Kappa index in the diagnostic work-up of autoimmune encephalitis.

BACKGROUND: The presence of inflammatory changes in the cerebrospinal fluid (CSF), including immunoglobulin intrathecal synthesis (IS), can support the diagnosis of autoimmune encephalitis (AE) and allow prompt treatment. The main aim of our study was to calculate the Kappa index as a marker of IS, in patients with AE. METHODS: Charts of patients undergoing a diagnostic work-up for suspected AE between 2009 and 2023 were reviewed and the Graus criteria applied. CSF and serum kappa free light chains were determined using the Freelite assay (The Binding Site Group) and the turbidimetric Optilite analyzer. RESULTS: We identified 34 patients with "definite" AE (9 anti-NMDAR AE and 25 limbic AE) and nine patients with "possible" AE. Five patients (15%) with definite AE had pleocytosis and twelve (34%) showed CSF-restricted oligoclonal bands (OCB) at isoelectric focusing. The Kappa index was >6 in 29.4% and > 3 in 50% of the definite AE patients. It was elevated (>3) in 36.4% of patients with definite AE who resulted negative to OCB testing and was the only altered parameter suggestive of an ongoing inflammatory process in the CNS in three definite AE patients with otherwise normal CSF findings (i.e. normal cell count and protein levels, no OCBs). In the possible AE group, one patient had a Kappa index >3 in the absence of OCB. CONCLUSIONS: The Kappa index could be useful, as a more sensitive marker of IS and as a supportive marker of neuroinflammation, in the diagnostic work-up of suspected AE.

Infrequent patterns in cerebrospinal fluid isofocusing test: Clinical significance and contribution of IgG index and Reiber diagram to their interpretation.

Cerebrospinal fluid (CSF) isoelectrofocusing (IEF) is considered as the gold standard for detecting an intrathecal synthesis of IgG, which is a hallmark of multiple sclerosis (MS). This corresponds to the presence of CSF-restricted IgG oligoclonal bands (OCB) (typically type 2 pattern). Moreover, this technique can also detect a systemic immune reaction with passive transfer of IgG (type 3 and 4 patterns) for which the clinical relevance is less understood. The aim of our study was to determine the frequency and disease associations of IEF type 3 and 4 patterns and to investigate the potential usefulness of including quantitative data (IgG index and Reiber Diagram) in interpreting such IEF profiles. Among 544 patients who underwent CSF IEF (Hydragel CSF isofocusing kit, Sebia®, France) in our Laboratory during a six-year-period, those who presented type 3 or 4 patterns were selected. Clinical data and results of other immunological tests were analyzed for 27 patients followed in the Neurological Department. Frequencies of type 3 and type 4 patterns were relatively low (2.3 % and 3.4 % respectively). Among patients with type 3 pattern included in our study (n = 10), 5 were diagnosed with MS. For the 5 other patients, the diagnosis was a clinically isolated syndrome (CIS) (2 cases), a probable auto-immune encephalitis (2 cases) and a possible genetic neurodegenerative disease (1 case). MS patients had an IgG index >0.7 and fell into area 4 of Reiber diagram while non-MS patients had an IgG index <0.7 and fell into area 1, except the last case. Regarding type 4 pattern (n = 17), the diagnoses were as follows: MS (3), CIS (4), Neuromyelitis optica spectrum disorders with positive anti-AQP4 antibodies (3) and anti-NMDAR autoimmune encephalitis (1). The remaining cases had central nervous system impairment related to vascular, metabolic or tumoral etiologies (3) or peripheral nervous system impairment (3). In this group (type 4 pattern), IgG index was <0.7 in 15/17 cases. Interpretation using Reiber diagram showed an abnormal blood-brain barrier for 8/17 patients. Type 3 and 4 IEF patterns are infrequently observed in routine neurology practice. It is important for the diagnostic laboratory professional as well as for the neurologist to understand their clinical relevance. Our findings highlight the contribution of quantitative evaluation of CSF (IgG index, Reiber diagram) for the interpretation of such situations. Despite the small size of our study population, our results emphasize the importance of reporting the exact type of IEF pattern and not only the positivity or not of OCB.

[The therapeutic effect and prognostic value of oligoclonal bands after autologous stem cell transplant in patients with multiple myeloma].

