Academic Center for Neuro-inflammation

The primary aim of the Academic Center for Neuro-inflammation (AC Neuro-inflammation) is to raise the first expertise center in The Netherlands for the diagnostics, clinical care, education and research of neuro-inflammatory diseases and improve the perspectives for patients with these diseases. All expertise was already available at Erasmus MC previously, but in the AC Neuro-inflammation we joined forces to collaborate and together cover and further explore the full spectrum of neuro-inflammatory diseases.

The AC Neuro-inflammation has the following key characteristics:

  • Erasmus MC already is a nationally and internationally acknowledged expertise center for specific neuro-inflammatory diseases for at least 10-20 years, especially regarding auto-immune encephalitis, paraneoplastic syndromes, Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP).
  • Immunodiagnostics for neuro-inflammatory diseases is a rapidly evolving area and the objective of the center is to remain the leading national reference center for neuro-immunological diagnostic tests. At present Erasmus MC is already providing the widest range of diagnostic tests within the Netherlands and has the ISO 15189:2012 international accreditation. The aim is to add new tests to the diagnostic panel, to validate and optimize the current diagnostic tests and to fully integrate these tests in clinical care.
  • The center will focus especially on improving clinical care for rare and complex forms of neuro-inflammatory diseases requiring advanced (and often expensive) diagnostics and treatment. Most of the complex care for these patients needs to be developed or improved, explaining the importance to have the patient care in the same center as the translational and applied research of these disorders. There is a special need to improve the care for children with neuro-inflammatory diseases and for patients with unknown or recently discovered or variant forms of neuro-inflammatory diseases.
Academic Center of Excellence

Research Activities

The AC Neuro-inflammation has the following aims in research:

  • All activities are focused on patient-oriented clinical, translational and immunological research.
  • Research is multidisciplinary and based on the combined expertise at the neurology and immunology departments, but there is additional collaboration with the microbiology and virology departments for post-infectious disorders and with the department of Public Health.
  • A common goal in all research projects of the center is to elucidate the pathogenesis and identify immune mechanisms that determine the clinical course of neuro-inflammatory diseases.
  • We aim to initiate, coordinate and participate in national and international observational cohort studies and therapeutic phase II-III studies in patients with neuro-inflammatory diseases. The data/biobanks obtained in these national and international studies are of great value for translational research.
  • The leading principal investigators are workgroup leaders of the Molecular Medicine subthemes 'Immune regulation and autoimmunity' (EMC MM-02-72-02), 'Neuromuscular and Neuroinflammatory Disorders' (EMC MM-04-44-02) or 'Neuro-oncology and Pain (EMC MM-03-44-06).

Specific ongoing collaborative research projects conducted in the AC Neuro-inflammation are:

  • SOMA scan study on prognostic factors in auto-immune encephalitis (Schreurs/Titulaer)
  • Preceding infections and treatment development for GBS in Bangladesh (Endtz/Jacobs)
  • Antibody to (para)nodal targets in patients with neuropathy (Huizinga/Titulaer/Jacobs)
  • Neuro-inflammatory complications of biologicals (Jacobs/Titulaer/van Doorn/Sillevis Smitt/Verdijk)
  • Glyco-array screening of antibodies in patients with neuropathy (Huizinga/Jacobs/Schreurs)
  • Validation of diagnostic value anti-GD1b antibodies (Schreurs/Jacobs/Huzinga) (publication JPNS in press)
  • Validation of anti-GAD65 antibody test (Schreurs/Titulaer)
  • Validation of anti-GQ1b antibody test (Schreurs/Jacobs)
  • Anti-GABA-R encephalitis and anti-KCTD16 antibodies (Schreurs/Titulaer) (patent applied)

Type of

Collaborations

A specific aim of the center is to initiate, coordinate and participate in national and international observational cohort studies and therapeutic phase II-III studies in patients with neuro-inflammatory diseases. The data/biobanks obtained in these national and international studies are of great value for translational research. Examples of such extensive collaborations are the International GBS Outcome Study (IGOS), an observational cohort study conducted in >150 hospitals from 20 countries (and 5 continents) coordinated by Erasmus MC.

