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Vacuolar myopathy in a patient with positive LE cell preparations.

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ARTHRITIS ROUNDS
Vacuolar Myopathy in a Patient with Positive
LE Cell Preparations
By DYRC
F. SIBRANSAND HOWARD
L. HOLLEY
R
we have had the opportunity
to study a patient with progressive
muscle weakness and positive lupus erythematosus cell preparations. A muscle biopsy
was obtained which showed a vacuolar myopathy. This was a sufficiently rare finding
to warrant further investigation. Pearsonl
first described such a relationship in 1958.
Microscopic muscle lesions are observed
not uncommonly in systemic lupus erythematosus (SLE). Several different types of
changes are noted, none of which are felt
to be specific for SLE. The types previously
classified as myopathy of SLE are: (1)
interstitial polymyositis, very similar to that
seen in rheumatoid arthritis and acute rheumatic fever; (2) acute hyaline necrosis or
waxy degeneration of parts of single muscle
fibers, a frequent finding in biopsies from
patients with polymyositis; ( 3 ) a focal
arteritis or vasculitis; ( 4 ) fibrinoid changes
in the connective tissue surrounding muscle.2 A review of the subject of vacuolar
myopathy was undertaken to evaluate the
possibility that the above mentioned finding
might be specific for SLE.
ECENTLY
CASEREPORT
H. G., a 29 year old white female, was admitted to the University Hospital on April 20,
1965, complaining of profound muscle weaknesg
From the Division of Rheumatic Diseases, Departnient of Medicine, University of Alabama
Medical Center, Birmingham, Alabama.
DYRCF. SIBRANS,M.D.: Assistant Resident in
Medicine. HOWARDL. HOLLEY.M.D.: Professor
of Medicine and Director, Division of Rheumatology.
This inoestigation was supported by Public
Health Service Grant T1 AM 5000 from the
of the extremities and associated difficulty in
swallowing. She had been in good health until
the summer of 1962, when she noted a pigmented maciilar rash on the malar eminences
which spread rapidly to the chin, neck, and
anterior chest. The rash persisted throughout the
summer and faded spontaneously during the following winter months. At that time her only other
complaint was persistent nausea.
I n January, 1963, she became lethargic and
noted the onset of an insidious bnt progressive
muscular weakness. The muscle weakness was
initially confined to the arms but iater appeared
also in the legs. Her hair began to thin and an
erythematous macular rash developed in a butterfly distribution over her face. She denied any
joint symptoms, pleurisy, easy bruisibility, or
urinary symptoms. The muscle weakness progressed, and two months later she could no
longer elevate her arms above her head and dress
herself. She was hospitalized elsewhere and on the
basis of repeated positive L.E. cell preparations a
diagnosis of SLE was made and a daily dose of
40 mg. prednisone was inrtituted.* She was subseqnently maintained on a daily dose of 10 mg.
prednisone. The muscle weakness was only moderatelv improved, but she was able to return
to work.
In December 1964 the patient experienced an
acute exacerbation of muscle weakness which was
again accompanied by a facial skin rash. The
prednisone was increased to a daily dose of
30 mg. with improvement in the rash, but the
muscle weakness persisted. At that time she complained of difficulty and pain on swallowing.
There was no weight loss.
National Institute of Arthritis and Metabolic
Diseases and Merck Sharp and Dohme, West
Point, Pennsylvania.
*Several of these L.E. cell preparations were
re-examined in the Division of Rheumatic Disease
Laboratory, University of Alabama Medical Center,
Birmingham, Alabama.
141
142
SIBRANS A h D HOLLE1
Fig. l.-Biopsy
of deltoid muscle. Skeletal muscle fibers c u t in cross section and
obliquely. The vacuoles vary in size and number. In some of the muscle cells they
have replaced sarcoplasm almost completely. The sarcolemmal nuclei tend to be central in location and are not increased in number. Inflammatory cellular infiltration is
not present. (Hematoxylin Eosin) ( x 880).
The patient became progressively weaker and
was confined to bed for the three weeks prior
to admission.
Physical Examination: On admission there appeared a chronically ill cushingoid young woman
with a weak voice, butterfly rash over her face,
with obvious generalized muscle weakness. She
had prominent striae of the breasts, abdomen,
hips, and thighs. The vital signs were B.P. 140/90,
pulse 76, resp., 16, temperature 98 F. There was
no lymphadenopathy or hepatosplenomegaly. The
lung fields were clear. A grade II/VI systolic ejection murmur was heard in the pulmonic area.
