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Non-MS autoimmune demyelination
Clinical Neurology and Neurosurgery 110 (2008) 905–912
Review
Non-MS autoimmune demyelination Nada Cikes ∗ , Dubravka Bosnic, Mirna Sentic Division of Clinical Immunology and Rheumatology, Department of Medicine, School of Medicine and University Hospital Center Zagreb, Kispaticeva 12, 10000 Zagreb, Croatia Received 27 May 2008; accepted 5 June 2008
Abstract Connective tissue diseases can be characterised by central nervous system (CNS) involvement, in some patients manifested by demyelination areas in the white matter of the brain and spinal cord, which are difficult to differentiate from multiple sclerosis (MS) and other demyelinating processes, such as transverse myelitis and optic neuritis. Demyelinating process may be the feature of nervous impairment in systemic lupus erythematosus, Behcet’s disease (BD), Sjoegren’s syndrome (SS), systemic sclerosis (SSc) or very rarely other systemic autoimmune diseases. An acute isolated neurological syndrome, as the most common symptom of MS can sometimes be the only feature or even first manifestation of nervous impairment in connective tissue disease, hence presenting the diagnostic problem. Although the white matter abnormalities seen by magnetic resonance imaging may be similar in non-MS autoimmune demyelination and MS, it is the most important diagnostic tool in the differential diagnosis of the mentioned conditions. Investigating the presence of various autoantibodies potentially involved in the pathogenesis of demyelinating lesions as well as cerebrospinal fluid (CSF) analysis can be helpful. © 2008 Elsevier B.V. All rights reserved. Keywords: Connective tissue diseases; Demyelinating autoimmune diseases, CNS; Multiple sclerosis; Progressive multifocal leukoencephalopathy; Differential diagnosis
Contents 1. 2. 3. 4. 5. 6. 7.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Systemic lupus erythematosus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Antiphospholipid syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sjoegren’s syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Behcet’s syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Systemic sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Demyelination in the course of biologic treatment of rheumatic diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction It is well known that connective tissue diseases can be characterised by highly diverse central nervous system (CNS) involvement. Particularly many data are available about the nervous impairment in systemic lupus erythematosus (SLE) with great variability ranging from 18 to 70% of patients [1,2]. Behcet’s disease (BD) is a syndrome with character∗
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istically presented neurologic manifestation in 10–50% of patients [3]. In Sjoegren’s syndrome (SS) the CNS lesion may be present in 25–30% of patients [4,5]. The neurologic lesion may be found in some vasculitides: giant cell arteritis, Takayasu arteritis, Wegener’s granulomatosis and isolated angiitis of the CNS, but rarely in other connective tissue diseases as systemic sclerosis (SSc), rheumatoid arthritis. Patients may be presented by demyelination areas in the white matter of the brain and spinal cord, which are difficult to differentiate from multiple sclerosis (MS) and
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other demyelinating processes, such as transverse myelitis and optic neuritis [6,7]. CNS pathologic findings reported on autopsies in patients with connective tissue disease mostly are multiple micro infarcts, noninflammatory thickening of small vessels by intimal proliferation, thrombotic occlusion of major vessels, intracerebral haemorrhage, embolism (mostly associated with mitral valve pathology) or “true” vasculitis with inflammatory cell infiltrates and fibrinoid necrosis [6–8]. Types of brain abnormality in connective tissue diseases found on magnetic resonance imaging (MRI) including MR spectrometry changes most often are: cortical atrophy, ventricular dilatation, focal lesions, gross infarcts, white matter abnormalities. Forms of white matter damage can be small punctuate MRI lesions (vasculopathy), demyelinating plaques (demyelinating encephalomyelitis), lesions of optic nerves and the spinal cord (vacuolar myelin degeneration, axonal loss, white matter necrosis) and extensive leucoencephalopathy (oedema or confluent small lesions) [6,8]. The acute isolated neurological syndrome, which is the most common finding in MS, can also be the only feature or first manifestation of SLE, antiphospholipid syndrome (APS), BD or SS. Antinuclear antibodies (ANA) or antiphospholipid antibodies (aPL) can also occur in MS. Thus a number of patients with systemic autoimmune disease and demyelinating lesion can be misdiagnosed for MS. Demyelinating features as transverse myelitis or optic neuritis may be manifestations of MS, SLE, APS, SS and BD, or may be isolated syndrome. In demyelinating diseases the diagnosis is established on the basis of clinical presentation, MRI, cerebrospinal fluid (CSF) examination, visual evoked potentials and autoantibody investigation [6].
2. Systemic lupus erythematosus There is a high prevalence of CNS involvement in SLE, reported in up to 70% of patients. Patients may have polymorphic manifestations with various histopathological findings. Main pathologic findings described in patients with neurological impairment in SLE are ischaemia, haemorrhage, white matter damage, neurological dysfunction, deficient psychological reactions. Factors contributing to CNS ischemia may be antibodies (particularly aPL), atherosclerosis, small vessel vasculopathy, thrombosis of arteries and veins, emboli, dissection, vasculitis and vessel spasms. Pathogenic mechanisms specifically related to accelerated atherosclerosis in SLE are traditional risk factors (hypertension, diabetes, dyslipidemia, body mass index, sex, smoking, homocysteinemia), therapy with glucocorticoids, systemic inflammation (proinflammatory cytokines), humoral immune mediators (aPL and other autoantibodies,), high prevalence of heart valve involvement in SLE (associated or not associated with aPL); high prevalence of carotid artery atherosclerotic plaques, cerebral emboli as additional cause of ischemic events. Small vessel angiopathy is a predominant abnor-
Fig. 1. T2 axial MR image showing bilateral paraventricular confluent hyperintensities in white matter in a female patient with systemic lupus erythematosus and secondary antiphospholipid syndrome.
