Osteopontin (OPN) is a proinflammatory marker produced by systemic immune and central nervous system (CNS) resident cells. We examined, if the level of OPN in the cerebrospinal fluid (CSF) and blood is associated with late-time regional brain volumes and white matter (WM) lesion load in MS. Concentrations of OPN in blood and CSF were related to MRI findings 10.1 ± 2.0 years later in 46 patients with MS. OPN concentration was measured by ELISA, while regional brain volumes and lesion load was assessed by magnetic resonance imaging (MRI) using 3D MPRAGE sequence and automated MR volumetry. OPN measured in the CSF was associated with several regional brain volumes and WM lesion load measured 10.1 ± 2.0 years later. CSF OPN concentration correlated with long-term enlargement of lateral- and inferior lateral ventricles and the elevation of gross CSF volume, in conjunction with the reduction of several cortical/subcortical gray matter and WM volumes. Serum OPN showed no long-term association with regional brain volumes. OPN measured from the CSF but not from the serum was associated with lower regional brain volumes measured a decade later, indicating the primary role of inflammation within the CNS in developing long-term brain related alterations.
Patients with ongoing seizures are usually not allowed to drive. The prognosis for seizure freedom is favorable in patients with autoimmune encephalitis (AIE) with antibodies against NMDA receptor (NMDAR), leucine-rich glioma-inactivated 1 (LGI1), contactin-associated protein-like 2 (CASPR2), and the gamma-aminobutyric-acid B receptor (GABA
The role of autoimmune responses against central nervous system (CNS) antigens in encephalitis presenting with non-classified neurologic or psychiatric symptoms has been appreciated in the past decade. Paraneoplastic limbic encephalitis has a poor prognosis and is most commonly associated with lung, ovarium, and testicular neoplasms, leading to immune reactions against intracellular antigens (anti-Hu/ANNA1, anti-Ri/ANNA2, anti-CV2/CRMP5 and anti-Ma2/Ta). In contrast, the recently described autoimmune encephalitis subtypes present with a broad spectrum of symptoms, respond to autoimmune therapies well and usually associate with autoantibodies against neuronal cell surface receptors (NMDAR, GABABR, AMPAR) or synaptic proteins (LGI1, CASPR2).Our aim is to bring to awareness the increasing number of autoimmune encephalitis patients requiring neurologic, psychiatric and intensive care and to emphasize the significance of detecting various autoantibodies in diagnosing patients.In the past 6 years, our laboratory received 836 autoimmune encephalitis diagnostic test requests from a total of 717 patients. Serum and cerebrospinal fluid (CSF) samples were analysed with indirect immunofluorescence using a BIOCHIP consisting of cell lines transfected with 6 different receptor proteins.IgG autoantibodies against receptor proteins were present in 7.5% of patients. The frequency of positive samples was the following: NMDAR > LGI1 > GABABR > CASPR2.Detecting autoantibodies facilitates the diagnosis of autoimmune encephalitis in an early stage. Patients diagnosed early can be effectively treated with plasmapheresis and immunosuppressive drugs. The efficiency of therapies can be monitored by autoantibody detection. Therefore, the diagnostic immune laboratory plays an important role in proper diagnosis and in the prevention of rapidly progressing symptoms. Orv Hetil. 2018; 159(3): 107-112.
Resting-state functional magnetic resonance imaging (rs-fMRI) has been widely utilized to investigate plasticity mechanisms and functional reorganization in multiple sclerosis (MS). Among many resting state (RS) networks, a significant role is played by the salience network (SN, ventral attention network). Previous reports have demonstrated the involvement of osteopontin (OPN) in the pathogenesis of MS, which acts as a proinflammatory cytokine ultimately leading to neurodegeneration. Concentration of serum OPN was related to MRI findings 10.22±2.84 years later in 44 patients with MS. Local and interhemispheric correlations (LCOR, IHC), ROI-to-ROI and seed-based connectivity analyses were performed using serum OPN levels as independent variable along with age and gender as nuisance variables. We found significant associations between OPN levels and local correlation in right and left clusters encompassing the central opercular- and insular cortices (p-FDR = 0.0018 and p-FDR = 0.0205, respectively). Moreover, a significant association was identified between OPN concentration and interhemispheric correlation between central opercular- and insular cortices (p-FDR = 0.00015). Significant positive associations were found between OPN concentration and functional connectivity (FC) within the SN (FC strength between the anterior insula ventral division and 3 other insular regions, F(2,13) = 7.84, p-FDR = 0.0117). Seed-based connectivity analysis using the seven nodes of the SN resulted in several positive and inverse associations with OPN level. Serum OPN level may predict FC alterations within the SN in 10 years.
