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Differential diagnosis of multiple sclerosis and other inflammatory CNS diseases

Open AccessPublished:October 15, 2019DOI:https://doi.org/10.1016/j.msard.2019.101452

      Highlights

      • MRI remains the cornerstone of differential diagnosis of MS.
      • Excessive reliance on radiological features may generate diagnostic errors.
      • Inaccurate diagnosis of MS may impose potentially pernicious consequences.
      • Rheumatic diseases are an underrated cause of white matter lesions on brain MRI.
      • Further search for highly specific biomarkers seems to be of primary importance.

      Abstract

      Multiple sclerosis (MS) is the most common acquired demyelinating disorder of the central nervous system (CNS). Diagnosing MS can be very challenging owing to its variable clinical features and lack of specific tests. Magnetic resonance imaging (MRI) is a key measure in this process. Although white matter lesions on brain MRI are regarded as a hallmark of MS, they are a common radiological finding and their pattern may overlap in particular CNS inflammatory diseases. The increasing availability of therapies for MS and the knowledge of benefits associated with an early treatment underscore the importance of precise and quick diagnosis. Despite an extensive research, currently no fully specific diagnostic test is available to distinguish between CNS inflammatory disorders. In this review, we discuss characteristic findings and distinctive features of CNS inflammatory disorders, with particular focus on rheumatic diseases.

      Keywords

      Abbreviations:

      AC-13 (apolipoprotein A1 C-terminal fragment), aCL (anticardiolipin antibodies), ADEM (acute disseminated encephalomyelitis), ANA (antinuclear antibodies), ANCA (antineutrophil cytoplasmic antibodies), anti-dsDNA (anti-double stranded DNA), anti-P (anti-ribosomal P), anti-Sm (anti-Smith), anti-β2GP1 (anti-beta2glycopretein 1), aPL (antiphospholipid antibodies), AQP4 (aquaporin-4), BBB (blood-brain barrier), BD (Behҫet disease), BLyS (B-lymphocyte stimulator), CIS (clinically isolated syndrome), CNS (central nervous system), CRP (C-reactive protein), CSF (cerebrospinal fluid), DIS (dissemination in space), DIT (dissemination in time), EAN (European Academy of Neurology), ECTRIMS (European Committee of Treatment and Research in Multiple Sclerosis), EGPA (eosinophilic granulomatosis with polyangitis), ESR (erythrocyte sedimentation rate), GABAR (gamma-aminobutyric acid receptor), GFAP (glial fibrillary acid protein), GPA (granulomatosis with polyangitis), HLA (human leukocyte antigen), ICAM (Intercellular Adhesion Molecule), IgG (immunoglobulin G), IL (interleukin), INF (interferon), LAC (lupus anticoagulant), LETM (longitudinally extensive transverse myelitis), MAGNIMS (Magnetic Resonance Imaging in Multiple Sclerosis), MOG (myelin oligodendrocytes glycoprotein), MPA (microscopic polyangitis), MPO (myeloperoxidase), MRI (magnetic resonance imaging), MS (multiple sclerosis), NBD (Neuro-Behҫet disease), NMDA (N-methyl-D-aspartate), NMO (neuromyelitis optica), NMOSD (neuromyelitis optica spectrum disorders), NPSLE (neuropsychiatric systemic lupus erythematosus), NR2 (anti-N-methyl-D-aspartate receptor subtype 2 receptors), OCBs (oligoclonal bands), OCT (optical coherence tomography), PCNSV (primary central nervous system vasculitis), PPMS (primary progressive multiple sclerosis), Qalb (abumin quotient), RRMS (relapsing-remitting multiple sclerosis), SLE (systemic lupus erythematosus), SPMS (secondary progressive multiple sclerosis), STM (short transverse myelitis), TIA (transient ischemic attack), VCAM (vascular cell adhesion molecule), VEGF (vascular endothelial growth factor), WML (white matter lesions)

      1. Introduction

      White matter lesions (WML) on brain magnetic resonance imaging (MRI) are common findings and in high percentage of cases they imply further diagnosis of multiple sclerosis (MS) and related demyelinating disorders. The reported prevalence of MS is increasing (
      • Browne P.
      • Chandraratna D.
      • Angood C.
      • et al.
      Atlas of multiple sclerosis 2013: a growing global problem with widespread inequity.
      ), which is at least partially a consequence of growing consciousness of MS in the society and also a wider availability of diagnostic tools, especially MRI. This situation, together with an inappropriate use of the diagnostic criteria, results in a considerable proportion of misdiagnoses. Since early implementation of treatment is crucial for its efficacy, precise diagnosis seems to be essential. Recent studies have emphasized the issue of erroneous diagnosis of MS and potential pernicious consequences which it entails, including aggressive immunosuppressive therapy (
      • Solomon A.J.
      • Bourdette D.N.
      • Cross A.H.
      • et al.
      The contemporary spectrum of multiple sclerosis misdiagnosis: a multicenter study.
      ;
      • Siva A.
      Common clinical and imaging conditions misdiagnosed as multiple sclerosis: a current approach to the differential diagnosis of multiple sclerosis.
      ;
      • Solomon A.J.
      • Klein E.P.
      • Bourdette D.
      “Undiagnosing” multiple sclerosis: the challenge of misdiagnosis in MS.
      ;
      • Solomon A.J.
      • Weinshenker B.G.
      Misdiagnosis of multiple sclerosis: frequency, causes, effects, and prevention.
      ). Studies have revealed that the most frequent disorder misdiagnosed as MS is migraine alone or in combination with other diagnosis, and it accounts for 22% of incorrectly diagnosed patients. Other conditions commonly misdiagnosed as MS are fibromyalgia, nonspecific white matter lesions, psychiatric disorders and neuromyelitis optica spectrum disorders (NMOSD). White matter lesions due to vasculitis also should not be disregarded (
      • Solomon A.J.
      • Bourdette D.N.
      • Cross A.H.
      • et al.
      The contemporary spectrum of multiple sclerosis misdiagnosis: a multicenter study.
      ). Additionally, acute disseminated encephalomyelitis (ADEM) has to be considered as a cause of the first demyelinating episode, especially in the pediatric population. Differential diagnosis of MS involves also a broad spectrum of disorders eg. genetic metabolic disorders, such as Alexander disease, X-linked adrenoleukodystrophy, metachromatic leukodystrophy, Canavan disease, infectious diseases, mostly opportunistic such as toxoplasmosis, progressive multifocal leukoencephalopathy, neuroborreliosis and lymphoproliferative diseases (
      • Siva A.
      Common clinical and imaging conditions misdiagnosed as multiple sclerosis: a current approach to the differential diagnosis of multiple sclerosis.
      ). On the other hand, delayed MS diagnosis in people who obtain treatment for another disorder even for years is an equally important issue. Although MRI is currently the most valuable tool in differential diagnosis of MS, excessive reliance on radiological features is often responsible for diagnostic errors. Because the issue of MS misdiagnosis is of such a paramount importance, further search for specific biomarkers seems mandatory. In this review, we shall discuss MS and other demyelinating autoimmune disorders of the central nervous system (CNS), with a particular focus on rheumatic diseases, and highlight the distinctive features which may facilitate the proper diagnosis.