Objective: To investigate the therapeutic effect and prognostic value of oligoclonal bands (OB) in multiple myeloma (MM) patients after autologous stem cell transplant (ASCT). Methods: The data of 156 patients with MM who underwent ASCT after inductive treatment in the Department of Hematology, Jiangsu Provincial People's Hospital from December 2013 to February 2022 were retrospectively analyzed, including 91 males and 65 females. The median age was 56 (26, 71) years. Patients were divided into two groups according to OB formation after ASCT treatment, including OB group (n=60) and non-OB group (n=96). The last follow-up date was August 31, 2023, and the follow-up period was 42 (18, 117) months. The clinical baseline characteristics and efficacy of the two groups were compared. Progression-free survival (PFS) and overall survival (OS) were compared between the two groups by Kaplan-Meier method. Cox risk regression modal was used to analyze the risk factors associated with prognosis. Results: There were no significant differences in age, type, stage, risk stratification, extramedullary disease (EMD), proportion of circulating plasma cells and induction therapy regimen between OB and non-OB groups (all P>0.05). The proportion of patients in OB group who achieved complete response (CR) or above after ASCT treatment was 93.3% (56/60), which was higher than that in non-OB group (80.2%, 77/96) (P=0.024). The negative rate of minimal residual disease (MRD) in OB group was 66.7% (40/60), which was higher than that in non-OB group (34.4%, 33/96) (P=0.001). The median PFS and OS in the OB group were not reached, and the median PFS and OS in the non-OB group were 28 (2, 80) months and 86 (2, 100) months, respectively. The PFS (P<0.001) and OS (P=0.017) of patients with OB were considerably longer. In the Cox multivariate analysis, OB was an independent prognostic factor for PFS in MM patients (HR=0.314, 95%CI: 0.153-0.644, P=0.002). Subgroup analysis showed that among high-risk patients with mSMART, the OS of patients in OB group was not reached, which was significantly better than that of non-OB group [71 (2, 90) months, P=0.046]. However, no significant difference was observed in the OS of patients with OB and those with non-OB in standard risk group (not reached vs not reached, P=0.103). In those with EMD at diagnosis, patients with OB had significantly better OS than those with non-OB [not reached vs 47 (6, 74) months, P=0.037]. However, no significant difference was observed in the OS of patients with OB and those with non-OB in those without EMD at diagnosis [not reached vs 86 (2, 100) months, P=0.130]. Conclusions: OB formation after ASCT treatment in MM patients is related to the efficacy and prognosis. OB formation can increase the negative MRD rate, prolong the OS and improve the prognosis, especially for newly diagnosed patients with extramedullary disease or patients with high-risk genetic characteristics.

The elusive nature of the oligoclonal bands in multiple sclerosis.

Intrathecal immunoglobulin G (IgG) and oligoclonal bands (OCBs) detected in both the brain and cerebrospinal fluid (CSF) are seminal features of multiple sclerosis (MS). The presence of OCBs correlates with elevated disease burden and severity and supports the diagnosis of MS. Despite numerous investigations into the potential viral and autoantigen targets, the precise antigenic specificity of OCBs has remained elusive. We have little knowledge of the nature regarding these oligoclonal IgG bands. Here, we present compelling evidence highlighting the key findings that both OCBs and intrathecal IgG antibodies are under genetic control and that OCBs originate from clonal B-cells in both the periphery and CNS. We propose that MS OCBs are IgG immune complexes composed of IgG1 and IgG3 antibodies and that the pathological role of OCB stems from the IgG effector functions of these complexes, leading to demyelination and axonal injuries. We present additional evidence regarding the nature of MS OCBs: (1) disease-modifying therapies have been shown to affect CSF OCB; (2) OCBs have also been detected in several neuroinfectious diseases; (3) Epstein-Barr virus (EBV) has been particularly linked with MS pathogenesis, and its association with OCB is an important area of study. Although OCBs are closely associated with MS, more meticulously planned research is necessary to clarify the precise role of OCB in MS, both in terms of disease pathogenesis and diagnosis.

Assessment of oligoclonal bands in cerebrospinal fluid and serum of dogs with meningoencephalitis of unknown origin.

BACKGROUND: Meningoencephalitis of unknown origin (MUO) is an inflammatory disease of the canine central nervous system (CNS) that shares several features with multiple sclerosis (MS) in humans. In approximately 95% of MS patients, ≥ two immunoglobulin G (IgG) oligoclonal bands (OCBs) are detectable exclusively in the cerebrospinal fluid (CSF). HYPOTHESIS/OBJECTIVES: To investigate OCBs in CSF and serum in dogs affected by MUO, intervertebral disc disease (IVDD), idiopathic epilepsy (IE), intracranial neoplasia (IN), steroid-responsive meningitis-arteritis (SRMA), and diseases outside the CNS. We hypothesize that the highest prevalence of CSF-specific OCBs (≥ two OCBs uniquely in the CSF) would be found in dogs affected by MUO. ANIMALS: Client-owned dogs (n = 121) presented to the neurology service due to neurological deficits. METHODS: Prospective study. Measurement of IgG concentration in CSF and serum via a canine IgG ELISA kit. OCB detection via isoelectric focusing (IEF) and immunoblot. RESULTS: Presence of CSF-specific OCBs was significantly higher in dogs with MUO (57%) compared to 22% in IN, 6% in IE, 15% in SRMA, 13% in IVDD, and 0% in the non-CNS group (p < .001). Dogs with MUO were 9.9 times more likely to show CSF-specific OCBs than all other diseases together (95% confidence interval, 3.7-26.4; p < .001). CONCLUSIONS AND CLINICAL IMPORTANCE: MUO showed the highest prevalence of CSF-specific OCBs, indicating an inflammatory B cell response. Future studies are needed to evaluate the prevalence in the specific MUO subtypes and a possible similarity with human MS.

