The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

November 3, 2009 — The most general lesion in SLE is a vasculopathy characterized by fibrinoid necrosis primarily involving small arteries, arterioles, and capillaries. Interstitial collagen and membranes such as pleura, serosa, and joint capsules may also be involved, and the disease is characterized by some characteristic organ-specific responses, such as focal and diffuse proliferative glomerulonephritis and Libman-Sacks endocarditis. Vasculitis occurs in some patients and is best classified as a hypersensitivity angiitis. More recently, a thrombotic, mainly microangiopathy, has been described that affects up to 50% of SLE patients with circulating antiphospholipid antibodies (APAs), as well as patients without SLE who have these antibodies. 36 This results in infarcts ranging from 2 mm to 3 cm in size. This disorder plays a particularly important role in the pathogenesis of central nervous system (CNS) disease, and currently the relative roles of lupus vasculopathy and antiphospholipid-associated microangiopathy in producing CNS manifestations of SLE are uncertain.

The incidence of SLE is 1.8-7.6/100,000/year, and the prevalence is 39 to 51/100,000. The disease is six to nine times more common among women and is several times more common among African-Americans. It may affect people of any age but is primarily a disease of young and middle-aged adults. Major clinical manifestations are detailed in Table 1 and neurologic manifestations in Table 2. In 85% of cases, neuropsychiatric manifestations develop in the context of systemic disease activity; however, seizures, chorea, and myelopathy may appear early, before the diagnosis of SLE has been made, and stroke, which is usually caused by APAS, may occur at any time because fluctuations in the titers of these antibodies are not tightly correlated with Systemic disease activity.

The dementia of SLE may acutely be characterized by Attention impairment with impaired alertness, distractibility, delirium, or coma, in which case CNS or systemic infection must also be considered. Psychotic features may develop in this setting. Cognitive disorders such as aphasia, apraxia, and visuospatial dysfunction may also be caused by large vessel distribution hemispheric stroke; however, there is also some evidence of insidious chronic cognitive decline in patients with SLE, more certainly in those who have experienced acute episodes of delirium, but also in patients who have never exhibited overt acute cognitive dysfunction. 15 The most consistent deficits involve verbal and nonverbal memory, visuospatial skills, verbal production, and psychomotor speed. Evidence of cerebral atrophy is common.

Table 1.  Major clinical manifestations of systemic lupus erythematosus*

*From 21, 24, 26, 30, 39, 55

Table 2.  Neuropsychiatric manifestations of systemic lupus erythematosus*

*From 21, 24, 26, 30, 39, 55.

Seizures may be focal or generalized and often are temporally limited to the duration of a flare of CNS disease.

Cranial nerve signs most often reflect intra-axial lesions. Oculomotor disorders (including gaze palsies, intemuclear ophthalmoplegia, and skew deviation), and seventh nerve palsies are the most common, but optic neuritis and sensorineural hearing loss have been reported. 26,30,38,39,41

Although many clinicians have inferred an increased risk of migraine in patients with SLE, a recent case control study failed to demonstrate a prevalence different from that in a control population. 64 Pseudotumor cerebri has been reported and in a number of cases related to venous sinus thrombosis. Aseptic meningitis occurs rarely in SLE, but more often the meningitis is caused by infectious organisms, and rarely is it associated with treatment (nonsteroidal anti-inflammatory drugs or azathioprine).

More than 100 cases of myelopathy have been reported, most often presenting as acute transverse myelitis, usually localized to the thoracic cord, and often in association with optic neuritis. 46 It is typically an early manifestation of SLE. A mild CSF pleocytosis, at times polymorphonuclear predominant, is noted in 50% of cases, and hypoglycorrhachia has been reported in 100% of patients tapped acutely Some patients may experience recurrence.

Chorea has been reported in nearly 100 cases of SLE, often as an initial manifestation and usually in young patients (average age 19).