      2. Multiple sclerosis

      MS is presumed to be the most common acquired demyelinating disorder of the central nervous system. MS is assumed to affect over 2.5 million people globally, and is regarded as one of the primary causes of disability, especially among young adults (
      • Pelletier D.
      • Hafler D.A.
      Fingolimod for multiple sclerosis.
      ). The prevalence of MS is highly heterogeneous. The incidence of MS differs between populations and reaches even 10 new cases per 100 000 (
      • Kingwell E.
      • Zhu F.
      • Marrie R.A.
      • et al.
      High incidence and increasing prevalence of multiple sclerosis in British Columbia, Canada: findings from over two decades (19912010).
      ;
      • Grytten N.
      • Aarseth J.H.
      • Lunde H.M.
      • Myhr K.M.
      A 60- year follow-up of the incidence and prevalence of multiple sclerosis in Hordaland county, Western Norway.
      ). Although a meta-analysis, including 59 countries, revealed a statistically significant latitudinal gradient for MS prevalence (
      • Simpson S.J.
      • Blizzard L.
      • Otahal P.
      • et al.
      Latitude is significantly associated with the prevalence of multiple sclerosis: a meta-analysis.
      ), other studies have shown no remarkable latitudinal or longitudinal gradient in some regions (
      • Poppe A.
      • Wolfson C.
      • Zhu B.
      Prevalence of multiple sclerosis in Canada: a systematic review.
      ;
      • Melcon M.
      • Gold L.
      • Carra A.
      • et al.
      Argentine patagonia: prevalence and clinical features of multiple sclerosis.
      ). The risk of developing MS is determined by genetic as well as environmental factors. Current data on genetic, epigenetic, and transcriptome studies in monozygotic twins has proven discordance for MS (
      • Mumford C.J.
      • Wood N.W.
      • Kellar-Wood H.
      • et al.
      The British Isles survey of multiple sclerosis in twins.
      ;
      • Baranzini S.E.
      • Mudge J.
      • van Velkinburgh J.C.
      • et al.
      Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis.
      ).
      Even though demyelination is regarded as the pathologic hallmark of MS, studies indicate that axonal injury is playing a key role in the persistence of neurological deficits (
      • van Waesberghe J.H.
      • Kamphorst W.
      • De Groot C.J.
      • et al.
      Axonal loss in multiple sclerosis lesions: magnetic resonance imaging insights into substrates of disability.
      ;
      • Fisher E.
      • Chang A.
      • Fox R.J.
      • et al.
      Imaging correlates of axonal swelling in chronic multiple sclerosis brains.
      ). The exact etiology and pathomechanisms of MS remain not fully known. However, the leading role of autoimmune and neurodegenerative processes has long been postulated. The cascade of MS pathology comprises demyelination, oligodendrocyte loss, neuronal loss, axonal damage, astrogliosis, and progressive failure of remyelination (
      • Zeydan B.
      • Kantarci O.H.
      ;
      • Lassmann H.
      • van Horssen J.
      • Mahad D.
      Progressive multiple sclerosis: pathology and pathogenesis.
      ). It is assumed that inflammatory reaction associated with different cell types including T cells, B cells, activated microglia, macrophages and their products results in demyelination (
      • Lassmann H.
      Review: the architecture of inflammatory demyelinating lesions: implications for studies on pathogenesis.
      ), whereas various inflammation induced and/or mediated processes e.g. oxidative stress leading to mitochondrial injury perpetuate neurodegeneration (
      • Lassmann H.
      Review: the architecture of inflammatory demyelinating lesions: implications for studies on pathogenesis.
      ). All the processes coincide at every stage of the disease, though their intensity varies in time and the progressive phase of MS becomes clinically apparent when the axonal damage threshold is surpassed (
      • Confavreux C.
      • Vukusic S.
      • Adeleine P.
      Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process.
      ). The present disease course classification comprises the relapsing-remitting MS (RRMS) and progressive MS, which is divided into primary progressive MS (PPMS) and secondary progressive MS (SPMS) (
      • Lublin F.D.
      • Reingold S.C.
      • Cohen J.A.
      • et al.
      Defining the clinical course of multiple sclerosis: the 2013 revisions.
      ;
      • Miller D.H.
      • Leary S.M.
      Primary-progressive multiple sclerosis.
      ). Each phenotype is further defined by the status of disease activity and progression (
      • Lublin F.D.
      • Reingold S.C.
      • Cohen J.A.
      • et al.
      Defining the clinical course of multiple sclerosis: the 2013 revisions.
      ).
      Current 2017 McDonald diagnostic criteria for multiple sclerosis include clinical, imaging and laboratory findings (
      • Thompson A.J.
      • Banwell B.L.
      • Barkhof F.
      • et al.
      Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria.
      ). MRI is of utmost importance in the diagnosis of MS. Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) network and the Consortium of Multiple Sclerosis Centers have given recommendations on the use of MRI in MS diagnosis (
      • Wattjes M.P.
      • Rovira A.
      • Miller D.
      • et al.
      Evidence-based guidelines: magnims consensus guidelines on the use of MRI in multiple sclerosis-establishing disease prognosis and monitoring patients.
      ;
      • Traboulsee A.
      • Simon J.H.
      • Stone L.
      • et al.
      Revised recommendations of the consortium of MS centers task force for a standardized MRI protocol and clinical guidelines for the diagnosis and follow-up of multiple sclerosis.
      ). Brain and spinal cord MRI may replace clinical features to meet the dissemination in space (DIS) or dissemination in time (DIT) criteria. Typical MS MRI findings are T2-hyperintense lesions in four areas of the CNS: periventricular, cortical or juxtacortical, infratentorial and spinal cord (
      • Thompson A.J.
      • Banwell B.L.
      • Barkhof F.
      • et al.
      Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria.
      ). Besides the diagnostic criteria of MS, MRI is highly advantageous in detecting findings suggestive of disorders other than MS. Awareness of such features seems to be essential for understanding the concept of ‘no better explanation’ (
      • Charil A.
      • Yousry T.A.
      • Rovaris M.
      • et al.
      MRI and the diagnosis of multiple sclerosis: expanding the concept of "no better explanation”.
      ). Table 1 shows common MS MRI findings and “red flags”- suggestive of other inflammatory CNS diseases. Fig. 1 (a-f) demonstrates different types of white matter lesions. Although cerebrospinal fluid (CSF) examination is not obligatory to set the diagnosis of MS, 2017 revisions of McDonald criteria has emphasized the significance of the presence of CSF-specific oligoclonal bands (OCBs), which may substitute MRI criterion for DIT in patients with clinically isolated syndrome (CIS) (
      • Thompson A.J.
      • Banwell B.L.
      • Barkhof F.
      • et al.
      Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria.
      ). Moreover, the presence of CSF oligoclonal bands was shown to represent an independent predictor of a second attack in patients with CIS (
      • Andreadou E.
      • Chatzipanagiotou S.
      • Constantinides V.C.
      • Rombos A.
      • Stamboulis E.
      • Nicolaou C.
      Prevalence of cerebrospinal fluid oligoclonal IgG bands in Greek patients with clinically isolated syndrome and multiple sclerosis.
      ;
      • Dobson R.
      • Ramagopalan S.
      • Davis A.
      • Giovannoni G.
      Cerebrospinal fluid oligoclonal bands in multiple sclerosis and clinically isolated syndromes: a meta-analysis of prevalence, prognosis and effect of latitude.
      ). On the other hand, such CSF findings as elevated protein concentration above 100 mg/dL, pleocytosis over 50 cells/mm3 or presence of neutrophils, eosinophils or atypical cells are uncommon in MS, and should imply consideration of other diagnosis (
      • Stangel M.
      • Fredrikson S.
      • Meinl E.
      • Petzold A.
      • Stuve O.
      • Tumani H.
      The utility of cerebrospinal fluid analysis in patients with multiple sclerois.
      ). Until now, no fully specific biomarker of MS is available, which makes careful exclusion of other possible causes of observed clinical symptoms mandatory (
      • Miller D.H.
      • Weinshenker B.G.
      • Filippi M.
      • et al.
      Differential diagnosis of suspected multiple sclerosis: a consensus approach.
      ). It is worth to mention, that neurofilament light chain (NfL) levels in serum of MS patients are associated with clinical and MRI-related measures of disease activity and neuroaxonal damage and have prognostic, but not diagnostic value (
      • Kuhle J.
      • Kropshofer H.
      • Haering D.A.
      • Kundu U.
      • Meinert R.
      • Barro C.
      • Dahlke F.
      • Tomic D.
      • Leppert D.
      • Kappos L.
      Blood neurofilament light chain as a biomarker of MS disease activity and treatment response.
      ). The European Committee of Treatment and Research in Multiple Sclerosis (ECTRIMS) and the European Academy of Neurology (EAN) have issued practical guidelines on the pharmacological MS treatment (
      • Montalban X.
      • Gold R.
      • Thompson A.J.
      • et al.
      ECTRIMS/EAN guideline on the pharmacological treatment of people with multiple sclerosis.
      ). Despite the knowledge of a few prognostic factors (
      • Tintore M.
      • Rovira A.
      • Rio J.
      • et al.
      Defining high, medium and low impact prognostic factors for developing multiple sclerosis.
      ;
      • Jokubaitis V.G.
      • Spelman T.
      • Kalincik T.
      • et al.
      Predictors of long-term disability accrual in relapse-onset multiple sclerosis.
      ), there is still an unmet need for biomarkers, which would facilitate the stratification of patients into groups suited for particular treatment approach.
      Table 1MRI ‘red flags’ (
      • Jog N.R.
      • James J.A.
      Biomarkers in connective tissue diseases.
      ;
      • Ungprasert P.
      • Matteson E.L.
      Neurosarcoidosis.
      ;
      • Maggi P.
      • Absinta M.
      • Grammatico M.
      • et al.
      Central vein sign differentiates multiple sclerosis from central nervous system inflammatory vasculopathies.
      ;
      • Chen J.J.
      • Carletti F.
      • Young V.
      • Mckean D.
      • Quaghebeur G.
      MRI differential diagnosis of suspected multiple sclerosis.
      ;
      • Ramanathan S.
      • Prelog K.
      • Barnes E.H.
      • et al.
      Radiological differentiation of optic neuritis with myelin oligodendrocyte glycoprotein antibodies, aquaporin-4 antibodies, and multiple sclerosis.
      ;
      • Charil A.
      • Yousry T.A.
      • Rovaris M.
      • et al.
      MRI and the diagnosis of multiple sclerosis: expanding the concept of "no better explanation”.
      ).
      MRI findingtypical for MS‘red flags’
      shape and size of lesionsovoid, perivenular, Dawson's fingersmassive, confluent
      U-fibers involvementyesno
      lesion morphologyregular, distinct borderfluffy, indistinct border
      gadolinium enhancementhomogeneous; ring, open ring; pattern changing in successive MRIsheterogeneous enhancement; cloud-like, pencil-thin; pattern persistent over months
      locationperiventricular, juxtacortical/ asymmetricalperipheric, cortical/ symmetrical
      mass effectrare, eg. in tumefactive MSprominent in granulomatous diseases
      optic neuritismore than half of the length of the optic nerve, comprising intracranial segment, typically extending to the chiasm and optic tract
      corpus callosumsmall ovoid lesions, atrophy in later phaseependymal surface involvement; “arch bridge” appearance - NMOSD
      posterior fossa-brainstem lesionssmallupward/downward extension of brainstem lesion - NBD
      spinal cord lesionsshort (less than 3 vertebral segments); <50% of the cross-sectional area; peripherallongitudinally extensive (at least 3 vertebral segments); >50% of the cord area; central gray matter
      meningeal involvementnoyes, leptomeningeal and pachymeningeal
      infarcts or hemorrhagesnoyes, especially multiple
      calcificationsnoyes
      typical signcentral vein signBagel sign - NBD; punctuate enhancement and swelling of basal ganglia – NPSLE; diencephalon involvement – NMOSD; area postrema involvement - NMOSD; bright spotty lesions in the spinal cord - NMOSD; “string of pearls” (clusters of snowball-like callosal lesions) – Susac syndrome
      Fig 1
      Fig. 1Different types of white matter lesions in CNS inflammatory diseases. (a). Typical MRI findings in MS: T2-hyperintense periventricular and juxtacortical lesions. (b). T1 scan showing ring and open ring gadolinium enhancement pattern of lesions present in Fig.1a. (c). Subcortical FLAIR-hyperintense white matter lesions in a patient with APS secondary to SLE. (d). Cortical-subcortical malacia after an ischaemic stroke in the same patient with APS secondary to SLE presented in fig. 1c. (e). T2 dark fluid-hyperintense lesion in area postrema in a patient with SLE which needs to be differentiated from NMOSD. (f). Diffuse T2-hyperintense lesion at the level Th1 to Th4 affecting white as well as gray matter of spinal cord in NMO patient. Small T2-hyperintense lesions visible also at the level of Th8 and Th10.