There was no apparent muscle atrophy and muscle
tone appeared normal, but marked weakness of
flexors and extensors of arms, legs, and trunk was
observed. The cranial nerves were intact. The
biceps, triceps, patellar, and Achilles deep tendon
reflexes were absent bilaterally. No sensory disturbances were noted.
Laboratory Work: Hct. 41, WBC 7,000, segs.
74. Iynphs. 12, monos. 9, eosim;. 5, platelets
adequate. Corrected sedimentation rate was 42
( Wintrobe). Urinalysis revealed 4 white blood
cells and 5 red blood cells per high power
field and 3-t acetone, but negative for sugar
and protein. Serum chemistries included Na 135.
K 3.9. C1 100, CO, 26 mEq/L., total protein
6.85 Gm., albumin 2.97, alpha-1 0.32, alpha-2
0.70, beta 1.45, gamma 1.41 Gm. per cent; LE
cell preparations negative x3; anti-nuclear factor
negative; AS0 titer-250 Todd units; P B 1 4 . 8 pg
per cent; and a stool guaiac test was positive.
The serum creatine phosphokinase was 1.3 units
(normal values 0.3 to 3 units), while the BSP,
creatinine clearance, blood glucose, BUN, bleeding
and clotting times, VDRL, and urinary coproporphyrins and uroporphyrins were normal. The
SGOT was 35, 29, 43, and 25 units. The normal
values for SGOT in this laboratory are 5 to 25
units.
After admission the patient was given 40 mg.
of prednisone daily. Potassium chloride was added
to the regimen dne to the initial finding of .I
143
VACUOLAR MYOPATHY
Fig. B.--Skeletal muscle fibers c u t longitudinally. Note spotty distribution of t h e
vacuolar change. No increase in adipose or fibrous connective tissue is noted. (Hematoxylin Eosin) ( X 880).
low serum potassium. and a peptic ulcer regimen
was begun. The patient was initially considered
to be suffering from polymyositis. A therapeutic
trial of neostigmine failed to improve muscle
strength. A biopsy was obtained from the deltoid
muscle. Microscopic examination revealed considerable vacuolization of groups of muscle cells
(Figs. 1, 2 ) . Decrease in size and loss of fine architectural detail was noted in the affected cells.
The vacuoles varied markedly in size. In some
cells, multiple small vacuoles imparted a honeycomb appearance. In other muscle cells, large
vacuoles appeared to replace most of the sarcoplasm. The sarcolemmal nuclei tended to be
central in location, and in a few instances were
within vacuoles. These nuclei appeared prominent
and reactive, but were not increased in number.
Muscle weakness continued and the Prednisone
dosage was increased to 60 mg. daily. An electromyogram (EMG) was performed. Localized areas
of irritability of muscle were demonstrated. These
were characterized by a decrease in amplitude of
motor unit potentials after voluntary contractures.
At rest, fibrillation potentials were present in tested
areas of muscle. Conduction velocity in the ulnar
nerve was normal. On the 15th hospital day the
patient had an acute gastrointestinal hemorrhage
which was treated with whole blood transfusions
and nazogastric suction. An emergency upper GI
series was reported as normal. Because of the
hemorrhage the prednisone dosage was gradually
reduced. She was given depo-testosterone in an
attempt to establish a positive nitrogen balance
after discovery of the vacuolar myopathy. The
patient went home on the 37th hospital day with
little or no improvement in muscle strength. She
was discharged on a daily dose of 20 mg. Prednisone, together with supplemental potassium salts.
A recent follow-up examination on 10/24/66
revealed improvement. Her muscle strength has
increased gradually and she has been able to
resume most of her household chores. The patient
still fatigues easily; she has been taking 10 mg.
prednisone daily. The follow-up laboratory work
revealed a negative LE cell preparation, negative
antinuclear antibody; the SCOT was normal; the
hematocrit was 34 and the corrected sedimentation
rate (Wintrohe) was 30 mni.
