Secondary Progressive Disease Research Articles

Recent Advances in Metabolomics and Lipidomics Studies in Human and Animal Models of Multiple Sclerosis.

Multiple sclerosis (MS) is a neurodegenerative and inflammatory disease of the central nervous system (CNS) that leads to a loss of myelin. There are three main types of MS: relapsing-remitting MS (RRMS) and primary and secondary progressive disease (PPMS, SPMS). The differentiation in the pathogenesis of these two latter courses is still unclear. The underlying mechanisms of MS are yet to be elucidated, and the treatment relies on immune-modifying agents. Recently, lipidomics and metabolomics studies using human biofluids, mainly plasma and cerebrospinal fluid (CSF), have suggested an important role of lipids and metabolites in the pathophysiology of MS. In this review, the results from studies on metabolomics and lipidomics analyses performed on biological samples of MS patients and MS-like animal models are presented and analyzed. Based on the collected findings, the biochemical pathways in human and animal cohorts involved were investigated and biological mechanisms and the potential role they have in MS are discussed. Limitations and challenges of metabolomics and lipidomics approaches are presented while concluding that metabolomics and lipidomics may provide a more holistic approach and provide biomarkers for early diagnosis of MS disease.

Fatigue and depression influence the prevalence of anxiety in patients with multiple sclerosis.

There is scarce information in Middle-Eastern Europe regarding the prevalence of anxiety in patients with multiple sclerosis (pwMS) and its association with different clinical-demographic factors. We aimed to determine the prevalence of anxiety in Hungarian MS patients and to analyze associated factors. We evaluated 260 PwMS with the STAI-5 anxiety questionnaire. Fatigue (FIS), depression (BDI-II) and cognition (BICAMS) were also measured. Patients underwent standard neurological evaluations to evaluate Expanded Disability Status Scale (EDSS), and also measured the fine motor skills of the hand with the 9-hole peg test (9HPT), and the walking distance with the 25-foot walking test (T25FW). We identified 23.1% (N = 60) of the patients with anxiety (only state, trait or both forms concurrently). According to our two univariate, multivariable logistic regression analysis, fatigue and depression are strongly associated with both state and trait anxiety. In the absence of fatigue, the odds of trait anxiety are 82% lower (OR: 0.18; 95% CI: 0.06-0.53; p = 0.002), while in the case of pwMS without depression, the odds are reduced by 81% (OR: 0.19; CI95%= 0.07-0.51, p = 0.001). This association with fatigue (OR: 0.33; CI95%= 0.13-0.85, p = 0.021) and depression (OR: 0.14; CI95%=0.06-0.35; p < 0.001) can also be statistically verified on state anxiety. Importantly, a significant association with state anxiety was found in SPSM patients as well (OR: 34.94; CI95%=2.55-479.61; p = 0.008). Anxiety was strongly associated with fatigue, depression, and secondary progressive disease form. These results emphasize the burden of psychiatric morbidity in pwMS.

Siponimod following Alemtuzumab in secondary progressive MS: investigating sequential therapy–A case series

Alemtuzumab, a humanized anti‐CD52 monoclonal antibody, is approved for treatment of highly active relapsing multiple sclerosis (MS) but requires vigilant post-treatment monitoring due to associated risks. The prescription of subsequent therapies following Alemtuzumab, as mandated by label guidance for a treatment-free period of at least 5 years, presents a complex challenge, particularly if there is concurrent conversion to secondary progressive disease course.We described a case-series of five patients starting therapy with Siponimod and followed up for 12 months period converted to secondary progressive MS previously exposed to Alemtuzumab. All patients received Siponimod 2 mg. Clinical evaluation measured with Expanded Disability Status Scale and cognitive evaluation measured with Brief International Cognitive Assessment for Multiple Sclerosis were stable after 12 months on therapy. No severe lymphopenia was recorded, nor serious adverse events.In conclusion, the long-term management of patients treated with Alemtuzumab transitioning to secondary progressive MS requires a proactive and multidisciplinary approach.By addressing the challenges associated with treatment limitations and short-term monitoring recommendations while considering alternative therapeutic options like Siponimod, clinicians can optimize outcomes and ensure continuity of care for individuals with MS.

Potential biomarkers for multiple sclerosis stage from targeted proteomics and microRNA sequencing.