      3. Neuromyelitis optica spectrum disorders

      NMOSD, including neuromyelitis optica (NMO) or Devic's syndrome, comprise a group of the central nervous system (CNS) inflammatory conditions, affecting preferentially optic nerves and spinal cord (
      • Bruscolini A.
      • Sacchetti M.
      • La Cava M.
      • Gharbiya M.
      • Ralli M.
      • Lambiase A.
      • De Virgilio A.
      • Greco A.
      Diagnosis and management of neuromyelitis optica spectrum disorders - An update.
      ). NMO is a relatively uncommon disease, with the incidence and prevalence ranging from 0.05–0.4 and 0.52–4.4 per 100,000, respectively. NMO primarily affects young adults, with a mean age 32.6–45.7 years. A significant predominance in women is observed, who constitute from 68% to 88% of the affected population (
      • Pandit L.
      • Asgari N.
      • Apiwattanakul M.
      • et al.
      Biorepository for neuromyelitis, demographic and clinical features of neuromyelitis optica: a review.
      ). The core clinical characteristics of NMOSD are optic neuritis, acute myelitis, area postrema syndrome, acute brainstem syndrome, symptomatic narcolepsy or acute diencephalic clinical syndrome with NMOSD-typical diencephalic MRI lesions and symptomatic cerebral syndrome with NMOSD-typical brain lesions (
      • Wingerchuk D.M.
      • Banwell B.
      • Bennett J.L.
      • et al.
      International consensus diagnostic criteria for neuromyelitis optica spectrum disorders.
      ). Acute optic neuritis, in particular bilateral or rapidly sequential, and longitudinally extensive transverse myelitis (LETM), are the most usual manifestations of NMO (
      • Wingerchuk D.M.
      • Hogancamp W.F.
      • O'Brien P.C.
      • Weinshenker B.G.
      The clinical course of neuromyelitis optica (Devic's syndrome).
      ). Thus, the most common symptoms involve ocular pain with a severe visual acuity loss, symmetric paraplegia, sensory loss and bladder dysfunction (
      • Wingerchuk D.M.
      • Lennon V.A.
      • Lucchinetti C.F.
      • et al.
      The spectrum of neuromyelitis optica.
      ). Other alarm signs are nausea/vomiting, intractable hiccups, diplopia and nystagmus, hearing and balance disorder, narcolepsy, obesity or even acute respiratory failure (
      • Bruscolini A.
      • Sacchetti M.
      • La Cava M.
      • Gharbiya M.
      • Ralli M.
      • Lambiase A.
      • De Virgilio A.
      • Greco A.
      Diagnosis and management of neuromyelitis optica spectrum disorders - An update.
      ;
      • Sahraian M.A.
      • Radue E.W.
      • Minagar A.
      Neuromyelitis optica: clinical manifestations and neuroimaging features.
      ).
      Current criteria divide NMOSD into two subtypes according to the seropositivity of aquaporin-4 immunoglobulin G (AQP4-IgG): NMOSD with AQP4-IgG (NMOSD- AQP4-IgG) and NMOSD without AQP4-IgG or with unknown AQP4-IgG status (
      • Wingerchuk D.M.
      • Banwell B.
      • Bennett J.L.
      • et al.
      International consensus diagnostic criteria for neuromyelitis optica spectrum disorders.
      ). The diagnosis of NMOSD is based on clinical manifestations, serological testing and MRI. In the presence of AQP4-IgG, only one of the core clinical characteristics is sufficient to make the diagnosis, provided that alternative diagnoses have been excluded. In patients with a negative AQP4-IgG test or when the test is unavailable, at least two core characteristics of NMOSD have to be present (one of them obligatory being optic neuritis, acute myelitis with LETM or area postrema syndrome) alongside with supportive MRI features and an exclusion of alternative diagnoses (
      • Wingerchuk D.M.
      • Banwell B.
      • Bennett J.L.
      • et al.
      International consensus diagnostic criteria for neuromyelitis optica spectrum disorders.
      ). AQP4 is the key target in NMO pathogenesis. AQP4 is an astrocyte water channel protein which promotes the movement of water across cell membranes in response to osmotic gradients (
      • Papadopoulos M.C.
      • Verkman A.S.
      Aquaporin 4 and neuromyelitis optica.
      ). AQP4 is primarily expressed in astrocyte foot processes, in particular within the optic nerves, spinal cord, periventricular areas, hypothalamus, subpial regions in cerebellar hemispheres, brainstem and area postrema (
      • Zekeridou A.
      • Lennon V.A.
      Aquaporin-4 autoimmunity.
      ). The clinical course of NMOSD seems to vary between AQP4-IgG-seropositive and seronegative patients. In the AQP4-IgG-seropositive group, more severe and frequent relapses, higher female to male ratio, more unfavorable outcomes and more often coexisting autoimmune disorders should be expected (
      • Jarius S.
      • Ruprecht K.
      • Wildemann B.
      • et al.
      Contrasting disease patterns in seropositive and seronegative neuromyelitis optica: a multicentre study of 175 patients.
      ). In addition to AQP4, a few other immune pathogenic targets have been revealed in the context of NMOSD, mainly myelin oligodendrocytes glycoprotein (MOG), but also glial fibrillary acid protein (GFAP), S100 protein, metalloprotease-9, VEGF A, ICAM-1, VCAM-1 (
      • Lennon V.A.
      • Wingerchuk D.M.
      • Kryzer T.J.
      • et al.
      A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis.
      ;
      • Jarius S.
      • Wildemann B.
      • Paul F.
      Neuromyelitis optica: clinical features, immunopathogenesis and treatment.
      ). The available information regarding the MOG-IgG-positive patients with NMOSD indicate that the disease usually starts at a younger age, the female to male ratio is lower, is more often monophasic and with a less severe outcome than in AQP4-IgG-positive NMOSD (
      • Sato D.K.
      • Callegaro D.
      • Lana-Peixoto M.A.
      • et al.
      Distinction between MOG antibody-positive and AQP4 antibody-positive NMO spectrum disorders.
      ;
      • van Pelt E.D.
      • Wong Y.Y.
      • Ketelslegers I.A.
      • Hamann D.
      • Hintzen R.Q.
      Neuromyelitis optica spectrum disorders: comparison of clinical and magnetic resonance imaging characteristics of AQP4-IgG versus MOG-IgG seropositive cases in the Netherlands.
      ;
      • Jurynczyk M.
      • Geraldes R.
      • Probert F.
      • et al.
      Distinct brain imaging characteristics of autoantibody-mediated CNS conditions and multiple sclerosis.
      ). The recently described concept of MOG antibody disease comprises a group of autoimmune disorders with a predilection for optic nerve and spinal cord involvement (
      • Denève M.
      • Biotti D.
      • Patsoura S.
      • Ferrier M.
      • Meluchova Z.
      • Mahieu L.
      • Heran F.
      • Vignal C.
      • Deschamps R.
      • Gout O.
      • Champfleur N.M.
      • Ayrignac X.
      • Dallière C.C.
      • Labauge P.
      • Dulau C.
      • Tourdias T.
      • Dumas H.
      • Cognard C.
      • Brassat D.
      • Bonneville F.
      MRI features of demyelinating disease associated with anti-MOG antibodies in adults.
      ;
      • Lana-Peixoto M.A.
      • Talim N.
      Neuromyelitis optica spectrum disorder and Anti-MOG syndromes.
      ).
      MRI is of great importance in the process of NMOSD diagnosis, especially among the AQP4-negative patients. Optic neuritis in NMOSD is commonly bilateral and longitudinally extensive, involving over one half of the optic nerve, most typically in the posterior segment prolonging to the chiasm and optic tract (
      • Ramanathan S.
      • Prelog K.
      • Barnes E.H.
      • et al.
      Radiological differentiation of optic neuritis with myelin oligodendrocyte glycoprotein antibodies, aquaporin-4 antibodies, and multiple sclerosis.
      ). On the contrary, optic neuritis associated with MOG antibody localizes typically in the anterior part of the nerve, is stretched, oedematous, with more prominent inflammation than in AQP-4-IgG positive patients (
      • Carra-Dalliere C.
      • Menjot de Champfleur N.
      • Ayrignac X.
      • Labauge P.
      Optic chiasmand oculomotor nerves involvement in active multiple sclerosis.
      ). Characteristic MRI feature of MOG antibody disease is enhancement of the peri‑optic nerve sheath, partly extending into the surrounding orbital fat (
      • Ramanathan S.
      • Prelog K.
      • Barnes E.H.
      • Tantsis E.M.
      • Reddel S.W.
      • Henderson A.P.
      • et al.
      Radiological differentiation of optic neuritis with myelin oligodendrocyteglycoprotein antibodies, aquaporin-4 antibodies, and multiple sclerosis.
      ). LETM, as the manifestation of NMOSD, extends for at least three adjacent vertebral segments and involves primarily the central gray matter of the spinal cord and over 50% of the cord area, constituting transversally extensive lesions (
      • Pekcevik Y.
      • Mitchell C.H.
      • Mealy M.A.
      • et al.
      Differentiating neuromyelitis optica from other causes of longitudinally extensive transverse myelitis on spinal magnetic resonance imaging.
      ;
      • Dumrikarnlert C.
      • Siritho S.
      • Chulapimphan P.
      • Ngamsombat C.
      • Satukijchai C.
      • Prayoonwiwat N.
      The characteristics of spinal imaging in different types of demyelinating diseases.
      ). Lesions within the cervical spine, typically spread to the area postrema (
      • Kim H.J.
      • Paul F.
      • Lana-Peixoto M.A.
      • et al.
      MRI characteristics of neuromyelitis optica spectrum disorder: an international update.
      ). Bright spotty lesions with a strong hyperintensity on axial T2-weighted images, with higher signal intensity than the surrounding cerebrospinal fluid, without flow void effects are suggested as one of the most characteristic CNS MRI features in NMOSD (
      • Yonezu T.
      • Ito S.
      • Mori M.
      • et al.
      “Bright spotty lesions” on spinal magnetic resonance imaging differentiate neuromyelitis optica from multiple sclerosis.
      ). Cord swelling and irregular enhancement on T1-weighted images can be observed in acute phase. The ring enhancement pattern in NMOSD LETM has a lens-shaped appearance on sagittal scans (
      • Zalewski N.L.
      • Morris P.P.
      • Weinshenker B.G.
      • et al.
      Ring-enhancing spinal cord lesions in neuromyelitis optica spectrum disorders.
      ). Besides LETM, the most typical NMOSD lesion, short transverse myelitis (STM), previously considered contradictory to NMOSD, is the first sign of 14,5% of all NMO myelitis (
      • Flanagan E.P.
      • Weinshenker B.G.
      • Krecke K.N.
      • et al.
      Short myelitis lesions in aquaporin-4-IgG-positive neuromyelitis optica spectrum disorders.
      ). However, STM in NMO is generally located in the central gray matter and is often longer than the spinal lesion in MS (
      • Huh S.Y.
      • Kim S.H.
      • Hyun J.W.
      • et al.
      Short segment myelitis as a first manifestation of neuromyelitis optica spectrum disorders.
      ). Interestingly, conus involvement is highly specific for MOG antibody disease (
      • Jarius S.
      • Paul F.
      • Aktas O.
      • et al.
      MOG encephalomyelitis: international recommendations on diagnosis and antibody testing.
      ). Accurate diagnosis of myelopathy is crucial as irreversible neurological deterioration may develop promptly without adequate treatment. Moreover, results of a recently published retrospective analysis suggest that the majority of patients diagnosed with idiopathic transverse myelitis have other specific myelopathy (
      • Zalewski N.L.
      • Flanagan E.P.
      • Keegan B.M.
      Evaluation of idiopathic transverse myelitis revealing specific myelopathy diagnoses.
      ). Brain lesions are not an uncommon phenomenon in NMOSD, as they can be detected in 25–59% of patients (
      • Wang F.
      • Liu Y.
      • Duan Y.
      • Li K.
      Brain MRI abnormalities in neuromyelitis optica.
      ;
      • Chan K.H.
      • Tse C.T.
      • Chung C.P.
      • et al.
      Brain involvement in neuromyelitis optica spectrum disorders.
      ). Most importantly, 16% of these lesions are found to meet the Barkhof MRI criteria for MS (
      • Wingerchuk D.M.
      • Banwell B.
      • Bennett J.L.
      • et al.
      International consensus diagnostic criteria for neuromyelitis optica spectrum disorders.
      ). The prevailing brain NMO lesions are confluent hyperintensities on FLAIR/T2-weighted images scattered asymmetrically in periependymal areas. The ependymal surface of corpus callosum, diencephalon and brainstem, involving the area postrema, are the key sites of NMO brain lesions (
      • Wingerchuk D.M.
      • Banwell B.
      • Bennett J.L.
      • et al.
      International consensus diagnostic criteria for neuromyelitis optica spectrum disorders.
      ). Cortical lesions are incompatible with NMO, and thus they are considered a ‘red flag’ implying the need for other diagnosis. Nevertheless, cortical involvement, particularly in the subpial layer associated with leptomeningeal enhancement, has been reported (
      • Pekcevik Y.
      • Orman G.
      • Lee I.H.
      • Mealy M.A.
      • Levy M.
      • Izbudak I.
      What do we know about brain contrast enhancement patterns in neuromyelitis optica?.
      ). The most frequent patterns of enhancement are cloud-like enhancement and the periependymal linear pattern, or pencil-thin enhancement, along the ventricular surface system. When existing together, these two patterns might present a flame-like impression. Ring and ‘open ring’ enhancement indicate rather the diagnosis of MS (
      • Pekcevik Y.
      • Orman G.
      • Lee I.H.
      • Mealy M.A.
      • Levy M.
      • Izbudak I.
      What do we know about brain contrast enhancement patterns in neuromyelitis optica?.
      ). However, MRI of patients with acute optic neuritis may be normal. In these cases, visual evoked potentials and optical coherence tomography (OCT) are substantial. OCT is a valuable tool in the assessment of optic nerve fibers damage, and it was suggested that this parameter may potentially serve as a marker of disease progression and treatment response (
      • Bennett J.L.
      • de Seze J.
      • Lana-Peixoto M.
      • et al.
      Neuromyelitis optica and multiple sclerosis: seeing differences through optical coherence tomography.
      ). Importantly, OCT in NMOSD shows a more apparent than in MS retinal nerve fiber layer and ganglion cells layer thinning (
      • Bennett J.L.
      • de Seze J.
      • Lana-Peixoto M.
      • et al.
      Neuromyelitis optica and multiple sclerosis: seeing differences through optical coherence tomography.
      ). Unlike in MS, CSF tests in NMOSD more often show elevated pleocytosis (in 35%), especially with predominant neutrophils or eosinophils (
      • Wingerchuk D.M.
      • Banwell B.
      • Bennett J.L.
      • et al.
      International consensus diagnostic criteria for neuromyelitis optica spectrum disorders.
      ). Another differentiating factor between NMOSD and MS is an increased CSF level of IL-6 in the former disease (
      • Uzawa A.
      • Mori M.
      • Kuwabara S.
      Neuromyelitis optica: concept, immunology and treatment.
      ). Although CSF oligoclonal bands might be transiently detectable during exacerbations, their absence is considered as supportive evidence for NMOSD (
      • Wingerchuk D.M.
      • Banwell B.
      • Bennett J.L.
      • et al.
      International consensus diagnostic criteria for neuromyelitis optica spectrum disorders.
      ). The proper differentiation between MS and NMOSD is crucial for therapy planning. Several maintenance therapies approved for MS have been found ineffective or even aggravating the severity of clinical symptoms in NMOSD (
      • Uzawa A.
      • Mori M.
      • Kuwabara S.
      Neuromyelitis optica: concept, immunology and treatment.
      ). Furthermore, recently published results of clinical trials have proved effectiveness of therapeutic approaches based on the pathomechanism of NMOSD such as intervention in the cascade of complement (
      • Pittock S.J.
      • Berthele A.
      • Fujihara K.
      • et al.
      Eculizumab in aquaporin-4-positive neuromyelitis optica spectrum disorder.
      )