mality, characterised by intimal cell proliferation, fibrosis, mucoid hyperplasia and hyalinisation, thrombosis, surrounding microglia clusters, small infarcts, haemorrhages, white matter necrosis and perivascular inflammatory infiltrates [1,2,7–10]. Neurological manifestations described in patients with SLE are seizures (grand mal, petit mal; focal, temporal lobe), stroke syndrome, movement disorder, headache, transverse myelitis, cranial and peripheral neuropathy [1,2,8]. In our study of 207 SLE patients, 43% had neurological manifestations with major presenting symptoms being headache in 28, paresthesias in 13, dizziness in 11, weakness in 9, motor disorders in 7, visual disturbances in 6, concentration problems in 6 patients. At the time of the study we did not investigate the frequency of demyelinating lesions in our patients with neuropsychiatric SLE, but later on the association of demyelination and aPL was found (Fig. 1) [7]. In 1999, nineteen different syndromes with neurological and psychiatric manifestations of SLE were classified by American College of Rheumatology (ACR), as case definitions for neuropsychiatric syndromes; demyelinating syndrome and myelopathy are two of them [11]. Demyelinating syndrome is defined as an acute or relapsing demyelinating encephalomyelitis with evidence of discrete neurologic lesions distributed in place and time. Diagnostic criteria for this condition include: (1) Multiple discrete areas of damage to white matter within central nervous system, causing 1 or more limbs to become weak with sensory loss; (2) Transverse myelopathy; (3) Optic neuropathy; (4) Diplopia due to isolated nerve palsies or internuclear
N. Cikes et al. / Clinical Neurology and Neurosurgery 110 (2008) 905–912
ophthalmoplegia; (5) Brain stem disease with vertigo, vomiting, ataxia, dysarthria or dysphagia; (6) Other cranial nerve palsies. Diagnosis can be established if two or more of the mentioned criteria are met, each occurring at different times, or one of the mentioned criteria occurs at least on two different occasions [11]. Myelopathy is defined as disorder of the spinal cord characterised by rapidly evolving paraparesis and/or sensory loss, with a demonstrable motor and/or sensory cord level (may be transverse) and/or sphincter involvement. Usually, the condition has rapid onset (hours or days) of one or more of the following diagnostic criteria: (1) Bilateral weakness of legs with or without arms (paraplegia/quadriplegia), which may be asymmetric; (2) Sensory impairment with cord level similar to that of motor weakness, with or without bowel and bladder dysfunction [11]. The most important diagnostic tool in the differential diagnosis of neuropsychiatric SLE is MRI. Types of white matter lesions are: (1) small punctuate MRI lesions predominantly in the periventricular and subcortical white matter; (2) demyelinating plaques in brain and brainstem; (3) lesions of optic nerves and lesions of the spinal cord extending over two vertebrae or more, as in Devic’s syndrome; (4) extensive white matter lesion by MRI or CT, in brain and brainstem, reversible in at least some cases, due to oedema or confluent small lesions [8]. The morphology of the lesions is important: the absence of multifocal lesions on brain MRI is not predictive for later development of MS. Small multifocal demyelinating lesions may be found not only in MS but also in SLE and APA, although clinically silent; they can also be produced by small strokes. Subcortical lesions predominate in SLE and APS, while periventricular and particularly corpus callosum lesions are common in MS. Elongated ovoid shaped lesions and “black holes” are more characteristic of MS. Other diagnostic tools in the differential diagnosis usually include CSF analysis (finding of oligoclonal bands is in favor of MS), visual evoked potentials (normal finding is unusual in MS) and ANA (high titer is very suggestive for SLE or other systemic autoimmune disease) [6,8]. Although rare (in 1–2% of patients) transverse myelitis is a serious neuropsychiatric manifestation of SLE. Thus SLE or APS should be considered in all patients with transverse myelitis and aPL in blood. MRI lesions in SLE myelopathy are longer than those in patients with MS and similar to findings in Devic’s syndrome and may extend over the entire length of the spinal cord. Peripheral nervous system involvement, characteristically absent in MS, can be found in SLE and APS [7,8]. Autoimmune optic neuropathy is also rare (in 1% of patients) but well-defined manifestation of SLE, often monolateral, focal neurological disease, associated with CNS affection. The optic damage is diagnosed by visual field examination and visual evoked potentials [6,8]. A condition described as SLE presenting with widespread neurological
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signs and symptoms suggestive of MS have usually been called lupoid sclerosis [8,12]. Endothelium is apparently one of the most important targets for CNS involvement in SLE. The pathogenesis of the small vessels angiopathy is not entirely clear, but it is reported to be more frequent in aPL positive patients. The role of aPL in pathogenic mechanisms can be based on the interference with the Protein C/S system, impairment of fibrinolytic activity, interference with anticoagulant proteins (annexin V), interference with endothelial cells and monocytes. Main target of aPL is 2GPI, while anti-2GPI antibodies bind to endothelial cells of different anatomical localisation. 2GPI is apparently more expressed on brain and skin microvascular endothelial cells. The additional role for anti-endothelial antibodies (AECA) in neuropsychiatric SLE was suggested. The important role of AECA is explained by several facts: AECA can be detectable in up to 70% of SLE sera, directed against constitutive endothelial cell antigens as well as against “planted” antigens (DNA/histone complexes; 2GPI), usually associated with active disease, can induce endothelial cell activation or apoptosis in experimental models. Specific antigens such as ribosomal P protein, Nedd 5, To 52/SS-A may be expressed on the surface of endothelial cells after apoptosis and supporting a direct pathogenic role of these autoantibodies in neuropsychiatric SLE [12–15]. Several mechanisms contribute to immunopathogenesis of neuropsychiatric manifestations in SLE including direct interaction of autoantibodies with autoantigens on neuronal cell membranes, interference with neurotransmission, loss of neuronal structure and cell death, aPL-mediated ischaemia, microthrombosis and noninflammatory vasculopathy and local production of cytokines inducing neuronal cytotoxicity [16,17]. Investigation and detection of antibodies in serum and cerebrospinal fluid associated with specific neuropsychiatric SLE manifestations can lead to possible mechanisms that are involved in the clinical pictures. Twenty antibodies were detected in the serum and/or CSF lupus patients and they are classified into two groups [14]: - Autoantibodies to brain components: anti neuronal antibodies, brain reactive antibodies (BRAA), anti-N-Methyld-aspartate receptor antibodies (anti-NMDA antibodies), anti-microtubule-associated protein 2 (MAP-2) antibodies, antineurofilament antibodies, antiganglioside antibodies, anti-NS tissue antibodies, antibrain synaptosomal antibodies, anti triosephosphate isomerase antibodies, anti-glial fibrillary acidic protein (aGFAP), antiserum lymphocytotoxic antibodies and - systemic autoantibodies: antiphospholipid/anticardiolipin antibodies (aCL), lupus anticoagulant (LAC), anti-B2Glycoprotein 1 antibodies, antiribosomal P antibodies (anti-P), anti Ro antibodies, anti Sm antibodies, antiendothelial cell antibodies (AECAs), antiserine proteinase 3 (Anti-PR3/C-ANCA) antibodies, anti-NEDD5 antibodies, autoantibody Burden) [14].
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The most frequent autoantibodies are antineuronal, BRAA and aPL. Brain specific autoantibody as antineuronal antibodies can be associated with cognitive dysfunction, psychosis, seizures, BRAA with psychosis and seizures, NMDA with cognitive dysfunction and depression, MAP-2 with psychosis, neuropathy, cerebritis, seizures, gangliozide antibodies with migraine, depression, cognitive dysfunction, peripheral neuropathy, neurofilament antibodies with diffuse neuropsychiatric manifestations. Diamond and colleagues demonstrated that anti ds-DNA from SLE patients cross-react with neuronal glutamate receptors (NR2) in the CNS, that these autoantibodies also mediate apoptotic death of neurons in vitro and in vivo and mediate some of non-vasculitic CNS abnormalities [14–16]. A role for chemokines has been reported. The chemokine monocyte chemotactic protein 1 (MCP-1)/CCL2 is higher in cerebrospinal fluid of neuropsychiatric lupus patients and correlate with intensity of inflammation. The same role have anti triosephosphate isomerase antibodies which concentration in cerebrospinal fluid is associated with neuropsychiatric SLE. A genetic component can also be involved in different populations [18,19]. In summary, there are some characteristics of pathogenicity in neuropsychiatric SLE: autoantibodies directed to intracellular autoantigen may exert pathogenic effects by binding to extracellularly expressed cognate autoantigens or cross-reactive epitopes; autoantibody specificity is not necessarily restricted to a single pathogenic mechanism; no single autoantibody would account for all forms of injury; activated lymphocytes can cross the intact blood–brain barrier (BBB); disruption of the BBB allows inflow of activated B and T cells, monocytes/macrophages, pathogenic serum autoantibody; B cells can synthesize in situ autoantibodies within the CNS de novo; immune complex mediated inflammation is not the central mechanism for CNS lupus; the identification of neural tissue-specific autoantibody cannot be construed as necessarily indicative of pathogenicity.
