EDITORIAL

Multiple Sclerosis and S jogren’s Syndrome: A Problem in Diagnosis or in Definition of

Two Disorders of Unknown Etiology?

Neurological abnormalities in patients with collagen- vascular diseases vary in frequency depending on the disorder. Central nervous system lesions are relatively uncommon in scleroderma and frequent in systemic lupus erythematosus (SLE). Symptoms and signs refer- rable to the nervous system may be the first mani- festation of one of these diseases/syndromes, and the patient may not manifest extra-nervous system in- volvement for months or years 111. These disorders are immunopathologically mediated. Disease may re- sult from immune complex deposition, autoantibodies, cellular infiltrates, and cell-mediated cytotoxicity. We have learned much about the different mechanisms in- volved in tissue damage, but there are still major un- answered questions 121.

In some of these disorders, especially those in which a primary or secondary vasculitis or vasculopathy oc- curs, deposition of immune complexes seems to be the important disease-inducing process. In other disorders, such as certain of the primary vasculitides, including isolated angiitis of the nervous system, a cell-mediated disorder or an antibody-triggered process against a vas- cular antigen or both may be important 131. Finally, antibodies directed at a cellular antigen, especially when that antigen is a component of the cell surface membrane, can cause cell dysfunction, cell sequestra- tion, or direct cell destruction. In SLE several mecha- nisms may be important in the production of different manifestations of the disease. Nephritis, mononeurop- athy multiplex, and microhemorrhagic infarcts likely represent, in large part, immune complex deposition. Hemolytic anemia, thrombocytopenia, and perhaps certain more diffuse nervous system manifestations, such as seizures and psychosis, may result from anti- bodies directed at surface components of the target cell.

There are well-established criteria for some of these disorders, such as SLE 141, but for others, including primary Sjogren’s syndrome (SS), this is not the case. SS is a chronic autoimmune inflammatory disease char- acterized by diminished lacrimal and salivary gland se- cretion resulting in keratoconjunctivitis sicca and xero- stomia. It is usually a relatively benign disease of older women but it may progress to a malignant lymphoma. Primary and secondary forms of SS appear to exist, the

latter associated with rheumatoid arthritis and other autoimmune diseases. In the primary form, the classic symptoms are dry eyes and dry mouth [5,6]. There is a strong genetic component (HLA-B8-DR3). Patients usually have lymphocytic infiltration on lip biopsy and the presence of antinuclear antibodies to ROES-A and WSS-B. Both peripheral and central nervous system abnormalities occur in patients with SS. The common trigeminal neuropathy is due to a vasculitis and there is evidence for a vasculitic component of the peripheral neuropathies and the central nervous system signs 17-91.

There is no consensus on the specificity and sensitiv- ity of minor salivary gland biopsy and serological tests for Sjogren’s syndrome, as is noted in the article by Mir6 and associates in this issue 1101 and the accom- panying correspondence by Drs Alexander and McFarland 11 11 and Dr Noseworthy and his associates 1121. Consequently there is controversy regarding the need to perform some of these studies, especially in a group of patients who otherwise have clinically definite multiple sclerosis (MS) with paraclinical and/or labora- tory support 1131.

Autoantibody formation is a normal, transient phe- nomenon of both humans and animals and most often a part of the preimmune B cell repertoire C14, 151. In several diseases, specific circulating antibodies are per- sistent 1161. The anti-Ro/SS-A and anti-WSS-B are a group of antibodies that bind to biologically interesting nonsurface components of cells. Ro/SS-A consists of two proteins (60 and 52 kDa) complexed with 4 to 5 small RNAs. WSS-B is a 48-kDa protein required for the termination of RNA polymerase transcription 1171. It is frequently in close but elusive association with SS-AIR0 [lb}. These antibodies are relatively specific for SS but may have little or nothing to do with pathogenic mechanisms in this disease. In addition there is some problem with intralaboratory variability in the assays for these antibodies.

MS is a multifocal inflammatory demyelinating dis- ease of the central nervous system of unknown cause. Although it seems clear that it is mediated by cells of the immunological system and therefore is probably immunopathologically mediated, it is far from certain that it is autoimmune in etiology.

Copyright 0 1990 by the American Neurological Association 585

Despite the enormous advances in techniques for imaging (magnetic resonance imaging) and clinical neu- rophysiology (evoked potentials) to demonstrate dis- semination within the nervous system and the greater availability of sensitive measures for studying abnor- malities in spinal fluid immunoglobulins and their syn- thesis, the diagnosis of MS still remains clinical 1131. There is no “laboratory test” for MS, and one of the criteria for MS is that there be no other reasonable alternative diagnosis. The possibility that a patient has another disorder, including a collagen-vascular or con- nective tissue disease, should always be kept in mind, especially early in the course of the disease. Certainly SLE, Behget’s syndrome, and primary SS are among these possible alternative diagnoses in some patients, and Dr Alexander has done a service in reminding neurologists of this possibility. The work of Mir6 and colleagues and Noseworthy and colleagues, however, suggests that the incidence of SS as an alternative diag- nosis to MS among a population of randomly selected patients who otherwise meet the criteria for clinically definite MS with or without paraclinical and/or labora- tory support or clinically probable MS with similar support is very low indeed. This seems to be true even if the answer to the questions “Do you have dry eyes? Do you have a dry mouth?” is yes in as many as one- third of the MS patients for each question.

It is certainly possible that patients with MS may have secondary SS which is associated with other puta- tive autoimmune/immunopathologically mediated dis- eases, including rheumatoid arthritis, primary biliary cirrhosis, and scleroderma. The presence of anti-Ro or anti-La does not insure that a patient has primary SS 116, 181. Patients with MS may have modest elevations of antinuclear antibody titers 1191 or immune com- plexes [ZO]. There are reports of MS and myasthenia gravis in the same patient 1211 and some have sug- gested that there is a higher incidence of other non- nervous system autoimmune diseases in patients with MS.

Until we have tests that can unequivocally diagnose and define MS and primary SS and apply these to a population-based study of MS patients, the debate will and should continue. As clinicians, we must always consider alternative or additional diagnoses in patients with MS.

Patricia M . Moore, MD Robert P . Lisak, MD Department of Neurology Wayne State University School of Medicine Detroit, MI

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