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Transverse myelitis in mixed connective tissue disease.

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982
CASE REPORT
TRANSVERSE MYELITIS IN MIXED
CONNECTIVE TISSUE DISEASE
TERRY D. WEISS, JAMES S. NELSON, ROBERT M. WOOLSEY, JACK ZUCKNER, and
ANDREW R. BALDASSARE
Neurologic disease is reported to occur in just 10%
of patients with mixed connective tissue disease (MCTD).
Most commonly, this is manifested by mild trigeminal
neuralgia. This report details the clinical and neuropathologic findings of transverse myelitis in a patient with
MCTD. Neurologic features include progressive areflexic
paraplegia with loss of bowel and bladder function. Neuropathologically there was thinning of the thoracic cord,
widespread loss of axons and myelin sheaths, reactive
astrocytosis, macrophage formation, vascular thickening
with perivascular chronic inflammatory cell infiltration,
and calcium deposits. This case demonstrates that severe
neurologic disease unresponsive to therapy can occur in
MCTD.
Mixed connective tissue disease (MCTD) is a
recently described syndrome sharing features of systemic lupus erythematosus (SLE), progressive systemic
sclerosis (PSS), and polymyositis (1,2). Serologically,
these patients are characterized by having antibody to
ribonucleoprotein (RNP), an extractable nuclear antigen (ENA) that digests with ribonuclease (RNAse).
This antibody produces a speckled antinuclear antibody
(ANA) pattern. Neurologic disease occurs in only 10%
of patients and, most commonly, is manifest by mild
trigeminal neuralgia (3). We report a case of MCTD
with severe neurologic involvement, namely, transverse
myelitis. Neuropathologic findings in mixed connective
tissue disease, not previously published, are detailed in
this report.
From the Department of Internal Medicine, Division of
Rheumatology, and the Department of Neurology, St. Louis University School of Medicine, and the Department of Pediatrics, Division of
Pathology and the Department of Pathology, Division of Neuropathology, Washington University School of Medicine, St. Louis, Missouri.
Terry D. Weiss, M.D.: Assistant Clinical Professor of Medicine, St. Louis University School of Medicine; James S . Nelson, M.D.:
Professor of Pathology, Division of Neuropathology, Professor of
Pathology in Pediatrics, Washington University School of Medicine;
Robert M. Woolsey, M.D.: Professor of Neurology, St. Louis University School of Medicine; Jack Zuckner. M.D.: Clinical Professor of
Medicine, St. Louis University School of Medicine; Andrew R. Baldassare, M.D.: Assistant Clinical Professor of Medicine, St. Louis
University School of Medicine.
Address reprint requests to Terry D. Weiss, M.D., St. Louis
University Hospital, 1325 South Grand Boulevard, St. Louis, M O
63104.
Submitted for publication March 20. 1978; accepted July 18,
1978.
CASE REPORT
Arthritis and Rheumatism, Vol. 21, No. 8 (November-December 1978)
JT, a 24-year-old black female, was admitted to the
hospital in October, 1975 for evaluation of arthritis and weakness in the lower extremities. Since November, 1973 she had
had pain and swelling in the proximal interphalangeal joints,
knees, ankles, and toes. She denied rashes, Raynaud’s phenomenon, subcutaneous nodules, and morning stiffness. She
had been hospitalized in December, 1973 for evaluation of
chills, fever, and migratory arthralgias. She was found to have
a granulocytopenia with a white blood cell (wbc) count of
1,500/mms with 76% lymphocytes and 24% monocytes. The
bone marrow showed agranulocytosis. The creatine phosphokinase (CPK) as 240 mU/ml (n = 25-140), serum glutamate oxalacetate (SGOT) was 5 mU/ml (n = 15-40), and the
A N A negative. The fever resolved and the wbc count returned
to normal spontaneously and she was discharged.
In May, 1974 she w a s hospitalized for fever and gener-
983
TRANSVERSE MYELITIS IN MCTD
alized weakness. The SGOT was 170 mU/ml and the C P K 730
mU/ml. A latex test for rheumatoid factor, an ANA, and a
lupus erythematosus (LE) cell preparation were positive. The
patient was treated with gold salts and steroids and improved.
