iron stain,
XlO).
standard clinical doses. A total blood volume of 5 L was
assumed.
T r e a t m e n t of the P T M fibroblasts with cytotoxic drugs
was started on the fourth day a f t e r implanting a n d was
continued f o r five days. On the tenth day, the fibroblasts
were extracted with 1.3 N potassium hydroxide to measure
the DNA a n d protein. Hyaluronic acid synthesis by P T M
fibroblasts a n d normal control fibroblasts was measured with
a modified carbazole reaction. 8 T h e effect of the cytotoxic
drugs on P T M fibroblasts was measured in a separate set of
Petri dishes. A n o t h e r set of Petri dishes was used for collagen extraction and estimation of hydroxyproline. 9 T h e fibroblast cultures were examined with phase-contrast microscopy. Some cultures were grown on cover slips and
stained with hematoxylin and eosin, Giemsa, and PAS.
Results. Results are shown in Table 1. P T M fibroblasts
treated with cytotoxic drugs showed a marked decrease in
D N A content c o m p a r e d with untreated P T M and normal
control fibroblasts. Melphalan caused the greatest reduction
in the a m o u n t of hyaluronic acid released. T h e P T M fibroblasts p r o d u c e d more hyaluronic acid than normal even
a f t e r t r e a t m e n t with each of the f o u r cytotoxic drugs. T h e r e
was n o statistically significant difference between the f o u r
drugs with r e g a r d to their effect on P T M fibroblasts. T h e
DNA-total protein ratio showed no statistically significant
change f r o m normal. Collagen was f o r m e d in a normal
T a b l e 1.
a m o u n t by P T M fibroblasts compared to normal control
fibroblasts (Table 2).
P T M fibroblasts were larger than normal and had larger
nuclei when examined with phase-contrast microscopy. A
peculiar vacuoladon of the fibroblasts not otherwise observed in vitro was present.
Clinical course. T h e patient u n d e r w e n t orbital decompression procedures for several months with reduction of the
bilateral exophthalmos. Daily leg pumpings and intralesional
steroids were administered to the dorsal aspect of the feet
and legs and resulted in temporary softening of the indurated verrucous areas. Topical steroids were not beneficial.
Excision and grafting of the extremely thickened skin was
considered too great a risk because the patient weighed
more than 300 pounds, and he showed little interest in
reducing his weight. In addition, surgery was contraindicated since unsuccessfully g r a f t e d areas of skin might have
left large areas of exposed tissue.
In view of the gradually worsening P T M with the continued appearance of new red verrucous nodules on the legs,
systemic chemotherapy was considered. In vitro studies had
shown that melphalan had the greatest cytotoxic effect on
the P T M fibroblasts; consequently, the d r u g was administered orally (8 m g / d a y ) for f o u r consecutive days. This
regimen was repeated monthly for six months. T h e diameters of the upper legs and ankles both decreased by 6 cm
H y a l u r o n i c acid s y n t h e s i s b y n o r m a l c o n t r o l f i b r o b l a s t s , P T M f i b r o b l a s t s , a n d P T M f i b r o b l a s t s
t r e a t e d with antimitotic d r u g s
Sample
N o r m a l c o n t r o l fibroblasts
P T M fibroblasts ( u n t r e a t e d )
P T M fibroblasts (treated)
Melphalan
Cyclophosphamide
Methotrexate
Nitrogen mustard
DNA
(Hgm)
Total
protein
1 lyaluronic
acid
(mg)
DNA/total
protein
Hyaluronic
acid/DNA
60.01
59.89
499.82
497.08
104.86
332.96
0.12
0.12
1.74
5.56
23.90
30.91
32.90
25.89
265.98
396.80
388.08
353.19
130.00
199.20
171.20
180.60
0.09
0.08
0.08
0.08
5.40
5.40
5.20
6.90
Downloaded from www.ccjm.org on September 9, 2014. For personal use only. All other uses require permission.
'186
Vol. 50, N o . 2
Cleveland Clinic Quarterly
Table 2.