144
EIBRAXS A S D HOLLEI.
frequently in the past two years. The musDISCUSSION
A review of the literature revealed that cle wasting and weakness appear to be
nine cases of vacuolar myopathy have been reversible, however, and improvement bereported associated with systemic lupus gins within a short time after withdrawal
erythematosus. These have been based on of the drug. The toxicity appears to be
the microscopic criteria initially described dose and time related. Unfortunately, few
by Pearson and Yamazaki in their original muscle histologic studies have been carried
case rep0rt.l Their patient had a pruritic out to confirm the clinical observations.
skin rash, fatigue, and generalized malaise. EMG studies performed on patients with
LE preparations were originally negative, chloroquine myopathy have been interbut later became positive. Muscle weak- preted as consistent with a myopathy or
ness was not demonstrated. Markedly ele- a neuropathy.
Whisnant’ has shown in his review of
vated SGOTs prompted a muscle biopsy.
chloroquine
neuromyopathy that a vacuoThey described the plump, swollen, sarlar
myopathy
may develop after prolonged
colemmal nuclei with prominent nuclei
or
high
dosage
of the drug. It is difficult,
more centrally located in the muscle fiber
if
not
impossible,
to differentiate clinically
and often found within a vacuole. They
and
histologically
these changes from the
felt that this finding differentiated the
vacuolar
myopathy
reported by Pearson
vacuolar myopathy associated with SLE
occurring
in
SLE.
from other types of vacuolar myopathy.
A myopathy occurring during steroid
Pearson suggests that the vacuolar myopathy of SLE is a diffuse disease which therapy has been recognized for some time
may occur with or without muscle weakness and there have been frequent reports in
or serum enzyme changes3 Three addi- the literature. Clinically, this is evident in
tional cases have been described, and primary Cushing’s disease with marked
the histologic lesion is now considered proximal muscle weakness and wasting.
In the iatrogenic form, however, the ocspecific for vacuolar myopathy in SLE.4
Vacuolar myopathy has been reported currence of myopathy does not appear to
to occur with hypokalemia, periodic pa- be dose-related. Apparently the majority of
ralysis, thyrotoxic myopathy, polymyositis, the patients have had symptoms of muscle
dermatomyositis, muscle damage after weakness within three weeks of initiation
burns or secondary to ischemia, and in of therapy. Several cases of vacuolar myoppatients under treatment with steroids and athy have been reported occurring during
chloroquine. The vacuolar myopathy seen steroid therapy,lozll especially triamcinoduring steroid and chloroquine therapy, lone.12l4 However, apparently all of the
however, has almost invariably been asso- 17-hydroxycorticosteroids are capable of
ciated with muscle wasting and accom- producing this phenomenon.15-17 Again,
panied in some cases with mildly elevated the muscle weakness and wasting appears
SGOT’s. Documented incidences of myop- to begin in the proximal muscles of the
athy secondary to chloroquine have only legs. Perkoff et a1.,l5 in a review of myoprecently been reported, but isolated cases athy associated with steroid5, stated that
the most consistent histologic feature was
of muscle weakness have been noted.5
Muscle weakness and atrophy confined the presence of large empty vacuoles and
primarily to the extensors of the proximal an increase in the number of sarcolemmal
muscles of the lower extremities during nuclei. No mention was made of their shape
chloroquine therapy have been reported or position in the muscle fiber. This myop-
145
VACUOLAR MYOPATHY
Table 1.-Review
of Case Reports of Vacuolar Myopathy Occurring in Patients
with Systemic Lupus Erythematosus
Number
of
Cases
-
Pearsonl
1
Positive
LE
Preps
Yes
Muscle
Weakness
Priorto
Therapy
No
Duration of Therapy
Prior to Biopsies
Steroids
Chloroquine
Decreased Muscle
Weakness
on Therapy
3-4 Weeks
0
Yes
Decreased Muscle
Weakness when
Therapy Stopped
or Changed
( Prednisone)
No information
given
Pearson?
3
Humphrey22
1
Yes
No
Lang24
1
Yes
No
5 Years
( Prednisone)
( Celestonen )
Jagerl9
1
No
Yes
(4mo.)
5 Days
(Decadron' )
12-16 mg.
5 Yrs.
(500 mg. )
No
Yes
(On Prednisone)
(Chloroquine
stopped )
5 Yrs.
(dose not
given)
NO
Yes
(Both drugs
stopped)
Prednisone
started
0
Died
Died
Levy20
1
No
Yes
0
0
Yes
(on Prednisone)
Erbsloe21
1
No
Yes
0
0
Yes
(on Prednisone)
Sibrans
1
Yes
Yes
( 3 mo.)
0
Transiently
initially
"Decadron
-
2.5 Years
(Prednisone)
15-60 mg.