Decreased expression of TLR homolog CD180 in peripheral blood B cells and its potential role in antibody production have been described in autoimmune diseases. Effectiveness of anti-CD20 therapy in neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) strengthens the role of B cells in the pathogenesis. Therefore, we aimed to investigate the CD180 expression of peripheral blood B cell subsets in NMOSD and MS patients and analyze the levels of natural anti-citrate synthase (CS) IgG autoantibodies and IgG antibodies induced by bacterial infections reported to play a role in the pathogenesis of NMOSD or MS.We analyzed the distribution and CD180 expression of peripheral blood B cell subsets, defined by CD19/CD27/IgD staining, and measured anti-CS IgM/G natural autoantibody and antibacterial IgG serum levels in NMOSD, RRMS, and healthy controls (HC).We found decreased naïve and increased memory B cells in NMOSD compared to MS. Among the investigated four B cell subsets, CD180 expression was exclusively decreased in CD19+CD27+IgD+ nonswitched (NS) memory B cells in both NMOSD and MS compared to HC. Furthermore, the anti-CS IgM natural autoantibody serum level was lower in both NMOSD and MS. In addition, we found a tendency of higher anti-CS IgG natural autoantibody levels only in anti-Chlamydia IgG antibody-positive NMOSD and MS patients.Our results suggest that reduced CD180 expression of NS B cells could contribute to the deficient natural IgM autoantibody production in NMOSD and MS, whereas natural IgG autoantibody levels show an association with antibacterial antibodies.
Paraneoplastic neurologic syndromes (PNS) and autoimmune encephalitis (AE) are rare neurological disorders, which have similar symptoms, but vary in outcome and treatment strategy. In our retrospective statistical study we evaluated the autoantibody test results of serum and CSF from 2362 patients with suspected PNS and 1034 patients with suspected AE. For autoantibody testing, immunoblot assay (PNS) and cell-based indirect immunofluorescence assay (AE) were used. Autoantibodies were present in 8% of patients with suspected PNS: anti-Yo > anti-Hu > anti-Ma2 > anti-CV2 > anti-titin > anti-Zic4 > anti-amphiphysin > anti-Ri > anti-GAD65 > anti-Sox1 > anti-recoverin. Mostly elderly women were affected. Autoantibodies were present in 5.8% of patients with suspected AE: anti-NMDAR (young women) > anti-LGI1 (middle-aged men) > anti-GABABR (elderly men) > anti-Caspr2 (adult men). Our results correspond to the data described in the literature. The number of patients with suspected PNS and AE shows an increasing tendency, where the autoantibody testing with modern laboratory diagnostic methods helps in the early introduction of the appropriate therapy.A paraneopláziás neurológiai szindrómák (PNS) és az autoimmun enkefalitiszek (AE) ritka idegrendszeri kórképek, melyek hasonló tünettannal jelentkeznek az érintett betegekben, azonban prognózisuk és kezelésük eltér. Jelenlegi retrospektív statisztikai elemzésünk során 2362 PNS- és 1034 AE-gyanús beteg szérum- és likvormintái laboratóriumi teszt eredményeinek értékelését végeztük el. Az autoantitestek kimutatása céljából PNS esetén line-immunoblot assay-t, AE esetén sejtalapú indirekt immunfluoreszcens assay-t alkalmaztunk. Analízisünk során a PNS-gyanús betegek 8%-ában találtunk autoantitestet a következõ megoszlással: anti-Yo > anti-Hu > anti-Ma2 > anti-CV2 > anti-titin > anti-Zic4 > anti-amfifizin > anti-Ri > anti-GAD65 > anti-Sox1 > anti-recoverin, melyek elõfordulása idõsebb nõkben volt gyakoribb. Az AE-gyanús betegek 5,8%-ában találtunk autoantitestet: anti-NMDAR (fiatal nõkben) > anti-LGI1 (középkorú férfiakban) > anti-GABABR (idõsebb férfiakban) > anti-Caspr2 (felnõtt férfiakban). Eredményeink az autoantitestek gyakoriságát, nem és életkor szerinti megoszlását tekintve a szakirodalmi adatokkal nagyfokú hasonlóságot mutattak. A PNS és AE diagnózisának felállítását segíti az autoantitestek kimutatása, amely a modern labordiagnosztikai módszerek bevezetésével egyre több beteg számára lehetõvé teszi a kezelés korai bevezetését.