Collagen synthesis in normal control and
PTM fibroblasts
Sample
N o r m a l c o n t r o l fibroblasts
P T M fibroblasts
Collagen
(mg)
Collagen/
DNA
51.10
51.77
0.85
0.84
during the first two months of treatment. T h e patient could
see the improvement, and reported that his legs felt more
comfortable. By the fourth month, however, his legs had
enlarged again to the pretreatment state. T w o more months
of therapy resulted in no improvement. Separate courses of
nitrogen mustard administered intravenously, and cyclophosphamide and methotrexate administered orally were
given for periods of four to six months with no improvement. Another trial of melphalan showed no improvement.
On two occasions, with discontinuation of systemic chemotherapy for several months, cellulitis developed in the right
leg. Apparently, a large fissure between the toes gave rise
to the infection in both instances. T h e cellulitis promptly
responded to treatment with antibiotics administered intravenously and bed rest. T h e patient was instructed to soak
his legs in a povidone-iodine solution at home on a daily
basis to suppress the bacterial growth that had colonized in
the deep leg fissures.
T h e patient was doing well when last seen in February
1979; however, leg measurements showed a slow progression of the disease.
Discussion
T h e growth rate of P T M fibroblasts in o u r
patient was the same as the growth rate of normal
control fibroblasts. T h e most characteristic feat u r e of P T M fibroblasts is their ability to p r o d u c e
three times as much hyaluronic acid as normal
control fibroblasts. This could have been anticipated as Sisson 10 r e p o r t e d that plaques of P T M
contained six to 16 times m o r e acid mucopolysaccharide than normal skin. In addition, C h e u n g
et a l " r e p o r t e d increased hyaluronic acid synthesis by fibroblasts in a tissue culture f r o m the
pretibial areas of patients with P T M . Hyaluronic
acid makes u p nearly 100% of the acid mucopolysaccharide in P T M , but only 57% in normal
skin. Beierwaltes and Bollet 12 f o u n d a higher
content of acid mucopolysaccharide in the normal-appearing skin of P T M patients than in normal controls. A circulating factor such as L A T S
may be able to transform normal-appearing fibroblasts into abnormal cells, which p r o d u c e
large a m o u n t s of hyaluronic acid. Kriss et al 13
hypothesized that P T M is caused by an antigenantibody reaction in the area of the skin disease
and that L A T S might be t h e antibody involved.
T h e antigen, however, was not f o u n d by
S c h e r m e r et al 5 when using direct immunofluorescence to identify antigen-antibody reactions in
tissue sections f r o m P T M lesions. Possibly, no
localized antigen-antibody reaction occurs in the
P T M lesions; however, the presence of L A T S or
some o t h e r undefined systemic factor transforms
the pretibial fibroblasts into abnormal mucinproducing cells. T h e mucin accumulation in the
dermis then leads to the clinical lesions of P T M .
Increased amounts of acid mucopolysaccharide
on histochemical staining of normal-appearing
f o r e a r m and eyelid skin suggest f u r t h e r that a
systemic factor is involved in P T M .
Exophthalmic goiter with associated P T M may
be an a u t o i m m u n e disorder even t h o u g h a localized antigen-antibody reaction may not be present in P T M lesions. This is suggested by the fact
that exophthalmic goiter has been associated with
n u m e r o u s a u t o i m m u n e conditions, including
pernicious anemia, r h e u m a t o i d arthritis, myasthenia gravis, lymphocytic infiltration of the thyroid, struma lymphomatosa, a n d enlargement of
the thymus. Autoantibodies against gastric parietal-cell microsomes, an intrinsic factor, a n d thyroid tissue fractions have been identified. T h e
thyroid antigen release caused by iodine 131,
thyroiditis, or hyperthyroidism could result in
the production of an antibody such as LATS. 1 3
T h e antibody would then circulate and cause
fibroblasts in the lower leg a n d other areas to
p r o d u c e excess mucin.