Glutamic acid decarboxylase antibody-associated neurological syndromes: Clinical and antibody characteristics and therapy response.

BACKGROUND: Antibodies against glutamic acid decarboxylase (GAD-abs) at high serum levels are associated with diverse autoimmune neurological syndromes (AINS), including cerebellar ataxia, epilepsy, limbic encephalitis and stiff-person syndrome. The impact of low serum GAD-ab levels in patients with suspected AINS remains controversial. Specific intrathecal GAD-ab synthesis may serve as a marker for GAD-ab-associated nervous system autoimmunity. We present characteristics of a multicentric patient cohort with suspected AINS associated with GAD antibodies (SAINS-GAD+) and explore the relevance of serum GAD-ab levels and intrathecal GAD-ab synthesis. METHODS: All patients with SAINS-GAD+ included in the registry of the German Network for Research on Autoimmune Encephalitis (GENERATE) from 2011 to 2019 were analyzed. High serum GAD-ab levels were defined as RIA>2000 U/mL, ELISA>1000 U/mL, or as a positive staining pattern on cell-based assays. RESULTS: One-hundred-one patients were analyzed. In descending order they presented with epilepsy/limbic encephalitis (39%), cerebellar ataxia (28%), stiff person syndrome (22%), and overlap syndrome (12%). Immunotherapy was administered in 89% of cases with improvements in 46%. 35% of SAINS-GAD+ patients had low GAD-ab serum levels. Notably, unmatched oligoclonal bands in CSF but not in serum were more frequent in patients with low GAD-ab serum levels. GAD-ab-levels (high/low) and intrathecal GAD-ab synthesis (present or not) did not impact clinical characteristics and outcome. CONCLUSIONS: Overall, immunotherapy in SAINS-GAD+ was moderately effective. Serum GAD-ab levels and the absence or presence of intrathecal GAD-ab synthesis did not predict clinical characteristics or outcomes in SAINS-GAD+. The detection of unmatched oligoclonal bands might outweigh low GAD-ab serum levels.

Oligoclonal band versus chitinase-3-like protein-1 in CSF of newly diagnosed relapsing remitting multiple sclerosis.

Multiple sclerosis (MS) is a chronic autoimmune-mediated demyelinating disease of the central nervous system (CNS) that is usually associated with varying degrees of progressive disability. Chitinase-3-like protein-1 (CHI3L1) has attracted growing attention as a marker of ongoing inflammation and oncogenic transformation. The aim of this work was to assess the diagnostic accuracy of CHI3L1 versus IgG oligoclonal bands (OCBs) in the cerebrospinal fluid (CSF) of newly diagnosed relapsing remitting MS (RRMS) patients to throw light on a new simpler non subjective potential diagnostic marker in MS. This cross-sectional study of MS patients was carried at Ain Shams University Hospitals during the period from January 2021 till January 2022. Subjects included in this study were 40 patients diagnosed as having RRMS, based on their magnetic resonance imaging (MRI) findings, clinical presentation and according to the revised McDonald criteria 2017. The group included 10 males and 30 females; their ages ranged from 20 to 45 years. We found a significant correlation between CSF CHI3L1 levels and presence of oligoclonal bands (p=0.001), and that a cut off value of 30 ng/ml could be used for diagnosis of MS with sensitivity 84.85% and specificity 85.71%. A significant association was also found between CHI3L1 levels in CSF and Expanded Disability Status Scale (EDSS) score (p=0.002). We concluded that there were high levels of CHI3L1 in the CSF of MS patients and there was a significant correlation between CHI3L1 and oligoclonal bands and that CHI3L1 may be considered a promising diagnostic marker of MS.

Multiple Sclerosis Followed by Neuromyelitis Optica Spectrum Disorder: From the National Multiple Sclerosis Society Case Conference Proceedings.