In the latter part of July, 1974 she reported becoming “blind”
in both eyes. She recovered in an unknown period of time with
residual visual impairment in the left eye.
She was hospitalized in May, 1975 for left lower quadrant abdominal pain and vaginal bleeding. A tuba1 pregnancy
was suspected and she underwent an exploratory celiotomy
which revealed a left ovarian cyst. At the time the C P K was
1120 mU/ml and the SGOT was 210 mU/ml. Steroid therapy
was continued and the patient discharged.
She was again hospitalized in July, 1975 with a 4-week
history of fever, generalized weakness, and polyarthritis. She
again had leukopenia with a wbc count of 2,600/mm8 with 1%
bands, 63% polymorphonuclear leukocytes, 43% lymphocytes,
and 1% monocytes. The hemoglobin was 9.6 gm, hematocrit
30.2%, with a positive Coombs’ test. C P K was 1600 mU/mI,
SGOT 225 mU/ml. ANA and an L E cell preparation were
positive. She was again treated with steroid therapy. Shortly
thereafter she developed persistent urinary incontinence and
occasional fecal incontinence.
In September, 1975, 4 weeks prior to admission, the
patient began to notice weakness in her legs. One week before
admission she began to “drag” her right leg and several days
later she was unable to stand because of leg weakness. She had
been taking 5 to 10 mg of prednisone daily until 2 or 3 days
prior to admission when she discontinued the medication.
On physical examination the temperature was
100.2’F, pulse 100/minute, and blood pressure 110/70 mm
Hg. She was a well developed, well nourished, edentulous,
black female who appeared chronically ill. There were no skin
rashes. Some alopecia was present in the left temporal area.
Funduscopic examination disclosed prominent optic atrophy
on the left and mild atrophy on the right. Visual acuity was 20/
50 in the right eye and 20/200 in the left. There was no residual
evidence of a uveitis. On joint examination there was swelling
and tenderness in distal and proximal interphalangeal joints,
pain with motion in hips and shoulders, with normal range of
motion in these joints.
Mental status examination showed normal results.
Cranial nerves I through XI1 were intact though there was
mild weakness in the sternomastoid and trapezius muscles and
optic nerve atrophy as noted above. Vibratory and position
sense were present but severely impaired in the lower extremities. The upper extremities were mildly weak in the distal
portions. Truncal muscles were good and the patient could sit
up with miminal support. All lower extremity muscles were
very weak and the patient was unable to lift her legs from the
bed. There was loss of rectal sphincter tone and the patient was
incontinent of urine during vaginal examination. Tendon reflexes were normal in the upper extremities; they were present
but hypoactive in the lower extremities. The left plantar response was extensor and the right flexor. Twelve days later the
patient was unable to move her legs at all except for flexion
and extension of the left great toe. The legs were flaccid and
the ankle jerks absent. Both plantar responses were extensor.
The patient was hypalgesic below TI0 and Beevor’s sign was
positive. Her neurologic state remained unchanged until her
death.
Laboratory evaluation included: hemoglobin 10 gm,
hematocrit 30.2%, wbc count 4,100/mma with 65% polymorphonuclear leukocytes, 1% stabs, 15% lymphocytes, 1% monocytes. Red cell indices were normocytic hypochromic. Platelet
count was 327,000/mms. Prothrombin time and partial
thromboplastin time were normal as was the urinalysis. The
erythrocyte sedimentation rate was 51 mm/hour (Westergren).
Chest x-ray was normal except for two calcified lymph nodes
in the superior mediastinal area on the left side. X-rays of the
lumbar spine, pelvis, and hips showed normal findings. EKG,
blood sugar, BUN, creatinine, serum electrolytes, calcium,
phosphorous, cholesterol, bilirubin, alkaline phosphatase, and
uric acid were normal. The SGOT was 230 mU/ml. A latex
test for rheumatoid factor was negative. L E cell preparations
were positive. Serum protein electrophoresis showed hypergammaglobulinemia. ANAs were present in all three classes of
immunoglobulins (IgG, IgM, IgA). The IgG ANA titer was
greater than 1 :6400 with a rim pattern at 1 :400 and a speckled
pattern at higher dilutions. The IgM ANA titer was 1: 1600
with a rim and diffuse pattern. The IgA titer was positive at a
I : 1600 dilution with a rim pattern a t 1: 100 and a speckled
pattern at 1 :800. Anti-native D N A (nDNA) antibodies could
not be detected by the Farr technique. The ENA antibody titer
was greater than 1 : 100,OOO and completely eliminated after
digestion with RNAse. Sm antigen could not be detected by
immunodiffusion. (Courtesy of Dr. Gordon Sharp, University
of Missouri School of Medicine, Columbia, Missouri.)