Background: In our previous single-center study of autoimmune encephalitis (AE) related autoantibody test results we found positivity in 60 patients out of 1,034 with suspected AE from 2012 through 2018 as part of a Hungarian nationwide program. In our current multicenter retrospective study, we analyzed the clinical characteristics and outcome of AE patients with positive neuronal cell surface autoantibody test results. Methods: A standard online questionnaire was used to collect demographic and clinical characteristics, laboratory and imaging data, therapy and prognosis of 30 definitive AE patients in four major clinical centers of the region. Results: In our study, 19 patients were positive for anti-NMDAR (63%), 6 patients (20%) for anti-LGI1, 3 patients for anti-GABABR (10%) and 3 patients for anti-Caspr2 (10%) autoantibodies. Most common prodromal symptoms were fever or flu-like symptoms (10/30, 33%). Main clinical features included psychiatric symptoms (83%), epileptic seizures (73%) and memory loss (50%). 19 patients (63%) presented with signs of central nervous system (CNS) inflammation, which occurred more frequently in elder individuals ( p = 0.024), although no significant differences were observed in sex, tumor association, time to diagnosis, prognosis and immunotherapy compared to AE patients without CNS inflammatory markers. Anti-NMDAR encephalitis patients were in more severe condition at the disease onset ( p = 0.028), although no significant correlation between mRS score, age, sex and immunotherapy was found. 27% of patients ( n = 8) with associated tumors had worse outcome ( p = 0.045) than patients without tumor. In most cases, immunotherapy led to clinical improvement of AE patients (80%) who achieved a good outcome (mRS ≤ 2; median follow-up 33 months). Conclusion: Our study confirms previous publications describing characteristics of AE patients, however, differences were observed in anti-NMDAR encephalitis that showed no association with ovarian teratoma and occurred more frequently among young males. One-third of AE patients lacked signs of inflammation in both CSF and brain MRI, which emphasizes the importance of clinical symptoms and autoantibody testing in diagnostic workflow for early introduction of immunotherapy, which can lead to favorable outcome in AE patients.
Abstract Objective Autoantibody detection is crucial for the early diagnosis of autoimmune encephalitis (AIE) since prompt therapy can determine the disease outcome. Here, we report a single‐center 6‐year retrospective study of autoantibody testing in AIE in the Hungarian population. Methods Serum and/or cerebrospinal fluid (CSF) autoantibody tests were performed using cell‐based indirect immunofluorescence assay for AIE diagnosis. Samples were provided by neurology clinics as part of a nationwide program. Test results were analyzed for samples received during the period from 2012 to 2018. Results We tested 1,247 samples from 1,034 patients with suspected AIE. Autoantibodies were present in 60 patients (5.8% of total). The distribution of patients with different autoantibodies by age and sex was as follows: NMDAR (70%), mostly in young females, LGI1 (15%) in middle‐aged males, GABA B R (12%) in elderly males, and Caspr2 (7%) in males. Long‐term follow‐up was conducted in 30 patients with repeated test requests, of which 17 remained positive, and 13 switched to negative. Conclusion We report the most comprehensive clinical laboratory study of autoantibody testing in AIE in the Hungarian population. Our results show that the frequency of different autoantibody types in AIE corresponds to the data described in the literature.