L A T S is a 7S gamma globulin, which has been
f o u n d in most patients with P T M . 5 , 1 4 - 1 7 T h e
serum L A T S titers d o not correlate well with the
severity of the skin lesions. 5 O u r patient, however, had severe P T M and high L A T S titer. T h e
site of origin of L A T S is unknown, b u t its antigen
may be in the microsomal portion of thyroid
tissue. 18 It is not known if L A T S is a pathogenetic
agent in P T M or just a manifestation of altered
immunity. Cell-mediated immunity may also
play a role. 1 9 ' 2 0
McKenzie et al 21 believe that the technique
whereby cyclic A M P (adenosine 3':5'-cyclic phosphate) is measured in incubated h u m a n thyroid
slices is m o r e sensitive for detecting L A T S than
the traditional mouse bioassay technique.
W h e t h e r this new technique will allow L A T S to
be measured in all patients with P T M remains to
be demonstrated.
T h e precise cause of exophthalmos in Graves'
disease is unknown. L A T S may be a causative
factor; however, it is not the sole factor responsible. It can be present or absent in t h e serum of
patients with minimal to severe exophthalmos. 2 2
Animal studies have shown that the increase in
Downloaded from www.ccjm.org on September 9, 2014. For personal use only. All other uses require permission.
Summer 1983
Pretibial myxedema
volume of the fatty retro-orbital tissues in experimental exophthalmos is caused by increased
a m o u n t s of acid mucopolysaccharide. 2 3 T h e increase in acid mucopolysaccharide is accompanied by a corresponding increase in water,
which presumably produces the exophthalmos.
However, Rundle et al 24 reports that some cases
of exophthalmos are d u e to enlargement of the
intrinsic eye musculature. Although either intrinsic eye muscle enlargement or retro-orbital mucin accumulation may p r o d u c e exophthalmos, it
is not clear why one process predominates in an
individual.
Although the fissures of the elephantiasic f o r m
of P T M d o not always lead to infection, 4 o d o r
should immediately alert the clinician to infection. We believe that daily immersions of the legs
a n d feet in a povidone-iodine solution a r e effective in minimizing such infection in o u r patient.
O n two occasions when o u r patient h a d been
neglecting his daily soakings, cellulitis of the right
leg developed. In both instances, one of us was
able to identify an infected d e e p fissure on the
foot that presumably had p r e c e d e d the cellulitis
on the leg. Fortunately, the cellulitis responded
rapidly to antibiotics administered intravenously.
It is not known why P T M preferentially affects
the legs. Schermer et al 5 believed that hydrostatic
forces play a role. Venous stasis, varicosities, focal
extravasation of blood, and local trauma might
all lead to focal accumulations of mucin on the
legs.
A n u m b e r of therapies; such as thyroid preparations administered orally, 25 tri-iodothyronine 2 6
a n d hyaluronidase 4 administered intralesionally,
and radiation; 4 have been tried f o r P T M , usually
with negative or inconsistent results. Positive results have been r e p o r t e d with prednisone administered orally, triamcinolone administered intralesionally, and 0.2% fluocinolone cream with
plastic occlusion administered topically. 17 ' 27 O u r
patient could not tolerate long-term systemic
prednisone therapy; steroids administered topically a n d intralesionally failed.
T h e severe elephantiasic f o r m of P T M has
been
treated
infrequently
with
surgery.
Patterson' r e p o r t e d a patient with rapid recurrence of the P T M following excision and grafting
of the verrucous dorsal foot tissues. Theoretically, m a j o r problems with infection can occur if
the skin grafts d o not heal a n d large areas of
exposed tissue a r e created. O u r patient, because
he was overweight, was a p o o r operative risk.
T h e appearance of keloidlike areas on his fore-
187
a r m following skin biopsies of normal-appearing
skin was a n o t h e r contraindication. 4
We decided to initiate trials with cytotoxic
agents f o r t h r e e reasons: (1) o u r patient's P T M
was becoming steadily worse; (2) traditional
methods of treatment, such as steroids administered topically and intralesionally had failed; and
(3) the results of in vitro susceptibility studies
with fibroblast cultures had been encouraging
since all f o u r cytotoxic agents r e d u c e d the
a m o u n t of hyaluronic acid p r o d u c e d by P T M
fibroblasts. Melphalan a n d m e t h o t r e x a t e had the
greatest effect on P T M fibroblasts in tissue culture. In addition, melphalan was useful in the
t r e a t m e n t of scleromyxedema, a n o t h e r disease
involving dermal mucin deposition. 2 8 Clinically,
melphalan had the greatest effect of t h e f o u r
drugs that were tried. T h e improvement, however, was temporary, a n d the P T M was worse
f o u r months later in spite of continued treatment.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
Lynch PJ, Maize J C , Sisson J C . Pretibial m y x e d e m a a n d n o n thyrotoxic thyroid disease. A r c h D e r m a t o l 1973; 1 0 7 : 1 0 7 111.