3. Antiphospholipid syndrome Antiphospholipid syndrome, also called Hughes’s syndrome, is usually defined by clinical features—thromboses and missed abortions (earlier thrombocytopenia) associated with laboratory findings presented by the elevated level of aPL, namely lupus anticoagulant, anticardiolipin antibodies and anti-beta2GPI antibodies. In secondary APS the condition is associated with underlying autoimmune disorder, most often being SLE [12,20]. Neurologic manifestations in APS may include cerebrovascular thrombosis, transitory ischemia, cognitive dysfunction, migraine, chorea, transverse myelopathy, seizures and psychologic disturbances. In some patients difficulties in differentiating between multiple sclerosis, SLE and APS may be present. Namely, in patients clinically diagnosed with MS the high levels of aPL may be found, while in patients
clinically diagnosed with SLE and/or APS the MRI studies may reveal the subcortical white matter lesions. Furthermore, in some patients with APS having sensory or motor dysfunction, optic neuritis or transverse myelitis the MRI studies can show multiple T2 hyperintense brain lesions, which may not be easy to differentiate from MS. Some authors suggest that lesions associated with APS, found on repeated MRI studies are usually static compared with the more dynamic lesions seen in MS. It is also suggested that magnetization transfer imaging combined with standard MRI can differentiate MS from APS. Although transverse myelitis and autoimmune optic neuropathy are rare manifestations of primary or secondary APS reported in 0.4 and 1% of patients, respectively, it is recommended that SLE and secondary APS must be suspected in patients with those conditions [6,12,21]. As mentioned above, in patients with SLE and APS the significant role of aPL is recognized. Speaking about pathogenesis of neurologic disorder in APS some studies propose the interactions between antibodies to anionic phospholipid protein complexes and antigen targets on platelets, endothelial cells or components of the coagulation cascade. There is also a possibility that aPL may react with brain lipids as cephalin or sphingomyelin; aPLs may contribute to neurological damage by reacting with brain cells by means of beta2GPI interaction. Expression of beta2GPI mRNA by astrocytes, neuronal and endothelial cells suggest that these cells can be a target of autoantibodies in the APS. The prevalence of aPL in patients with MS is very variable, reported to be between 4.8 and 44%. Some authors report on the higher frequency found in patients with transverse myelitis and optic neuritis, some found that association of consistent presence of high level of aPL in patients with probable or definite diagnosis of MS speaks in favor of slower progression, while others did not find any correlation. Thus, in the differential diagnosis of MS, patients with MS should be tested for aPL. Patients with absence of oligoclonal bands in cerebrospinal fluid and higher level of aPL in serum should be considered as having APS. It is recommended that anticoagulation therapy is administered to MS patients with aPL, particularly those with atypical forms of disease together with manifestations of APS [6,12,22]. Catastrophic antiphospholipid syndrome is described with clinical involvement of three or more organ systems with histopathological evidence of microangiopathy and multiple thromboembolic events, associated with the high titer of aPL, developing within the period of few days to few weeks. Clinical manifestations are reported with following (falling down) prevalence of organ system involvement: renal 80%, pulmonary 67%, CNS 57%, cardiac 48%, skin 49%, gastrointestinal 35%, adrenal thrombosis 26%. Characteristic laboratory findings include: thrombocytopenia 69%, hemolytic anemia 25%, DIC 27%, LAC 95%, ACL 95%, ANA 57%, anti dsDNA 87% in patients with SLE. Outcome in catastrophic APS is very serious with death occurring in 49% of patients. Causes of death can be cardiac events (microthrombi or myocardial infarction), ARDS
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or alveolar haemorrhage, cerebrovascular or gastrointestinal (esophageal perforation, bowel infarction) involvement [20,22].
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ance and allows the emergence of self-reactive B cells that efficiently present antigen to T cells. BAFF may stimulate T cell independent activation of B cells with Toll like receptors [25,26].
4. Sjoegren’s syndrome 5. Behcet’s disease Primary SS is a chronic inflammatory autoimmune disorder classically manifested with xerostomia and xerophtalmia (called also sicca syndrome), characterised by infiltration of the affected tissues (i.e. parotid glands) by lymphocytes. In about 50% of patients the condition not only involve gland inflammation but is also associated with other autoimmune disorder such as rheumatoid arthritis, SLE, systemic sclerosis, vasculitis, polymyositis or quite often autoimmune thyroiditis etc.; this condition is called secondary SS. The characteristic autoantibodies in the syndrome are Ro (SS-A) and La (SS-B). Neurologic manifestations are reported in 25–30% of patients as demyelination, autonomic disturbance, cerebrovascular accident, peripheral lesions (symmetric and multiple mononeuritis), transverse myelopathy. SS can mimic MS clinically and radiologically, particularly if neurological manifestations precede the immunological abnormalities including anti Ro/SS-A and anti La/SS-B antibodies. These patients may have rare oligoclonal bands in CSF immunoglobulin analysis. Transverse myelitis can be found in patients with SS, probably associated with vasculitic lesion of spinal cord; in some patients transverse myelitis was described in patients with SS and primary biliary cirrhosis. Autoimmune optic neuropathy has also been reported in patients with SS. Since several autoantibodies can be found even in patients with definite MS, most common being antiRo/SS-A (in 2–15% of patients), ANA and aCL, it is recommendable to evaluate the differential diagnosis towards the better treatable systemic autoimmune disease [3,4,6,23]. The CSF analysis is helpful in ruling out other causes of CNS diseases. IgG/total protein ratio is often elevated, IgG index is increased in about 50% of patients, oligoclonal bands and a CSF pleocytosis occur in subsets of CNS-SS patients. Antineuronal antibodies and antiribosomal P may be present, but in contrast to SLE they are not implicated as the mechanism of destruction. SS-A by gel diffusion is associated with larger lesions on MRI, abnormal cerebral angiography and serious focal CNS findings [24]. B cell dysfunction is a dominant feature of SS. Autoantibodies can be organ specific or organ nonspecific and include SS-A and SS-B antibodies, histones, ssDNA, alfa fodrin antibodies and rheumatoid factor. The excessive B cell activating factor (BAFF) production can be found, which can be linked to the development of SS. Nonlymphoid cell types such as astrocytes, gland epithelial cells, vascular cell adhesion molecule-1-positive bone marrow stromal cells also express BAFF. The critical role of BAFF and B cells in the pathogenesis of SS and its association with B lymphomas is demonstrated. Excess BAFF possibly corrupts B cell toler-
BD is a chronic systemic vasculitis involving the small blood vessels, characterised by relapsing oral and/or genital ulcerations, ophtalmologic lesions (uveitis, retinal vasculitis). Arthritis, involvement of the gastrointestinal system and CNS as well as skin lesions (erythema nodosum, pseudopholiculitis, papulopustulous and/or akneiform lesions) are common. It is more frequent and severe in patients from the Eastern Mediterranean and Asia [3]. Neurologic disturbances in BD affecting 5–50% of patients, can be manifested as the meningeal lesions (aseptic meningitis), inflammatory lesions (encephalitis, myelitis) or vascular changes (thrombosis, arteritis). Patients with BD and neurological injury (neuro–BD) are associated with a poorer prognosis. Musculoskeletal lesions in Behcet’s disease are clinical features of seronegative spondylarthropathy [3,27]. Clinical course of CNS affected patients with BD may clinically and radiologically mimic MS. On MRI studies patients with neurological involvement in BD may have single or multiple hemispherical and/or spinal cord white matter lesions (Fig. 2), often extending from the brain stem to basal ganglia. Typical for the later stage of the neuro–BD is the atrophy of the brain stem without cortical atrophy. The differential diagnosis between neuro–BD and MS may be difficult if neurological manifestations develop before the systemic appearance fulfilling diagnostic criteria for BD. The course of MS is more often polyphasic, while neuro–BD is more progressive; the main neurological manifestation of neuro–BD progressive pseudobulbar palsy is rarely seen in MS. Cerebrospinal fluid in neuro–BD may be normal or pathological, sometimes oligoclonal banding patterns of immunoglobulin may be demonstrated [27,28]. There are several main lines of research in the pathogenesis of BD, but it is still not understood. In genetic studies–HLA B51 (particularly B5101 subcomponent) was found to be the main allele associated with BD. Vasculitis of the vasa vasorum seems to be the major site of pathology in large vessel disease. Coagulation abnormalities in the pathogenesis are not clear. Same studies were connected with Factor V Leiden mutation. A recent focus of attention are T cell costimulatory molecules–anti-CTLA-4 which are associated with eye disease and CNS involvement [29–31].