A woman presented at age 18 years with partial myelitis and diplopia and experienced multiple subsequent relapses. Her MRI demonstrated T2 abnormalities characteristic of multiple sclerosis (MS) (white matter ovoid lesions and Dawson fingers), and CSF demonstrated an elevated IgG index and oligoclonal bands restricted to the CSF. Diagnosed with clinically definite relapsing-remitting MS, she was treated with various MS disease-modifying therapies and eventually began experiencing secondary progression. At age 57 years, she developed an acute longitudinally extensive transverse myelitis and was found to have AQP4 antibodies by cell-based assay. Our analysis of the clinical course, radiographic findings, molecular diagnostic methods, and treatment response characteristics support the hypothesis that our patient most likely had 2 CNS inflammatory disorders: MS, which manifested as a teenager, and neuromyelitis optica spectrum disorder, which evolved in her sixth decade of life. This case emphasizes a key principle in neurology practice, which is to reconsider whether the original working diagnosis remains tenable, especially when confronted with evidence (clinical and/or paraclinical) that raises the possibility of a distinctively different disorder.

[The Clinical Significance of Oligoclonal Bands in Patient with Multiple Myeloma].

OBJECTIVE: To investigate the clinical value of oligoclonal bands (OB) in patients with multiple myeloma (MM). METHODS: The laboratory test and clinical data of 624 newly diagnosed MM patients admitted to Blood Diseases Hospital of Chinese Academy of Medical Sciences from January 2013 to December 2019 were retrospectively analyzed, including 30 patients with OB, and the clinical characteristics, treatment effects and survival of OB and non-OB patients were analyzed and compared. RESULTS: OB occurred in 11.8% (22/187) of patients who received autologous stem cell transplantation(ASCT) and only 1.8% (8/437) of patients who did not receive ASCT (P=0.000). The median time to the appearance of oligoclonal bands was 3.2(0.6-10.5) months after transplantation. The M protein types of oligoclonal bands mainly include IgG κ, IgG λ, IgM λ and λ light chains. In the presence of oligoclonal bands, 90% of patients were evaluated as complete remission (CR) and above. There were no statistically significant differences in disease stage, tumor burden, and genetic abnormalities between OB and non-OB patients. Among the all patients, the prognosis of OB patients was significantly better than that of non-OB patients, and OB patients showed deeper disease remission (significantly higher CR rate, MRD negative rate, and longer MRD negative duration). Among patients who underwent ASCT, OB patients showed earlier immune recovery, but the depth of treatment response and survival outcomes were similar between OB and non-OB patients, it was no statistically difference. Although OB patients showed earlier immune reconstitution, this did not translate into better survival, suggesting that the better prognosis of OB patients was mainly related to deeper and durable remission rather than early immune reconstitution. Further analysis in patients who received ASCT and obtained MRD negative indicated that there was no additional survival benefit in patients with OB. CONCLUSION: The better prognosis of OB patients may be related to the deeper treatment response, but not to the early immune reconstitution. The appearance of OB is only a sign of deep remission and early immune reconstitution in patients, it cannot be translated into survival benefit of MM patients.

A case report of possible concurrent vasculitis in vertebral bodies and partial transverse myelitis following COVID-19 vaccination.

INTRODUCTION: Cases with organ-specific and systemic vasculitis associated with corona virus disease 2019 (COVID-19) vaccination have been reported. However, acute partial transverse myelitis (APTM) is rare adverse events following received COVID-19 vaccines. To the best of our knowledge, there is no report on vaccine-associated APTM accompanied by possible concurrent vasculitis. Herein we present a case with possible concurrent spinal vasculitis and APTM following the second dose of inactivated COVID-19 vaccine. CASE SUMMARY: A 33-year-old man presented with weakness of left lower limb and aberrant sensation of his left lower trunk and limb (from T9 level to toes) for 2 days following receipt of an inactivated COVID-19 vaccine. Remarkable demyelinating lesion at T7 spinal cord was showed by 3.0T magnetic resonance imaging (MRI) scan. Moreover, vertebral bodies of T3-T7 also presented high signal in T-2 weighted imaging (T2WI) accompanied by multiple sites of flowing void effect indicating possible vasculitis. Oligoclonal band was positive in cerebrospinal fluid (CSF) while it was negative in sera. Intravenous methylprednisolone (1 g/d) was administrated for 5 days followed by subsequent dose-tapering prednisone. His limb weakness and aberrant sensation both improved and he was able to walk unaided after treatment. The MRI recheck also showed remarkable improvement on the lesions in spinal cord and vertebral bodies. CONCLUSION: this case illustrates the concurrence of possible vasculitis in vertebral bodies and acute transverse myelitis (ATM) following COVID-19 vaccination.

Clinical Reasoning: A 43-Year-Old Man With Subacute Onset of Vision Disturbances, Jaw Spasms, and Balance and Sleep Difficulties.