Polyneuropathy in SLE is usually modest, limited to sensory manifestations confined to the legs and minor involvement of foot musculature, but mononeuritis multiplex, reflecting superimposed vasculitis, may be seen. Approximately half of SLE patients have pathologic evidence of myopathy but in most cases, this is limited to scant inflammatory infiltrates, type II fiber atrophy (related to steroid treatment), or subclinical vacuolar myopathy (not always associated with chloroquine (Aralen) treatment), and only rarely is there actual polymyositis.

• Pathogenesis and Clinicopathologic Correlation

SLE represents the most complex and variable of the connective tissue diseases. Nevertheless, rapid progress is being achieved in sorting out the immunopathogenesis; it is not possible to review this now sizable literature here. Comparable progress has been made in understanding the pathogenesis of neurologic manifestations. Most neurologic manifestations can be accounted for in terms of antineuronal antibodies, APAS, lupus vasculitis, or lupus vasculopathy

• AntineuronalAntibodies

Observed neuropathologic changes have never appeared to offer a satisfactory explanation for encephalopathy and psychosis in SLE. Serum antibodies to neuronal and glial antigens, antilymphocyte antibodies that cross-react with brain tissue, and antiglycolipid antibodies that cross-react with lymphocytes are found in up to 90% of SLE patients, and a number of studies show strong associations between such antibodies and CNS disease. There is compelling evidence implicating at least three particular antineuronal antibodies in the causation of CNS manifestations. Several groups of investigators have found that serum antibodies to the cytoplasmic antigen, ribosomal protein P, are both sensitive and specific for depression and psychosis in SLE. 11,65,69 Serial measurements of anti- P titers correlate with clinical signs. Bluestein et al 10,76 found elevated cerebrospinal fluid (CSF) immunoglobulin antibody titers to a neuroblastoma cell line, SK-N-SH, in 75% of patients with active CNS lupus, including 90% of those with psychosis, dementia, or seizures, compared with only 10% of, SLE patients without active CNS disease, and 5% of non- SLE neurologic controls. Finally, a high prevalence of serum antibodies to neurofilaments has been reported in SLE patients with nonfocal CNS disease (delirium, confusion, memory loss, psychosis, affective dis, seizures). 6,60

• Antiphospholipid Antibodies

Most thrombotic events in SLE occur in association with a heterogeneous mix of circulating IgG and IgM antibodies molecules that have in common a strong affinity for negatively charged phospholipids, hence the name APAS. Some of these APAs can bind to the phospholipid that forms, with coagulation factors V and X, the prothrombin activator complex, thereby inhibiting the conversion of prothrombin to thrombin. Thus, they have anticoagulant properties in vitro, hence the name lupus anticoagulant (LAC). In vivo, many APAS, including some LACS, are procoagulant. The mechanism underlying this effect is uncertain. LAC is measured with functional assays, such as an LAC-sensitive activated partial thromboplastin time (aPTT), or a dilute Russell’s viper venom time (DRVVT). In an effort to develop a more convenient assay for APAS, investigators at Hammersmith Hospital in London, capitalizing on the common association between LAC and a biologic false-positive VDRL, developed the anticardiolipin antibody (aCL) test, now available as an enzyme-linked immunosorbent assay (ELISA). 33 Unfortunately, not all aCLs have LAC activity, and many aCLs and antibodies with LAC activity do not have prothrombotic effects, thus accounting for the substantial number of patients who have APAs but no evidence of a thrombotic diathesis. This has vastly complicated the task of understanding the roles of APAs in various thrombotic phenomena and frustrated clinicians attempting to use these assays to guide treatment.

Antiphospholipid antibodies are associated with venous and arterial thrombosis, spontaneous abortion (probably caused by placental thrombosis), and thrombocytopenia. 5 These features define the APA syndrome-primary when it occurs in isolation (approximately 50% of the time), secondary when it occurs in the context of SLE. High titers of aCL (5 SD above the mean is the usual cut-off) have much better specificity for thrombotic events. IgG aCL is more strongly associated with thrombosis than IgM aCL, which can be generated under a variety of circumstances (most particularly infections) that have nothing to do with SLE or thrombotic risk. APA titers tend to remain stable for long periods of time and are not particularly linked to systemic SLE activity. Stroke risk associated with APAs is potentiated by the presence of other risk factors for stroke, such as oral contraceptive use, smoking, and hypertension. Strokes of all types have been reported, but cortical branch artery occlusions are the most common and there is often evidence of multiple infarcts. Many affected patients have multiple small areas of increased signal in the centrum semiovale on T2-weighted or fluid attenuated inversion recovery (FLAIR) magnetic resonance images. Cerebral atrophy is a common late finding. Although cardiac valvular pathology is frequently observed in these patients (aortic and mitral valve thickening and regurgitation), vegetations are rarely seen, and it remains unclear whether these various ischemic events reflect in situ thrombosis or cardiogenic embolism.