Biopsies of skin and muscle were done and routine
histologic as well as immunofluorescent staining obtained. The
skin stained with hematoxylin and eosin was normal. With
immunofluorescent staining there was 2+ to 3+/4+ epidermal
nuclear staining with a rim and speckled pattern. Most of the
staining was for IgG, with IgM giving a weaker response and
IgA being equivocal. IgE, C3, fibrin, and fibrinogen were not
detected. There was no staining of the dermal-epidermal junction. The muscle, stained with hematoxylin and eosin. showed
mononuclear cell infiltrates in the perimesium and endomesium with muscle fiber degeneration and necrosis. There was
marked interstitial edema. Varying stages of vasculitis were
present involving small and medium sized arteries with mononuclear cell infiltrates. Immunofluorescent study showed
3+/4+ extensive large globular deposits in the interstitium
and strong staining of muscle nuclei. Staining for IgG gave a
2+/4+ result. Staining for IgM demonstrated 3+ coarse granular interstitial deposits, 3+ vascular staining, and 2+ nuclear
staining. Staining for IgA showed 2+ coarse granular deposits.
There was I vascular staining for C 3 and 1 fibridfibrinogen scattered in the interstitium.
The patient was treated with prednisone, 80 mg/day in
divided doses, and azathioprine, 2.5 mg/kg/day in divided
doses. On this therapy the SGOT fell from 155 to 46 mU/ml,
the C P K from 612 to 60 mU/ml, and the aldolase rose from 18
to 22 mU/ml (n = 1-8). The patient developed a herpes zoster
infection on the right thigh and the azathioprine was discontinued.
Lumbar puncture after institution of high dose steroids yielded clear, colorless, cerebrospinal fluid (CSF). The
opening pressure was 110 mm C S F with normal manometrics.
The CSF contained 0 wbc, 1 rbc, protein 43 mg%, sugar 37
mg%. A VDRL and cultures of the C S F were negative. Serum
complement studies revealed C3, 99 mg% (n = 55-120), and
+
+
984
WEISS ET AL
Figure 1. Left corpus striatum. Thickened blood vessel wall with chronic
inflammatory cell infiltrate. perivascular calcification( A). and parenchymal loss (B). (Hematoxylin and eosin; original magnification X 100.1
Figure 2. LeJi corpus striatum. Markedly thickened blood vessel walls
with extensive perivascular calcifications. (Hematoxylin and eosin; original magnification X 100.1
C4, 59 mg% (n = 20-50). Spinal fluid values were C3, 1.3 mg%
and C4, 0.6 mg%.
The patient was discharged and cared for in a chronic
care facility. She had two subsequent hospitalizations, one for
rupture of the urinary bladder and another for ureteroiliostomy and sigmoid colostomy. She died of complications
from the latter surgical procedure on August 11. 1976. A
postmortem examination was performed.
General autopsy findings relating to the patient’s connective tissue disease involved the kidneys and skeletal muscles. There was moderate focal thickening of glomerular loops
with an eosinophilic hyalin material, and occasional glomerular adhesions. Hematoxylin bodies and wire loop changes were
absent. An inflammatory myopathy of limited extent was evi-
dent in sections from several skeletal muscles. Other lesions
included extensive bilateral bronchopneumonia and right hydronephrosis and hydroureter.
Figure 3. Upper thoracic spinal cord. Marked parenchymal loss in
posterior and lateral columns. (Seuier-Munger silver stain; original magnification X 12.)
Neuropathologic Findings
Grossly the external surfaces of the cerebrum, brain
stem and cerebellum, leptomeninges, and arteries at the base
of the brain were unremarkable. Examination of coronal sections of the cerebral hemispheres disclosed circumscribed foci
of softened, partially calcified parenchyma not exceeding 2.5
cm in maximum diameter in the grey and white matter of the
corpus striatum bilaterally, and in the subcortical white matter of the right middle frontal gyrus. A similar lesion involved
the right pes pedunculi.