The AC Neuro-inflammation has initated collaborations with other ACEs involving the departments of Virology, Neuro-oncology, Internal Oncology, Pulmonary diseases, Neuroscience and Proteomics.

Educational

Contributions

The contribution of the AC Neuro-inflammation to the educational programs of Erasmus MC are for the bachelor Medicine, Clinical technology and Erasmus University College, (research) master Medicine, Infection & Immunity, Molecular Medicine, Clinical technology and organize a minor in pediatric neurology, PhD education in Molecular Medicine graduate school, both at the teaching and at the management level (Board, committees), resident (AIOS) level (medical specialization) coordinate and manage the yearly national teaching course about infections and immunity for residents in neurology.

In addition we are involved in the coordination of the yearly, Boerhaave courses in (inflammatory) neuromuscular diseases and regularly in the yearly, Biemond courses (Dutch Society of Neurology [NVN]) about neuro-inflammatory diseases for residents and specialists in neurology.

All neurology residents participate in the care of patients with neuro-inflammatory disorders (both outpatients and inpatients). A national 2-day course on neuro-inflammatory disorders is organized yearly for all Dutch 3rd year Neurology residents (compulsory) by the ACE. The evaluation of this course by the residents ranges from very good to excellent. The results of the DRECT involve the entire Neurology residency program (overall score 3.15 – 4.12).

The SET-Q shows high scores for all ACE members. The recent visitation (March 31st) of the residency program concluded that the program was 'excellent' (oral judgment of visitation committee; no formal RGS conclusions yet). The ACE is an important part of 2 MolMed programs and participated in the recent MolMed SEP evaluation (result: excellent).

We are organizeing a national 1-day-symposium in Rotterdam on inflammatory neuropathies for May 17th, 2019.

Patient

Care Activities

Academic nature of the provided patient care: Our ACE is the national referral center for neuro-inflammation, and ROBIJN analysis for 2014 showed that 1272/1535 (83%) of patients are labeled as academic (see 14 for measured diagnoses). We are the one national (NFU designated) center for Guillain-Barre Syndrome (GBS), and for Autoimmune Encephalitis (AIE, including Paraneoplastic Neurological Syndromes [PNS]).

The Erasmus MC is 'expertise centrum', according to the TRF portal for GBS, CIDP, central nervous system inflammations (including AIE), neurological complications of cancer (PNS), both for adults and children. The ACE has applied to become part of the European Reference Network (ERN, sections Immunology and Neuromuscular Diseases). The ACE is the national reference clinic and laboratory for these diseases, including antibody diagnosis, verification and the discovery of novel (specific) antibodies. We have specialized care paths for GBS, CIDP, and AIE (including PNS).

Depending on the disease entity, we have a weekly or biweekly multidisciplinary meeting to discuss difficult cases. We participate actively in the international guidelines for GBS (chair), AIE, and PNS tumor screening. We chaired the National Guidelines on 'Polyneuropathy' and 'GBS". We are the primary responsible physicians for the local ErasmusMC guidelines, extensively used throughout the country. Feedback from (quality)reports: Recent audit of quality (March 31st, kwaliteitsvisitatie) by the Nederlandse Vereniging voor Neurologie concluded us to be innovative, active and well-organized. Contribution to innovation: The research groups that will be united in the ACE Neuro-inflammation have all been highly innovative previously. Examples are the discovery of novel preceding infections and antibodies causing GBS, the prognostic models to predict in individual patients the chance of respiratory failure (EGRIS) and outcome (mEGOS).