A number of studies implicate APAs in the eventual development of vascular dementia. Insidious cognitive decline in the absence of evidence of vascular lesions may be related to the presence of antineuronal anti- bodies. Lupus chorea is strongly associated with the presence of APAS; however, pathologic studies do not provide any evidence of vascular lesions in the basal ganglia in affected patients. Cerebral venous sinus thrombosis is linked to APAs in many cases.

• Vasculitis

CNS Vasculitis is uncommon in SLE. There is an association between Vasculitis (usually defined pathologically, occasionally through angiography) and both ischemic and hemorrhagic CNS events; however, most ischemic events, as noted, are related to the presence of APAS. Thus, it is intracranial hemorrhage, both parenchymal and subarachnoid, that is the strongest clinical index of CNS Vasculitis. In an autopsy series, Ellis and Verity 23 found hemorrhage (gross or microscopic) in 86% of patients with demonstrable Vasculitis and 36% of those without; subarachnoid hemorrhage was found in 71% of those with Vasculitis and 24% of those without. Vasculitis should also be considered in the lupus patient with ischemic stroke, normal echocardiography, and no evidence of APAS, particularly in the presence of very active systemic disease.

• Uncertain or Multifactorial Pathogenesis

The pathogenesis of several neurologic manifestations of SLE is either uncertain or likely to be multifactorial. Lupus myelitis appears to be ischemic in origin, but it is unclear whether this reflects the effects of lupus vasculopathy, APAS, or lupus Vasculitis. Anecdotal reports have linked migraine in SLE to the presence of APAS, but several case-control studies have failed to support this conclusion. Seizures have been linked to micro-infarcts and APAS, but tend to occur during flares of systemic and CNS lupus activity (encephalopathy), thereby indirectly implicating antineuronal antibodies or immune-related vasculopathy in their pathogenesis.

• Diagnosis

The diagnosis of SLE is a clinical one. The American Rheumatism Association criteria (Table 3) provide a useful guideline. The presence of four or more criteria achieves a 96% sensitivity and 96% specificity for SLE.

Of all the serologic tests available, the fluorescent antinuclear antibody test is the most sensitive but the least specific. Antibodies to any one of several antigens will produce a positive test, and the pattern of fluorescence observed provides some information regarding the antibody. Anti- n-dsDNA (native, double-stranded DNA) produces a homogeneous pattern. It has modest sensitivity for SLE (<70%) but very high specificity (95%). Anti-Smith (Sm) or anti-RNP (the combination of which constitutes so-called extractable nuclear antigen), produces a speckled pattern. It is often present in very high titer, and is the least specific pattern. Antibody to nucleolar ribonucleic acid (RNA) produces a nucleolar pattern. Most lupus patients have antibodies to a large variety of native antigens: nuclear, cytoplasmic, and membranous. Complement assays are most useful as a measure of disease activity. Tests for APA (both LAC and aCL) should be obtained in all patients with CNS involvement. At least two different assays should be used for LAC (e.g., LAC-sensitive APTT, kaolin clotting time, thromboplastin inhibition test, DRVVT, hexagonal phase assay). Only high-titer IgG aCL is likely to be significant. Many laboratories also routinely test for antibodies to antiphosphotidyl serine and antiphosphotidyl inositol. There is scant clinical evidence that these antibodies are predictive of a thrombotic diathesis. Beta-2 glycoprotein-1 is an essential component of the antigen complex recognized by aCL. Assays for antibodies to this factor (not yet widely available) show greater sensitivity and specificity for thrombotic events than aCL. 5