Multiple sclerosis is a chronic demyelinating disease of the central nervous system. There is a need for new circulating biomarkers for multiple sclerosis, in particular, markers that differentiate multiple sclerosis subtypes (relapsing-remitting, secondary progressive and primary progressive multiple sclerosis), as this can help in making treatment decisions. In this study, we explore two classes of potential multiple sclerosis biomarkers-proteins and microRNAs-circulating in the cerebrospinal fluid and serum. Targeted medium-throughput proteomics (92 proteins) and microRNA sequencing were performed on serum samples collected in a cross-sectional case-control cohort (cohort I, controls n = 30, multiple sclerosis n = 75) and a prospective multiple sclerosis cohort (cohort II, n = 93). For cohort I, we also made these measurements in paired cerebrospinal fluid samples. In the cohort I cerebrospinal fluid, we observed differences between multiple sclerosis and controls for 13 proteins, including some previously described to be markers for multiple sclerosis [e.g. CD27, C-X-C motif chemokine 13 (CXCL13) and interleukin-7 (IL7)]. No microRNAs were significantly differentially expressed between multiple sclerosis and controls in the cerebrospinal fluid. In serum, 10 proteins, including angiopoietin-1 receptor (TIE2), and 16 microRNAs were significantly different between relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis after performing a meta-analysis combining both cohorts. In the prospective part of the study, participants with relapsing-remitting multiple sclerosis were followed for around 3 years, during which time 12 participants converted to secondary progressive multiple sclerosis. In these longitudinally collected serum samples, we observed a peak in granzyme B, A and H proteins around the time of conversion. Single-sample enrichment analysis of serum microRNA profiles revealed that the peak in granzyme B levels around conversion coincides with enrichment for microRNAs that are enriched in CD4+, CD8+ and natural killer cells (e.g. miRNA-150). We identified several proteins and microRNAs in serum that represent potential biomarkers for relapsing-remitting and secondary progressive multiple sclerosis. Conversion to secondary progressive disease is marked by a peak in granzyme B levels and enrichment for immune-related microRNAs. This indicates that specific immune cell-driven processes may contribute to the conversion of relapsing-remitting multiple sclerosis to secondary progressive multiple sclerosis.

Targeted Therapy of Multiple Sclerosis: A Case for Antigen-Specific Tregs.

Multiple sclerosis is an autoinflammatory condition that results in damage to myelinated neurons in affected patients. While disease-modifying treatments have been successful in slowing the progression of relapsing-remitting disease, most patients still progress to secondary progressive disease that is largely unresponsive to disease-modifying treatments. Similarly, there is currently no effective treatment for patients with primary progressive MS. Innate and adaptive immune cells in the CNS play a critical role in initiating an autoimmune attack and in maintaining the chronic inflammation that drives disease progression. In this review, we will focus on recent insights into the role of T cells with regulatory function in suppressing the progression of MS, and, more importantly, in promoting the remyelination and repair of MS lesions in the CNS. We will discuss the exciting potential to genetically reprogram regulatory T cells to achieve immune suppression and enhance repair locally at sites of tissue damage, while retaining a fully competent immune system outside the CNS. In the future, reprogramed regulatory T cells with defined specificity and function may provide life medicines that can persist in patients and achieve lasting disease suppression after one cycle of treatment.

Anti-Glycolipid Antibody Examination in Five EAE Models and Theiler's Virus Model of Multiple Sclerosis: Detection of Anti-GM1, GM3, GM4, and Sulfatide Antibodies in Relapsing-Remitting EAE.