      4. Neuropsychiatric systemic lupus erythematosus

      Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease displaying a wide variety of clinical manifestations (
      • Jafri K.
      • Patterson S.L.
      • Lanata C.
      Central nervous system manifestations of systemic lupus erythematosus.
      ). Central nervous system involvement in SLE is associated with a more severe course of the disease and a worse prognosis (
      • Cervera R.
      • Khamashta M.A.
      • Font J.
      • et al.
      Morbidity and mortality in systemic lupus erythematosus during a 5-year period. A multicenter prospective study of 1,000 patients. European working party on systemic lupus erythematosus.
      ). The reported prevalence of neuropsychiatric SLE (NPSLE) differs considerably, ranging from 14% to 75% of all SLE cases, most probably due to the vast variety of symptoms and changing rules of assignment to the primary disease (
      • Unterman A.
      • Nolte J.E.S.
      • Boaz M.
      • et al.
      Neuropsychiatric syndromes in systemic lupus erythematosus: a meta-analysis.
      ). The American College of Rheumatology defined 19 manifestations of NPSLE, which affect central, peripheral or autonomic nervous system. Among the CNS manifestations of SLE, cerebrovascular disease and epilepsy are considered the most clinically important. Demyelinating syndrome, aseptic meningitis and psychiatric disorders also need to be mentioned as significant medical challenges (
      • Hanly J.G.
      ACR classification criteria for systemic lupus erythematosus: limitations and revisions to neuropsychiatric variables.
      ;
      • Hanly J.G.
      Diagnosis and management of neuropsychiatric SLE..
      ). NPSLE manifestations can be categorized as diffuse or focal, depending on the prevailing pathomechanism. Diffuse manifestations include headaches, affective disorders, psychosis, cognitive dysfunction and acute confusional state (
      • Jafri K.
      • Patterson S.L.
      • Lanata C.
      Central nervous system manifestations of systemic lupus erythematosus.
      ). Crucial focal manifestations of NPSLE are cerebrovascular disease and epilepsy. Cerebrovascular events are reported in 5% to 18% of SLE patients. The increased risk of stroke is contributed to procoagulant factors such as antiphospholipid antibodies (aPL), endothelial activation and vasculitis, as well as accelerated atherosclerosis (
      • Hanly J.G.
      • Li Q.
      • Su L.
      • et al.
      Cerebrovascular events in systemic lupus erythematosus: results from an international inception cohort study.
      ). Seizures affect 8% to 18% of SLE patients (
      • Muscal E.
      • Brey R.L.
      Neurologic manifestations of systemic lupus erythematosus in children and adults.
      ) and are associated with the presence to anti-Smith antibodies (
      • Mikdashi J.
      • Krumholz A.
      • Handwerger B.
      Factors at diagnosis predict subsequent occurrence of seizures in systemic lupus erythematosus.
      ) and aPL antibodies in serum (
      • Herranz M.T.
      • Rivier G.
      • Khamashta M.A.
      • et al.
      Association between antiphospholipid antibodies and epilepsy in patients with systemic lupus erythematosus.
      ). Another focal NPSLE manifestation is transverse myelitis, which mimics NMOSD. There is a strong association between transverse myelitis and the presence of aPL antibodies in patients with SLE (
      • Kovacs B.
      • Lafferty T.L.
      • Brent L.H.
      • et al.
      Transverse myelopathy in systemic lupus erythematosus: an analysis of 14 cases and review of the literature.
      ). Histopathological studies have shown that the predominant process in NPSLE is a noninflammatory microangiopathy with concomitant brain microinfarction. Other reported pathological findings have been glial hyperplasia and diffuse neuronal and axonal loss (
      • Sibbitt Jr, W.L.
      • Brooks. W.M.
      • Kornfeld M.
      • et al.
      Magnetic resonance imaging and brain histopathology in neuropsychiatric systemic lupus erythematosus.
      ). It is also assumed that NPSLE may be a result of the blood-brain barrier (BBB) disruption, resulting from complex immune disturbances (
      • Hanly J.G.
      Diagnosis and management of neuropsychiatric SLE.
      ). Among them, antibody production and immune complex formation are of primary importance in the pathogenesis of SLE. Until now, as many as 180 different autoantibodies have been detected in SLE patients (
      • Yaniv G.
      • Twig G.
      • Shor D.B.-.A.
      • et al.
      A volcanic explosion of autoantibodies in systemic lupus erythematosus: a diversity of 180 different antibodies found in SLE patients.
      ). In routine clinical practice, usually only anti-double stranded DNA (anti-dsDNA) and aPL are evaluated. Other important antibodies associated with NPSLE are anti-ribosomal P (anti-P), anti-GABARB1b and anti-GABARB2, anti-neuronal and anti-endothelial antibodies (
      • Clark K.E.
      • Clark C.N.
      • Rahman A.
      A critical analysis of the tools to evaluate neuropsychiatric lupus.
      ). Anti-dsDNA antibodies are highly specific (92% to 96%) and of moderate sensitivity (57% to 67%) for SLE (
      • Cozzani E.
      • Drosera M.
      • Gasparini G.
      • Parodi A.
      Serology of lupus erythematosus: correlation between immunopathological features and clinical aspects.
      ). High levels of anti-dsDNA antibodies are found in 70% of patients presenting NPSLE symptoms (
      • Joseph F.G.
      • Lammie G.A.
      • Scolding N.J.
      CNS lupus: a study of 41 patients.
      ). A subset of anti-dsDNA antibodies cross-react with anti-N-methyl-D-aspartate receptor subtype 2 receptors (NR2). Anti-NR2 antibodies in the CSF can be identified in one third of all SLE patients, which is a higher prevalence than in any other autoimmune disease (
      • Gono T.
      • Kawaguchi Y.
      • Kaneko H.
      • Nishimura K.
      • Hanaoka M.
      • Kataoka S.
      • et al.
      Anti-NR2A antibody as a predictor for neuropsychiatric systemic lupus erythematosus.
      ). Bound to active NMDA receptors, the anti-NR2 antibodies induce excess calcium influx leading to neuronal dysfunction and cell death (
      • Faust T.W.
      • Chang E.H.
      • Kowal C.
      • et al.
      Neurotoxic lupus autoantibodies alter brain function through two distinct mechanisms.
      ). Antiphospholipid antibodies comprise anticardiolipin antibodies (aCL), lupus anticoagulant (LAC) and anti-beta2glycoprotein 1 (anti-β2GP1) antibodies. Among focal NPSLE manifestations, aPL are highly prevalent in patients with transverse myelitis, which involves especially the thoracic cord (
      • Kovacs B.
      • Lafferty T.L.
      • Brent L.H.
      • et al.
      Transverse myelopathy in systemic lupus erythematosus: an analysis of 14 cases and review of the literature.
      ). aCL antibodies are the most sensitive and the least specific finding. Importantly, aCL antibodies can be temporarily induced by many drugs and infections. LAC has a strong correlation with cerebrovascular disease, particularly sinus thrombosis (
      • Hanly J.G.
      • Urowitz M.B.
      • Su L.
      • Bae S.C.
      • Gordon C.
      • Clarke A.
      • et al.
      Autoantibodies as biomarkers for the prediction of neuropsychiatric events in systemic lupus erythematosus.
      ). Anti-β2GP1 antibodies are more specific for thrombotic events than aCL (
      • Bertolaccini M.L.
      • Khamashta M.A.
      Laboratory diagnosis and management challenges in the antiphospholipid syndrome.
      ). Anti-P antibodies are detected in 15% to 20% of SLE patients (
      • Zandman-Goddard G.
      • Chapman J.
      • Shoenfeld Y.
      Autoantibodies involved in neuropsychiatric SLE and antiphospholipid syndrome.
      ) and are considered to have a strong association with psychosis and depression (
      • Hirohata S.
      • Arinuma Y.
      • Takayama M.
      • Yoshio T.
      Association of cerebrospinal fluid anti-ribosomal p protein antibodies with diffuse psychiatric/neuropsychological syndromes in systemic lupus erythematosus.
      ). Besides the abovementioned antibodies, serum analysis may reveal an elevated erythrocyte sedimentation rate (ESR) with normal C-reactive protein levels (
      • Joseph F.G.
      • Lammie G.A.
      • Scolding N.J.
      CNS lupus: a study of 41 patients.
      ) and decreased concentrations of complement – finding typical of active disease (
      • Magro-Checa C.
      • Schaarenburg R.A.
      • Beaart H.J.
      • Huizinga T.W.
      • Steup-Beekman G.M.
      • Trouw L.A.
      Complement levels and anti-C1q autoantibodies in patients with neuropsychiatric systemic lupus erythematosus.
      ). Cerebrospinal fluid analysis should be performed in each case of suspected NPSLE. The usual mild non-specific abnormalities observed in NPSLE are: slightly raised white cell count (typically lymphocytosis), elevated protein and IgG index with a decreased or normal glucose level (
      • Joseph F.G.
      • Lammie G.A.
      • Scolding N.J.
      CNS lupus: a study of 41 patients.
      ). It might be useful to assess BBB integrity. Since albumin is not generated intrathecally, the relatively high leakage across the BBB may be demonstrated by the assessment of albumin concentration gradient between CSF and plasma - albumin quotient (Qalb) (
      • Abbott N.J.
      • Mendonca L.L.
      • Dolman D.E.
      The blood-brain barrier in systemic lupus erythematosus.
      ). CSF oligoclonal bands can be found in 15% to 85% of NPSLE cases (
      • Clark K.E.
      • Clark C.N.
      • Rahman A.
      A critical analysis of the tools to evaluate neuropsychiatric lupus.
      ), which may indicate considerable heterogeneity of investigated SLE patient populations. CNS MRI is the key measure in diagnosis of NPSLE. The primary MRI manifestations of SLE are large infarcts and multifocal white matter T2-hyperintense lesions. White matter T2-hyperintense lesions are the most common radiological finding in NPSLE and it seems crucial to differentiate them from MS lesions. In contrary to MS, SLE white matter lesions more often exhibit a vascular distribution (
      • Jennekens K.G.I.
      • Kater L.
      The central nervous system in systemic lupus erythematous. Part 2. Pathogenetic mechanisms of clinical syndromes: a literature investigation.
      ). Another distinction from MS is the bilateral involvement of basal ganglia, with swelling and punctuate enhancement. Calcifications in the basal ganglia, dentate nucleus, centrum ovale and corticosubcortical junctions can also be observed (
      • Raymond A.A.
      • Zariah A.A.
      • Samad S.A.
      • et al.
      Brain calcification in patients with cerebral lupus.
      ). Leptomeningeal enhancement may be also present in CNS MRI of SLE patients. Spinal cord lesions are often longitudinally extensive (
      • Jog N.R.
      • James J.A.
      Biomarkers in connective tissue diseases.
      ). Importantly, MRI findings in NPSLE may in some cases fulfill the radiologic diagnostic criteria for MS, which underlines the need for development of specific biomarkers. Given the abundant psychiatric manifestations of SLE, neuropsychological assessment should be performed. Treatment strategies of NPSLE depend on the prevailing manifestations and severity of the disease. Interestingly, it is suggested that the optimal treatment window in NPSLE occurs much earlier than the average time of diagnosis. Thus, the therapy should be introduced without delay, in patients with unspecific clinical syndrome and multifocal brain and spinal cord lesions. Unfortunately, no specific test allows early and definite diagnosis of NPSLE. Thus, further research is required to facilitate the diagnostic strategy.

