Neuroimmunology Registry and Biobank

Официальное название

Registry for Patients With Antibody-mediated Neuroimmunological Diseases

Обзор

A variety of antineuronal antibodies have been detected in the cerebrospinal fluid (CSF) of patients with neurological diseases. This raises the question of whether these antibodies are disease-specific or merely an epiphenomenon of inflammatory processes in the brain. The registry was established with the following objectives: \[1\] Are antineuronal antibodies much more common than previously thought in various neurological disorders for which the etiology has not yet been elucidated? \[2\] Can further correlations, such as those between HSV infection and NMDA receptor autoimmunity, be identified? \[3\] Are these antibodies mainly non-specific epiphenomena or are they crucial for the pathogenesis? \[4\] What is the clinical course of patients with antineuronal antibodies and their response to therapy? These questions will be addressed in a broad immunohistological screening of a large number of CSF samples and a clinical database of patients with neurological disorders.

Подробное описание

The hypothesis that autoimmunity is a driving force behind many neurological diseases has become an established view in adult and pediatric neurology. This is particularly true for diseases of the central nervous system that are mediated by or at least associated with autoantibodies against neuronal surface antigens, the group of "autoimmune encephalitis".

This group of diseases has become increasingly important in adult neurology over the past 15 years and is now gaining importance in pediatric neurology. Since the first description of a fulminant encephalitis with autoantibodies against the N-methyl-D-aspartate (NMDA) receptor in 2007, researchers and physicians are beginning to understand that many patients worldwide with encephalopathy or epileptic and psychiatric symptoms may be suffering from previously unrecognized but treatable autoimmune diseases. As a result, the new field of "autoimmune encephalitis" has been established and new diagnostic tools are being developed. Despite a rapidly growing list of disease entities - now ranging from relatively common diagnoses such as anti-NMDA receptor, anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, or anti-leucine-rich glioma-inactivated 1 (LGI1) receptor encephalitis to rare entities caused by antibodies against the metabotropic glutamate receptor 5 (mGuR5) - the field of autoimmune encephalitis is still in its infancy. The field of autoimmune encephalitis continues to evolve.

A better understanding of autoimmune encephalitis could improve the chances of treatment and even cure for many patients with previously unexplained diagnoses. This is especially true for antibody-negative autoimmune encephalitis and rare syndromes with only suspected autoantibody associations, such as corea minor and other autoimmune movement disorders, as well as ataxias, opsoclonus-myoclonus syndrome, antibody-associated motor neuronopathies, and juvenile amyotrophic lateral sclerosis (ALS). The goal of this registry is to gain new insights into the etiology of autoimmune encephalitis and non-encephalitic overlap syndromes and to investigate the role of neuronal autoantibodies in these and other neurological diseases.

The investigators will enroll patients with suspected neurologic autoimmune diseases into the database. The database will record their medical history, cardinal symptoms of the current disease, diagnostic results with emphasis on CSF analysis and imaging, as well as final diagnosis, therapy, and disease course. Residual CSF samples from lumbar punctures performed as part of the routine diagnostic workup are collected, cataloged, and stored in a CSF biobank.

The following methods are used to detect and characterize anti-neuronal antibodies: \[1\] highly sensitive immunofluorescence staining of fresh mouse brain (tissue-based assay, TBA), \[2\] immunoprecipitation from mouse brain homogenates and analysis of bound proteins by mass spectrometry, \[3\] flow cytometric methods (FACS, fluorescence-activated cell sorting and cell sorting), isolation and cloning of specific monoclonal autoantibodies from B-cells and plasma cells, and functional characterization studies.

Первичные конечные точки

• Screening for a panel of anti-neuronal antibodies via commercial assays [Срок оценки: at recruitment]
• Screening for unknown anti-neuronal antibodies via immunofluorescence staining on fresh mouse brain (tissue-based assay, TBA) [Срок оценки: at recruitment]
• Determination of the molecular weight of the antibody target [Срок оценки: at recruitment]
• CSF cell count [Срок оценки: at recruitment]
• CSF protein [Срок оценки: at recruitment]
• CSF albumin [Срок оценки: at recruitment]
• CSF glucose [Срок оценки: at recruitment]
• CSF lactate [Срок оценки: at recruitment]
• CSF IgG [Срок оценки: at recruitment]
• CSF oligoclonal bands [Срок оценки: at recruitment]

Вторичные конечные точки (6)

• Basic clinical data [Срок оценки: at recruitment, month 1, month 3, month 6, month 12, year 2, year 3, year 4, year 5]
• Duration from symptom onset to diagnosis [Срок оценки: at recruitment]
• Assessment of the severity of ataxia [Срок оценки: at recruitment, month 1, month 3, month 6, month 12, year 2, year 3, year 4, year 5]
• Assessment for the severity of psychiatric symptoms [Срок оценки: at recruitment, month 1, month 3, month 6, month 12, year 2, year 3, year 4, year 5]
• Assessment of the severity of motor symptoms [Срок оценки: at recruitment, month 1, month 3, month 6, month 12, year 2, year 3, year 4, year 5]
• Start and end and kind of immunotherapy [Срок оценки: Follow-up of 5 years]