6. Systemic sclerosis SSc is a multisystem disease primarily affecting the skin, but may involve other organs like lung and kidneys. Although
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We present a 51-year-old female patient with a history of headaches who developed scleroderma, 7 years later was treated (surgery and chemotherapy) for breast cancer, then slowly developed features of CREST syndrome (calcinosis, Raynaud’s phenomenon, esophageal disturbances, sclerodactilia and teleangiectasiae). She also had bilateral pulmonary fibrosis, peripheral neuropathy and progressive demyelinating lesions (Fig. 3).
7. Demyelination in the course of biologic treatment of rheumatic diseases
Fig. 2. T2 axial MR image with isolated focal hypersensitivity in subcortical white matter of right frontal superior gyrus in a male patient with Behcet’s disease.
there are reports of the peripheral nervous system involvement, the CNS affections appear to be rare. Only a few cases of coexistence of SSc and MS have been described, particularly the transverse myelopathy in the setting of SSc, localised or linear scleroderma. Since several connective tissue diseases are associated with transverse myelitis, including SLE and Sjoegren’s syndrome, there was a discussion whether the transverse myelitis in a patient with SSc is an independent overlapping event or a manifestation of SSc [32,33].
Progressive multifocal leucoencephalopathy (PML) is a progressive neurological disease with areas of demyelination in the central nervous system and rapidly fatal outcome. It occurs in severely immunosuppressed patients with lymphoma, solid organ malignancies, and organ transplant recipients. PML was a rare disease until it became an AIDSdefining illness in the 1980s. PML is caused by reactivation of latent polyoma virus JC, leading to the death of myelinproducing oligodendrocytes. Recent interest in the disorder has been elicited by its appearance in patients treated with the monoclonal antibodies Natalizumab and Rituximab as well as TNF alpha antagonist therapy. PML has been reported in rheumatic diseases with and without biologic therapeutic agents [34–36]. We describe two patients who developed PML in the course of their rheumatic diseases. A 35-year-old female patient presenting with arthralgias was diagnosed to have SLE with diffuse proliferative glomerulonephritis. She was successfully treated with glucocorticoids and cyclophosphamide. Three years later with clinical and laboratory features of low activity SLE she developed bulbar symptoms which progressed together with the development of pyramid and extrapyramid symptoms. Brain CT and MRI scan showed major demyelination area (Fig. 4). With the progression of neurological symptoms the patient died in a few months time. On autopsy large destruction of white matter
Fig. 3. Two axial T2 images with diffusely distributed large demyelinating lesions progressing to leucomalacia or formation of cysts in a female patient with CREST syndrome.
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Fig. 6. FLAIR axial MR image showing subcortically distributed focal hyperintensities, dominantly distributed on white–gray matter border in a female patient with rheumatoid arthritis who developed multifocal leucoencephalopathy after treatment with Infliximab.
Fig. 4. T2 axial MR image showing large confluent hyperintensity in insular and periinsular region also with two focal hyperintensities, one of them lateral from optic radiation on right side and other lesion in the region of posterior part of internal capsula on left side in a patient with systemic lupus erythematosus and multifocal leucoencephalopathy.
was found (Fig. 5). Histologic examination revealed significant loss of myelin and numerous reactive astrocytes with bizarre, enlarged hyperchromatic nuclei; the oligodendrocytes with the violaceous intranuclear inclusions were found. Based on all that the diagnosis of PML was confirmed. In the second case of a 50-year-old female patient the diagnosis of rheumatoid arthritis was established. After the unsuccessful treatment with the combination of disease
modified antirheumatic drugs including Methotrexate, the application of Infliximab, an anti-TNF-alfa monoclonal antibody, was started. During the 2 years of treatment with Infliximab the positive effect on rheumatoid arthritis activity was noted, but the patient developed neurological symptoms (transitory paresis of the right leg, facial paresthesias, a drop attack). In the extensive neurologic investigation the brain MRI revealed the demyelination area without any diagnostic criteria for MS. After the application of Infliximab was stopped, the neurological symptoms spontaneously disappeared; patient is now followed for 3-year period without any sign of neurologic disease (Fig. 6). With current and future treatments that suppress and manipulate the immune system, there is a risk for severe acute infections and reactivation of latent infections, such as JC virus reactivation leading to PML. Patients presenting with new CNS symptoms following treatment with antiTNF-alfa agents should be evaluated for JC virus infection [37].
References
Fig. 5. Large destruction of white matter without destruction of gray matter found on autopsy of a patient with systemic lupus erythematosus and multifocal leucoencephalopathy.
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[6] Theodoridou A, Settas L. Demyelination in rheumatic diseases. Postgrad Med J 2008;84:127–32. [7] Cikes N. Central nervous system involvement in systemic connective tissue diseases. Clin Neurol Neurosurg 2006;108:311–7. [8] Jennekans FGI, Kater L. The central nervous system in systemic lupus erythematosus. Part 2. Pathogenetic mechanisms in clinical syndromes: a literature investigation. Rheumatology 2002;41:619–30. [9] Roman MJ, Shanker BA, Davis A, et al. Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus. N Engl J Med 2003;349:2399–406. [10] Jimenez S, Garcia-Criado MA, Tassies D, et al. Preclinical vascular disease in systemic lupus erythematosus and primary antiphospholipid syndrome. Rheumatology (Oxford) 2005;44:756–61. [11] ACR nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum 1992;42:599–608. [12] Ferreira SD, Cruz DP, Hughes GRV. Multiple sclerosis, neuropsychiatric lupus and antiphospholipid syndrome: where do we stand? Rheumatology 2005;44:434–42. [13] Valesini G, Alessandri C, Celestino D. Anti-Endothelial antibodies and neuropychiatric systemic lupus erythematosus. Ann NY Acad Sci 2006;1069:118–28. [14] Zandman-Goddard G, Chapman J, Shoenfeld Y. Autoantibodies involved in neuropsychiatric SLE and antiphospholipid syndrome. Semin Arthritis Rheum 2007;36:297–325. [15] Diamond B, VolpeBruce T. Antibodies and brain disease: a convergence of immunology and physiology. Plos Med 2006;3(12 December): E498. [16] Senecal JL, Raymond Y. The Pathogenesis of neuropsychiatric manifestations in systemic lupus erythematosus: a disease in search of autoantibodies, or autoantibodies in search of a disease? J Rheumatol 2004;31:2093–8. [17] Karassa FB, Ioannidis JPA, Touloumi G, Boki KA, Moutsopoulos HM. Risk factors for central nervous system involvement in systemic lupus erythematosus. QJM 2000;93:169–74. [18] Likuni N, Okamoto H. Raised monocyte chemotactic protein-1 (MCP1)/CCL2 in cerebrospinal fluid of patients with neuropsychiatric lupus. Ann Rheum Dis 2006;65:253–6. [19] Sasajima T, Watanabe H, Sato S, Sato Y, Ohira H. Anti-triosephosphate isomerase antibodies in cerebrospinal fluid are associated with neuropsychiatric lupus. J Neuroimmunol 2006;181:150–6. [20] Hughes GRV. The antiphospholipid syndrome. A historical view. Lupus 1998;7(Suppl. 2):S1–4.