A brainstem syndrome is recognizable in patients presenting with a combination of visual disturbances, incoordination, gait problems, speech and swallowing difficulties, and new-onset sleep symptomatology. Brainstem disorders of subacute onset (onset and progression with accumulation of disabling deficits in 6-12 weeks) are generally of autoimmune, infectious, inflammatory, or infiltrative neoplastic cause. An autoimmune or infectious brainstem disorder may be referred to as brainstem encephalitis or rhombencephalitis. We describe a patient with paraneoplastic autoimmune rhombencephalitis, in whom diagnostic clues included the following: diverse visual and sleep symptoms, trismus, and choking in the history; see-saw nystagmus, opsoclonus, dysarthria, jaw dystonia, and episodic laryngospasm on examination; subtle but longitudinal and nonenhancing T2 MRI abnormalities in the brainstem and upper cervical cord; and oligoclonal bands in the CSF. His movement disorder-specific neural IgG profile revealed ANNA-2 (anti-Ri) and KLHL-11-IgG. Both are biomarkers of paraneoplastic brainstem encephalitis. KLCHL-11-IgG has been reported to accompany germ cell tumors, which was found in a solitary metastasis to the left inguinal lymph node in our patient, along with an atrophic left testis. Multidisciplinary treatment (autoimmune neurology, sleep medicine, ophthalmology, and physiatry) led to significant clinical improvements. This case provides a framework for the evaluation of patients with subacute-onset brainstem syndromes and the investigation and management of those with paraneoplastic and other autoimmune diseases.

Prognosis Prediction Using Magnetic Resonance Spectroscopy and Oligoclonal Bands in Central Nervous System Methotrexate-associated Lymphoproliferative Disorder.

Central nervous system methotrexate-associated lymphoproliferative disorder (CNS-MTX-LPD) is rare, but its spontaneous regression has been observed in some patients after withdrawal of agents. We herein report three cases of primary CNS-MTX-LPD that received oral MTX for rheumatoid arthritis. Epstein-Barr virus and oligoclonal bands (OCBs) were positive, while proton magnetic resonance spectroscopy (1H-MRS) showed an elevated lipid peak and slightly elevated choline/N-acetylaspartate ratio in common. After MTX withdrawal, brain lesions showed spontaneous regression in all cases. Our patient's 1H-MRS findings and OCBs may reflect a non-monoclonal lymphoproliferative histology as benign-type lesions in CNS-MTX-LPD.

Cerebrospinal fluid findings in COVID-19: a multicenter study of 150 lumbar punctures in 127 patients.

BACKGROUND: Comprehensive data on the cerebrospinal fluid (CSF) profile in patients with COVID-19 and neurological involvement from large-scale multicenter studies are missing so far. OBJECTIVE: To analyze systematically the CSF profile in COVID-19. METHODS: Retrospective analysis of 150 lumbar punctures in 127 patients with PCR-proven COVID-19 and neurological symptoms seen at 17 European university centers RESULTS: The most frequent pathological finding was blood-CSF barrier (BCB) dysfunction (median QAlb 11.4 [6.72-50.8]), which was present in 58/116 (50%) samples from patients without pre-/coexisting CNS diseases (group I). QAlb remained elevated > 14d (47.6%) and even > 30d (55.6%) after neurological onset. CSF total protein was elevated in 54/118 (45.8%) samples (median 65.35 mg/dl [45.3-240.4]) and strongly correlated with QAlb. The CSF white cell count (WCC) was increased in 14/128 (11%) samples (mostly lympho-monocytic; median 10 cells/µl, > 100 in only 4). An albuminocytological dissociation (ACD) was found in 43/115 (37.4%) samples. CSF L-lactate was increased in 26/109 (24%; median 3.04 mmol/l [2.2-4]). CSF-IgG was elevated in 50/100 (50%), but was of peripheral origin, since QIgG was normal in almost all cases, as were QIgA and QIgM. In 58/103 samples (56%) pattern 4 oligoclonal bands (OCB) compatible with systemic inflammation were present, while CSF-restricted OCB were found in only 2/103 (1.9%). SARS-CoV-2-CSF-PCR was negative in 76/76 samples. Routine CSF findings were normal in 35%. Cytokine levels were frequently elevated in the CSF (often associated with BCB dysfunction) and serum, partly remaining positive at high levels for weeks/months (939 tests). Of note, a positive SARS-CoV-2-IgG-antibody index (AI) was found in 2/19 (10.5%) patients which was associated with unusually high WCC in both of them and a strongly increased interleukin-6 (IL-6) index in one (not tested in the other). Anti-neuronal/anti-glial autoantibodies were mostly absent in the CSF and serum (1509 tests). In samples from patients with pre-/coexisting CNS disorders (group II [N = 19]; including multiple sclerosis, JC-virus-associated immune reconstitution inflammatory syndrome, HSV/VZV encephalitis/meningitis, CNS lymphoma, anti-Yo syndrome, subarachnoid hemorrhage), CSF findings were mostly representative of the respective disease. CONCLUSIONS: The CSF profile in COVID-19 with neurological symptoms is mainly characterized by BCB disruption in the absence of intrathecal inflammation, compatible with cerebrospinal endotheliopathy. Persistent BCB dysfunction and elevated cytokine levels may contribute to both acute symptoms and 'long COVID'. Direct infection of the CNS with SARS-CoV-2, if occurring at all, seems to be rare. Broad differential diagnostic considerations are recommended to avoid misinterpretation of treatable coexisting neurological disorders as complications of COVID-19.