Table 3. Revised american rheumatism association criteria for classification of systemic lupus erythematosus,

• Malar rash
• Discoid lupus
• Photosensitivity
• oral ulcers
• Arthritis
• Proteinuria > 0.5 gm/day or cellular casts
• Seizures or psychosis
• Pleuritis or pericarditis or lymphopenia or thrombocytopenia
• Hemolytic anemia or leukopenia E ceus, or false-positive VDRL
• Antibody to DNA or Sm antigen, presence of L
• Positive fluorescent antinuclear antibody test

Patients with diffuse CNS manifestations are likely to have antineuronal antibody disease, and appropriate serum and CSF assays for these may be helpful. Patients with focal CNS manifestations and focal abnormalities on MRI may have clinically significant APAs or cerebral vasculitis. The diagnosis of vasculitis is favored if the CNS disease occurs in the context of very active systemic disease, if there is evidence of intracranial hemorrhage, or if assays for APAs are negative and echocardiography is normal.

• Treatment

The general treatment of SLE has become complex and nuanced and cannot be adequately summarized here, where the focus is exclusively on neurologic disease.

The treatment of choice for lupus encephalopathy is corticosteroids in moderate dosages (e.g., 60-100 mg/day, prednisone equivalent). Megadose pulse steroids (1 gm/day for 3 days) are often employed but there is no evidence that they offer an advantage, but they clearly increase risk of infection. Worsening of encephalopathy or the development of psychosis during steroid treatment should always raise the question of intercurrent infection, but most often it will reflect the effects of steroids on emotional tone, stress associated with hospitalization, and sleep disruption in patients already cognitively impaired by their disease. Assuming infection has been ruled out, steroids should be maintained and suitable measures taken to ensure adequate sleep and an appropriate day-night cycle. Most experienced clinicians advocate rapid tapering as soon as encephalopathy subsides.

There is accumulating evidence that the acute administration of megadose -pulse corticosteroids may have a substantial impact on the outcome of lupus myelitis, if initiated sufficiently early. 56

Monthly pulse intravenous cyclophospha nide (Cytoxan) (up to I gm/ m) may be indicated if there is CNS (e.g., i intracerebral hemorrhage or myelopathy) or peripheral evidence (e.g., mononeuritis multiplex) of vasculitis, and has been employed in patients NA ho most likely have had antineuronal antibody mediated disease; however, there have been no controlled trials. Plasmapheresis has not been systematically tested either, but has theoretical rationale in patients with either vasculitis or antineuronal antibody-mediated disease.

There has never been a randomized controlled trial of anticoagulation or anti-platelet agents in the treatment of venous or arterial thrombotic events associated with APAS; however, a well-done retrospective study suggests that only high-intensity anticoagulation with warfarin (Coumadin) (INR 3), with or without adjuvant aspirin, substantially lowers thromboembolic risk. 42 There is no evidence that immunosuppressive agents have a significant impact on APAS. Despite its association with APAS, chorea does not clearly respond to anticoagulants or immunosuppressants, and is overwhelmingly a self-limited phenomenon, resolving within a month in 58% of patients and only rarely persisting beyond 6 months. 14

Several drugs, including phenytoin (Dilantin), are implicated in the causation of a lupus-like syndrome, most likely because of induced immunoresponsiveness to the DNA-histone complex; however, there is no contraindication to using these drugs when clinically indicated in the patient with SLE.

