Optic neuritis transverse myelitis and anti-DNA antibodies nine years after thymectomy for myasthenia gravis.

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OPTIC NEURITIS, TRANSVERSE MYELITIS, AND ANTI-DNA
ANTIBODIES NINE YEARS AFTER THYMECTOMY FOR
MYASTHENIA GRAVIS
MICHEL GOLDMAN, ALAIN HERODE, SAMUEL BORENSTEIN. and ANDRE ZANEN
The occurrence of several autoimmune disorders in the same individual is a frequent observation.
An impairment of T suppressor cells could be involved
in the pathogenesis of these syndromes, as suggested
by the T cell abnormalities that are often encountered
in patients with autoimmune diseases. We report the
occurrence of optic neuritis and transverse myelitis
associated with serologic features of systemic lupus
erythematosus (SLE) in a young woman who underwent thymectomy for myasthenia gravis. A particular
genetic background and T cell abnormalities could
have played a role in the development of this autoimmune syndrome. The problem raised by the diagnosis
of SLE in patients with neurologic symptoms and the
possible confusion with multiple sclerosis will be emphasized.
Case report. A IZyear-old girl was examined in
1958 for dipoplia and diffuse muscular weakness. Her
family history was unremarkable except that her mother suffered from systemic lupus erythematosus. Electromyographic studies showed typical features of myasthenia gravis, and anticholinesterase drugs initially
resulted in dramatic improvement of the symptoms. In
~~
From the Departments of Nephrology, Ophthalmology, and
Neurology, HBpital Erasme, Universite Libre de Bruxelles. Brussels. Belgium.
Michel Goldman, MD: Resident, Department of Nephrology; Alain Herode. MD: Resident, Departmcnt of Ophthalmology;
Samuel Borenstein, MD: Senior Consultant, Department of Neurology; Andrk Zanen, MD: Chief, Department of Ophthalmology.
Address reprint requests to Michel Goldman, MD, Department of Nephrology, HBpital Erasme, UniversitC Libre de Bruxelles. 808 Route de Lennick. B-1070 Brussels, Belgium.
Submitted for publication Ahgust 30, 1983; accepted in
revised form January 10, 1984.
Arthritis and Rheumatism, Vol. 27, No. 6 (June 1984)
1971 however, the disease worsened and a thymectomy was performed. Myasthenic symptoms were thereafter well-controlled with low doses of ambenonium
chloride.
In September 1980, she suddenly complained of
blurred vision in the left eye. The visual impairment
progressed rapidly to nearly complete loss of vision in
the left eye with decreased visual acuity (3/10) in the
right eye. Paresis of the upward conjugate gaze and
dissociated nystagmus of the abducting eye were noted. The optic disc and retina were normal in both eyes.
Studies of visual evoked cortical potentials revealed a
marked delay in her responses, especially after stimulation of the left eye. Laboratory test values were
remarkable only for an increased erythrocyte sedimentation rate (48 mmihour) and plasma fibrinogen level
(557 mg/dI). Urine sedimentation was normal and no
proteinuria was found. Examination of cerebrospinal
fluid gave the following results: leukocytes 15/mm3,
erythrocytes 2/mm3, glucose 54 mg/dl, protein 70 mg/
dl with an increased gamma globulin fraction (20%),
and presence of oligoclonal bands on isoelectrofocusing analysis. Prednisolone 30 mg/day was started, the
optic neuritis improved, and there was a complete
recovery of right eye vision, but a central scotoma
persisted in the left eye.
One year later, she was admitted to our institution for rapidly progressive right-sided hemiparesis
and sensitory defect in the left arm. A diagnosis of
transverse myelitis was made, and increased immunoglobulin level in the cerebrospinal fluid was noted
again with the same oligoclonal pattern as previously
observed. At that time, serum was found to contain
antinuclear antibodies giving a homogeneous pattern
at a titer of 1 :2,560, with the presence of anti-Sm and
702
anti-double-stranded DNA antibodies as assessed by a
Farr assay and by immunofluorescence testing on Crithidiu luciliue (titer 1 :80). Hematologic values and
complement levels were normal. Coombs’ test, VDRL
test, and a rheumatoid factor assay gave negative
results. No cryoglobulin was found.
Quantification of T cell subsets, expressed as a
percentage of circulating mononuclear cells, gave the
following results: OKT3 + cells 60% (normal 50-80%),
OKT4-t (helperhnducer) cells 47% (normal 38-55%),
OKT8+ (suppressorkytotoxic) cells 13% (normal 1830%). HLA typing was A l , Aw31; B27, B8; Cw2, DR5
DRw6. High-dose corticosteroids were administered
and the right hemiparesis progressively improved.
After a transient episode of left arm hemiparesis, the
patient recovered a satisfactory neurologic status, and
the corticosteroid dosage was gradually tapered. One
year later, antinuclear antibodies were still present,
but T cell subset abnormalities had disappeared
(OKT3+ cells 65%, OKT4+ cells 47%, OKT8+ cells
20%).
Discussion. This patient with serologic features
of SLE successively developed transient optic neuritis
and transverse myelitis that improved after corticosteroid therapy. Although the criteria for classification of
SLE (1) were not fulfilled, the presence of antidouble-stranded DNA and of anti-Sm antibodies is
strongly suggestive of an SLE-related autoimmune
disease. Indeed, the clinical spectrum of neurologic
abnormalities in SLE includes optic neuritis and transverse myelitis that may occur as isolated manifestations of the disease (2-5).