Aplicación de un método in house para el estudio de la esclerosis múltiple / Application of an in-house method for the study of multiple sclerosis

Resumen El método de referencia para el estudio bioquímico de la esclerosis múltiple (EM) es el isoelectroenfoque (IEE) y la evaluación de las cadenas livianas libres (CLL) podría brindar una información adicional de relevancia. Por lo tanto, se propone evaluar la presencia de las CLL y la aplicabilidad de los estados de polimerización en el estudio de la EM. Se puso a punto un método compuesto por una separación electroforética en gel de poliacrilamida al 12,5% con posterior electrotransferencia (PAGE-WB) y se realizó la evaluación de 121 pacientes con sospecha de EM en simultáneo al IEE. Los patrones de PAGE-WB relacionados con la EM fueron el aumento de la concentración de monómeros Kappa o dímeros Lambda en líquido cefalorraquídeo (LCR) en comparación con el suero. Este método tuvo una muy alta significación de asociación con el IEE (p<0,0001) con sensibilidad del 95%, especificidad del 90%, VPP 83% y VPN 97%. La síntesis intratecal de CLL quedó evidenciada por el aumento de intensidad del monómero Kappa y/o el dímero Lambda observado en LCR. La técnica de PAGE-WB para CLL demostró ser un método alternativo para detectar la síntesis intratecal en pacientes con sospecha de EM.

Abstract The reference method for the biochemical study of multiple sclerosis (MS) is isoelectric focusing (IEF) and the evaluation of free light chains (FLC) could provide additional information of relevance. Therefore, it is proposed here to evaluate the presence of FLC and the applicability of the polymerisation states in the study of MS. A method consisting of a 12.5% polyacrylamide gel electrophoretic separation with a subsequent electrotransfer (PAGE-WB) was developed and the evaluation of 121 patients with suspected MS was carried out simultaneously with the IEF. MS-related PAGE-WB patterns were the increase in the concentration of Kappa monomers or Lambda dimers in CSF compared to serum. This method had a very high significance of association with the IEF (p<0.0001) with 95% sensitivity, 90% specificity, 83% PPV and 97% NPV. Intrathecal synthesis of FLC was evidenced by the increased intensity of the Kappa monomers and/or Lambda dimers observed in CSF. The PAGE-WB technique for FLC proved to be an alternative method to detect intrathecal synthesis in patients with suspected MS.

Resumo O método de referência para o estudo bioquímico da esclerose múltipla (EM) é a focalização isoelétrica (IEE) e a avaliação de cadeias leves livres (CLL) poderiam fornecer informações adicionais de relevância. Assim, propõe-se avaliar a presença das CLL e a aplicabilidade dos estados de polimerização no estudo de EM. Foi desenvolvido um método que consiste na separação eletroforética em gel de poliacrilamida a 12,5% com posterior eletrotranferência (PAGE-WB) e a avaliação de 121 pacientes com suspeita de EM foi realizada paralelamente à IEE. Os padrões de PAGE-WB relacionados com a EM foram o aumento na concentração de monômeros Kappa ou dímeros Lambda em líquido cefalorraquidiano (LCR) em comparação com o soro. Este método teve uma associação de significância muito alta com o IEE (p<0,0001) com sensibilidade de 95%, especificidade de 90%, VPP 83% e VPN 97%. A síntese intratecal de CLL foi evidenciada pelo aumento de intensidade do monômero Kappa e/ou dímero Lambda observado em LCR. A técnica PAGE-WB para CLL mostrou-se um método alternativo para detectar a síntese intratecal em pacientes com suspeita de EM.

Chemotherapy-induced autoimmune-mediated encephalitis during germinoma treatment.