      5. Antiphospholipid syndrome

      As mentioned above, aPL antibodies are of paramount importance in the context of the pathogenesis of neuropsychiatric lupus manifestations. Antiphospholipid syndrome (APS) is an acquired systemic disorder related to the circulating aPL antibodies. Current classification criteria for APS include fulfillment of at least one of clinical criteria such as vascular thrombosis or particular pregnancy related conditions and at least one of the laboratory criteria which is a positive test for aPL antibodies: LAC, aCL or anti-β2GP1, present on 2 or more occasions not less than 12 weeks apart (
      • Miyakis S.
      • Lockshin M.D.
      • Atsumi T.
      • et al.
      International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS).
      ). APS might be primary or secondary to other autoimmune disease, with SLE being the most common cause of secondary APS (
      • Graf J.
      Chapter 23. Antiphospholipid antibody syndrome.
      ). Besides vascular thrombosis and pregnancy morbidity, APS comprises a wide spectrum of symptoms, including hematological, cutaneous, renal, cardiac and pulmonary involvement (
      • Negrini S.
      • Pappalardo F.
      • Murdaca G.
      • et al.
      The antiphospholipid syndrome: from pathophysiology to treatment.
      ). Hematological manifestations of APS are aPL-associated idiopathic thrombocytopenic purpura and autoimmune hemolytic anemia (
      • Cervera R.
      • Piette J.C.
      • Font J.
      • et al.
      Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients.
      ). Livedo reticularis is the hallmark of APS (
      • Cervera R.
      • Piette J.C.
      • Font J.
      • et al.
      Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients.
      ) and has been proposed as an independent risk factor of arterial thrombosis (
      • Frances C.
      • Niang S.
      • Laffitte E.
      • Pelletier F.
      • Costedoat N.
      • Piette J.C.
      Dermatologic manifestations of the antiphospholipid syndrome: two hundred consecutive cases.
      ). APS nephropathy can be acute or chronic and in secondary APS may coexist with immune-complex-mediated lupus nephritis (
      • Pons-Estel G.J.
      • Cervera R.
      Renal involvement in antiphospholipid syndrome.
      ;
      • Alchi B.
      • Griffiths M.
      • Jayne D.
      What nephrologists need to know about antiphospholipid syndrome.
      ). Other systemic manifestations of APS involve Libman-Sacks endocarditis, intraalveolar hemorrhage, acute respiratory distress syndrome and fibrosing alveolitis (
      • Hojnik M.
      • George J.
      • Ziporen L.
      • Shoenfeld Y.
      Heart valve involvement (Libman–Sacks endocarditis) in the antiphospholipid syndrome.
      ;
      • Kanakis M.A.
      • Kapsimali V.
      • Vaiopoulos A.G.
      • Vaiopoulos G.A.
      • Samarkos M.
      The lung in the spectrum of antiphospholipid syndrome.
      ;
      • Barnini T.
      • Silvestri E.
      • Emmi G.
      • et al.
      Pulmonary fibrosis and lymphocytic alveolitis associated with triple antiphospholipid antibody positivity: a diagnostic puzzle.
      ). The most frequently affected arterial system in APS is the cerebral circulation and consequently the most prevalent neurological complication of APS is a cerebrovascular event (
      • Rodrigues C.E.M.
      • Carvalho J.F.
      • Shoenfeld Y.
      Neurological manifestations of antiphospholipid syndrome.
      ). Ischemic stroke may be related to vessels of any size and located in any area of the brain, without typical predilection (
      • Tanne D.
      • Hassin-Baer S.
      Neurologic manifestations of the antiphospholipid syndrome.
      ). It is estimated that at least 20% of stroke cases under the age of 45 can be attributed to APS (
      • Hughes G.R.V.
      Migraine, memory loss, and “multiple sclerosis.” neurological features of the antiphospholipid (Hughes’) syndrome.
      ). In particular, in patients with secondary APS, LAC is a remarkably stronger predictor of CNS ischemic events than the aCL antibodies (
      • de Amorim L.C.D.
      • Maia F.M.
      • Rodrigues C.E.M.
      Stroke in systemic lupus erythematosus and antiphospholipid syndrome: risk factors, clinical manifestations, neuroimaging, and treatment.
      ;
      • Petri M.
      • Rheinschmidt M.
      • Whiting-O'Keefe Q.
      • et al.
      The frequency of lupus anticoagulant in systemic lupus erythematosus. A study of sixty consecutive patients by activated partial thromboplastin time, Russell viper venom time, and anticardiolipin antibody level.
      ). Cognitive symptoms are another important manifestation of APS. It has been demonstrated that between 42% and 80% of APS patients exhibit global cognitive impairment (
      • Yelnik C.M.
      • Kozora E.
      • Appenzeller S.
      Non-stroke central neurologic manifestations in antiphospholipid syndrome.
      ;
      • Brey R.
      • Muscal E.
      • Chapman J.
      Antiphospholipid antibodies and the brain: a consensus report.
      ). Studies have shown a positive correlation between cognitive dysfunction and aCL antibodies (
      • Jacobson M.W.
      • Rapport L.J.
      • Keenan P.A.
      • et al.
      Neuropsychological deficits associated with antiphospholipid antibodies.
      ;
      • Menon S.
      • Jameson-Shortall E.
      • Newman S.P.
      • et al.
      A longitudinal study of anticardiolipin antibody levels and cognitive functioning in systemic lupus erythematosus.
      ;
      • Hanly J.G.
      • Hong C.
      • Smith S.
      • et al.
      A prospective analysis of cognitive function and anticardiolipin antibodies in systemic lupus erythematosus.
      ). Epilepsy is considered as one of the main CNS manifestations of APS. It is more frequent in secondary APS, in which it affects 13,7% of patients (
      • Shoenfeld Y.
      • Lev S.
      • Blatt I.
      • et al.
      Features associated with epilepsy in the antiphospholipid syndrome.
      ). Although epileptogenic foci secondary to ischemic events are considered as the most important cause of seizures in APS, autoimmune process is presumed to be also substantially involved. It needs to be indicated that clinical features of APS might resemble MS. Possible MS-like manifestations of APS encompass e.g. optic neuritis or transverse myelitis with CNS MRI revealing MS-type white matter lesions. It may be particularly misleading, as scattered hyperintensive subcortical white matter lesions are the most common MRI finding in APS (
      • Zhu D.-.S.
      • Fu J.
      • Zhang Y.
      • et al.
      Neurological antiphospholipid syndrome: clinical, neuroimaging, and pathological characteristics.
      ). Taking into consideration the lack of fully specific diagnostic tests, differential diagnosis in such cases may prove to be complex and difficult (
      • Rodrigues C.E.M.
      • Carvalho J.F.
      • Shoenfeld Y.
      Neurological manifestations of antiphospholipid syndrome.
      ). Similarly to NPSLE, treatment approach in APS needs to be adjusted to the prevailing manifestations and severity of symptoms.