Anti-glycolipid antibodies have been reported to play pathogenic roles in peripheral inflammatory neuropathies, such as Guillain-Barré syndrome. On the other hand, the role in multiple sclerosis (MS), inflammatory demyelinating disease in the central nervous system (CNS), is largely unknown, although the presence of anti-glycolipid antibodies was reported to differ among MS patients with relapsing-remitting (RR), primary progressive (PP), and secondary progressive (SP) disease courses. We investigated whether the induction of anti-glycolipid antibodies could differ among experimental MS models with distinct clinical courses, depending on induction methods. Using three mouse strains, SJL/J, C57BL/6, and A.SW mice, we induced five distinct experimental autoimmune encephalomyelitis (EAE) models with myelin oligodendrocyte glycoprotein (MOG)35-55, MOG92-106, or myelin proteolipid protein (PLP)139-151, with or without an additional adjuvant curdlan injection. We also induced a viral model of MS, using Theiler's murine encephalomyelitis virus (TMEV). Each MS model had an RR, SP, PP, hyperacute, or chronic clinical course. Using the sera from the MS models, we quantified antibodies against 11 glycolipids: GM1, GM2, GM3, GM4, GD3, galactocerebroside, GD1a, GD1b, GT1b, GQ1b, and sulfatide. Among the MS models, we detected significant increases in four anti-glycolipid antibodies, GM1, GM3, GM4, and sulfatide, in PLP139-151-induced EAE with an RR disease course. We also tested cellular immune responses to the glycolipids and found CD1d-independent lymphoproliferative responses only to sulfatide with decreased interleukin (IL)-10 production. Although these results implied that anti-glycolipid antibodies might play a role in remissions or relapses in RR-EAE, their functional roles need to be determined by mechanistic experiments, such as injections of monoclonal anti-glycolipid antibodies.

Multimodal diagnostics in multiple sclerosis: predicting disability and conversion from relapsing-remitting to secondary progressive disease course – protocol for systematic review and meta-analysis

BackgroundThe number of patients diagnosed with multiple sclerosis (MS) has increased significantly over the last decade. The challenge is to identify the transition from relapsing-remitting to secondary progressive MS. Since...

Spinal cord and brain corticospinal tract lesions are associated with motor progression in tumefactive multiple sclerosis

Spinal cord lesions have been associated with progressive disease in individuals with typical relapsing remitting MS (RRMS). In the current study, we aimed to determine if progressive disease is associated with spinal cord lesions in those with tumefactive multiple sclerosis (MS). Retrospective chart review of individuals presenting to Mayo Clinic with tumefactive MS with spinal cord MRIs available (n=159). Clinical data were extracted by chart review. Brain and spinal cord MRIs were reviewed to characterize the tumefactive demyelinating lesion(s) and assess the burden of spinal cord disease. A total of 69 (43%) had spinal cord lesions. Progressive demyelinating disease was documented in 13 (8%); the majority (11/13) with secondary progressive disease. The method of progression was myelopathic in 8/13 (62%), cognitive in 3/13 (23%), motor from a supratentorial lesion in 2/13 (16%). EDSS at last follow-up was higher in those with progression than those without (median 6.0 (2.0-10.0) vs. 2.5 (0-10.0), p=< 0.001). Progressive demyelinating disease occurred in a minority. Patients with progression typically experienced progressive motor impairment, and this occurred exclusively in individuals with lesions in the corticospinal tracts of the brain and/or the spinal cord.

Ublituximab: First Approval.

Ublituximab (ublituximab-xiiy; BRIUMVI™) is a glycoengineered anti-CD20 monoclonal antibody developed by TG Therapeutics, Inc. for the treatment of multiple sclerosis (MS). The mechanism of action of ublituximab involves the depletion of B cells via antibody-dependent cellular cytotoxicity, as B cells have a key role in the pathogenesis of MS. Ublituximab is the first anti-CD20 treatment that is administered twice-yearly as one hour infusions, following the initial doses. In December 2022, ublituximab received its first global approval in the USA for the treatment of adults with relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease. This article summarizes the milestones in the development of ublituximab leading to this first approval in this indication.

Ocular motor impairment in early-stage multiple sclerosis: a video-oculography assessment

BackgroundEye movement disorders in multiple sclerosis (MS) are frequently misdiagnosed and frequently overlooked during clinical examinations. Even at a preclinical state, these defects frequently cause impairment and weariness.MethodsWe conducted a cross-sectional observational study including 20 individuals with a confirmed MS diagnosis. The inclusion criteria were an EDSS score of 4 or less and a 6-month interval between the last relapse and enrolment. As part of the MS assessment, a routine ORL, neurology exam, eye exam, assessment of eye movement using Ulmer’s videonystagmography battery tests, and routine brain MRI were performed on the patient.ResultsA total of 75% of the patients in our series are female, with a mean age of 39 years and a range of 24 to 59 years. The average age of MS onset is 32 years. The relapsing-remitting type of multiple sclerosis (RRMS) accounts for 95% of all cases. There is only a single case of secondary progressive disease course (SPMS). Principal VNG manifestations are related to subclinical eye movements abnormalities. Rotatory vertigo caused by vestibular dysfunction was less prevalent than other balance disorders. There were found to be two types of nystagmus: pendular and central positional nystagmus.Discussion and conclusionVNG is sensitive for detecting vestibular system dysfunction in MS patients. It is also beneficial for diagnosing subtle eye movement abnormalities that are usually overlooked.