Other examples are the identification of novel autoantibodies in patients with neuro-inflammatory diseases including: DNER, mGluR1, PRG5, glycolipid(complexes). Our ACE has a patent on the detection of novel autoantibody (DNER) licensed to EUROIMMUN (diagnostic test commercially available). In addition, we have provided a first proof of concept that central nervous system disorders can be caused by pathogenic autoantibodies. Contribution to (academic) care: Erasmus MC has a reputation for diagnosing and treating neuro-inflammatory disorders and we are consulted on a daily basis by many centers from all over the Netherlands and abroad. For example, we have a 'GBS telephone' that can be called by all neurologists in the Netherlands (24/7) for questions about GBS, CIDP and its mimics. In addition, we coordinate and participate in many clinical trials in neuro-inflammatory disorders. We are the reference laboratory for the Netherlands and are also consulted from abroad regarding immunodiagnostics for neuro-inflammatory disorders. The Laboratory Medical immunology for antibody diagnostics is ISO 15189 certified.

Societal Relevance to Research, Education and Patient Care

We are the only expertise center for Neuro-inflammation in the Netherlands that covers both inflammatory disorders of the central and peripheral nervous system. Patients and diagnostic samples are referred to our center from all over the Netherlands. Neuro-immunological disorders in general are rare, complex and severe, yet often treatable when diagnosed and treated accurately. Treatment however is also complex and expensive and requires expertise available in our center. We have developed and chaired the national (CBO) guidelines for "Polyneuropathy", and GBS.

We were involved in international guidelines for GBS, CIDP (PNS/EFNS), other immune-mediated neuropathies, AIE, and tumor screening for paraneoplastic neurological syndromes (EFNS). We have obtained a patent for DNER, and have a patent pending for a novel antibody. We contribute to the curriculum of bachelor and master students as previously indicated, but we also manage and coordinate the national Infection and Immunity course for residents in Neurology. We are actively involved in patient organizations (SN [Spierziekten Nederland] for GBS and CIDP, Encephalitis Society and AEA [Autoimmune Encephalitis Alliance] for AIE) and the GBS/CIDP Foundation International (scientific board members).

Viability of Research, Education and Patient Care

Knowledge sharing (between disciplines and across ages) within ACE to maintain the continuity: Within the ACE there is a healthy mix of experienced professors and clinicians/researchers in the early stages of their career as a principal investigator. Most PIs have experience abroad, and all have multiple international collaborations and publications (Universities of Glasgow, Barcelona, London, Philadelphia,, Paris, and with NIH, CDC and WHO).

Number of PhD students starting an international career: There is exchange of PhD students when useful to improve knowledge and collaborations. Two foreign PhD students (Bangladesh) are employed here for their PhD, one of them has finished this. The application of talent identification, monitoring and review within the ACE: PhD students and post-docs / junior consultants (mainly neurologists) all attend international conferences and publish in international peer-reviewed top-tier journals. Talents are encouraged to gain experience abroad, and are assisted in obtaining funding.

Preference is is given to personal funding, like Erasmus MC fellowships, NWO clinical fellowships and PBF neuromyology fellowships. In addition young investigators are guided in obtaining project funding. This is currently done on a personal basis, not formalized. Bibliometric network analysis (if available) to identify the participation of the ACE in the international top: The CWTS (mean normalized citation score MNCS) analysis for the period 2010 – 2013 indicated the following scores : 1.46 for 'Immune regulation and autoimmunity' (EMC MM-02-72-02), 1.36 for 'Neuromuscular and Neuroinflammatory Disorders' (EMC MM-04-44-02) and 1.94 for 'Neuro-oncology and Pain (EMC MM-03-44-06) (1.81 for Neurology in general).