No
Dexamethasone, Merck Sharp & Ilohme.
athy appears to be reversible when the
steroid is discontinued or in some instances
when the type of steroid is changed. EMG
studies performed on patients with Cushings disease and on patients being treated
with steroids have shown the characteristic
pattern of a primary myopathy.1°J7Js
Both steroids and chloroquine have been
used in the treatment of SLE, as well as
other diseases from which the majority of
the information on their myopathic-producing qualities has been obtained. It
would seem safe to assume that a similarity
between the vacuolar myopathy associated
with SLE and that of other vacuolar myopathies does exist and must be considered
in the evaluation of the specificity of this
muscular lesion in SLE.
A review of the reported cases (Table 1)
shows that only three19-21had a history
of muscle weakness prior to treatment with
steroids and/or chloroquine, However,
steroids had been given to Jager's patient
before the muscle biopsy was taken.
Humphrey's22 patient had had 500 mg.
chloroquine per day for three years before
the onset of muscle weakness and wasting
and five years before biopsy. The muscle
biopsy showed a vacuolar myopathy indistinguishable from that described by Pearson. In a review of the same case with
electron microscopic studies the possibiIity
of chloroquine toxicity was raised.23Langs
patient ? ( had had both steroid, prednisone
146
SIBRANS A N D HOLLEY
initially, then Celestone,* and chloroquine
treatment for 4 years prior to the onset of
muscle weakness and 5 years prior to
biopsy. When steroids were decreased and
chloroquine was discontinued, the patient
had almost complete return of previous
muscle strength. Jager’s patient revealed a
profound muscle weakness, rapidly progressive over a four-month period, and was
preceded by a facial rash. The muscle
weakness involved even the respiratory
inuscles. No L.E. cell preparations were
obtained. This patient was on steroid therapy for about five days prior to the muscle
biopsy. Histologically, the vacuolization
was found to be severe and involved every
muscle biopsied, including cardiac muscle.
The diagnosis of SLE was made on history
of rash and fever, the presence of leukopenia and thrombopenia, and the autopsy
findings of “onion skin” lesions in splenic
arterioles and “wire loop” changes in the
renal glomeruli. Pearson’s patient had no
evidence of muscle weakness but did have
clinical and ECG evidence of carditis. The
patient had been taking prednisone for only
3-4 weeks prior to the muscle biopsy. A
facial rash and progressive muscle weakness had begun ten months prior to the
time a diagnosis of SLE was made. He
was started on prednisone in large doses
with initial improvement in general status
but the muscle weakness continued.
It appears, therefore, that the etiology
of vacuolar myopathy found in SLE is still
in a state of limbo, and Pearson, himself,
describes it as a “bizarre manifestation of
a multisystem disease, or, indeed, as a
result of our treatment of the disease.”
Denny Brownz5 feels that the plump,
sarcolemmal nuclei are a manifestation of
a regeneration of muscle fibers or a reactive change to chronic inflammation. He
classifies vacuolar myopathy as a chronic
progressive polymyositis. The apparent
ability of steroids and chloroquine to produce a myopathy with vacuolization clouds
the issue considerably. The lack of evidence of vacuolization of muscle in SLE
before the institution of these modes of
therapy is an argument in favor of an
iatrogenic production of this phenomenon.
Yet the history of profound muscle weakness before steroid therapy in some cases
cannot be ignored. The possibility that this
is another of the overlap syndrome between
SLE and polymyositis must also be considered. The elucidation of the specificity
of this lesion for SLE remains in doubt,
particularly since a strikingly similar lesion
can be produced by drugs frequently used
in the treatment of this disease; more work
is needed on the mode of action of chloroquine and steroids on muscles as well as
on the muscle changes in untreated SLE.
It is only from such studies that the true
nature of the vacuolar myopathy will bc
determined.
ACKNOWLEDGMENT
We wish to thank Dr. L. H. Robinson, Professor
of Pathology, Department of Pathology, Universit!
of Alabama Medical Center, for reviewing the
microscopic material presented in this paper, and
Dr. Ellis Sparks, Huntsville, Alabama, for hi\
help in obtaining a followup examination of thk
patient.
*Celestone - betamethasone, Schering Corp.
SUMMARY
A case report is presented of a patient with muscle weakness, positive LE cell
preparations and a diffuse vacuolar myopathy. A review of the causes of vacuolar
myopathy is given, with special emphasis an chloroquine and corticosteroids, since
these two drugs are frequently used in the therapy of systemic lupus erythematosus
(SLE). Our patient, together with other reported cases, is discussed in terms of
whether this myopathy is due to the disease process or is secondar!- to therapy.