The thoracic spinal cord was markedly thin. O n its cut
surface, the normal anatomic markings in the posterior and
lateral columns were effaced. Secondary degenerative changes
involving the posterior and lateral columns were evident above
and below the atrophic thoracic segment.
Microscopically the lesions in the cerebrum and midbrain were similar, consisting of circumscribed parenchymal
necrosis, glial proliferation, and macrophage formation. The
blood vessel walls within the lesions were thickened and contained small numbers of chronic inflammatory cells including
plasma cells (Figure 1 ). Perivascular collections of rounded,
basophilic masses were evident in all of the lesions (Figures 1
and 2). These masses stained positively for calcium with the
von Kossa stain. Toward the periphery of the collections iron
was demonstrated in some of the masses with Perk’ method.
In the spinal cord the most severe lesions were evident
in the upper thoracic segments where there was widespread
loss of axons and myelin sheaths, reactive astrocytosis, and
TRANSVERSE MYELITIS IN MCTD
macrophage formation in the posterior and lateral columns,
and to a lesser extent, in the anterior columns (Figure 3).
Blood vessel changes and deposition of calcific masses similar
to the alterations in the cerebrum accompanied the lesions in
the posterior and lateral columns. The grey mqtter was also
affected at this level with marked loss of neurons from the
anterior and posterior horns. The anterior roots were atrophic
and the pia thickened. Subarachnoid vessels were intact.
Throughout the thoracic cord, similar but less severe lesions
were seen. Secondary degeneration of ascending and descending tracts was evident above and below the thoracic cord.
Sections of the optic nerves, chiasm, and tracts showed
loss of axons and myelin sheaths which was most marked on
the left. Vascular lesions and calcification were absent.
Immunofluorescent studies of the neural tissue were
not performed.
DISCUSSION
The diagnosis of mixed connective tissue disease
can be problematic. As recently reported (4)Raynaud’s
phenomenon, swollen hands, and sclerodermatous
changes occur with much greater frequency in patients
with MCTD than in those with SLE. Our patient lacked
these features. Myositis occurs in both MCTD and SLE
but is more common in the former. As pointed out by
Reichlin ( 5 ) , however, MCTD lacks pathognomic clinical features. The only constant feature is the presence of
antibody t o nuclear RNP; diagnosis of the syndrome
requires serologic confirmation.
This patient meets the serologic criteria for the
diagnosis of MCTD (4). Antibodies to native DNA
were not found by the Farr technique. N o anti-Sm antibody was present by immunodiffusion. The ANA had a
speckled pattern with high titer ENA which completely
digested with RNAse. Other ANA patterns (diffuse and
rim) probably result from antibody against deoxyribonucleoprotein (dNP) (6) particularly since the more sensitive Farr assay for anti-nDNA antibodies was negative.
The immunofluorescent findings on muscle biopsy,
although nonspecific, have previously been reported to
occur in MCTD (7). The presence of epidermal nuclear
staining by direct immunofluorescence has also been
reported as a feature of this syndrome (8).
The central feature in this report is the occurrence of transverse myelitis, a distinctly unusual clinical
manifestation of mixed connective tissue disease. Neurologic abnormalities occur in 10%of patients with this
disease. Most commonly this is a mild trigeminal neuralgia (3). Transverse myelitis has not been reported in
MCTD though it is well recognized as a complication of
SLE. Andrianakos et al. (9) recently reviewed the clinical features of the 17 previously reported cases of my-
985
elopathy associated with SLE and added 3 cases of their
own. Most patients showed anesthetic areflexic paraplegia with loss of bowel or bladder function which
evolved over a day or less. I n 5 patients the myelopathy
developed over a week or more. Half the patients died in
less than 6 weeks. Seven patients had a partial or complete recovery but response to therapy was uncertain or
poor. The clinical aspects of the myelopathy in our
patient do not differ from these cases.