References

1. Akman-Demir G, Baykan-Kurt B, Serdaroglu P, et al: Seven-year follow-up of neurologic involvement in Behcet syndrome. Arch Neurol 53:691-694,1996

2. Akman-Demir G, Serdaroglu P, Tasci B: Clinical patterns of neurological involvement in Behcet ‘s disease: Evaluation of 200 patients. Brain 122:2171-2182,1999

3. Alexander E McFarland H: Sjogren’s syndrome and multiple sclerosis. Neurol 29:45-56, 1991

4. Allen NB, Cox CC, Cobo M, et al: Use of immunosuppressive agents in the treatment of severe ocular and vascular manifestations of Cogan’s syndrome. Am J Med 88:296-301, 1990

5. Amigo MC, Khamashta MA: Antiphospholipid (Hughes) syndrome in systemic lupus erythematosus. Rheum Dis Clin North Am 26:33-1-348,2000

6. Bell CL, Partington C, Robbins M, et al: Magnetic resonance imaging of central nervous system lesions in patients with lupus erythematosus. Correlation with clinical remission and antineurofilament and anticardiolipin antibody titers. Arthritis Rheum 34:432- 441,1991

7. Bennett RM, Bong DM, Spargo BH: Neuropsychiatric problems in mixed connective tissue disease. Am J Med 65:955-962,1978

8. Bennett RM, O’Connell DJ: Mixed connective tissue disease: A clinicopathologic study of 20 cases. Semin Arthritis Rheum 10:25-30,1980

9. Berg AM, Kasznica J, Hopkins P, Simms RW: Relapsing polychondritis and aseptic meningitis. J Rheumatol 23:567-569,1996

10. Bluestein HG, Pischel KD, Woods VL: Immunopathogenesis of the neuropsychiatric manifestations of systemic lupus erythematosus. Springer Semin Immunopathol 9:237- 249,1986

11. Bonfa E, Golombek Sj, Kaufinan LD, et al: Association between lupus psychosis and antiribosomal P protein antibodies. N Engl J Med 317:265-271, 1987

12. Brink H, Rademakers J, Verbeek A, et al: Ocular manifestations of relapsing polychondritis. Doc Ophthalmol 87:159-166,1994

13. Brod S, Booss J: Idiopathic CSF pleocytosis in relapsing polychondritis. Neurology 38:322-323,1988

14. Bruyn GW, Padberg G: Chorea and systemic lupus erythematosus. A critical review. Eur Neurol 23:278-290,1984

15. Carbotte RM, Denburg SD, Denburg JA: Cognitive deficit associated with rheumatic diseases: Neuropsychological perspectives. Arthritis Rheum 38:1363-1374, 1995

16. Casey ATH, Crockard A: In the rheumatoid patient: Surgery to the cervical spine. Br j Rheumatol 34:1078-1086,1995

17. Chajek T, Fainaru M: Behcet’s disease. Report of 41 cases and a review of the literature. Medicine 54:179-196,1975

18. Clements Pj, Furst DE, Campion DS, et al: Muscle disease in progressive systemic sclerosis. Arthritis Rheum 21:62-71, 1978

19. Dessein PH, Joffe BI, Metz RM, et al: Autonomic dysfunction in systemic sclerosis: Sympathetic overactivity and instability. Am J Med 93:143-150, 1992

20. Devlin T, Gray L, Allen NB, et al: Neuro-Behcet’s disease: Factors hampering proper diagnosis. Neurology 45:1754-1757,1995

21. Dubois EL, Tuffanelh DL: Clinical manifestations of systemic lupus erythematosus: Computer analysis of 520 cases. JAMA 190:104-111, 1964

22. Dyck PJB, Hunder GG, Dyck Pj: A case-control and nerve biopsy study of CREST multiple mononeuropathy. Neurology 49:1641-1645,1997

23. Ellis SG, Verity MA: Central nervous system involvement in systemic lupus erythematosus: A review of neuropathologic findings in 57 cases, 1955-1977. Semin Arthritis Rheum 8:212-221, 1979

24. Estes D, Christian CL: The natural history of systemic lupus erythematosus by prospective analysis. Medicine 50:85-95,1971

25. Farah S, Al-Shubaili A, Montaser A, et al: Behcet’s syndrome: A report of 41 patients with emphasis on neurological manifestations. j Neurol Neurosurg Psychiatry 64:382- 384,1998

26. Feinglass EJ, Arnett FC, Dorsch CA, et al: Neuropsychiatric manifestations of systemic lupus erythematosus: Diagnosis, clinical spectrum, and relationship to other features of the disease. Medicine 55:323-339,1976

