Research of the Dept. of Neurology in neuromuscular and neuroinflammatory disorders is focused

a. on Guillain-Barré syndrome (GBS) an immune-mediated disorder of the peripheral nervous system; and b. on MS, an inflammatory disorder of the central nervous system (CNS). Both disorders are considered to be diseases in which infections, genetic background and - at least in GBS - molecular mimicry plays an important role.

Our research is typically translational in which large patient cohorts have been established and are followed for a long period of time. In GBS, these cohorts are mainly derived form the RCT’s that we have executed over the years. In MS, we have established the ErasMS center. This forms the basis of our immunologic and genetic studies that are done on close collaboration with several groups from ErasmusMC, especially from the Departments of Immunology, Genetic-epidemiology, Microbiology and Virology and with leading groups around the world.

GBS

GBS is a post-infectious immune-mediated polyneuropathy leading to a severe paresis within days to weeks. Recovery generally takes a long time and is often far from complete. Our patient cohorts are primarily based upon several randomized controlled clinical trials that we have conducted over the years. Our trials have been pivotal in showing that IVIg is effective for GBS, and for its chronic variety CIDP. IVIg currently is (world-wide) the first treatment choice for GBS. Using the data of the different studies, we have been able to establish one of the world’s largest bio-bank (serum DNA, skin biopsies and PBMC) with detailed long-term clinical information. Extensive studies on clinical associations with anti-ganglioside antibodies and DNA variants (SNP) have been performed, mainly in close collaboration with the Department of Immunology (Prof dr J. Laman). Using our clinical databank, we successfully started studies on prognostic modeling (Prof dr. E.W. Steyerberg)  

MS

MS (multiple sclerosis) is an inflammatory disorder of the central nervous system (CNS) leading to neurodegeneration. It is the number one cause of neurological disability amongst young adults, who carry this ailment with them throughout their further life. MS can also have its onset during childhood, in approx. 3-5% of the cases. The cause of MS lies in a complex and poorly understood interplay of genetic and environmental factors (sunlight exposure, dietary conditions and infections). Next to the practical burden of neurological dysfunction, there is also the problem of uncertainty. Special uncertainty is felt after a first attack of what is suspected to evolve into MS at a later stage. There is an urgent need for better insight in the prognosis of an individual patient, in initiation of the proper therapy and, related to this, in the cause of MS. Our research focuses on the identification of biological factors that determine cause and course of the disease. The translational programme will also facilitate the identification of novel biomarkers.

Goals

One of the leading premises of ErasMS and GBS research is that excellent translational research can only be achieved in a centre with highly committed care facilities, and vice versa that patient care strongly benefits from a critical, academic research environment. Hence, our overall goal is to implement a high level translational approach on biological determinants of these diseases to further dissect cause and course. More specifically, we aim to directly link the top expertise of local departments (Neurology, Immunology, Genetics, Microbiology, Virology, Biomics facilities) to patient-oriented problems. Importantly, we desire to have an infrastructure for flexible research, directly applicable in case of novel insights into the field.

Our overall aims within the frame of GBS and MS are:

GBS

1. To determine why some persons get GBS, by studying:
   The immune-response to peripheral nerves triggered by preceding infections (host-pathogen interactions): focus on cross-reactive antibodies to nerve ganglioside (complexes); the role of dendritic cells and T- and B-cells in the initial phase of GBS; and on genetic host factors that contribute to occurrence of GBS (SNP studies).
2. To dissect factors that determine the prognosis of GBS (including pain and fatigue, and the transition to the chronic variety CIDP), by using:
   Clinical, serological, DNA, electrophysiological and skin biopsy data in advanced prognostic models.
   To establish and conduct a world-wide web-based study (supported by the Inflammatory Neuropathy Consortium/INC).
3. To find a better treatment for GBS patients with a poor prognosis, by starting:
   New therapeutic RCTs in selected patients with a poor prognosis, based upon prognostic modeling.
   A study we will start soon is a second dose IVIg study.
4. To determine the best way of studying outcome, by comparing outcome measurements (Perinoms study) and using Rasch methodology.

MS

1. To determine why adults and children develop MS using data and biosamples from the Rotterdam adult MS cohorts and a nationwide pediatric cohort.
2. To identify factors that are associated with development of chronic MS, after a single event of inflammation in the brain or spinal cord using data and biosamples of the PROUD cohort (Predicting the Outcome of a Demyelinating event).
3. To identify biomarkers that help in the often complex differential diagnosis of central nervous system inflammation-see above.
4. To develop novel immunotherapies for MS and reduce the chance of severe side effects such as opportunistic (viral) infections and EBV related lymphoma- ranging from patient cohort studies via functional in vitro and genetic analyses of patient material to several animal disease models in rodents and non-human primates.  Part of the strategy is to minimize the use of animal models, and focus as much as possible on human material.

