Rogier Q. Hintzen

International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions.

Background: There has been tremendous growth in research in pediatric multiple sclerosis (MS) and immune mediated central nervous system demyelinating disorders since operational definitions for these conditions were first proposed in 2007. Further, the International Pediatric Multiple Sclerosis Study Group (IPMSSG), which proposed the criteria, has expanded substantially in membership and in its international scope. Objective: The purpose of this review is to revise the 2007 definitions in order to incorporate advances in delineating the clinical and neuroradiologic features of these disorders. Methods: Through a consensus process, in which input was sought from the 150 members of the Study Group, criteria were drafted, revised and finalized. Final approval was sought through a web survey. Results: Revised criteria are proposed for pediatric acute disseminated encephalomyelitis, pediatric clinically isolated syndrome, pediatric neuromyelitis optica and pediatric MS. These criteria were approved by 93% or more of the 56 Study Group members who responded to the final survey. Conclusions: These definitions are proposed for clinical and research purposes. Their utility will depend on the outcomes of their application in prospective research.

A consensus protocol for the standardization of cerebrospinal fluid collection and biobanking

There is a long history of research into body fluid biomarkers in neurodegenerative and neuroinflammatory diseases. However, only a few biomarkers in CSF are being used in clinical practice. One of the most critical factors in CSF biomarker research is the inadequate powering of studies because of the lack of sufficient samples that can be obtained in single-center studies. Therefore, collaboration between investigators is needed to establish large biobanks of well-defined samples. Standardized protocols for biobanking are a prerequisite to ensure that the statistical power gained by increasing the numbers of CSF samples is not compromised by preanalytical factors. Here, a consensus report on recommendations for CSF collection and biobanking is presented, formed by the BioMS-eu network for CSF biomarker research in multiple sclerosis. We focus on CSF collection procedures, preanalytical factors, and high-quality clinical and paraclinical information. The biobanking protocols are applicable for CSF biobanks for research targeting any neurologic disease.

EFNS guidelines on diagnosis and management of neuromyelitis optica

Background and purpose:  Neuromyelitis optica (NMO) or Devic′s disease is a rare inflammatory and demyelinating autoimmune disorder of the central nervous system (CNS) characterized by recurrent attacks of optic neuritis (ON) and longitudinally extensive transverse myelitis (LETM), which is distinct from multiple sclerosis (MS). The guidelines are designed to provide guidance for best clinical practice based on the current state of clinical and scientific knowledge.

Transfer of Central Nervous System Autoantigens and Presentation in Secondary Lymphoid Organs

Dendritic cells are thought to regulate tolerance induction vs immunization by transferring Ags and peripheral signals to draining lymph nodes (LN). However, whether myelin Ag transfer and presentation in LN occurs during demyelinating brain disease is unknown. In this study, we demonstrate redistribution of autoantigens from brain lesions to cervical LN in monkey experimental autoimmune encephalomyelitis (EAE) and in multiple sclerosis (MS). Immunohistochemical analysis revealed significantly more cells containing myelin Ags in cervical LN of monkeys with EAE compared with those of healthy control monkeys. Myelin Ags were observed in cells expressing dendritic cell/macrophage-specific markers, MHC class II, and costimulatory molecules. Moreover, these cells were directly juxtaposed to T cells, suggesting that cognate interactions between myelin-containing APC and T cells are taking place in brain-draining LN. Indeed, myelin Ag-reactive T cells were observed in cervical LN from marmosets and rhesus monkeys. Importantly, these findings were paralleled by our findings in human tissue. We observed significantly more myelin Ag-containing cells in LN of individuals with MS compared with those of control individuals. These cells expressed APC markers, as observed in marmosets and rhesus monkeys. These findings suggest that during MS and EAE, modulation of T cell reactivity against brain-derived Ags also takes place in cervical LN and not necessarily inside the brain. A major implication is that novel therapeutic strategies may be targeted to peripheral events, thereby circumventing the blood-brain barrier.

Impact of recently diagnosed multiple sclerosis on quality of life, anxiety, depression and distress of patients and partners

Objectives – Studies demonstrating reduced quality of life and psychological well‐being in multiple sclerosis (MS) have typically investigated patients within more advanced stages of disease. The aim of the present paper was to evaluate the emotional burden and quality of life of recently diagnosed MS patients and their partners.

Selective retention of herpes simplex virus-specific T cells in latently infected human trigeminal ganglia

Primary infection with herpes simplex virus 1 (HSV-1) and varicella zoster virus (VZV) results in lifelong latent infections of neurons in sensory ganglia such as the trigeminal ganglia (TG). It has been postulated that T cells retained in TG inhibit reactivation of latent virus. The acquisition of TG specimens of individuals within hours after death offered the unique opportunity to characterize the phenotype and specificity of TG-resident T cells in humans. High numbers of activated CD8+ T cells expressing a late effector memory phenotype were found to reside in latently infected TG. The T cell infiltrate was oligoclonal, and T cells selectively clustered around HSV-1 but not VZV latently infected neurons. Neuronal damage was not observed despite granzyme B expression by the neuron-interacting CD8+ T cells. The TG-resident T cells, mainly CD8+ T cells, were directed against HSV-1 and not to VZV, despite neuronal expression of VZV proteins. The results implicate that herpesvirus latency in human TG is associated with a local, persistent T cell response, comprising activated late effector memory CD8+ T cells that appear to control HSV-1 latency by noncytolytic pathways. In contrast, T cells do not seem to be directly involved in controlling VZV latency in human TG.