27. Follansbee WP, Zerbe TR, Medsger TA: Cardiac and skeletal muscle disease in systemic sclerosis (scleroderma): A high risk association. Am Heart j 125:194-203, 1993

28. Grant IA, Hunder GG, Homburger HA, Dyck Pj: Peripheral neuropathy associated with sicca complex. Neurology 48:855-862,1997

29. Griffin JW, Cornblath DR, Alexander E, et al;: Ataxic sensory neuropathy and dorsal root ganglionitis associated with Sjogren’s syndrome. Ann Neurol 27:304-315,1990

30. Grigor R, Edmonds J, Lewkonia R, et al: Systemic lupus erythematosus: A prospective analysis. Ann Rheum Dis 37:121-128,1978

31. Hagen NA, Stevens JC, Nbchet Cj: Trigeminal sensory neuropathy associated with connective tissue disease. Neurology 38(Suppl 1):210A, 1988

32. Hanslik T, Wechsler B, Piette J-C, et al: Central nervous system involvement in relapsing polychondritis. Clin Exp Rheumatol 12:539-541, 1994

33. Harris EN, Gharavi AE, Boey ML, et al: Anti-cardiolipin antibodies: Detection by radioimmunoassay and association with thrombosis. Lancet 2:1211-1214,1983

34. Haynes BF, Kaiser-Kupfer ML Mason P, Fauci AS: Cogan’s syndrome: Studies in thirteen patients, long-term follow-up and a review of the literature. Medicine 59:426-441, 1980

35. Hughes JT- Spinal cord involvement by C4-C5 vertebral subluxation in rheumatoid arthritis: A description of 2 cases examined at necropsy. Ann Neurol 1:575-582, 1977

36. Hughson MD, McCarty GA, Sholer CM, Brumback RA: Thrombotic cerebral arteriopathy in patients with the antiphospholipid syndrome. Mod Pathol 6:644-653, 1993

37. Isaak BL, Liesegang Tj, Michet Cj: Ocular and systemic findings in relapsing polychondritis. Ophthalmology 93:681-689,1986

38. Jabs DA, Miller NR, Newman SA, et al: Optic neuropathy in systemic lupus erythematosus. Arch Ophthalmol 104:564-568,1986

39. Johnson RT, Richardson EP: The neurological manifestations of systemic lupus erythematosus. A clinical-pathological study of 24 cases and review of the literature. Medicine 47:337-369,1968

40. Kaplan JG, Rosenberg R, Reinitz E, et al: Peripheral neuropathy in Sjogren’s syndrome. Muscle Nerve 13:570-579,1990

41. Keane JR: Eye movement abnormalities in systemic lupus erythematosus. Arch Neurol 52:1145-1149,1995

42. Khamashta MA, Cuadrado Mj, Mujic F, et al: The management of thrombosis in the Antiphospholipid-antibody syndrome. N Engl J Med 332:993-997,1995

43. Kidd D, Steuer A, Demnan AM, Rudge P: Neurological complications in Behcet’s syndrome. Brain 122:2183-2194,1999

44. Kim RC: Rheumatoid disease with encephalopathy. Ann Neurol 7:86-91,1980

45. Klein Gunnewiek JMT, van de Putte LBA, van Venrooij Wj: The Ul snRNP complex: An autoantigen in connective tissue disease. An update. Clin Exp Rheumatol 15:549-560, 1997

46. Kovacs B, Lafferty TL, Brent LH, DeHoratius Rj: Transverse myelopathy in systemic lupus erythematosus: An analysis of 14 cases and review of the literature. Ann Rheum Dis 59:120-124, 2000

47. Kraus A, Palacios A, Muiioz L: Muscular involvement in systemic rheumatoid vasculitis. Br j Rheumatol 31:355-356,1992

48. Mire 0, Pedrol E, Casademont J, et al: Muscle involvement in rheumatoid arthritis: Clinicopathological study of 21 symptomatic cases. Semin Arthritis Rheum 25:421-428, 1996