[21] Rovaris M, Viti B, Ciboddo G, et al. Brain involvement in systemic immune mediated disease: magnetic resonance and magnetisation transfer imaging study. J Neurol Neurosurg Psychiatry 2000;68:170–7. [22] Ruiz-Irastoza G, Khamashta MA. Warfarin for multiple sclerosis? Q J Med 2000;93:497–9. [23] Lafitte C, Amoura Z, Cacoub P, et al. Neurological complications of primary Sjoegren’s syndrome. J Neurol 2001;248:557–84. [24] Cox PD, Hales RE. CNS Sjoegren’s syndrome: an underrecognized and underappreciated neuropsychiatric disorder. J Neuropsychiatry Clin Neurosci 1999;11:241–7. [25] Mackay F, Groom JR, Tangye SG. An important role for B Cell activation factor and B cells in the pathogenesis of Sjogren’s syndrome. Curr Opin Rheumatol 2007;19:406–13. [26] Mariette X, Roux S, Zhang J, et al. The level of BlyS(BAFF) correlates with the titre of autoantibodies in human Sjogren’ syndrome. Ann Rheum Dis 2003;62:168–71. [27] Serdaroglu P. Behcet’ disease and the nervous system. J Neurol 1998;245:197–205. [28] Tali ET, Atila S, Keskin T, et al. MRI in neuro-Behcet’ disease. Neuroradiology 1997;39:2–6. [29] Gul A, Inanc M, Ocal L, et al. Familial aggregation of Behcet’s disease in Turkey. Ann Rheum Dis 2000;59:622–65. [30] Salvarani C, Calamia K, Silingardi M, et al. Thrombosis associated with the prothrombin G–A20210 mutation in Behcet’s disease. J Rheumatol 2000;27:515–56. [31] Matsui T, Kurokawa M, Kobata T, et al. Autoantibodies to T cell costimulatory molecules in systemic autoimmune diseases. J Immunol 1999;162:4328–35. [32] Pelidou SH, Tsifetaki N, Giannopoulos S, et al. Multiple sclerosis associated with systemic sclerosis. Rheumatol Int 2007;27:771–3. [33] Torabi AM, Patel RK, Wolfe MD, et al. Transverse myelitis in systemic sclerosis. Arch Neurol 2004;61:126–8. [34] Berger J. Progressive multifocal leukoencephalopathy. Curr Neurol Neurosci Rep 2007;7:461–9. [35] Boren EJ, Cheema GS, Naguwa SM, Ansari AA, Gershwin ME. The emergence of progressive multifocal leukoencephalopathy (PML) in rheumatic diseases. J Autoimmun 2008;30:90–8. [36] Yousry TA, Major EO, Ryshkewitsch C, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med 2006;354:924–33. [37] Roos JCP, Ostor AJK. Neurological complications of Infliximab. J Rheumatol 2007;34:236–7.
Review
Non-MS autoimmune demyelination Nada Cikes ∗ , Dubravka Bosnic, Mirna Sentic Division of Clinical Immunology and Rheumatology, Department of Medicine, School of Medicine and University Hospital Center Zagreb, Kispaticeva 12, 10000 Zagreb, Croatia Received 27 May 2008; accepted 5 June 2008
Abstract Connective tissue diseases can be characterised by central nervous system (CNS) involvement, in some patients manifested by demyelination areas in the white matter of the brain and spinal cord, which are difficult to differentiate from multiple sclerosis (MS) and other demyelinating processes, such as transverse myelitis and optic neuritis. Demyelinating process may be the feature of nervous impairment in systemic lupus erythematosus, Behcet’s disease (BD), Sjoegren’s syndrome (SS), systemic sclerosis (SSc) or very rarely other systemic autoimmune diseases. An acute isolated neurological syndrome, as the most common symptom of MS can sometimes be the only feature or even first manifestation of nervous impairment in connective tissue disease, hence presenting the diagnostic problem. Although the white matter abnormalities seen by magnetic resonance imaging may be similar in non-MS autoimmune demyelination and MS, it is the most important diagnostic tool in the differential diagnosis of the mentioned conditions. Investigating the presence of various autoantibodies potentially involved in the pathogenesis of demyelinating lesions as well as cerebrospinal fluid (CSF) analysis can be helpful. © 2008 Elsevier B.V. All rights reserved. Keywords: Connective tissue diseases; Demyelinating autoimmune diseases, CNS; Multiple sclerosis; Progressive multifocal leukoencephalopathy; Differential diagnosis
Contents 1. 2. 3. 4. 5. 6. 7.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Systemic lupus erythematosus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Antiphospholipid syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sjoegren’s syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Behcet’s syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Systemic sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Demyelination in the course of biologic treatment of rheumatic diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction It is well known that connective tissue diseases can be characterised by highly diverse central nervous system (CNS) involvement. Particularly many data are available about the nervous impairment in systemic lupus erythematosus (SLE) with great variability ranging from 18 to 70% of patients [1,2]. Behcet’s disease (BD) is a syndrome with character∗
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istically presented neurologic manifestation in 10–50% of patients [3]. In Sjoegren’s syndrome (SS) the CNS lesion may be present in 25–30% of patients [4,5]. The neurologic lesion may be found in some vasculitides: giant cell arteritis, Takayasu arteritis, Wegener’s granulomatosis and isolated angiitis of the CNS, but rarely in other connective tissue diseases as systemic sclerosis (SSc), rheumatoid arthritis. Patients may be presented by demyelination areas in the white matter of the brain and spinal cord, which are difficult to differentiate from multiple sclerosis (MS) and
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other demyelinating processes, such as transverse myelitis and optic neuritis [6,7]. CNS pathologic findings reported on autopsies in patients with connective tissue disease mostly are multiple micro infarcts, noninflammatory thickening of small vessels by intimal proliferation, thrombotic occlusion of major vessels, intracerebral haemorrhage, embolism (mostly associated with mitral valve pathology) or “true” vasculitis with inflammatory cell infiltrates and fibrinoid necrosis [6–8]. Types of brain abnormality in connective tissue diseases found on magnetic resonance imaging (MRI) including MR spectrometry changes most often are: cortical atrophy, ventricular dilatation, focal lesions, gross infarcts, white matter abnormalities. Forms of white matter damage can be small punctuate MRI lesions (vasculopathy), demyelinating plaques (demyelinating encephalomyelitis), lesions of optic nerves and the spinal cord (vacuolar myelin degeneration, axonal loss, white matter necrosis) and extensive leucoencephalopathy (oedema or confluent small lesions) [6,8]. The acute isolated neurological syndrome, which is the most common finding in MS, can also be the only feature or first manifestation of SLE, antiphospholipid syndrome (APS), BD or SS. Antinuclear antibodies (ANA) or antiphospholipid antibodies (aPL) can also occur in MS. Thus a number of patients with systemic autoimmune disease and demyelinating lesion can be misdiagnosed for MS. Demyelinating features as transverse myelitis or optic neuritis may be manifestations of MS, SLE, APS, SS and BD, or may be isolated syndrome. In demyelinating diseases the diagnosis is established on the basis of clinical presentation, MRI, cerebrospinal fluid (CSF) examination, visual evoked potentials and autoantibody investigation [6].