BACKGROUND: Autoimmune mediated encephalitis (AME), which includes autoantibody-associated encephalitis and acute disseminated encephalomyelitis, is a common cause of encephalitis as well as infectious encephalitis in children. AME may be triggered by autoimmune responses to paraneoplastic syndromes and infections. Infectious encephalitis associated with an immunocompromised status caused by anti-cancer chemotherapy is well recognized; however, there have been few reports on the relationship between AME and chemotherapy. CASE REPORT: A ten-year-old previously healthy, developmentally normal girl was diagnosed with a pure germinoma in the suprasellar region. Following 30 days of induction chemotherapy, she developed a depressed level of consciousness with accompanying right hemiplegia, aphasia, and unexplained fever. Cerebrospinal fluid (CSF) analysis revealed positive oligoclonal bands and elevated neopterin levels. Neither atypical cells suggesting tumor exacerbation nor pathogens known to cause encephalitis were identified in the CSF. She was administrated immunosuppressive therapy and her symptoms rapidly improved. No known autoantibodies associated with autoantibody-associated encephalitis were identified in blood or CSF. However, the presence of oligoclonal bands and elevated neopterin levels in the CSF, and the favorable response to immunosuppressive therapy were consistent with an AME diagnosis. Thirteen days after the third course of chemotherapy, the patient developed a depressed level of consciousness again. Due to the recurrence of encephalitis, re-administration of immunosuppressive therapy was performed, which led to improvement in her symptoms. Recurrence of encephalitis has not occurred for 1 year after completion of chemotherapy. CONCLUSION: The chemotherapy-induced abnormal immune response might have triggered the AME.

Tumefactive Demyelination Appearing as Multiple Cystic Brain Lesions.

Tumefactive demyelinating lesions (TDLs) are a rare sequelae of idiopathic inflammatory demyelinating diseases of the central nervous system. Their propensity to mimic tumor and abscess poses a diagnostic challenge for the clinician. Our case depicts TDLs causing right-hand focal sensory seizures in an otherwise healthy 35-year-old female. The differential diagnosis of metastatic disease and infection were excluded on histology. Ensuing magnetic resonance imaging of the cord, in addition to cerebral spinal fluid analysis, supported the diagnosis of idiopathic inflammatory demyelinating diseases. This case highlights the need to consider the rare diagnosis of TDL when imaging shows cystic brain lesions in an otherwise healthy young adult.

Clinical characteristics and elevated ProGRP and positive oligoclonal bands of 13 Chinese cases with anti-GABABR encephalitis.

OBJECTIVE: To improve the clinical understanding of anti-gamma-aminobutyric-acid B receptor encephalitis (anti-GABABR encephalitis) by analyzing 13 cases. METHODS: We retrospectively studied demographic and clinical features including clinical symptoms, serum/cerebrospinal fluid (CSF) laboratory findings (including antibody test), brain magnetic resonance imaging (MRI), electroencephalogram (EEG), treatment plan, and treatment effect for 13 patients with a definitive diagnosis of anti-GABABR encephalitis. RESULTS: Seven patients (53.8%, 7/13) were complicated with lung cancer. Epileptic seizures were the most common symptoms at onset in 11 patients (84.6%, 11/13). All patients had seizures in the course of the disease. Abnormalities in craniocerebral MRI examination, including hippocampus, occipital lobe, insular lobe, were found in six of nine tested patients, and EEG abnormalities were found in seven out of nine tested patients. Elevated pro-gastrin releasing peptide (ProGRP) levels were found in 70% of patients with a median value of 490.10 pg/ml; and CSF oligoclonal bands were positive for 4 of 10 tested cases. However, there were no significant differences in modified Rankin Scale (mRS) between the ProGRP or CSF oligoclonal band positive and negative groups at admission and follow-up (p > .05). The value between SCLC and non-SCLC subgroup was significantly different (p < .05). Ten patients received immunotherapy (three patients refused treatment). After immunotherapy, the frequency of seizures was significantly reduced. There was a significant difference in mRS between admission and after treatment (p < .05). The average survival time after onset was 27.7 months. CONCLUSIONS: Epilepsy is the most common clinical manifestation of Anti-GABABR encephalitis. The prognosis of anti-GABABR encephalitis is poor. Section of anti-GABABR encephalitis patients have higher level of serum ProGRP and positive GSF oligoclonal bands. Elevated ProGRP or positive CSF oligoclonal bands with classic clinical features can potentially help to improve early recognition of anti-GABABR encephalitis.

Multiple myeloma with Echinococcus granulosus infection diagnosed by detection of oligoclonal bands: A case report.