Absztrakt: Bevezetes: Az elmult 10 evben a nem klasszifikalhato neurologiai
vagy pszichiatriai tunetegyuttes kepeben megjelenő encephalitisek eseten egyre
gyakrabban igazolodik be, hogy a hatterben a kozponti idegrendszer valamely
feherjeje ellen indulo autoimmun folyamat all. A paraneoplasias limbicus
encephalitisek eseteben intracellularis antigenek (anti-Hu/ANNA1, anti-Ri/ANNA2,
anti-CV2/CRMP5 es anti-Ma2/Ta) ellen indul immunreakcio, mely mogott tudő-,
ovarium- vagy heredaganat all, es jellemző a rossz prognozis. Ezzel szemben az
utobbi evekben felfedezett, szines klinikai keppel megjelenő autoimmun
encephalitisek mogott gyakran bizonyithato a neuronalis sejtfelszini receptor
(NMDAR, GABA B R, AMPAR) vagy szinaptikus feherje (LGI1, CASPR2) ellen
kepződő autoantitestek jelenlete, ami immunszuppresszios kezelesre jol reagal.
Celkitűzes: Celunk felhivni a figyelmet a neurologiai,
pszichiatriai es intenziv terapias ellatast igenylő autoimmun encephalitises
esetek emelkedő szamara, valamint az autoantitestek kimutatasanak jelentősegere.
Modszer: Laboratoriumunkba az elmult 6 evben 836 autoimmun
encephalitis iranyu, 717 beteghez tartozo vizsgalatkeres erkezett. A betegek
szerum- es liquormintait 6 kulonboző receptorfeherjevel transzfektalt
sejtvonalbol allo BIOCHIP-en vizsgaltuk indirekt immunfluoreszcens technikaval.
Eredmenyek: A vizsgalt betegek 7,5%-aban tudtunk valamelyik
receptorfeherje ellen IgG autoantitestet kimutatni. Gyakorisagi sorrendben NMDAR
> LGI1 > GABA B R > CASPR2 ellen talaltunk pozitiv eseteket.
Kovetkeztetes: Az autoantitest kimutatasa segit a betegseg
korai stadiumban valo felismereseben es a diagnozis felallitasaban. Mindez
fontos, mert az időben felismert betegek eredmenyesen kezelhetőek
plazmaferezissel vagy immunszuppressziv szerekkel, melyek hatekonysagat ismetelt
autoantitestmeghatarozassal lehet kovetni. Ezert a laboratoriumnak nagy szerepe
lehet a gyorsan progredialo koros idegrendszeri folyamatok megallitasaban. Orv
Hetil. 2018; 159(3): 107–112.
| Abstract: Introduction: The role of autoimmune responses against central
nervous system (CNS) antigens in encephalitis presenting with non-classified
neurologic or psychiatric symptoms has been appreciated in the past decade.
Paraneoplastic limbic encephalitis has a poor prognosis and is most commonly
associated with lung, ovarium, and testicular neoplasms, leading to immune
reactions against intracellular antigens (anti-Hu/ANNA1, anti-Ri/ANNA2,
anti-CV2/CRMP5 and anti-Ma2/Ta). In contrast, the recently described autoimmune
encephalitis subtypes present with a broad spectrum of symptoms, respond to
autoimmune therapies well and usually associate with autoantibodies against
neuronal cell surface receptors (NMDAR, GABA B R, AMPAR) or synaptic
proteins (LGI1, CASPR2). Aim: Our aim is to bring to awareness
the increasing number of autoimmune encephalitis patients requiring neurologic,
psychiatric and intensive care and to emphasize the significance of detecting
various autoantibodies in diagnosing patients. Method: In the
past 6 years, our laboratory received 836 autoimmune encephalitis diagnostic
test requests from a total of 717 patients. Serum and cerebrospinal fluid (CSF)
samples were analysed with indirect immunofluorescence using a BIOCHIP
consisting of cell lines transfected with 6 different receptor proteins.
Results: IgG autoantibodies against receptor proteins were
present in 7.5% of patients. The frequency of positive samples was the
following: NMDAR > LGI1 > GABA B R > CASPR2.
Conclusion: Detecting autoantibodies facilitates the
diagnosis of autoimmune encephalitis in an early stage. Patients diagnosed early
can be effectively treated with plasmapheresis and immunosuppressive drugs. The
efficiency of therapies can be monitored by autoantibody detection. Therefore,
the diagnostic immune laboratory plays an important role in proper diagnosis and
in the prevention of rapidly progressing symptoms. Orv Hetil. 2018; 159(3):
107–112.
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