2. Systemic lupus erythematosus There is a high prevalence of CNS involvement in SLE, reported in up to 70% of patients. Patients may have polymorphic manifestations with various histopathological findings. Main pathologic findings described in patients with neurological impairment in SLE are ischaemia, haemorrhage, white matter damage, neurological dysfunction, deficient psychological reactions. Factors contributing to CNS ischemia may be antibodies (particularly aPL), atherosclerosis, small vessel vasculopathy, thrombosis of arteries and veins, emboli, dissection, vasculitis and vessel spasms. Pathogenic mechanisms specifically related to accelerated atherosclerosis in SLE are traditional risk factors (hypertension, diabetes, dyslipidemia, body mass index, sex, smoking, homocysteinemia), therapy with glucocorticoids, systemic inflammation (proinflammatory cytokines), humoral immune mediators (aPL and other autoantibodies,), high prevalence of heart valve involvement in SLE (associated or not associated with aPL); high prevalence of carotid artery atherosclerotic plaques, cerebral emboli as additional cause of ischemic events. Small vessel angiopathy is a predominant abnor-
Fig. 1. T2 axial MR image showing bilateral paraventricular confluent hyperintensities in white matter in a female patient with systemic lupus erythematosus and secondary antiphospholipid syndrome.
mality, characterised by intimal cell proliferation, fibrosis, mucoid hyperplasia and hyalinisation, thrombosis, surrounding microglia clusters, small infarcts, haemorrhages, white matter necrosis and perivascular inflammatory infiltrates [1,2,7–10]. Neurological manifestations described in patients with SLE are seizures (grand mal, petit mal; focal, temporal lobe), stroke syndrome, movement disorder, headache, transverse myelitis, cranial and peripheral neuropathy [1,2,8]. In our study of 207 SLE patients, 43% had neurological manifestations with major presenting symptoms being headache in 28, paresthesias in 13, dizziness in 11, weakness in 9, motor disorders in 7, visual disturbances in 6, concentration problems in 6 patients. At the time of the study we did not investigate the frequency of demyelinating lesions in our patients with neuropsychiatric SLE, but later on the association of demyelination and aPL was found (Fig. 1) [7]. In 1999, nineteen different syndromes with neurological and psychiatric manifestations of SLE were classified by American College of Rheumatology (ACR), as case definitions for neuropsychiatric syndromes; demyelinating syndrome and myelopathy are two of them [11]. Demyelinating syndrome is defined as an acute or relapsing demyelinating encephalomyelitis with evidence of discrete neurologic lesions distributed in place and time. Diagnostic criteria for this condition include: (1) Multiple discrete areas of damage to white matter within central nervous system, causing 1 or more limbs to become weak with sensory loss; (2) Transverse myelopathy; (3) Optic neuropathy; (4) Diplopia due to isolated nerve palsies or internuclear
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ophthalmoplegia; (5) Brain stem disease with vertigo, vomiting, ataxia, dysarthria or dysphagia; (6) Other cranial nerve palsies. Diagnosis can be established if two or more of the mentioned criteria are met, each occurring at different times, or one of the mentioned criteria occurs at least on two different occasions [11]. Myelopathy is defined as disorder of the spinal cord characterised by rapidly evolving paraparesis and/or sensory loss, with a demonstrable motor and/or sensory cord level (may be transverse) and/or sphincter involvement. Usually, the condition has rapid onset (hours or days) of one or more of the following diagnostic criteria: (1) Bilateral weakness of legs with or without arms (paraplegia/quadriplegia), which may be asymmetric; (2) Sensory impairment with cord level similar to that of motor weakness, with or without bowel and bladder dysfunction [11]. The most important diagnostic tool in the differential diagnosis of neuropsychiatric SLE is MRI. Types of white matter lesions are: (1) small punctuate MRI lesions predominantly in the periventricular and subcortical white matter; (2) demyelinating plaques in brain and brainstem; (3) lesions of optic nerves and lesions of the spinal cord extending over two vertebrae or more, as in Devic’s syndrome; (4) extensive white matter lesion by MRI or CT, in brain and brainstem, reversible in at least some cases, due to oedema or confluent small lesions [8]. The morphology of the lesions is important: the absence of multifocal lesions on brain MRI is not predictive for later development of MS. Small multifocal demyelinating lesions may be found not only in MS but also in SLE and APA, although clinically silent; they can also be produced by small strokes. Subcortical lesions predominate in SLE and APS, while periventricular and particularly corpus callosum lesions are common in MS. Elongated ovoid shaped lesions and “black holes” are more characteristic of MS. Other diagnostic tools in the differential diagnosis usually include CSF analysis (finding of oligoclonal bands is in favor of MS), visual evoked potentials (normal finding is unusual in MS) and ANA (high titer is very suggestive for SLE or other systemic autoimmune disease) [6,8]. Although rare (in 1–2% of patients) transverse myelitis is a serious neuropsychiatric manifestation of SLE. Thus SLE or APS should be considered in all patients with transverse myelitis and aPL in blood. MRI lesions in SLE myelopathy are longer than those in patients with MS and similar to findings in Devic’s syndrome and may extend over the entire length of the spinal cord. Peripheral nervous system involvement, characteristically absent in MS, can be found in SLE and APS [7,8]. Autoimmune optic neuropathy is also rare (in 1% of patients) but well-defined manifestation of SLE, often monolateral, focal neurological disease, associated with CNS affection. The optic damage is diagnosed by visual field examination and visual evoked potentials [6,8]. A condition described as SLE presenting with widespread neurological
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signs and symptoms suggestive of MS have usually been called lupoid sclerosis [8,12]. Endothelium is apparently one of the most important targets for CNS involvement in SLE. The pathogenesis of the small vessels angiopathy is not entirely clear, but it is reported to be more frequent in aPL positive patients. The role of aPL in pathogenic mechanisms can be based on the interference with the Protein C/S system, impairment of fibrinolytic activity, interference with anticoagulant proteins (annexin V), interference with endothelial cells and monocytes. Main target of aPL is 2GPI, while anti-2GPI antibodies bind to endothelial cells of different anatomical localisation. 2GPI is apparently more expressed on brain and skin microvascular endothelial cells. The additional role for anti-endothelial antibodies (AECA) in neuropsychiatric SLE was suggested. The important role of AECA is explained by several facts: AECA can be detectable in up to 70% of SLE sera, directed against constitutive endothelial cell antigens as well as against “planted” antigens (DNA/histone complexes; 2GPI), usually associated with active disease, can induce endothelial cell activation or apoptosis in experimental models. Specific antigens such as ribosomal P protein, Nedd 5, To 52/SS-A may be expressed on the surface of endothelial cells after apoptosis and supporting a direct pathogenic role of these autoantibodies in neuropsychiatric SLE [12–15]. Several mechanisms contribute to immunopathogenesis of neuropsychiatric manifestations in SLE including direct interaction of autoantibodies with autoantigens on neuronal cell membranes, interference with neurotransmission, loss of neuronal structure and cell death, aPL-mediated ischaemia, microthrombosis and noninflammatory vasculopathy and local production of cytokines inducing neuronal cytotoxicity [16,17]. Investigation and detection of antibodies in serum and cerebrospinal fluid associated with specific neuropsychiatric SLE manifestations can lead to possible mechanisms that are involved in the clinical pictures. Twenty antibodies were detected in the serum and/or CSF lupus patients and they are classified into two groups [14]: - Autoantibodies to brain components: anti neuronal antibodies, brain reactive antibodies (BRAA), anti-N-Methyld-aspartate receptor antibodies (anti-NMDA antibodies), anti-microtubule-associated protein 2 (MAP-2) antibodies, antineurofilament antibodies, antiganglioside antibodies, anti-NS tissue antibodies, antibrain synaptosomal antibodies, anti triosephosphate isomerase antibodies, anti-glial fibrillary acidic protein (aGFAP), antiserum lymphocytotoxic antibodies and - systemic autoantibodies: antiphospholipid/anticardiolipin antibodies (aCL), lupus anticoagulant (LAC), anti-B2Glycoprotein 1 antibodies, antiribosomal P antibodies (anti-P), anti Ro antibodies, anti Sm antibodies, antiendothelial cell antibodies (AECAs), antiserine proteinase 3 (Anti-PR3/C-ANCA) antibodies, anti-NEDD5 antibodies, autoantibody Burden) [14].