147
VACUOLAR MYOPATHY
SUMMARIO
IN INTERLINGUA
Es reportate le caso de un patiente con asthenia muscular, positive preparatos d e
cellulas LE, e un diffuse myopathia vacuolar. Es presentate un revista del causas de myopathia vacuolar, con referentias special a chloroquina e le corticosteroides, viste que
iste duo pharmacos es usate frequentemente in le therapia de disseminate lupus erythematose. Le caso de nostre patinte-insimul con alteres a b le litteraturaes commentate
in relation a1 question de si iste myopathia es un effect0 del process0 morbide o un
disveloppamento secundnri a1 the rapia.
REFERENCES
1. Pearson, C. XI., and Yamazaki, J. N.: Vacuolar
myopathy in systemic lupus erythematosus.
Am. J. Clin. Path. 29:455, 1958.
2. Adams, R. D., Denny-Brown, D., and Pearson,
C. Xf.: Disease of Muscle; A Study in Pathology, ed. 2. New York, Harper and Row,
1962, p. 444.
3 . Pearson, C. M.: Personal Communication.
4. Adams, R. D., Eaton, L. M., and Shy, G. M.
(Eds.): Neuromuscular Disorders. Association
for Research in Nervous and Mental Diseases. Proceedings. 38:472, 1960.
5. Begg, T. B., and Simpson J. A.: Chloroquine
neuromyopathy. Brit. Med. J. 1:770, 1964.
6. Editorial: Chloroquine neuromyopathy. Brit.
Med. J. 1:452, 1964.
7. Whisnant, J. P., et al.: Chloroquine neuromyopathy. Proc. Mayo Clin. 38:501, 1963.
8. Loftus, L. R.: Peripheral neuropathy following
chloroquine therapy. Canad. M. A. J. 89:917,
1963.
9. Blom, S., and Lundberg, P. 0.: Reversible
myopathy in chloroquine treatment. Acta
Med. Scand. 177:685,1965.
10. Golding, D. N., and Begg, T. B.: Dexamethasone myopathy. Brit. Med. J. 2:1129, 1960.
11. Harman, J. B.: Muscular wasting and corticosteroid therapy. Lancet i:887, 1959.
12. Williams, R. S.: Triamcinolone myopathy.
Lancet i:698, 1959.
13. Strandberg, B.: The frequency of myopathy
in patients with rheumatoid arthritis treated
with triamcinolone. Acta Rheum. Scand.
8:31, 1962.
14. MacLean, K., and Schurr, P. H.: Reversible
amyotrophy complicating treatment with
fludrocortisone.Lancet i:701, 1959.
15. Perkoff, G. T., et al.: Studies in disorders of
muscle. XII. Myopathy due to the administration of therapeutic amounts of 17hydrocorticosteroids. Amer. J. Med. 26:891,
1959.
16. Barbhaiya, H. C.: Steroids and myopathy.
Lancet i:1161, 1964.
17. Hagstrom, J. W. C., et al.: Debilitating muscular weakness and steroid therapy. Arch.
Neurol. 5530, 1961.
18. Muller, R., and Kugelberg, E.: Myopathy in
Cushing’s sydnrome. J. Neurol., Neurosurg.,
Psychiat. 22:314, 1959.
19. Jager, w. A., and B&t,
S. &I.: Vacuolar
myopathy. Psychiat. Neurol. h’eurochir. 67:
469, 1964.
20. Levy, J, A.: Miopathia vacuolar de lupus
erithematoso. Arq. Neuropsiquiat. 20:142,
1962.
21. Erbsloe, F., and Baedecker, W. D.: Lupus
Myopathie, eine klinische, elektromyographische und bioptisch-histoloquische Studie.
Deutsch. Med. Wschr. 87:2464, 1962.
22. Humphrey, J. G., and Rewcastle, N. B.:
Vacuolar myopathy. A clinical and electron
microscopic study. Trans. Amer. Neurol. A.
88:225, 1963.
23. Rewcastle, N. B., and Humphrey, J. G.: Vacuolar myopathy. Arch. Neurol. 12:570, 1965.
24. Lang, P, A., et al.: Vacuolar myopathy in lupus
erythematosus. J.A.M.A. 191:49, 1965.