GBS

1. Assays to determine ganglioside-like LOS of Campylobacter jejuni to activate human dendritic cells and B-cells have been established. Assays of to determine anti-gangliosides and anti-MAG antibodies have been developed and validated.
2. Studies on the effect of functional SNPs related to occurrence and prognosis of GBS leaded to the identification of genetic modifiers of the clinical course in GBS. 
3. Advanced and accurate prognostic models to determine the risk to determine long-term outcome in individual GBS patients have been developed and validated.
4. Pharmacokinetic and -dynamic effect of IVIg in patients with GBS in relation to outcome has been defined.
5. International RCT on the additional effect of methylprednisolone when added to standard IVIg treatment in GBS was successfully finished.
6. RCT on the effect of various brands of IVIg in patients with CIDP (the chronic variety of GBS) has been finalized.

MS

1. Identification of novel MS risk genes
2. Proteomic identification of novel CSF biomarkers for autoimmune demyelination
3. National cohort of children with a first attack of CNS inflammatory disease
4. No evidence for active EBV infection in MS patients
5. Role of herpes viruses in autoimmune inflammation
6. RCT on VLA-4 blockade, effects of fumaric acid and fingolimod
7. Effect of bone marrow transplantation on MS disease course

GBS

1. Defining the mucosal immune response to Campylobacter resulting in the production of cross-reactive antibodies to peripheral nerves causing GBS.
2. Development and clinical validation of diagnostic assays for patients with immune mediated neuropathies.
3. Further development of prognostic modeling studies in GBS by using also data from web-based world-wide study on prognostic factors in GBS.
4. Establish world-wide largest GBS bio-bank enabling us to do genetic profiling studies.
5. Determining why some patients with GBS make transition to chronic disease (CIDP).
6. Start RCT studying the effect of second IVIg course in GBS patients with poor prognosis.
7. Start IVIg dose-finding study in CIDP.
8. Start clinical/immunological study on the effect of other immune-modulators in GBS.

MS

1. Study on gene-environment interactions in adult and pediatric MS (eg vitamin D and EBV).
2. Further identification of novel MS risk genes in adults, but also in children.
3. Viral and myelin specificity of infiltrating T-lymphocytes in MS lesions.
4. Vitamin D intervention study in MS.
5. Identification and validation of novel biomarkers in MS.
6. Factors that predict MS after a single attack of demyelination.
7. Identification of viruses that directly or indirectly trigger CNS inflammation.

1.      Van Koningsveld R, Schmitz PIM, van der Meché GFA, Visser LH, Meulstee J, van Doorn PA for the Dutch GBS Studygroup. Effect of methylprednisolone when added to standard treatment with intravenous immunoglobulin for Guillain-Barré syndrome. Lancet 2004;363:192-96.

2.      Van Doorn PA, Ruts L, Jacobs BC.  Clinical features, pathogenesis, and treatment of Guillain-Barré syndrome.  Lancet Neurology 2008;7:939-50.

3.      Van Koningsveld R, Steyerberg EW, Hughes RA, Swan AV, van Doorn PA, Jacobs BC. A clinical prognostic scoring system for Guillain-Barré syndrome. Lancet Neurol 2007;6:589-94.

4.      Halstead SK, Zitman FM, Humphreys PD, Greenshields K, Verschuuren JJ, Jacobs BC, Rother RP, Plomp JJ, Willison HJ.  Eculizumab prevents anti-ganglioside antibody-mediated neuropathy in a murine model.  Brain 2008;131:1197-1208

5.      Geleijns K, Roos A, Houwing-Duistermaat JJ, Van Rijs W, Tio-Gillen AP, Laman JD, van Doorn PA, Jacobs BC. Mannose-binding lection contributes to the severity of Guillain-Barré syndrome. J Immunol 2006;177:4211-7.

6.      Y Aulchenko , I Hoppenbrouwers, S Ramagopalan, L Broer, N Jafari , J Hillert , J Link , W Lundström , E Greiner , A Sadovnick , D Goossens , C van Broeckhoven , J Del-Favero, GC Ebers, B Oostra,  C van Duijn, RQ Hintzen. Genetic variation in the KIF1B locus influences susceptibility to multiple sclerosis. Nat Genet. 2008 Dec;40(12):1402-3.

7.      GM Verjans, RQ Hintzen, JM van Dun, A Poot, JC Milikan, JD Laman, AW Langerak, PR Kinchington, AD Osterhaus. Selective retention of herpes simplex virus-specific T cells in latently infected human trigeminal ganglia. Proc Natl Acad Sci U S A.2007;104:3496-501

8.      RF Neuteboom, M Boon, CE Catsman Berrevoets, JS Vles, RH Gooskens, H Stroink, RJ Vermeulen, JJ Rotteveel, IA Ketelslegers, E Peeters, BT Poll-The, JF De Rijk-Van Andel, A Verrips, RQ Hintzen. Prognostic factors after a first attack of inflammatory CNS demyelination in children. Neurology 2008:71:967-73

9.      T Vandercamme, RQ Hintzen, JH de Boer, A van der Lely. Herpetic Encephalitis is a risk factor for Acute Retinal Necrosis. Neurology 2008;71:1268-1274

10.  MP Stoop, LJ Dekker, MK Titulaer, PC Burgers, PA Sillevis Smitt, TM Luider, RQ Hintzen. Multiple sclerosis-related proteins identified in cerebrospinal fluid by advanced mass spectrometry. Proteomics. 2008;8:1576-85