Sex, aging and immunity in multiple sclerosis and experimental autoimmune encephalomyelitis: An intriguing interaction.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) with a profound neurodegenerative component early in the disease pathogenesis. Age is a factor with a well-described effect on the primary disease phenotype, namely, the relapsing-remitting vs. the primary progressive disease. Moreover, aging is a prominent factor contributing to the transition from relapsing-remitting MS (RRMS) to secondary progressive disease. However, sex also seems to, at least in part, dictate disease phenotype and evolution, as evidenced in humans and in animal models of the disease. Sex-specific gene expression profiles have recently elucidated an association with differential immunological signatures in the context of experimental disease. This review aims to summarize current knowledge stemming from experimental autoimmune encephalomyelitis (EAE) models regarding the effects of sex, either independently or as a factor combined with aging, on disease phenotype, with relevance to the immune system and the CNS.

Time to reconsider the classification of multiple sclerosis

Multiple sclerosis is an inflammatory demyelinating disease of the CNS, showing various clinical manifestations depending on the site, nature, and extent of the inflammatory lesions. In practice, multiple sclerosis is classified into clinical subtypes—relapsing-remitting, primary progressive, and secondary progressive—on the basis of the patient's clinical course. Since the turn of the century, the precise distinction between relapsing-remitting and secondary progressive multiple sclerosis has become important, because secondary progressive disease does not respond to most disease-modifying drugs approved for relapsing-remitting disease (although disability progression in people with secondary progressive multiple sclerosis can be slowed with siponimod).

Expert opinion on COVID-19 vaccines and cladribine tablets in MS: A plain language summary.

People with multiple sclerosis (shortened to MS) who are taking cladribine tablets may have concerns about whether they can be vaccinated against COVID-19. This summary details the findings from a previously published article, in which an international committee of 10 MS experts developed recommendations to answer some important questions about COVID-19 vaccines in people with MS (including relapsing-remitting or active secondary progressive disease) taking cladribine tablets. The committee identified 13 recommendations, which were all agreed upon by at least three-quarters (75%) of the 38 voting MS experts. Generally, they recommended that people with MS taking cladribine tablets should be vaccinated for COVID-19 as soon as possible, because the vaccine is thought to be both safe and effective, and vaccine responses were not likely to be affected by cladribine tablets. Overall, people with MS taking cladribine tablets should receive the COVID-19 vaccine to protect themselves, unless advised differently by their healthcare provider.

Bulbar Symptoms as an Unusual Presentation of Multiple Sclerosis: A Case Report.

Multiple sclerosis (MS) is a complex multifactorial disease with different clinical manifestations. Bulbar symptoms such as dysarthria and dysphagia are common in MS patients with advanced secondary progressive disease. However, they are not common at disease onset. We present the case of a 17-year-old male who initially presented with vomiting, dysarthria, and dysphagia. The investigations led to the diagnosis of MS, with an active lesion in the brainstem, more specifically in the area postrema region. Differential diagnoses were eliminated. The patient received intravenous methylprednisolone resulting in amelioration of symptoms. Treatment with fingolimod was started after discharge. The recognition of MS with atypical onsets is important to make an early accurate diagnosis and prescribe appropriate treatment for a disease known to be one of the most common causes of neurologic disability in young adults.LEARNING POINTSMultiple sclerosis can have atypical presentations.Bulbar symptoms such as dysarthria and dysphagia can be initial symptoms of multiple sclerosis, although uncommon.Clinicians should be able to recognize multiple sclerosis with atypical onsets in order to make an early accurate diagnosis.

Impact of CYBA genotypes on severity and progression of multiple sclerosis.