The cerebral, brainstem, and spinal cord parenchymal lesions represent the end stage of a focal or
multifocal necrotizing process. The pathogenesis of the
necrosis is uncertain. Considering the vascular alterations that accompanied the lesions and the circumscribed character of the cerebral and brainstem foci in
our patient, we believe the necrosis developed as a result
of a vasculitis with local tissue ischemia. Although vascular changes aye present within the thoracic cord lesions, the lesions are not so sharply defined as those in
the cerebrum. Nevertheless, the histologic characteristics of the thoracic lesions indicated they may have
developed by confluence of smaller circumscribed necrotic foci. The pathogenesis of the vascular abnormalities in this case is unknown. I n SLE it has been postulated that immune complex deposition leads to arteritis
in the central nervous system producing infarction
(9,lO).
In addition to the cerebral, brainstem, and spinal
cord lesions, optic nerve atrophy was present. Although
the coextensive loss of axons and myelin sheaths may
have resulted from a vasculitis, there is no direct histologic evidence to confirm this supposition.
Sharp has characterized mixed connective tissue
disease as having a “relatively good” prognosis (3). The
mortality rate is 4% in 100 patients followed with a mean
disease duration of 6 years. The incidence of renal disease is 5-10% and neurologic abnormalities 10%.There
is generally a salutary response to steroid therapy imparting significant prognostic implications to a diagnosis of MCTD. However, as Sharp suggests (4), there
may be difficulties in rigidly distinguishing between
MCTD and related rheumatic diseases. This patient had
alopecia, a nondeforming arthritis, leukopenia, and positive LE cell preparations thus meeting the preliminary
criteria for the classification of SLE (11). As noted
above, Raynaud’s phenomenon, swollen hands, and
sclerodermatous changes so characteristic of MCTD (4)
were lacking. This patient exemplifies the problems encountered in delineating SLE and MCTD. Much remains to be done in defining the syndrome, assessing its
clinical spectrum, and understanding its pathogenesis.
986
WEISS ET AL
ACKNOWLEDGMENT
The authors gratefully acknowledge Dr. Susan Wilson
for her help in preparing the neuropathologic material.
6.
REFERENCES
7.
1. Sharp GC, Irvin WS, Tan EM, Gould R G , Holman HR:
2.
3.
4.
5.
Mixed connective tissue disease-an apparently distinct
rheumatic disease syndrome associated with a specific
antibody to extractable nuclear antigen (ENA). Am J
Med 52:148-159, 1972
Sharp GC, Irvin WS, LaRouge RL, Velez C, Daly V.
Kaiser AD, Holman HR. Association of autoantibodies
to different nuclear antigens with clinical patterns of rheumatic disease and responsiveness t o therapy. J Clin Invest
50350-358, 1971
Sharp GC: Mixed connective tissue disease. Bull Rheum
Dis 25:828-831, 1975
Sharp GC, Irvin WS, May C M , Holman H R , McDuffie
FC, Hess EV, Schmid FR: Association of antibodies to
ribonucleoprotein and Sm antigens with mixed connective
tissue disease, systemic lupus erythematosus and other
rheumatic diseases. N Engl J Med 295: 1149-1 154, 1976
Reichlin M: Problems in differentiating SLE and mixed
8.
9.
10.
11.
connective tissue disease. N Engl J Med 295: 1194-1 195,
I976
Fernandez-Madrid F, Mattioli M: Antinuclear antibodies
(ANA): immunologic and clinical significance. Semin Arthritis Rheum 6:83-123, 1976
Oxenhandler R, Hart M, Corman L, Sharp G, Adelstein
E: Pathology of skeletal muscle in mixed connective tissue
disease. Arthritis Rheum 20:985-988, 1977
Gilliam JN, Prystowsky SD: Mixed connective tissue disease syndrome-cutaneous
manifestations of patients
with epidermal nuclear staining and high titer serum antibody to ribonuclease-sensitive extractable nuclear antigen. Arch Dermatol 113583-587, 1977
Andrianakos AA, Duffy J, Suzuki M , Sharp JT: Transverse myelopathy in systemic lupus erythematosus: a report of three cases and a review of the literature. Ann
Intern Med 83:616-624, 1975
Johnson RT, Richardson EP: The neurological manifestations of systemic lupus erythematosus. Medicine 47:337369, 1968
Cohen AS, Reynolds WE, Franklin EC, Kulka JP, Ropes
MW, Shulman LE, Wallace SL: Preliminary criteria for
the classification of SLE. Bull Rheum Dis 21:643-648,
1971
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