Sloan L W . Surgical t r e a t m e n t of h y p e r t h y r o i d i s m . New York
J Med 1 9 5 1 ; 5 1 : 2 8 9 7 - 2 9 0 1 .
T r o t t e r W R , Eden KC. Localized pretibial m y x o e d e m a in
association with toxic goitre. Q u a r t J Med 1942; 1 1 : 2 2 9 - 2 4 0 .
Gimlette T M . Pretibial m y x o e d e m a . Br M e d J 1960; 2 : 3 4 8 351.
S c h e r m e r D R , Roenigk H H J r , S c h u m a c h e r O P , McKenzie
J M . Relationship of long-acting t h y r o i d stimulator t o pretibial
m y x e d e m a . A r c h D e r m a t o l 1970; 1 0 2 : 6 2 - 6 7 .
E d m u n d o w i c z A C , Ivy H K , Randoll RV. Localized (pretibial)
m y x e d e m a . Postgrad Med 1964; 3 5 : 6 0 0 - 6 0 5 .
Patterson T J . Pretibial m y x e d e m a ; with r e p o r t of a case of
r e c u r r e n c e a f t e r excision a n d g r a f t i n g . Br J Plast S u r g 1958;
11:197-205.
Dische Z. A modification of t h e carbazole reaction of hexuronic acids f o r t h e study of polyuronides. J Biol C h e m 1950;
183:489-494.
B e r g m a n I, Loxley R. T w o i m p r o v e d a n d simplified m e t h o d s
f o r t h e s p e c t r o p h o t o m e t r i c d e t e r m i n a t i o n of h y d r o x y p r o l i n e .
Anal C h e m 1963; 3 5 : 1 9 6 1 - 1 9 6 5 .
Sisson J C . Hyaluronic acid in localized m y x e d e m a . J Clin
Endocrinol M e t a b 1968; 2 8 : 4 3 3 - 4 3 6 .
C h e u n g HS, Nicoloff J T , Kamiel MB, Spolter L, Nimni ME.
Stimulation of fibroblast biosynthetic activity by s e r u m of
patients with pretibial m y x e d e m a . J Invest D e r m a t o l 1978;
71:12-17.
Beierwaltes W H , Bollet AJ. Mucopolysaccharide c o n t e n t of
skin in patients with pretibial m y x e d e m a . J Clin Invest 1959;
38:945-948.
Kriss J P , Pleshakov V, Chien J R . Isolation a n d identification
of t h e long-acting thyroid stimulator a n d its relation t o hyperthyroidism a n d circumscribed pretibial m y x e d e m a . J Clin
Endocrinol M e t a b 1964; 2 4 : 1 0 0 5 - 1 0 2 8 .
Lipman LM, G r e e n DE, Snyder NJ, Nelson J C , Solomon D H .
Relationship of long-acting thyroid stimulator to t h e clinical
Downloaded from www.ccjm.org on September 9, 2014. For personal use only. All other uses require permission.
'188
Vol. 50, No. 2
Cleveland Clinic Quarterly
f e a t u r e s a n d c o u r s e of G r a v e s ' disease. A m J M e d
43:486-498.
1967;
15.
P i n c h e r a A, P i n c h e r a M G , S t a n b u r y J B . T h y r o t r o p i n a n d
long-acting t h y r o i d stimulator assays in t h y r o i d disease. J Clin
E n d o r i n o l M e t a b 1965; 2 5 : 1 8 9 - 2 0 8 .
22.