Background and purposeThe NOX2 enzyme of myeloid cells generates reactive oxygen species (ROS) that have been implicated in the pathology of multiple sclerosis (MS). We aimed to determine the impact of genetic variation within CYBA, which encodes the functional CYBA/p22 phox subunit of NOX2, on MS severity and progression.MethodsOne hundred three MS patients with up to 49 (median = 17) years follow‐up time from first MS diagnosis were genotyped at the single nucleotide polymorphisms rs1049254 and rs4673 within CYBA. Results were matched with disease severity and time to diagnosis of secondary progressive MS (SPMS). NOX2‐mediated formation of ROS was measured by chemiluminescence in blood myeloid cells from healthy donors (n = 55) with defined genotypes at rs1049254 and rs4673.ResultsThe rs1049254/G and rs4673/A CYBA alleles were associated with reduced formation of ROS and were thus defined as low‐ROS alleles. Patients carrying low‐ROS alleles showed reduced multiple sclerosis severity score (p = 0.02, N = 103, linear regression) and delayed onset of SPMS (p = 0.02, hazard ratio [HR] = 0.46, n = 100, log‐rank test). In a cohort examined after 2005, patients carrying low‐ROS CYBA alleles showed >20 years longer time to secondary progression (p = 0.003, HR = 0.29, n = 59, log‐rank test).ConclusionsThese results implicate NOX2 in MS, in particular for the development of secondary progressive disease, and point toward NOX2‐reductive therapy aiming to delay secondary progression.

Spinal Cord Atrophy Predicts Progressive Disease in Relapsing Multiple Sclerosis.

ObjectiveA major challenge in multiple sclerosis (MS) research is the understanding of silent progression and Progressive MS. Using a novel method to accurately capture upper cervical cord area from legacy brain MRI scans we aimed to study the role of spinal cord and brain atrophy for silent progression and conversion to secondary progressive disease (SPMS).MethodsFrom a single‐center observational study, all RRMS (n = 360) and SPMS (n = 47) patients and 80 matched controls were evaluated. RRMS patient subsets who converted to SPMS (n = 54) or silently progressed (n = 159), respectively, during the 12‐year observation period were compared to clinically matched RRMS patients remaining RRMS (n = 54) or stable (n = 147), respectively. From brain MRI, we assessed the value of brain and spinal cord measures to predict silent progression and SPMS conversion.ResultsPatients who developed SPMS showed faster cord atrophy rates (−2.19%/yr) at least 4 years before conversion compared to their RRMS matches (−0.88%/yr, p < 0.001). Spinal cord atrophy rates decelerated after conversion (−1.63%/yr, p = 0.010) towards those of SPMS patients from study entry (−1.04%). Each 1% faster spinal cord atrophy rate was associated with 69% (p < 0.0001) and 53% (p < 0.0001) shorter time to silent progression and SPMS conversion, respectively.InterpretationSilent progression and conversion to secondary progressive disease are predominantly related to cervical cord atrophy. This atrophy is often present from the earliest disease stages and predicts the speed of silent progression and conversion to Progressive MS. Diagnosis of SPMS is rather a late recognition of this neurodegenerative process than a distinct disease phase. ANN NEUROL 2022;91:268–281

Prognostic uncertainty in multiple sclerosis: A concept analysis.

To report an analysis of the concept of prognostic uncertainty in patients with multiple sclerosis (MS). The complexity and ambiguity involved in a diagnosis of MS lead to the occurrence of prognostic uncertainty among patients. A concept analysis is presented that analyses what prognostic uncertainty means to those experiencing the transition between relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis. Concept analysis. PubMed, Ovid Medline, Cumulative Index for Nursing and Allied Health Literature databases were searched for literature published within the last 10years using combinations of the terms prognostic and diagnostic uncertainty, and multiple sclerosis along with archival referencing. The Walker and Avant method was used to analyse the concept of prognostic uncertainty in patients with MS. The defining attributes identified that provide additional context to prognostic uncertainty are illness uncertainty, intolerance of uncertainty and progressive dwindling. Related, contrary, model and borderline cases are presented to further discuss the application of the key attributes to the concept. There are limited data on prognostic uncertainty and multiple sclerosis; however, patients and physicians express uncertainty in understanding one's disease trajectory and determining when a patient with relapsing-remitting multiple sclerosis has entered the secondary progressive multiple sclerosis disease course leading to ineffective communication and frustration. Genetics and genomics have the potential to provide a prognostic factor for addressing the concept of uncertainty as it relates to persons with multiple sclerosis. Moving beyond the concept analysis, a case is made for nurse involvement in genetic and genomic research to conduct trials, translate, and apply these findings to clinical practice and nursing curricula, addressing the uncertainty experienced by those afflicted with chronic illnesses, such as multiple sclerosis.