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The most frequent autoantibodies are antineuronal, BRAA and aPL. Brain specific autoantibody as antineuronal antibodies can be associated with cognitive dysfunction, psychosis, seizures, BRAA with psychosis and seizures, NMDA with cognitive dysfunction and depression, MAP-2 with psychosis, neuropathy, cerebritis, seizures, gangliozide antibodies with migraine, depression, cognitive dysfunction, peripheral neuropathy, neurofilament antibodies with diffuse neuropsychiatric manifestations. Diamond and colleagues demonstrated that anti ds-DNA from SLE patients cross-react with neuronal glutamate receptors (NR2) in the CNS, that these autoantibodies also mediate apoptotic death of neurons in vitro and in vivo and mediate some of non-vasculitic CNS abnormalities [14–16]. A role for chemokines has been reported. The chemokine monocyte chemotactic protein 1 (MCP-1)/CCL2 is higher in cerebrospinal fluid of neuropsychiatric lupus patients and correlate with intensity of inflammation. The same role have anti triosephosphate isomerase antibodies which concentration in cerebrospinal fluid is associated with neuropsychiatric SLE. A genetic component can also be involved in different populations [18,19]. In summary, there are some characteristics of pathogenicity in neuropsychiatric SLE: autoantibodies directed to intracellular autoantigen may exert pathogenic effects by binding to extracellularly expressed cognate autoantigens or cross-reactive epitopes; autoantibody specificity is not necessarily restricted to a single pathogenic mechanism; no single autoantibody would account for all forms of injury; activated lymphocytes can cross the intact blood–brain barrier (BBB); disruption of the BBB allows inflow of activated B and T cells, monocytes/macrophages, pathogenic serum autoantibody; B cells can synthesize in situ autoantibodies within the CNS de novo; immune complex mediated inflammation is not the central mechanism for CNS lupus; the identification of neural tissue-specific autoantibody cannot be construed as necessarily indicative of pathogenicity.
3. Antiphospholipid syndrome Antiphospholipid syndrome, also called Hughes’s syndrome, is usually defined by clinical features—thromboses and missed abortions (earlier thrombocytopenia) associated with laboratory findings presented by the elevated level of aPL, namely lupus anticoagulant, anticardiolipin antibodies and anti-beta2GPI antibodies. In secondary APS the condition is associated with underlying autoimmune disorder, most often being SLE [12,20]. Neurologic manifestations in APS may include cerebrovascular thrombosis, transitory ischemia, cognitive dysfunction, migraine, chorea, transverse myelopathy, seizures and psychologic disturbances. In some patients difficulties in differentiating between multiple sclerosis, SLE and APS may be present. Namely, in patients clinically diagnosed with MS the high levels of aPL may be found, while in patients
clinically diagnosed with SLE and/or APS the MRI studies may reveal the subcortical white matter lesions. Furthermore, in some patients with APS having sensory or motor dysfunction, optic neuritis or transverse myelitis the MRI studies can show multiple T2 hyperintense brain lesions, which may not be easy to differentiate from MS. Some authors suggest that lesions associated with APS, found on repeated MRI studies are usually static compared with the more dynamic lesions seen in MS. It is also suggested that magnetization transfer imaging combined with standard MRI can differentiate MS from APS. Although transverse myelitis and autoimmune optic neuropathy are rare manifestations of primary or secondary APS reported in 0.4 and 1% of patients, respectively, it is recommended that SLE and secondary APS must be suspected in patients with those conditions [6,12,21]. As mentioned above, in patients with SLE and APS the significant role of aPL is recognized. Speaking about pathogenesis of neurologic disorder in APS some studies propose the interactions between antibodies to anionic phospholipid protein complexes and antigen targets on platelets, endothelial cells or components of the coagulation cascade. There is also a possibility that aPL may react with brain lipids as cephalin or sphingomyelin; aPLs may contribute to neurological damage by reacting with brain cells by means of beta2GPI interaction. Expression of beta2GPI mRNA by astrocytes, neuronal and endothelial cells suggest that these cells can be a target of autoantibodies in the APS. The prevalence of aPL in patients with MS is very variable, reported to be between 4.8 and 44%. Some authors report on the higher frequency found in patients with transverse myelitis and optic neuritis, some found that association of consistent presence of high level of aPL in patients with probable or definite diagnosis of MS speaks in favor of slower progression, while others did not find any correlation. Thus, in the differential diagnosis of MS, patients with MS should be tested for aPL. Patients with absence of oligoclonal bands in cerebrospinal fluid and higher level of aPL in serum should be considered as having APS. It is recommended that anticoagulation therapy is administered to MS patients with aPL, particularly those with atypical forms of disease together with manifestations of APS [6,12,22]. Catastrophic antiphospholipid syndrome is described with clinical involvement of three or more organ systems with histopathological evidence of microangiopathy and multiple thromboembolic events, associated with the high titer of aPL, developing within the period of few days to few weeks. Clinical manifestations are reported with following (falling down) prevalence of organ system involvement: renal 80%, pulmonary 67%, CNS 57%, cardiac 48%, skin 49%, gastrointestinal 35%, adrenal thrombosis 26%. Characteristic laboratory findings include: thrombocytopenia 69%, hemolytic anemia 25%, DIC 27%, LAC 95%, ACL 95%, ANA 57%, anti dsDNA 87% in patients with SLE. Outcome in catastrophic APS is very serious with death occurring in 49% of patients. Causes of death can be cardiac events (microthrombi or myocardial infarction), ARDS
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or alveolar haemorrhage, cerebrovascular or gastrointestinal (esophageal perforation, bowel infarction) involvement [20,22].
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ance and allows the emergence of self-reactive B cells that efficiently present antigen to T cells. BAFF may stimulate T cell independent activation of B cells with Toll like receptors [25,26].