RATIONALE: Isoelectric focusing electrophoresis (IFE) is currently recognized as the gold standard for detecting oligoclonal bands (OCBs) in cerebrospinal fluid (CSF). To the best of our knowledge, however, no study has reported on type III OCBs using IFE. In this paper, we report on a rare case of multiple myeloma (MM) with Echinococcus granulosus infection diagnosed by IFE. PATIENT CONCERNS: A 71-year-old man complained of weakness of the right lower extremity accompanied with fever (temperature range 37.8°C-38.2°C) for more than 6 months. DIAGNOSES: MM with E granulosus infection. INTERVENTIONS: The IFE results identified a unique monoclonal band, indicating that the patient may have MM in conjunction with a distinct pathogen infection. He received anthelmintic treatment and bortezomib-thalidomide-dexamethasone therapy. OUTCOMES: The patient was followed up for 15 months. During that time, his temperature returned to normal, his Medical Research Council Grading of Muscle Power scale became 5, and his vital signs stabilized. LESSONS: Detection of OCB type III indicated that the patient was diagnosed with MM accompanied by E granulosus infection. Thus, IFE of CSF may be an auxiliary diagnostic method for MM in the future.

Absence of B Cells in Brainstem and White Matter Lesions Associates With Less Severe Disease and Absence of Oligoclonal Bands in MS.

OBJECTIVE: To determine whether B-cell presence in brainstem and white matter (WM) lesions is associated with poorer pathological and clinical characteristics in advanced MS autopsy cases. METHODS: Autopsy tissue of 140 MS and 24 control cases and biopsy tissue of 24 patients with MS were examined for CD20+ B cells and CD138+ plasma cells. The presence of these cells was compared with pathological and clinical characteristics. In corresponding CSF and plasma, immunoglobulin (Ig) G ratio and oligoclonal band (OCB) patterns were determined. In a clinical cohort of 73 patients, the presence of OCBs was determined during follow-up and compared to status at diagnosis. RESULTS: In 34% of active and 71% of mixed active/inactive lesions, B cells were absent, which correlated with less pronounced meningeal B-cell infiltration (p < 0.0001). The absence of B cells and plasma cells in brainstem and WM lesions was associated with a longer disease duration (p = 0.001), less frequent secondary progressive MS compared with relapsing and primary progressive MS (p < 0.0001 and p = 0.046, respectively), a lower proportion of mixed active/inactive lesions (p = 0.01), and less often perivascular T-cell clustering (p < 0.0001). Moreover, a lower CSF IgG ratio (p = 0.006) and more frequent absence of OCBs (p < 0.0001) were noted. In a clinical cohort, numbers of patients without OCBs in CSF were increased at follow-up (27.4%). CONCLUSIONS: The absence of B cells is associated with a favorable clinical and pathological profile. This finding may reflect extremes of a continuum of genetic or environmental constitution, but also a regression of WM humoral immunopathology in the natural course of advanced MS.

Antibodies from Multiple Sclerosis Brain Identified Epstein-Barr Virus Nuclear Antigen 1 & 2 Epitopes which Are Recognized by Oligoclonal Bands.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS), the etiology of which is poorly understood. The most common laboratory abnormality associated with MS is increased intrathecal immunoglobulin G (IgG) synthesis and the presence of oligoclonal bands (OCBs) in the brain and cerebrospinal fluid (CSF). However, the major antigenic targets of these antibody responses are unknown. The risk of MS is increased after infectious mononucleosis (IM) due to EBV infection, and MS patients have higher serum titers of anti-EBV antibodies than control populations. Our goal was to identify disease-relevant epitopes of IgG antibodies in MS; to do so, we screened phage-displayed random peptide libraries (12-mer) with total IgG antibodies purified from the brain of a patient with acute MS. We identified and characterized the phage peptides for binding specificity to intrathecal IgG from patients with MS and from controls by ELISA, phage-mediated Immuno-PCR, and isoelectric focusing. We identified two phage peptides that share sequence homologies with EBV nuclear antigens 1 and 2 (EBNA1 and EBNA2), respectively. The specificity of the EBV epitopes found by panning with MS brain IgG was confirmed by ELISA and competitive inhibition assays. Using a highly sensitive phage-mediated immuno-PCR assay, we determined specific bindings of the two EBV epitopes to IgG from CSF from 46 MS and 5 inflammatory control (IC) patients. MS CSF IgG have significantly higher bindings to EBNA1 epitope than to EBNA2 epitope, whereas EBNA1 and EBNA2 did not significantly differ in binding to IC CSF IgG. Further, the EBNA1 epitope was recognized by OCBs from multiple MS CSF as shown in blotting assays with samples separated by isoelectric focusing. The EBNA1 epitope is reactive to MS intrathecal antibodies corresponding to oligoclonal bands. This reinforces the potential role of EBV in the etiology of MS. Graphical abstract Antibodies purified from an MS brain plaque were panned by phage display peptide libraries to discern potential antigens. Phage displaying peptide sequences resembling Epstein-Barr Virus Nuclear Antigens 1 & 2 (EBNA1 & 2) epitopes were identified. Antibodies from sera and CSF from other MS patients also reacted to those epitopes.