ECTRIMS 2021 – Oral Presentations

Multiple sclerosis (MS) is a complex disease in which the innate and adaptive immune systems play a fundamental role and treatment with disease-modifying therapies (DMTs) reduces relapses of neurologic symptoms. Immune modulatory therapies have provided novel insights into disease pathology, for example, that long-neglected B cells actually play a relevant role or that early consequent treatment in the relapsing phase of the disease is able to prevent a later conversion into a secondary progressive disease course. When starting or switching treatment, it is essential to continuously monitor patients and perform the necessary laboratory assessment and vaccination status check-currently in particular against SARS-CoV2-as well as a thorough neurological examination and MRI of the brain at regular intervals (Wiendl, Gold . . . Zipp, Multiple Sclerosis Treatment Consensus Group (MSTKG): Position statement on disease modifying therapies for multiple sclerosis (white paper). TAND 2021, in press). Here, we will discuss whether, when and with which monitoring steps MS patients on DMT with poor response to treatment should switch to higher efficacy DMTs versus similar efficacy DMTs. When possible, published evidence should be taken into account, however many questions have not yet been addressed by larger investigations;here, consensus statements should be considered. Efficacy and potential risks as well as the intervals between different treatment regimens should be included in the decision-making process. Novel blood-based biomarkers such as neurofilaments might additionally help in patient treatment stratification (Bittner, Jiwon, Havrdova, Tintore, Zipp, The potential of serum neurofilament as biomarker for multiple sclerosis. Brain 2021). The overall goal is to achieve little-or ideally no-evidence of disease activity and also no progression independent of relapses (PIRA). However, addressing axonal damage in MS remains the largest challenge faced by clinical research and patient care.

Epilepsy as a predictor of disease progression in multiple sclerosis

Background: Epilepsy development during the course of multiple sclerosis (MS) is considered to be the result of cortical pathology. However, no long-term data exist on whether epilepsy in MS also leads to increasing disability over time. Objective: To examine if epilepsy leads to more rapid disease progression. Methods: We analyzed the data of 31,052 patients on the German Multiple Sclerosis Register in a case–control study. Results: Secondary progressive disease course (odds ratio (OR) = 2.23), age (OR = 1.12 per 10 years), and disability (OR = 1.29 per Expanded Disability Status Scale (EDSS) point) were associated with the 5-year prevalence of epilepsy. Patients who developed epilepsy during the course of the disease had a higher EDSS score at disease onset compared to matched control patients (EDSS 2.0 vs 1.5), progressed faster in each dimension, and consequently showed higher disability (EDSS 4.4 vs 3.4) and lower employment status (40% vs 65%) at final follow-up. After 15 years of MS, 64% of patients without compared to 54% of patients with epilepsy were not severely limited in walking distance. Conclusion: This work highlights the association of epilepsy on disability progression in MS, and the need for additional data to further clarify the underlying mechanisms.

What Guides Peripheral Immune Cells into the Central Nervous System?

Multiple sclerosis (MS), an immune-mediated demyelinating disease of the central nervous system (CNS), initially presents with a relapsing-remitting disease course. During this early stage of the disease, leukocytes cross the blood–brain barrier to drive the formation of focal demyelinating plaques. Disease-modifying agents that modulate or suppress the peripheral immune system provide a therapeutic benefit during relapsing-remitting MS (RRMS). The majority of individuals with RRMS ultimately enter a secondary progressive disease stage with a progressive accumulation of neurologic deficits. The cellular and molecular basis for this transition is unclear and the role of inflammation during the secondary progressive disease stage is a subject of intense and controversial debate. In this review article, we discuss the following main hypothesis: during both disease stages, peripheral immune cells are triggered by CNS-intrinsic stimuli to invade the brain parenchyma. Furthermore, we outline the different neuroanatomical routes by which peripheral immune cells might migrate from the periphery into the CNS.