25. Denny-Brown, D.: The nature of polymyositis
and related muscular diseases. Tr. Coll.
Physicians 28:14, 1960.
Discussion
THE STATUS OF “vacuolar myopathy” as
clinical entity, or indeed even as a
clinical syndrome, is still considerably in
doubt, as has been alluded to by Drs.
Sibrans and Holley. In fact, the finding of
;L
significant vacuolation in striated muscle
is usually an unexpected histopathologic
curiosity and often engenders reevaluation
of the patient’s clinical status from various
available approaches, inchding careful
14s
tabulation of the therapeutic menu, past
and present, and estimation of muscular
strength, serum enzyme measurements,
EMGs and almost invariably at least a
clinical pathological conference or, as in
the present instance, a case report. Thus,
even up to the present time it is a pathologic oddity of uncertain heritage and perhaps dubious specificity, unless more refined tools such as electron microscopy and
intrafibcr or even intravacuole electrical
potential recordings can eventually be
brought to bear on the nature of, or
differentiation between, the various causes
of muscle fiber vacuolation.
When I first reported a case of diffuse
vacuolation of striated muscle in a young
(age 15) male with unequivocal SLE, only
3 to 4 weeks of prednisone therapy and
no antimalarial treatment whatsoever, it
struck all of us as a most peculiar finding
since there was no demonstrable muscular
weakness (none has developed in the subsequent 8 years) and the biopsy was taken
from the sternocleidomastoid muscle only
incidental to a cervical lymph node biopsy.
The elevated serum enzymes had been
previously explained as a consequence of
an extremely active ‘‘lupus’’ myocarditis,
although in retrospect the latter may have
been only one contributor to these laboratory abnormalities. Several months after
prednisone therapy had been given to this
boy, nearly all clinical features of SLE
subsided and the serum enzymes had returned to normal; yet a repeat biopsy of
the same muscle again showed vacuolation,
although only about 20 per cent as extensive as had been noted before.
Sitbsequently we have done a rather
random sampling of one or more striated
muscles in 20 persons with acute or subacute SLli and have noted the following:
( a ) rare (nonspecific) fiber degeneration
and interstitial myositis (inflammatory infiltrates) in 10 patients ( 8 taking pred-
SIBRASS A S D HOLLEY
nisone and 2 of the 8 also taking hydroxychloroquine); ( b ) no changes in 3 patients
(all taking prednisone); ( c ) 7 persons with
minor or significant muscle fiber vacuolation ( 3 taking prednisone alone, 1 in
addition on hydroxychloroquine and 1 from
nnother hospital on triamcinolone and
Iargc doses of a combination of 3 antimalarials chloroquine, atabrine and camoquine). Thus, although this lesion usually
is found, by therapeutic necessity, in SLE
with steroid treatment, it need not be so
since two persons had no such treatment
of any sort (aside from aspirin, which to
my knowledge, does not produce these
lesions) prior to positive muscle biopsy.
We have been impressed in the muscle
biopsies that we have studied, that the
vacuolar lesions are: ( a ) variable in extent
and degree, sometimes being focal and
scanty and on other occasions appearing
to be widespread and quite extensive in
individual fibers; ( b ) almost always accompanicd by “alert” or prominent sarcolemma1 nuclei, usually in the confines of the
vacuoles as though some type of nuclear
activity or perinuclear reaction was responsible for the initiation and perpetuation of the individual lesion; ( c ) that the
histologic vacuolar lesions are not correlatable in any meaningful way with serum
enzyme levels or the rough clinical measurements of strength; and ( d ) that antecedent corticosteroid or antimalarial therapy
need not have been givcn for development
of the vacuolar lesions, although there is
no denying that either or both drugs may
have intensified a preexisting fiber vacuolation. The vacuolar lesions in one moderately
weakened patient (who had also been on
massive daily doses of antimalarials) also
contained large collections of an unidentified pigmentary material, possibly pyknotic
nuclear debris.
In the case under discussion I am moderately perplexed about two features which
DISCUSSION
I have not previously encountered in any
of my positive cases, namely ( a ) the absence of LE cells or antinuclear factors,
at least one of which was always found
in my patients at the time of biopsy, and
( b ) the relative lack of nuclear plumpness
or “activation,” at least in the illustrations
as shown.