Критерии участия

Критерии включения

• Differential diagnosis: suspected neuroimmunological disease in which a lumbar puncture is indicated for further diagnosis and treatment decision
• Individuals with unclear clinical diagnosis where additional CSF is to be collected for isolation of B cells and production of monoclonal antibodies. The clinical condition of the patients and his/her compliance have to allow an extra 2-3 ml of CSF to be collected.
• Age: all age groups
• Gender: patients of both sexes will be included

Критерии исключения

\[1\] Withdrawal of consent

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

Германия · 2 центра

• Charité - Universitätsmedizin Berlin — Berlin
• Universität Ulm — Ulm

Публикации

• Kreye J, Wright SK, van Casteren A, Stoffler L, Machule ML, Reincke SM, Nikolaus M, van Hoof S, Sanchez-Sendin E, Homeyer MA, Cordero Gomez C, Kornau HC, Schmitz D, Kaindl AM, Boehm-Sturm P, Mueller S, Wilson MA, Upadhya MA, Dhangar DR, Greenhill S, Woodhall G, Turko P, Vida I, Garner CC, Wickel J, Geis C, Fukata Y, Fukata M, Pruss H. Encephalitis patient-derived monoclonal GABAA receptor antibodi PMID 34546336
• Nikolaus M, Kuhne F, Tietze A, Thumfart J, Kempf C, Gratopp A, Knierim E, Bittigau P, Kaindl AM. Modified Zipper Method, a Promising Treatment Option in Severe Pediatric Immune-Mediated Neurologic Disorders. J Child Neurol. 2022 May;37(6):505-516. doi: 10.1177/08830738221089476. Epub 2022 Apr 18. PMID 35435761
• Wilpert NM, de Almeida Marcelino AL, Knierim E, Incoronato P, Sanchez-Sendin E, Staudacher O, Drenckhahn A, Bittigau P, Kreye J, Pruss H, Schuelke M, Kuhn AA, Kaindl AM, Nikolaus M. Pediatric de novo movement disorders and ataxia in the context of SARS-CoV-2. J Neurol. 2023 Oct;270(10):4593-4607. doi: 10.1007/s00415-023-11853-5. Epub 2023 Jul 29. PMID 37515734
• Cramer P, Nikolaus M, Loos S, Denecke J, Knierim E, Muller D, Weber LT, Taylan C, Thumfart J. Immunoadsorption is equally effective as plasma exchange in paediatric neuroimmunological disorders - A retrospective multicentre study. Eur J Paediatr Neurol. 2025 Jan;54:58-63. doi: 10.1016/j.ejpn.2024.12.005. Epub 2024 Dec 21. PMID 39752845
• Kauth F, Bertolini A, Wendel EM, Koukou G, Naggar IE, Chung J, Baumann M, Schodl C, Lechner C, Bigi S, Blaschek A, Hengstler JG, Schimmel M, Nosadini M, Sartori S, Puthenparampil M, Van's Gravesande KS, Drenckhahn A, Nikolaus M, Kauffmann B, Thiels C, Hausler MG, Eckenweiler M, Karenfort M, Marina AD, Selek A, Oncel I, Kornek B, Reindl M, Rostasy K. Characterization of children with early onset pe PMID 39879856
• Nikolaus M, Koch A, Stenzel W, Elezkurtaj S, Sahm F, Tietze A, Stoffler L, Kreye J, Hernaiz Driever P, Thomale UW, Kaindl AM, Schuelke M, Knierim E. Atypical NMDA receptor expression in a diffuse astrocytoma, MYB- or MYBL1-altered as a trigger for autoimmune encephalitis. Acta Neuropathol. 2022 Aug;144(2):385-389. doi: 10.1007/s00401-022-02447-y. Epub 2022 Jun 21. No abstract available. PMID 35727368
• Schnell S, Knierim E, Bittigau P, Kreye J, Hauptmann K, Hundsdoerfer P, Morales-Gonzalez S, Schuelke M, Nikolaus M. Hodgkin Lymphoma Cell Lines and Tissues Express mGluR5: A Potential Link to Ophelia Syndrome and Paraneoplastic Neurological Disease. Cells. 2023 Feb 13;12(4):606. doi: 10.3390/cells12040606. PMID 36831273
• Viezens I, Knierim E, Deubzer HE, Hauptmann K, Fassbender J, Morales-Gonzalez S, Kaindl AM, Schuelke M, Nikolaus M. Expression of mGluR5 in Pediatric Hodgkin and Non-Hodgkin lymphoma-A Comparative Analysis of Immunohistochemical and Clinical Findings Regarding the Association between Tumor and Paraneoplastic Neurological Disease. Cancers (Basel). 2024 Jul 4;16(13):2452. doi: 10.3390/cancers1613245 PMID 39001514

Идентификаторы

NCT: NCT06958341 · EA2_121_17

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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