Genetic variation in the KIF1B locus influences susceptibility to multiple sclerosis.

The few loci associated with multiple sclerosis (MS) are all related to immune function. We report a GWA study identifying a new locus replicated in 2,679 cases and 3,125 controls. An rs10492972[C] variant located in the KIF1B gene was associated with MS with an odds ratio of 1.35 (P = 2.5 × 10−10). KIF1B is a neuronally expressed gene plausibly implicated in the irreversible axonal loss characterizing MS in the long term.

B cells populating the multiple sclerosis brain mature in the draining cervical lymph nodes

In multiple sclerosis patients, B cells mature in the draining cervical lymph nodes before trafficking across the blood-brain barrier. B Cells Flip the Switch for MS B cells in multiple sclerosis (MS) patients may mature outside the central nervous system (CNS). Two complementary studies report that B cells found outside the CNS—in peripheral blood and draining cervical lymph nodes (CLNs)—share antigen specificity with intrathecal B cell repertoires. In patients with MS, immune cells attack the CNS; however, it remains unclear whether these cells mature in the CNS or traffic to the CNS as mature cells. Using paired tissues and high-throughput sequencing, Stern et al. found that clonally expanded B cells are found in both the CNS and CLNs but that founding members were more often found in the draining CLNs. Palanichamy et al. extend these findings by reporting a peripheral blood/CNS axis of mature B cells that have undergone class switch. These data support the therapeutic use of monoclonal antibodies that prevent lymphocytes from crossing the blood-brain barrier or induce peripheral B cell depletion in MS patients. Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) characterized by autoimmune-mediated demyelination and neurodegeneration. The CNS of patients with MS harbors expanded clones of antigen-experienced B cells that reside in distinct compartments including the meninges, cerebrospinal fluid (CSF), and parenchyma. It is not understood whether this immune infiltrate initiates its development in the CNS or in peripheral tissues. B cells in the CSF can exchange with those in peripheral blood, implying that CNS B cells may have access to lymphoid tissue that may be the specific compartment(s) in which CNS-resident B cells encounter antigen and experience affinity maturation. Paired tissues were used to determine whether the B cells that populate the CNS mature in the draining cervical lymph nodes (CLNs). High-throughput sequencing of the antibody repertoire demonstrated that clonally expanded B cells were present in both compartments. Founding members of clones were more often found in the draining CLNs. More mature clonal members derived from these founders were observed in the draining CLNs and also in the CNS, including lesions. These data provide new evidence that B cells traffic freely across the tissue barrier, with the majority of B cell maturation occurring outside of the CNS in the secondary lymphoid tissue. Our study may aid in further defining the mechanisms of immunomodulatory therapies that either deplete circulating B cells or affect the intrathecal B cell compartment by inhibiting lymphocyte transmigration into the CNS.

CD27: marker and mediator of T-cell activation?

CD27 is a lymphocyte-specific member of the tumour necrosis factor receptor (TNF-R) family, expression of which is tightly regulated during T-cell ontogeny. Recently, the ligand for CD27 was identified and was shown to be identical to CD70, a novel member of the TNF family. Functional experiments show that the interaction between CD27 and its ligand generates a co-stimulatory signal for T-cell activation. Here, Rogier Hintzen and colleagues integrate the phenotypic and functional data available on CD27 and its ligand, and propose a role for CD27 in the amplification of T-cell responses.

Anxiety and depression influence the relation between disability status and quality of life in multiple sclerosis.

Disability status, depression and anxiety are important determinants of quality of life (Q oL) in patients with multiple sclerosis (MS). We investigated whether anxiety and depression influence the relation between disability status and Q oL in our cohort of recently diagnosed patients. Disability status [Expanded Disability Status Scale (EDSS)], anxiety and depression [Hospital A nxiety and Depression Scale (HADS)], and Q oL (SF-36) were prospectively obtained in 101 MS patients. The relation between EDSS and SF-36 scales was examined using regression analyses, without and with adjustment for anxiety and depression. Interaction effects were investigated by comparing the relation between EDSS and Q oL in patients with high and low anxiety and depression. In the unadjusted analyses, EDSS was significantly related to all SF-36 physical and mental health scales. A fter adjustment for anxiety and depression, EDSS was significantly related only to the SF-36 physical functioning, role-physical functioning and bodily pain scales. The relation between EDSS and these SF-36 scales was consistently higher in patients with more symptoms of anxiety or depression, suggesting that anxiety and depression strengthened the association of EDSS in these SF-36 physical health scales. A fter adjustment for anxiety and depression, EDSS was not significantly related to the SF-36 mental health scales and the general health scale. This finding is compatible with the hypothesis that anxiety and depression are intermediate factors in the association of EDSS with these SF-36 scales. Screening for symptoms of anxiety and depression is recommended in studies that use Q oL as an outcome measure of treatment or intervention efficacy.