As mentioned by Dr. Sibrans and Holley,
vacuolation of muscle can be found in a
number of conditions in addition to drug
(steroid and antimalarial) intake. The
most common conditions in which this is
found are periodic paralyses of long duration (either hypokalemic or hyperkalemic’ 2,
and polymyositis.3 In the latter, the vacuolation is only one element of a spectrum
of pathologic changes, but the vacuolation
with nuclear prominence resembles that
seen in the lesion in lupus. In periodic
paralysis, the vacuoles may reach huge
dimensions and thus actually compress the
adjacent muscle sarcoplasm and myofibrils.
However, the muscle nuclei are atrophic,
pyknotic and not especially associated with
the vacuoles, thus separating this vacuolar
lesion from that noted in lupus.
By what process or processes does vacuolation occur in muscle? As noted a few
years ago, all striated muscle fibers possess
an elaborate network of ultramicroscopic
canals or channels4 These are called the
sarcotubular system and this system is
usually separated into three components:
( a ) the transverse tubular system, ( b ) the
triads or clusters of 3 tubules adjacent to
the Z-disc, and ( c ) the longitudinal tubular
system which courses between myofibrils.
The membranes of some of these canals
apparently are metabolically active and
conduct electrical or action potentials into
the fiber substance from the outer membrane of the fiber, whereas others seem to
have the ability to reversibly chelate and release calcium, thus affecting contraction or
relaxation of the contractile protei? actqmyosin and perhaps other contractile pro-
141)
teins. The channels contain water, some
eleotrolytes and perhaps variable solutes.
One would envision that various disease
states could disrupt the delicate balance
which is normally maintained by these
membranes, thus leading to accumulation
of a watery mixture of electrolytes, other
solutes and glycogen. Moreover, since the
perinuclear region is especially rich in
tubular structures, these could be maximally affected in SLE, possibly by the
localization of “antinuclear” antibodies in
these zones with consequent disruptive
changes leading to vacuolization.
There are other possible explanations for
vacuolization in muscle, including ( a ) excessive release of hydrolytic lysosomal
enzymes, ( b ) degeneration of sarcoplasm
and myofibrils due to unknown primary
factors, and ( c ) others. Careful electron
microscopic assessment of the early as well
as the more fully developed lesions in SLE
will tend to clarify which of these factors
is most prevalent. Preliminary evidence
suggests that it is the sarcotubular system
which is principally affected in nearly all
of the previously mentioned conditions, and
the same would also apply to certain druginduced vacuolar lesions.
In summary the following points can be
made: (1) Vacuolar myopathy in SLE is
not especially rare but its actual incidence
has not been systematically surveyed. ( 2 )
Clinically evident muscular weakness need
not be prominent or even present at all
and is not correlatable (at least within
certain limits) with the degree of vacuolation. ( 3 ) The lesion can be found in
SLE whether or not certain “vacuole-inducing” drugs are given. ( 4 ) The level of
serum enzymes is not a good guide to the
presence or absence of vacuoles. ( 5 ) The
muscle fiber lesion is diffuse and relatively
nonspecific, except if the vacuoles contain
within their confines large plump sarcolemma1 nuclei; then the associated cIinicaI disease is most IikeIy to be SLE, or less com-
150
SIBHAKS A N D IIOLLEY
monly polymyositis. ( 6 ) The actual vacuolar lesion seems to be brought about by an
inbibition of water and solutes within the
intramuscular tubular systems from an as
vet uncertain cause.
CARLM. PEARSON,
M.D.
Los Angeles, Calif.
REFERENCES
I . Pearsori. C. M.: The periodic paralyses: Differential features and pathological observations
in permanent myopathic weakness. Brain
87:341, 1964.
2. Howes. E. L., Price, H. M., Pearson, C. M..
Hlumberg, J . M.: Hypokalemic periodic
paralyses; electron microscopic changes in
sarcoplasni. Neurolcgy 16:242, 1966.
3. Denny-Brown, D.: The nature of polymyositis
and related muscular diseases. Trans. Coll.
Physicians 28:14, 1960.
4. Porter, K. R.: The sarcoplasinic reticulum. Its
recent history and present status. J. Biophys.
Biochem. Cytol. 10:219, 1961.
Dr. Pearson’s excellent discussion reemphasizes the importance of a more definitive study of muscle in SLE, indeed in
the whole spectrum of rheumatic diseases.
Obviously “vacnolar myopathy” is a much
more common lesion than has been previously appreciated. It is only through such
a study that a more meaningful explanation
of these muscle fiber changes can be made.
HOWARD
L. HOLLEY,,M.D.
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