Interestingly, these patients exhibit an increased incidence of anti-Sm antibodies (4) which
were present in our patient. Pathologic examination of
this type of lesion has only been obtained in few cases
(2,3). Small vessel changes were reported in most
observations whereas, in some patients, demyelinization without significant vascular lesions was a major
feature. Thus, the neurologic manifestations of SLE
may occasionally be very similar to those observed in
multiple sclerosis (5). The differential diagnosis can be
difficult, especially when oligoclonal banding in cerebrospinal fluid is present as in our observation. The
significance of oligoclonal banding in SLE (6) remains
to be determined. It could reflect a preferential activation of a limited number of B cell cloncs that are
involved in a local production of immunoglobulins.
Another possibility is that these oligoclonal
immunoglobulins represent circulating antineuronal
antibodies that crossed the blood-brain barrier, accu-
BRIEF REPORTS
mulated specifically in the neuronal tissues, and were
subsequently released in the cerebrospinal fluid (7).
Indeed, Zvaifler and Bluestein have suggested that
certain forms of neurologic disease in SLE could result
from the coexistence of serum antibodies against neuronal tissue and an alteration in the blood-brain barrier, presumably due to immune complexes (7). Isolated
neurologic manifestations in SLE may be more common than currently believed; our observation indicates
that one should systematically search for serologic
markers of SLE in patients with transient neurologic
disorders such as optic neuritis and transverse myelitis, even when cerebrospinal fluid displays oligoclonal
banding suggestive of multiple sclerosis. Unfortunately, precise criteria for the diagnosis of neurologic lupus
erythematosus are not well-established and there is a
need for a classification of this disorder (8).
Our patient initially presented with myasthenia
gravis and it is known that myasthenia gravis may be
associated with a variety of autoimmune diseases,
including SLE. Manifestations of SLE have usually
been found to follow the onset of myasthenia gravis,
with a highly variable time interval (9). In our patient,
thymectomy had been performed 9 years before the
occurrence of the SLE-related neurologic disease.
This sequence of events has previously been reported,
with an interval between thymectomy and diagnosis of
SLE ranging from 4-9 years (10). It has been suggested that this association could be favored by the loss of
T suppressor cells that follows thymectomy in patients
with myasthenia gravis ( 1 1).
A decrease in OKT8+ (suppressorkytotoxic) T
cells was found in our patient at the time of transverse
myelitis, but normal values were obtained after recovery. Thus, T cell subset modifications in our patient
appear merely to reflect disease activity rather than to
be directly involved in the pathogenesis of the autoimmune syndrome. It is likely that a particular genetic
background has played some role in this process.
There was a familial history of autoimmune disease,
and HLA typing disclosed B8 antigen that occurs
significantly more frequently in patients with myasthenia gravis (12). Moreover, in 3 of 7 cascs of myasthenia
gravis associated with SLE, the A1 B8 haplotype that
our patient had was found (9).
REFERENCES
1. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ,
Rothfield NF, Schaller JG, Tala1 N , Winchester RJ: The
BRIEF REPORTS
2.
3.
4.
5.
6.
1982 revised criteria for the classification of systemic
lupus erythematosus. Arthritis Rheum 25: 1271-1277,
1982
April RS, Vansonnenberg E: A case of neuromyelitis
optica (Devic’s syndrome) in systemic lupus erythematosus: clinicopathologic report and review of the literature. Neurology 26: 1066-1071, 1976
Andrianakos AA, Duffy J, Suzuki M, Sharp JT: Transverse myelopathy in systemic lupus erythematosus:
report of 3 cases and review of the literature. Ann Intern
Med 83:616-623, 1975
Winfield JB, Brunner CM, Koffler D: Serologic studies
in patients with systemic lupus erythematosus and central nervous system dysfunction. Arthritis Rheum
21:289-294, 1978
Fulford KWM, Catterall RD, Delhanty JJ, Doniach D,
Kremer M: A collagen disorder in the nervous system
presenting as multiple sclerosis. Brain 95:373-377, 1972
Hershey LA, Trotter JL: The use and abuse of the
cerebrospinal fluid IgG profile in the adult: a practical
evaluation. Ann Neurol 8:426-434, 1980
703
7. Zvaifler NJ, Bluestein HG: The pathogenesis of central
nervous system manifestations of systemic lupus erythematosus. Arthritis Rheum 25:862-866, 1982
8. Kassan SS, Lockshin MD: Central nervous system
lupus erythematosus: the need for classification. Arthritis Rheum 22:1382-1385, 1979
9. Mizon JP, Morcamp D, Lefebvre P, Froissart M, Guidicelli CP, Goasgen J: Associated myasthenia and systemic lupus erythematosus: a report of two cases and review
of the literature. Ann Med Interne (Paris) 11:489-500,
1979
10. Kennes B, Delespesse G, Vandenbosche JL, Sternon J:
Systemic lupus erythematosus triggered by adult thymectomy in myasthenia gravis patient: report of a case.
Acta Clin Beig 33: 110-1 16, 1978
1 1 . Birbaum G, Tsairis B: Suppressor lymphocytes in myasthenia gravis and effect of adult thymectomy. Ann NY
Acad Sci 274527-534, 1976
12. Pirkanen R: Genetic associations between myasthenia
gravis and the HLA system. J Neurol Neurosurg Psychiatry 39:23-33, 1976