      6. Primary central nervous system vasculitis

      Primary central nervous system vasculitis (PCNSV), also known as primary angitis of the CNS, is an insufficiently investigated inflammatory condition which affects vessels of brain, spinal cord and meninges (
      • Mandal J.
      • Chung S.A.
      Primary angiitis of the central nervous system.
      ). Due to an ample spectrum of clinical manifestations and absence of any specific diagnostic test, PCNSV remains a commonly overlooked disorder. Although rare, PCNSV should be taken into consideration in each case of suspected CNS vasculitis when secondary causes e.g. infectious, connective tissue diseases, or systemic vasculitis, cannot be confirmed. Unlike in secondary vasculitis, men are more susceptible to PCNSV than women, with the male to female ratio estimated at 2:1, and a mean age of onset being 50 years (
      • Salvarani C.
      • Brown R.D.
      • Calamia K.T.
      • et al.
      Primary central nervous system vasculitis: analysis of 101 patients.
      ). Patients with PCNSV may exhibit multiple symptoms. The disease usually starts with a protracted prodromal period, lasting weeks or months, during which headaches and mild cognitive disturbances often appear (
      • Salvarani C.
      • Brown Jr, R.D.
      • Christianson T.
      • et al.
      An update of the mayo clinic cohort of patients with adult primary central nervous system vasculitis: description of 163 patients.
      ). After prodromal phase, diverse neurological manifestations can emerge, such as visual disturbances, cranial neuropathies, stroke with focal deficits, cerebellar syndrome, epilepsy (
      • Boysson H.
      • Zuber M.
      • Naggara O.
      • et al.
      Primary angiitis of the central nervous system: description of the first fifty-two adults enrolled in the French cohort of patients with primary vasculitis of the central nervous system.
      ). Constitutional symptoms, such as fever and weight loss, are usually absent, and they imply rather the diagnosis of secondary vasculitis (
      • Salvarani C.
      • Brown Jr, R.D.
      • Christianson T.
      • et al.
      An update of the mayo clinic cohort of patients with adult primary central nervous system vasculitis: description of 163 patients.
      ). PCNSV is a highly heterogeneous disease, which may affect vessels of various size, mainly medium and small. Also the pathological findings differ considerably. Several PCNSV subtypes have been characterized, with granulomatous angitis of the CNS being the most common (
      • Salvarani C.
      • Brown R.D.
      • Calamia K.T.
      • et al.
      Primary central nervous system vasculitis: analysis of 101 patients.
      ). The clinical course of granulomatous angitis is indolent. The prodromal period with headaches and cognitive impairment lasts from 3 to 6 months, and is typically followed by focal deficits or epilepsy (
      • Suri V.
      • Kakkar A.
      • Sharma M.C.
      • et al.
      Primary angiitis of the central nervous system: a study of histopathological patterns and review of the literature.
      ). As granulomatous angitis typically involves small vessels, angiography usually shows no abnormalities (
      • Suri V.
      • Kakkar A.
      • Sharma M.C.
      • et al.
      Primary angiitis of the central nervous system: a study of histopathological patterns and review of the literature.
      ). Currently, there is no specific laboratory test available for PCNSV. Immunological tests, ESR and CRP should be assessed to exclude secondary vasculitis. CSF examination should be performed in each case of suspected PCNSV, mainly to differentiate with infections and neoplastic causes. In majority of patients with PCNSV some nonspecific CSF abnormality is found, usually mild lymphocytic pleocytosis or elevated protein level, with normal glucose (
      • Salvarani C.
      • Brown Jr, R.D.
      • Christianson T.
      • et al.
      An update of the mayo clinic cohort of patients with adult primary central nervous system vasculitis: description of 163 patients.
      ). Brain MRI is an obligatory step in the diagnosis of PCNSV and it typically shows multifocal, often bilateral, infarcts in numerous vascular territories, with parenchymal enhancement (
      • Boulouis G.
      • de Boysson H.
      • Zuber M.
      • et al.
      Primary angiitis of the central nervous system: magnetic resonance imaging spectrum of parenchymal, meningeal, and vascular lesions at baseline.
      ;
      • Goertz C.
      • Wegner C.
      • Bru¨ck W.
      • et al.
      Primary angiitis of the CNS with pure spinal cord involvement: a case report.
      ). Conventional cerebral angiography remains the basic tool to evaluate cases of highly probable PCNSV. Characteristic picture of “beading”, which is formed by alternating segments of stenotic and dilated vessels, is a cornerstone of diagnosis (
      • Edgell R.C.
      • Sarhan A.E.
      • Soomro J.
      • et al.
      The role of catheter angiography in the diagnosis of central nervous system vasculitis.
      ). Other possible findings include focal occlusion, collateral circulation, microaneurysms. Magnetic resonance angiography, in particular high resolution multicontrast wall and lumen imaging, with the use of the 3T scanner or stronger, can also prove beneficial (
      • Cosottini M.
      • Canovetti S.
      • Pesaresi I.
      • et al.
      3-T magnetic resonance angiography in primary angiitis of the central nervous system.
      ). Gold standard test for PCNSV diagnosis is brain and leptomeningeal biopsy. The biopsied sample needs to contain leptomeninges, cortex and subcortical white matter from radiologically altered location (
      • Hajj-Ali R.A.
      • Singhal A.B.
      • Benseler S.
      • et al.
      Primary angiitis of the CNS.
      ;
      • Miller D.V.
      • Salvarani C.
      • Hunder G.G.
      • et al.
      Biopsy findings in primary angiitis of the central nervous system.
      ).

      7. ANCA-vasculitis

      The antineutrophil cytoplasmic antibodies (ANCA)-associated CNS vasculitis is a group of primary systemic vasculitic diseases comprising granulomatosis with polyangitis (GPA), microscopic polyangitis (MPA) and eosinophilic granulomatosis with polyangitis (EGPA) (
      • Graf J.
      Central nervous system disease in antineutrophil cytoplasmic antibodies-associated vasculitis.
      ). GPA is an idiopathic necrotizing small-vessel disease related to ANCA specific for proteinase 3 (PR3) (
      • Graf J.
      Central nervous system disease in antineutrophil cytoplasmic antibodies-associated vasculitis.
      ). The most common neurological manifestation of GPA, observed in 60% of cases, is peripheral neuropathy. CNS is affected in 4% to 11% of GPA patients (
      • Dutra L.A.
      • de Souza A.W.
      • Grinberg-Dias G.
      • et al.
      Central nervous system vasculitis in adults: an update.
      ). Three different types of manifestations can be distinguished including: cerebral vasculitis and two predominantly granulomatous phenotypes - chronic hypertrophic pachymeningitis and pituitary disease (
      • Graf J.
      Central nervous system disease in antineutrophil cytoplasmic antibodies-associated vasculitis.
      ). The vascular phenotype can lead to ischemic as well as hemorrhagic complications. The imaging results of GPA ischemic lesions are nonspecific. Brain MRI might reveal both extensive cerebral infarctions and diffuse white matter lesions as seen in small-vessel vasculopathy (
      • De Luna G.
      • Terrier B.
      • Kaminsky P.
      • et al.
      Central nervous system involvement of granulomatosis with polyangiitis: clinical-radiological presentation distinguishes different outcomes.
      ). The size of involved vessels is often below the level of resolution of MRI or conventional angiography (
      • Ghinoi A.
      • Zuccoli G.
      • Pipitone N.
      • et al.
      Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis involving the central nervous system: case report and review of the literature.
      ). GPA affects more frequently pachymeninges than leptomeninges and intracranial dura matter is more often involved than spinal (
      • Holle J.U.
      • Gross W.L.
      Neurological involvement in Wegener's granulomatosis.
      ). Chronic hypertrophic pachymeningitis can manifest clinically with variety of symptoms such as headache, cranial neuropathy, ataxia, myelopathy, epilepsy and thickening of the dura on MRI scans (
      • Shimojima Y.
      • Kishida D.
      • Hineno A.
      • et al.
      Hypertrophic pachymeningitis is a characteristic manifestation of granulomatosis with polyangiitis: a retrospective study of anti-neutrophil cytoplasmic antibody-associated vasculitis.
      ). MPA is associated with ANCA directed against myeloperoxidase (MPO) and affects small- to medium-sized vessels (
      • Graf J.
      Central nervous system disease in antineutrophil cytoplasmic antibodies-associated vasculitis.
      ). Although MPA mostly exhibits as glomerulonephritis and diffuse alveolar hemorrhage, CNS may be involved as well (
      • Duvuru G.
      • Stone J.H.
      Microscopic polyangiitis.
      ). CNS vasculitis in the course of EGPA is a rare phenomenon and usually constitutes the final phase of the disease. The primary EGPA manifestations are asthma and nasal polyps or rhinosinusitis, followed by an eosinophilic phase characterized by peripheral eosinophilia and organ involvement (
      • Greco A.
      • Rizzo M.I.
      • De Virgilio A.
      • et al.
      Churg–Strauss syndrome.
      ). EGPA affects the CNS in 6% to 10% cases and causes encephalopathy, ischemic infarcts and hemorrhages (
      • Murthy S.B.
      • Khalaf N.
      • Shah S.
      • et al.
      Churg-Strauss syndrome.
      ).