16.
P r i m s t o n e BL, H o f f e n b e r g R, Black E. Parallel assays of
t h y r o t r o p h i n , long-acting t h y r o i d s t i m u l a t o r , a n d e x o p h t h a l m o s - p r o d u c i n g substance in e n d o c r i n e e x o p h t h a l m o s a n d pretibial m y x e d e m a . J Clin E n d o c r i n o l M e t a b 1964; 2 4 : 9 7 6 - 9 8 2 .
Kriss J P , Pleshakov V, R o s e n b l u m A, S h a r p G. T h e r a p y with
occlusive dressings of pretibial m y x e d e m a with f l u o c i n o l o n e
a c e t o n i d e . J Clin E n d o c r i n o l M e t a b 1967; 2 7 : 5 9 5 - 6 0 4 .
23.
17.
18.
19.
20.
21.
Beall G N , S o l o m o n D H . Inhibition of long-acting t h y r o i d
stimulator by t h y r o i d p a r t i c u l a t e f r a c t i o n s . J Clin Invest 1966;
45:552-561.
Mahieu P, W i n a n d R. D e m o n s t r a t i o n of delayed hypersensitivity to r e t r o b u l b a r a n d t h y r o i d tissues in h u m a n e x o p h t h a l mos. J Clin E n d o c r i n o l M e t a b 1972; 3 4 : 1 0 9 0 - 1 0 9 2 .
V o l p e R, E d m o n d s M, L a m k i L, C l a r k e P V , R o w V V . T h e
pathogenesis of Graves' disease; a d i s o r d e r of delayed h y p e r sensitivity? M a y o Clin P r o c 1972; 4 7 : 8 2 4 - 8 3 4 .
McKenzie J M , Zakarija M, D ' A m o u r P, J o a s o o A. T h e long-
24.
25.
26.
27.
28.
a c t i n g t h y r o i d stimulator; is it of i m p o r t a n c e in G r a v e s ' disease. N Z M e d J 1 9 7 5 ; 8 1 : 1 8 - 2 1 .
Scheie H G , A l b e r t D M . Medical o p h t h a l m o l o g y . In: Scheie
H G , A l b e r t DM, eds. T e x t b o o k of O p h t h a l m o l o g y . Philadelphia: W.B. S a u n d e r s , 1977: p p 4 3 0 - 4 3 1 .
L u d w i g A W , Boas N F , S o f f e r LJ. Role of mucopolysaccharides in p a t h o g e n e s i s of e x p e r i m e n t a l e x o p h t h a l m o s . P r o c Soc
E x p e r Biol M e d 1950; 7 3 : 1 3 7 - 1 4 0 .
R u n d l e FF, Finlay-Jones L R , N o a d KB. M a l i g n a n t e x o p h t h a l mos; a q u a n t i t a t i v e analysis o f t h e orbital tissues. Aust A n n
M e d 1953; 2 : 1 2 8 - 1 3 5 .
Gabrilove J L , Alvarez AS, C h u r g J . G e n e r a l i z e d a n d localized
(pretibial) m y x e d e m a ; e f f e c t of t h y r o i d a n a l o g u e s a n d a d r e n a l
glucocorticoids. J Clin E n d o c r i n o l M e t a b 1960; 2 0 : 8 2 5 - 8 3 2 .
W a r t h i n T A , Boshell BR. Pretibial m y x e d e m a ; t r e a t e d with
local injection of t r i i o d o t h y r o n i n e . A r c h I n t e r n M e d 1957;
100:319-321.
L a n g P G J r , Sisson J C , L y m c h PJ. Intralesional t r i a m c i n o l o n e
t h e r a p y f o r pretibial m y x e d e m a . A r c h D e r m a t o l 1975;
111:197-202.
F e l d m a n P, S h a p i r o L, Pick AI, Slatkin M H . S c l e r o m y x e d e m a ;
a d r a m a t i c r e s p o n s e to m e l p h a l a n . A r c h D e r m a t o l 1969;
99:51-56.
Downloaded from www.ccjm.org on September 9, 2014. For personal use only. All other uses require permission.