Key and relevant publications of the last five years

  • Willison HJ, Jacobs BC, van Doorn PA. Guillain-Barré syndrome. Lancet 2016 (epub)
  • Titulaer MJ, McCracken L, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis. Lancet Neurol 2013
  • Fokke C, ... van Doorn PA, Jacobs BC. Diagnosis of GBS and validation of Brighton criteria. Brain 2014
  • Gresa-Arribas N*, Titulaer MJ*, et al. Antibody titres at diagnosis and follow-up of anti-NMDA receptor encephalitis. Lancet Neurology 2014
  • Dalton HR, …. Jacobs BC. Hepatitis E virus and neurological injury. Nat Rev Neurol 2016
  • de Graaff E, Maat P, … Sillevis Smitt PA. Identification of DNER as the Tr antigen in paraneoplastic cerebellar degeneration. Ann Neurol. 2012
  • Graus F, Titulaer MJ, et al. A clinical approach to diagnosis of AIE. Lancet Neurology 2016
  • Van Sonderen A, Schreurs MW, ... Sillevis Smitt PA, Titulaer MJ. The relevance of VGKC positivity in the absence of LGI1 and Caspr2 antibodies. Neurology 2016
  • Van Sonderen A,* Ariño H,* Petit-Pedrol M, … Schreurs MW ... Sillevis Smitt PA, Titulaer MJ. The clinical spectrum of Caspr2-antibody associated disease. Neurology 2016 in press
  • Huizinga R, … van Doorn PA … Jacobs BC. Innate Immunity to Campylobacter jejuni in Guillain-Barré Syndrome. Ann Neurol. 2015

PhD theses of the last five years

  • Dr. Z. Islam: ‘Campylobacter infection and Guillain-Barré syndrome in Bangladesh’ (2010)
  • Dr. L. Ruts: ‘Pain, autonomic dysfunction, and course of disease in GBS’ (2010)
  • S.van Nes: ‘Improving and standardising assessment of patients with immune-mediated neuropathies. PeriNomS Study part 1’(2012)
  • E.K Vanhoutte. ‘Peripheral Neuropathy outcome measures Standardisation (PeriNomS) study part 2’ (2015)
  • Dr. D. de Costa: “Serum antibodies in lung cancer; a proteomics approach in the NELSON trial” (2013)
  • Dr. S. Shams’ili: “Paraneoplastic Neurological Syndromes – Clinical and serological studies” (2011)
  • Dr. M. de Graaf: “Cellular immunity in paraneoplastic neurological syndromes associated with anti-Hu antibodies” (2011)
  • Dr. A de Jongste: “Paraneoplastic neurological syndromes with anti-Hu antibodies; pathogenesis and treatment” (2015)
  • Dr. P. Maat: “Paraneoplastic antibodies: Molecular and clinical studies” (2016)
  • Prof.dr. PAE Sillevis Smitt holds a patent for the use of DNER as an autoantibody test (2013)
  • Prof.dr. B.C. Jacobs:"Regional variation of Guillain-Barré syndrome' (2018)

Non-scientific publications related to the ACE

  • Prof.dr. B.C. Jacobs in De Neuroloog (2018) over modernisering van het landelijke onderwijs over neuro-immunologie voor AIOS Neurologie.
  • Prof.dr. B.C. Jacobs in de NRC (2018) over de knikkebolziekte, als voorbeeld van een neuro-inflammatoire aandoening.
  • Prof.dr. B. C. Jacobs in de NRC (2016) over het Guillain-Barré syndroom, als voorbeeld van een neuro-inflammatoire aandoening
  • Prof.dr. B.C. Jacobs in Elseviers Weekblad (2017) over het Zika virus en de neuro-inflammatoire complicaties
  • Prof.dr. B.C. Jacobs en prof.dr. P.A. van Doorn (2017) in De Spierkrant van het Prinses Beatrix Spierfonds over inflammaoire neuropathie.
  • Prof.dr. B.C. Jacobs in De Spierkrant van het Prinses Beatrix Spierfonds over internationaal onderzoek en neuro-inflammatoire diagnostiek
  • Prof.dr. P.A. van Doorn: CBO Richtlijn Guillain-Barré syndroom (2011) en Polyneuropathie (2007)

Principal coordinator(s)

Collaborating investigator(s)

Last updated: 365 days ago.