      8. Neuro-Behҫet disease

      Behҫet disease (BD) is a chronic relapsing inflammatory vascular disease of not fully known etiopathogenesis. CNS presentation is described in 5% to 10% of BD cases (
      • Siva A.
      • Saip S.
      The spectrum of nervous system involvement in Behcet's syndrome and its differential diagnosis.
      ). Several genetic, environmental and microbiological factors have been postulated as risk factors for BD (
      • Onder M.
      • Gürer M.A.
      The multiple faces of Behçet's disease and its aetiological factors.
      ). Among genetic factors, a significant relationship has been found between human leukocyte antigen (HLA)-B51 and BD (
      • Demirseren D.D.
      • Ceylan G.G.
      • Akoglu G.
      • et al.
      HLA-B51 subtypes in Turkish patients with Behçet's disease and their correlation with clinical manifestations.
      ). HLA-B51 gene is presumed to be the strongest risk factor for BD (
      • Kirino Y.
      • Bertsias G.
      • Ishigatsubo Y.
      • et al.
      Genome-wide association analysis identifies new susceptibility loci for Behçet's disease and epistasis between HLA-B*51 and ERAP1.
      ). It has been also shown that HLA-B51 is associated with a lower frequency of neurological involvement (
      • Hamzaoui A.
      • Houman M.H.
      • Massouadia M.
      • et al.
      Contribution of Hla-B51 in the susceptibility and specific clinical features of Behcet's disease in Tunisian patients.
      ). However, this correlation may be more complicated and HLA-B51 subtype specific, since in one study an increased frequency of HLA-B5103 has been observed in BD patients with CNS involvement (
      • Demirseren D.D.
      • Ceylan G.G.
      • Akoglu G.
      • et al.
      HLA-B51 subtypes in Turkish patients with Behçet's disease and their correlation with clinical manifestations.
      ). As there is no pathognomonic test for BD, the diagnosis is based on clinical criteria. To meet current International Criteria for Behҫet Disease (ICBD), a patient needs to score at least 4 points, 2 points being ascribed for any of ocular lesions, oral aphthosis, genital aphthosis and 1 point for any of skin lesions, neurological manifestations, and vascular manifestations. An extra point may be assigned for positive pathergy test (
      International Team for the Revision of the International Criteria for Behçet's Disease (ITR-ICBD)
      The International Criteria for Behçet's Disease (ICBD): a collaborative study of 27 countries on the sensitivity and specificity of the new criteria.
      ). There are two major forms of Neuro-Behҫet disease (NBD). A vascular-inflammatory disease, also called parenchymal NBD, often mimics MS clinical picture. The other major NBD presentation - non-parenchymal NBD encompasses an isolated cerebral venous sinus thrombosis and intracranial hypertension (
      • Siva A.
      • Saip S.
      The spectrum of nervous system involvement in Behcet's syndrome and its differential diagnosis.
      ;
      • Al-Araji A.
      • Kidd D.P.
      Neuro-Behçet's disease: epidemiology, clinical characteristics, and management.
      ). Parenchymal NBD is usually more severe than non-parenchymal NBD, and it comprises such manifestations as meningoencephalitis involving brainstem, cranial nerve palsies and epilepsy (
      • Al-Araji A.
      • Kidd D.P.
      Neuro-Behçet's disease: epidemiology, clinical characteristics, and management.
      ). In contrary to MS, NBD affects men more often than women. Optic neuritis, spinal cord involvement and sensory symptoms are rare in NBD and thus should always warrant careful differential diagnostics with other possible causes e.g. MS (
      • Kocer N.
      • Islak C.
      • Siva A.
      • et al.
      CNS involvement in neuro-Behcet's syndrome: an MR study.
      ). MRI is the gold-standard in NBD diagnosis. Typical CNS MRI finding in NBD is a large lesion in brainstem, without apparent border, with a tendency to spread to diencephalon and basal ganglia, less frequently caudally (
      • Kocer N.
      • Islak C.
      • Siva A.
      • et al.
      CNS involvement in neuro-Behcet's syndrome: an MR study.
      ). Heterogeneous contrast enhancement may be observed in acute phase, resolving usually incompletely in subsequent imaging. Typically, brainstem lesions on MRI are much smaller in MS. As mentioned above, spinal cord involvement is uncommon in NBD, but when it occurs, the lesions are longitudinally extensive, resembling lesions characteristic of NMOSD (
      • Uygunoglu U.
      • Saip S.
      • Siva A.
      • et al.
      Behcet's syndrome and nervous system involvement.
      ). The most specific spinal MRI feature of NBD, described till now, is the “bagel sign” pattern, visible in axial T2WIs, and defined as a central spinal cord lesion with hypointense core and hyperintense rim, with or without contrast enhancement (
      • Uygunoglu U.
      • Zeydan B.
      • Ozguler Y.
      • et al.
      Myelopathy in Behc¸ et's disease: the bagel sign.
      ). CSF OCBs positivity in NBD patients is significantly less common than in MS, observed in only up to 15% of cases (
      • Siva A.
      Common clinical and imaging conditions misdiagnosed as multiple sclerosis: a current approach to the differential diagnosis of multiple sclerosis.
      ).

      9. Neurosarcoidosis

      Another inflammatory disease exhibiting multiple brain lesions on MRI is neurosarcoidosis, a chronic granulomatous disorder of unknown origin. Nervous system involvement is reported in 3% to 10% of patients with sarcoidosis, but such prevalence is presumed to be underestimated (
      • Ungprasert P.
      • Matteson E.L.
      Neurosarcoidosis.
      ). Although isolated neurosarcoidosis is a rare condition, in about 70% to 80% of patients neurological symptoms are one of the earliest disease manifestations (
      • Ferriby D.
      • de Seze J.
      • Stojkovic T.
      • et al.
      Long-term follow-up of neurosarcoidosis.
      ). The most prevalent neurological complication of sarcoidosis is cranial neuropathy, with a particular predilection for cranial nerves VII, II and III. Facial nerve palsy may be bilateral and is probably a result of epi‑ and perineural inflammation and external compression by granuloma (
      • Carlson M.L.
      • White J.R.
      • Espahbodi M.
      • et al.
      Cranial base manifestation of neurosarcoidosis: a review of 305 patients.
      ). Optic neuritis, often bilateral, has been observed as an initial disease presentation in even 35% of neurosarcoidosis cases (
      • Pawate S.
      • Moses H.
      • Sriram S.
      Presentations and outcomes of neurosarcoidosis: a study of 54 cases.
      ). Vestibulocochlear nerve injury is considered to result from granulomatous meningitis (
      • Kane K.
      Deafness in sarcoidosis.
      ). Brain parenchymal disease constitutes another significant issue and is presumed to be a result of chronic inflammation and consecutive atherosclerosis (
      • Pawate S.
      • Moses H.
      • Sriram S.
      Presentations and outcomes of neurosarcoidosis: a study of 54 cases.
      ). It can manifest as headache, cognitive impairment, affective disorders and epilepsy (
      • Ungprasert P.
      • Crowson C.S.
      • Matteson E.L.
      Risk of cardiovascular disease among patients with sarcoidosis: a population-based retrospective cohort study, 1976-2013.
      ). Sarcoidal granulomas may infiltrate the pituitary gland and hypothalamus, causing endocrinological disturbances (
      • Stern B.J.
      • Krumholz A.
      • Johns C.
      • et al.
      Sarcoidosis and its neurological manifestations.
      ), or spinal cord with a predilection for thoracic and cervical segments (
      • Cohen-Aubert F.
      • Galanaud D.
      • Grabli D.
      • et al.
      Spinal cord sarcoidosis. Clinical and laboratory profile and outcome of 31 patients in a case-control study.
      ). The most prevalent MRI findings in neurosarcoidosis are multiple nonenhancing periventricular white matter lesions, which imitate MS or vasculitis (
      • Smith J.K.
      • Matheus M.G.
      • Castillo M.
      Imaging manifestations of neurosarcoidosis.
      ). CSF findings are similar to those seen in SLE, including hypoglycorrhachia (
      • Terushkin V.
      • Stern B.J.
      • Judson M.A.
      • et al.
      Neurosarcoidosis. Presentations and management.
      ). Increased level of CSF angiotensin-converting enzyme is insensitive and not sufficiently specific, as it may be observed in other pathologic conditions i.e. MS (
      • Nozaki K.
      • Judson M.A.
      Neurosarcoidosis: clinical manifestations, diagnosis and treatment.
      ).

      10. Sjogren syndrome

      Primary Sjogren syndrome belongs to autoimmune diseases, which may affect CNS. The pathological process in primary Sjogren syndrome is associated with the presence of antinuclear antibodies, especially anty-Ro/SSA and anty-La/SSB. Although the main affected organs are salivary and lacrimal glands, neurologic symptoms may also appear (
      • Delalande S.
      • de Seze J.
      • Fauchais A.L.
      • et al.
      Neurologic manifestations in primary Sjogren syndrome: a study of 82 patients.
      ;
      • Massara A.
      • Bonazza S.
      • Castellino G.
      • et al.
      Central nervous system involvement in Sjogren's syndrome: unusual, but not unremarkable–clinical, serological characteristics and outcomes in a large cohort of Italian patients.
      ). Peripheral neuropathies, mainly distal sensory and sensorimotor, are the most common neurological manifestations in primary Sjogren syndrome (
      • Pavlakis P.P.
      • Alexopoulos H.
      • Kosmidis M.L.
      • et al.
      Peripheral neuropathies in Sjogren's syndrome: a critical update on clinical features and pathogenetic mechanisms.
      ;
      • Brito-Zeron P.
      • Akasbi M.
      • Bosch X.
      • et al.
      Classification and characterisation of peripheral neuropathies in 102 patients with primary Sjogren's syndrome.
      ). However, CNS involvement might be the first presentation of primary Sjogren syndrome and comprises diverse neurological syndromes such as multiple sclerosis-like disease, encephalopathy, psychiatric disorders, NMOSD – like disease, cerebellar syndromes and movement disorders (
      • Margaretten M.
      Neurologic manifestations of primary sjögren syndrome.
      ). The underlying pathology is mainly mononuclear inflammatory vasculopathy (
      • Alexander E.L.
      Neurologic disease in Sjogren's syndrome: mononuclear inflammatory vasculopathy affecting central/peripheral nervous system and muscle. A clinical review and update of immunopathogenesis.
      ). However, small vessel vasculitis can be observed in a remarkable percentage of primary Sjogren syndrome patients with the use of cerebral angiography. It has been found that such angiographic findings are associated with anti-Ro/SSA antibodies seropositivity (
      • Alexander E.L.
      • Ranzenbach M.R.
      • Kumar A.J.
      • et al.
      Anti-Ro (SS-A) autoantibodies in central nervous system disease associated with Sjogren's syndrome (CNS-SS): clinical, neuroimaging, and angiographic correlates.
      ). CSF analysis might reveal increased lymphocytosis, elevated IgG index and protein concentration as well as oligoclonal bands (
      • Delalande S.
      • de Seze J.
      • Fauchais A.L.
      • et al.
      Neurologic manifestations in primary Sjogren syndrome: a study of 82 patients.
      ).
      MRI abnormalities in primary Sjogren syndrome are nonspecific. In majority of patients with focal CNS involvement, diffuse hyperintense T2-weighted lesions are observed (
      • Manthorpe R.
      • Manthorpe T.
      • Sjoberg S.
      Magnetic resonance imaging of the brain in patients with primary Sjogren's syndrome.
      ). Lesions are often located in areas typically observed in MS (
      • Massara A.
      • Bonazza S.
      • Castellino G.
      • et al.
      Central nervous system involvement in Sjogren's syndrome: unusual, but not unremarkable–clinical, serological characteristics and outcomes in a large cohort of Italian patients.
      ). In contrary to other autoimmune diseases, primary Sjogren syndrome itself is not related to an elevated risk of ischemic stroke. However, aPL antibodies and LAC, associated with increased risk of thrombotic events, are commonly detected in this condition (
      • Pasoto S.G.
      • Chakkour H.P.
      • Natalino R.R.
      • et al.
      Lupus anticoagulant: a marker for stroke and venous thrombosis in primary Sjogren's syndrome.
      ).