4. Sjoegren’s syndrome 5. Behcet’s disease Primary SS is a chronic inflammatory autoimmune disorder classically manifested with xerostomia and xerophtalmia (called also sicca syndrome), characterised by infiltration of the affected tissues (i.e. parotid glands) by lymphocytes. In about 50% of patients the condition not only involve gland inflammation but is also associated with other autoimmune disorder such as rheumatoid arthritis, SLE, systemic sclerosis, vasculitis, polymyositis or quite often autoimmune thyroiditis etc.; this condition is called secondary SS. The characteristic autoantibodies in the syndrome are Ro (SS-A) and La (SS-B). Neurologic manifestations are reported in 25–30% of patients as demyelination, autonomic disturbance, cerebrovascular accident, peripheral lesions (symmetric and multiple mononeuritis), transverse myelopathy. SS can mimic MS clinically and radiologically, particularly if neurological manifestations precede the immunological abnormalities including anti Ro/SS-A and anti La/SS-B antibodies. These patients may have rare oligoclonal bands in CSF immunoglobulin analysis. Transverse myelitis can be found in patients with SS, probably associated with vasculitic lesion of spinal cord; in some patients transverse myelitis was described in patients with SS and primary biliary cirrhosis. Autoimmune optic neuropathy has also been reported in patients with SS. Since several autoantibodies can be found even in patients with definite MS, most common being antiRo/SS-A (in 2–15% of patients), ANA and aCL, it is recommendable to evaluate the differential diagnosis towards the better treatable systemic autoimmune disease [3,4,6,23]. The CSF analysis is helpful in ruling out other causes of CNS diseases. IgG/total protein ratio is often elevated, IgG index is increased in about 50% of patients, oligoclonal bands and a CSF pleocytosis occur in subsets of CNS-SS patients. Antineuronal antibodies and antiribosomal P may be present, but in contrast to SLE they are not implicated as the mechanism of destruction. SS-A by gel diffusion is associated with larger lesions on MRI, abnormal cerebral angiography and serious focal CNS findings [24]. B cell dysfunction is a dominant feature of SS. Autoantibodies can be organ specific or organ nonspecific and include SS-A and SS-B antibodies, histones, ssDNA, alfa fodrin antibodies and rheumatoid factor. The excessive B cell activating factor (BAFF) production can be found, which can be linked to the development of SS. Nonlymphoid cell types such as astrocytes, gland epithelial cells, vascular cell adhesion molecule-1-positive bone marrow stromal cells also express BAFF. The critical role of BAFF and B cells in the pathogenesis of SS and its association with B lymphomas is demonstrated. Excess BAFF possibly corrupts B cell toler-
BD is a chronic systemic vasculitis involving the small blood vessels, characterised by relapsing oral and/or genital ulcerations, ophtalmologic lesions (uveitis, retinal vasculitis). Arthritis, involvement of the gastrointestinal system and CNS as well as skin lesions (erythema nodosum, pseudopholiculitis, papulopustulous and/or akneiform lesions) are common. It is more frequent and severe in patients from the Eastern Mediterranean and Asia [3]. Neurologic disturbances in BD affecting 5–50% of patients, can be manifested as the meningeal lesions (aseptic meningitis), inflammatory lesions (encephalitis, myelitis) or vascular changes (thrombosis, arteritis). Patients with BD and neurological injury (neuro–BD) are associated with a poorer prognosis. Musculoskeletal lesions in Behcet’s disease are clinical features of seronegative spondylarthropathy [3,27]. Clinical course of CNS affected patients with BD may clinically and radiologically mimic MS. On MRI studies patients with neurological involvement in BD may have single or multiple hemispherical and/or spinal cord white matter lesions (Fig. 2), often extending from the brain stem to basal ganglia. Typical for the later stage of the neuro–BD is the atrophy of the brain stem without cortical atrophy. The differential diagnosis between neuro–BD and MS may be difficult if neurological manifestations develop before the systemic appearance fulfilling diagnostic criteria for BD. The course of MS is more often polyphasic, while neuro–BD is more progressive; the main neurological manifestation of neuro–BD progressive pseudobulbar palsy is rarely seen in MS. Cerebrospinal fluid in neuro–BD may be normal or pathological, sometimes oligoclonal banding patterns of immunoglobulin may be demonstrated [27,28]. There are several main lines of research in the pathogenesis of BD, but it is still not understood. In genetic studies–HLA B51 (particularly B5101 subcomponent) was found to be the main allele associated with BD. Vasculitis of the vasa vasorum seems to be the major site of pathology in large vessel disease. Coagulation abnormalities in the pathogenesis are not clear. Same studies were connected with Factor V Leiden mutation. A recent focus of attention are T cell costimulatory molecules–anti-CTLA-4 which are associated with eye disease and CNS involvement [29–31].
6. Systemic sclerosis SSc is a multisystem disease primarily affecting the skin, but may involve other organs like lung and kidneys. Although
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We present a 51-year-old female patient with a history of headaches who developed scleroderma, 7 years later was treated (surgery and chemotherapy) for breast cancer, then slowly developed features of CREST syndrome (calcinosis, Raynaud’s phenomenon, esophageal disturbances, sclerodactilia and teleangiectasiae). She also had bilateral pulmonary fibrosis, peripheral neuropathy and progressive demyelinating lesions (Fig. 3).
7. Demyelination in the course of biologic treatment of rheumatic diseases
Fig. 2. T2 axial MR image with isolated focal hypersensitivity in subcortical white matter of right frontal superior gyrus in a male patient with Behcet’s disease.
there are reports of the peripheral nervous system involvement, the CNS affections appear to be rare. Only a few cases of coexistence of SSc and MS have been described, particularly the transverse myelopathy in the setting of SSc, localised or linear scleroderma. Since several connective tissue diseases are associated with transverse myelitis, including SLE and Sjoegren’s syndrome, there was a discussion whether the transverse myelitis in a patient with SSc is an independent overlapping event or a manifestation of SSc [32,33].
Progressive multifocal leucoencephalopathy (PML) is a progressive neurological disease with areas of demyelination in the central nervous system and rapidly fatal outcome. It occurs in severely immunosuppressed patients with lymphoma, solid organ malignancies, and organ transplant recipients. PML was a rare disease until it became an AIDSdefining illness in the 1980s. PML is caused by reactivation of latent polyoma virus JC, leading to the death of myelinproducing oligodendrocytes. Recent interest in the disorder has been elicited by its appearance in patients treated with the monoclonal antibodies Natalizumab and Rituximab as well as TNF alpha antagonist therapy. PML has been reported in rheumatic diseases with and without biologic therapeutic agents [34–36]. We describe two patients who developed PML in the course of their rheumatic diseases. A 35-year-old female patient presenting with arthralgias was diagnosed to have SLE with diffuse proliferative glomerulonephritis. She was successfully treated with glucocorticoids and cyclophosphamide. Three years later with clinical and laboratory features of low activity SLE she developed bulbar symptoms which progressed together with the development of pyramid and extrapyramid symptoms. Brain CT and MRI scan showed major demyelination area (Fig. 4). With the progression of neurological symptoms the patient died in a few months time. On autopsy large destruction of white matter
Fig. 3. Two axial T2 images with diffusely distributed large demyelinating lesions progressing to leucomalacia or formation of cysts in a female patient with CREST syndrome.
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Fig. 6. FLAIR axial MR image showing subcortically distributed focal hyperintensities, dominantly distributed on white–gray matter border in a female patient with rheumatoid arthritis who developed multifocal leucoencephalopathy after treatment with Infliximab.
Fig. 4. T2 axial MR image showing large confluent hyperintensity in insular and periinsular region also with two focal hyperintensities, one of them lateral from optic radiation on right side and other lesion in the region of posterior part of internal capsula on left side in a patient with systemic lupus erythematosus and multifocal leucoencephalopathy.
was found (Fig. 5). Histologic examination revealed significant loss of myelin and numerous reactive astrocytes with bizarre, enlarged hyperchromatic nuclei; the oligodendrocytes with the violaceous intranuclear inclusions were found. Based on all that the diagnosis of PML was confirmed. In the second case of a 50-year-old female patient the diagnosis of rheumatoid arthritis was established. After the unsuccessful treatment with the combination of disease
modified antirheumatic drugs including Methotrexate, the application of Infliximab, an anti-TNF-alfa monoclonal antibody, was started. During the 2 years of treatment with Infliximab the positive effect on rheumatoid arthritis activity was noted, but the patient developed neurological symptoms (transitory paresis of the right leg, facial paresthesias, a drop attack). In the extensive neurologic investigation the brain MRI revealed the demyelination area without any diagnostic criteria for MS. After the application of Infliximab was stopped, the neurological symptoms spontaneously disappeared; patient is now followed for 3-year period without any sign of neurologic disease (Fig. 6). With current and future treatments that suppress and manipulate the immune system, there is a risk for severe acute infections and reactivation of latent infections, such as JC virus reactivation leading to PML. Patients presenting with new CNS symptoms following treatment with antiTNF-alfa agents should be evaluated for JC virus infection [37].
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Fig. 5. Large destruction of white matter without destruction of gray matter found on autopsy of a patient with systemic lupus erythematosus and multifocal leucoencephalopathy.
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