49. Molina JA, Benito-Len J, Bermejo F, et al: Intravenous immunoglobulin therapy in sensory neuropathy associated with Sjogren’s syndrome. J Neurol Neurosurg Psychiatry 60:699, 1996

50. Nadeau SE: Neurologic manifestations of vasculitis and connective tissue disease. In Joynt Rj, Griggs RC (eds): Baker’s Clinical Neurology on CD-ROM. Philadelphia, Lippincott Williams and Wilkins, 2000

51. Nakano KK, Schoene WC, Baker RA, Dawson DM: The cervical myelopathy associated with rheumatoid arthritis: An analysis of 32 patients, with 2 postmortem cases. Ann Neurol 3:144-151,1978

52. O’Duffy JD, Robertson DM, Goldstein NP: Chlorambucil in the treatment of uveitis and meningoencephalitis of Behcet’s disease. Am j Med 76:75-84, 1984

53. O’Leary CP, Willison Hj: Autoimmune ataxic neuropathies (sensory ganglionopathies). Curr Opin Neurol 10:366-370,1997

54. Olsen NJ, King LE, Park JH: Muscle abnormalities in scleroderma. Rheum Dis Clin North Am 22:783-796,1996

55. Pistiner M, Wallace DJ, Nessim S, et al: Lupus erythematosus in the 1980s: A survey of 570 patients. Semin Arthritis Rheum 21:55-64,1991

56. Propper DJ, Bucknall RC: Acute transverse myelopathy complicating systemic lupus erythematosus. Ann Rheum Dis 48:512-515,1989

57. Provost TT, Vasily D, Alexander E: Sjogren’s syndrome. Cutaneous, immunologic, and nervous system manifestations. Neurol Clin 5:405-427,1987

58. Pu6chal X, Said G, Hilfiquin P, et al: Peripheral neuropathy necrotizing vasculitis in rheumatoid arthritis. A clinicopathologic and prognostic study of thirty-two patients. Arthritis Rheum 38:1618-1629,1995

59. Ragnaud JM, Tahbaz A, Morlat P, et al: Recurrent aseptic purulent meningitis in a patient with relapsing polychondritis. Clin Infect Dis 22:374-375,1996

60. Robbins ML, Komguth SE, Bell CL, et al: Antineurofilament antibody evaluation in neuropsychiatric systemic lupus erythematosus. Combination with anticardiolipin antibody assay and magnetic resonance imaging. Arthritis Rheum 31:623-631, 1988

61. Sakane T, Takeno M, Suzuki N, Inaba G: Behcet’s disease. N Engl J Med 342:1284-1291, 1999

62. Salih AM, Gray RES, Mills KR, Webley M: A clinical, serological and neurophysiological study of restless legs syndrome in rheumatoid arthritis. Br j Pheumatol 33:60-63, 1994

63. Serdaroglu P: Behcet’s disease and the nervous system. J Neurol 245:197-205,1998

64. Sfikakis PP, Mitsikostas DD, Manoussakis MN, et al: Headache in systemic lupus erythematosus: A controlled study. Br j Rheumatol 37:300-303, 1998

65. Shneebaum AB, Singleton JD, West SG, et al: Association of psychiatric manifestations with antibodies to ribosomal P proteins in systemic lupus erythematosus. Am j Med 90:54-62,1991

66. Sobue G, Yasuda T, Kachi T, et al: Chronic progressive sensory ataxic neuropathy: Clinicopathological features of idiopathic and Sjogren’s syndrome-associated cases. j Neurol 240:1-7,1993

67. Sunahara N, Matsunaga S, Mori T, et al: Clinical course of conservatively managed rheumatoid arthritis patients with myelopathy. Spine 22:2603-2608,1997

68. Trentham DE, Le CH: Relapsing polychondritis. Ann Intern Med 129:114-122,1998

69. Tzioufas AG, Tzortzakis NG, Panou-Pomonis E, et al: The clinical relevance of anti- bodies to ribosomal-P common epitope in two targeted systemic lupus erythematosus populations: A large cohort of consecutive patients and patients with active central nervous system disease. Ann Rheum Dis 59:99-104,2000