      11. Practical considerations

      Differential diagnosis of disseminated white matter lesions is very complex and apart from MS, primarily systemic diseases including connective tissue disorders, diverse vasculopathies e.g. genetic and infectious diseases have to be taken into account. Symptoms such as impaired consciousness, rapidly progressive cognitive deficits, aphasia and epilepsy should make us consider diagnoses other than MS. A fulminant course of the disease is also rare in MS. Extrapyramidal symptoms should imply rather a suspicion of a hereditary or metabolic disorder. Apparent symmetricity of symptoms and lack of involvement of the optic nerves also raise the probability of disease other than MS. In clinical practice, an absolute lack of response to intravenous methylprednisolone treatment is not typical of MS (
      • Siva A.
      Common clinical and imaging conditions misdiagnosed as multiple sclerosis: a current approach to the differential diagnosis of multiple sclerosis.
      ). Despite extensive search for biomarkers, until now no laboratory test has proven 100% specific of MS. Nonetheless, such findings as an elevated ESR and lymphopenia indicate the need for search for a systemic disease. On the other hand, positive ANA tests have been observed in 22.5% to 30.4% of MS patients without any systemic autoimmune disease. However, in most cases of such nonspecific autoantibodies presence, ANA titers are usually not higher than 1:320 (
      • Barned S.
      • Goodman A.D.
      • Mattson D.H.
      Frequency of antinuclear antibodies in multiple sclerosis.
      ). One study in MS population has shown ANA positivity in as much as 51.0% and a positivity for either aCL or anti-β2GP1 antibodies was observed in 32.6% of participants (
      • Roussel V.
      • Yi F.
      • Jauberteau M.O.
      • et al.
      Prevalence and clinical significance of anti-phospholipid antibodies in multiple sclerosis: a study of 89 patients.
      ). Although such nonspecific prevalence of these autoantibodies is considerably high, the possibility of coexisting autoimmune disease should not be neglected, especially in NMOSD (
      • Siva A.
      Common clinical and imaging conditions misdiagnosed as multiple sclerosis: a current approach to the differential diagnosis of multiple sclerosis.
      ). Taking into consideration the dynamic development of the idea of NMO spectrum and most recently MOG spectrum disorders, other antibodies may prove to be useful in the diagnosis of atypical cases, including AQP4-IgG, anti-MOG, anti-NMDAr antibodies and panels for rheumatologic, infectious and paraneoplastic disorders (
      • Siva A.
      Common clinical and imaging conditions misdiagnosed as multiple sclerosis: a current approach to the differential diagnosis of multiple sclerosis.
      ). According to the latest revisions of McDonald criteria for MS, CSF examination and especially OCBs detection should be a standard diagnostic step. Although OCBs are not specific and are often present in other disorders e.g. connective tissue diseases, their presence is reported in approximately 90% of MS patients. Consequently, lack of CSF OCBs should raise the suspicion of disorder other than MS (
      • Stangel M.
      • Fredrikson S.
      • Meinl E.
      • et al.
      The utility of cerebrospinal fluid analysis in patients with multiple sclerosis.
      ). The pattern of OCBs is also a valuable information (
      • Gastaldi M.
      • Zardini E.
      • Franciotta D.
      An update on the use of cerebrospinal fluid analysis as a diagnostic tool in multiple sclerosis.
      ). Vast majority of MS patients show type 2 pattern, that is CSF OCBs positivity with no corresponding abnormality in serum. In some cases of MS type 3 OCBs can be detected, which means the IgG bands are present both in the CSF and serum with additional bands detected in the CSF. Identical CSF and serum OCBs constitute type 4 positivity and are usually detected in systemic inflammatory diseases or infections (
      • Deisenhammer F.
      • Bartos A.
      • Egg R.
      • et al.
      Guidelines on routine cerebrospinal fluid analysis. Report from an EFNS task force.
      ). Moreover, CSF pleocytosis higher than 20–30 cells/µL and protein level increased over 60 mg/dL should raise clinician's vigilance (
      • Stangel M.
      • Fredrikson S.
      • Meinl E.
      • et al.
      The utility of cerebrospinal fluid analysis in patients with multiple sclerosis.
      ;
      • Zettl U.K.
      • Tumani H.
      Multiple Sclerosis & Cerebrospinal Fluid.
      ). Table 2 presents serological/CSF findings characteristic of all abovementioned CNS inflammatory disorders.
      Table 2Serum/CSF typical findings in CNS inflammatory disorders (
      • Jog N.R.
      • James J.A.
      Biomarkers in connective tissue diseases.
      ;
      • Clark K.E.
      • Clark C.N.
      • Rahman A.
      A critical analysis of the tools to evaluate neuropsychiatric lupus.
      ;
      • Bruscolini A.
      • Sacchetti M.
      • La Cava M.
      • Gharbiya M.
      • Ralli M.
      • Lambiase A.
      • De Virgilio A.
      • Greco A.
      Diagnosis and management of neuromyelitis optica spectrum disorders - An update.
      ;
      • Graf J.
      Chapter 23. Antiphospholipid antibody syndrome.
      ;
      • Mandal J.
      • Chung S.A.
      Primary angiitis of the central nervous system.
      ;
      • Siva A.
      Common clinical and imaging conditions misdiagnosed as multiple sclerosis: a current approach to the differential diagnosis of multiple sclerosis.
      ;
      • Dutra L.A.
      • de Souza A.W.
      • Grinberg-Dias G.
      • et al.
      Central nervous system vasculitis in adults: an update.
      ;
      • Stangel M.
      • Fredrikson S.
      • Meinl E.
      • et al.
      The utility of cerebrospinal fluid analysis in patients with multiple sclerosis.
      ;
      • Gastaldi M.
      • Zardini E.
      • Franciotta D.
      An update on the use of cerebrospinal fluid analysis as a diagnostic tool in multiple sclerosis.
      ;
      • Nozaki K.
      • Judson M.A.
      Neurosarcoidosis: clinical manifestations, diagnosis and treatment.
      ;
      • Massara A.
      • Bonazza S.
      • Castellino G.
      • et al.
      Central nervous system involvement in Sjogren's syndrome: unusual, but not unremarkable–clinical, serological characteristics and outcomes in a large cohort of Italian patients.
      ).
      DiseaseTypical serological/CSF findingComment
      MSCSF IgG OCBsOCBs positivity in 90% of MS usually type 2, in some cases type 3
      CSF pleocytosis <30 cells/µL

      CSF protein <60 mg/Dl
      NMOSDAQP4-IgGs

      MOG-IgGs
      sensitivity 73%, specificity 91%, present in 68%−91%

      present in 10%−25%
      NPSLEANA, eg.

      - anti-dsDNA

      - anti-Sm

      - anti-P

      -anti-NR2

      - antineuronal

      - anti-Ro/SSA

      Anti-GABARB1b IgGs

      Anti-GABARB2 IgGs

      Nitrated nucleosome levels

      Increased erythrocyte C4d levels

      Increased B-cell C4d levels

      Decreased C3 and C4 levels

      Increased INF-γ, IL-5, IL-6

      Increased BLyS (B-lymphocyte stimulator)
      titer 1:80

      high specificity

      high specificity

      associated with psychosis and depression

      associated with cognitive dysfunction

      typical of NPSLE and not SLE

      Sjogren syndrome, vasculitis

      exclusive to SLE, present in 15%

      exclusive to SLE, present in 15%

      serum titers twice as high in NPSLE flares
      APSAnticardiolipin antibody

      Anti-β−2-glycoprotein I antibody

      Lupus anticoagulant
      Antiphospholipid antibodies should be tested on at least 2 occasions more than 12 weeks and less than 5 years apart
      PCNSVnoneExtremely elevated erythrocyte sedimentation rate argues against

      PCNSV
      EGPAANCA, mainly MPO-ANCAactive EGPA
      Eosinophilia >1500 cells/μlactive EGPA
      Increased eotaxin-3 (CCL26)

      Increased CCL17
      MPAMPO-ANCAnon-specific
      AC-13 (apolipoprotein A1 C-terminal fragment)activity marker
      GPAANCA, mainly PR3-ANCA
      Increased High-mobility group box 1 protein

      Increased serum S100A8/A9 levels
      activity marker
      Behçet's diseaseless than 15% positivity for CSF OCBs, prominent pleocytosis and protein levelnon-specific
      Neurosarcoidosisincreased level of CSF angiotensin-converting enzymeinsensitive, not fully specific
      Sjögren's syndromeANA, particularly to Ro/SSA and La/SSB

      12. Conclusion

      Despite the growing availability of tools, diagnosis of CNS inflammatory disorders remains complex and often extends over time. Although MRI is the cornerstone of this process, in some cases it may be a source of confusion, as radiological findings in certain conditions can overlap. Taking into consideration the abovementioned data, the need for specific biomarkers seems to be of primary importance. It appears that serological markers deserve particular attention. Unlike CSF, peripheral blood samples are easily obtainable in routine ambulatory care on numerous time points, and thus they would not only facilitate proper diagnosis, but also enable non-invasive monitoring of treatment response. Nevertheless, a thorough combination of clinical examination, radiological assessment, laboratory tests and often an interdisciplinary approach remains currently mandatory to provide a proper diagnosis.

      Declaration of Competing Interest

      None of the authors has any potential financial conflict of interest related to this manuscript.
      Our manuscript has not, in whole or in part, been published previously and is not under consideration for publication elsewhere.

      Acknowledgments

      This work has not been supported by any funding sources.

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