Objective

To contrast differences in pain and treatment outcomes between neuromyelitis optica (NMO) and multiple sclerosis (MS).

Design

Retrospective, cross-sectional cohort study.

Setting

Academic MS center.

Patients

Complete ascertainment of an academic MS center cohort of NMO and an MS comparison sample cohort.

Main Outcome Measures

Current pain was quantified by a 10-point scale and the McGill Pain Questionnaire. Expanded Disability Status Scale score and number of involved spinal cord levels were collected in addition to testing for cognition, fatigue, depression, and quality of life. Number and types of pain medications were tabulated.

Results

Current pain was more common in subjects with NMO (n=29) vs MS (n=66) (86.2% vs 40.9%; P<.001) and more severe on a 10-point scale (5.38 vs 1.85; P <.001). Pain remained more common after controlling for disability and number of spinal cord segments (P=.03). Prescription pain medication was used more frequently in subjects with NMO compared with subjects with MS (75.9% vs 37.8%; P<.001), often requiring more than 1 medication (65.5% vs 15.2%; P<.001). No subject with NMO taking pain medication (22 of 29) rated their current pain as 0 of 10, whereas almost half of those taking pain medication with MS were currently free of pain (0% vs 48%; P=.006).

Conclusions

Neuromyelitis optica is frequently associated with severe pain that appears insufficiently controlled by pharmacologic interventions. Future studies should evaluate the efficacy of a multidisciplinary and multimodal approach to pain management.

Multiple sclerosis is characterized by inflammatory demyelination and irreversible axonal injury leading to permanent neurological disabilities. Diffusion tensor imaging demonstrates an improved capability over standard magnetic resonance imaging to differentiate axon from myelin pathologies. However, the increased cellularity and vasogenic oedema associated with inflammation cannot be detected or separated from axon/myelin injury by diffusion tensor imaging, limiting its clinical applications. A novel diffusion basis spectrum imaging, capable of characterizing water diffusion properties associated with axon/myelin injury and inflammation, was developed to quantitatively reveal white matter pathologies in central nervous system disorders. Tissue phantoms made of normal fixed mouse trigeminal nerves juxtaposed with and without gel were employed to demonstrate the feasibility of diffusion basis spectrum imaging to quantify baseline cellularity in the absence and presence of vasogenic oedema. Following the phantom studies, in vivo diffusion basis spectrum imaging and diffusion tensor imaging with immunohistochemistry validation were performed on the corpus callosum of cuprizone treated mice. Results demonstrate that in vivo diffusion basis spectrum imaging can effectively separate the confounding effects of increased cellularity and/or grey matter contamination, allowing successful detection of immunohistochemistry confirmed axonal injury and/or demyelination in middle and rostral corpus callosum that were missed by diffusion tensor imaging. In addition, diffusion basis spectrum imaging-derived cellularity strongly correlated with numbers of cell nuclei determined using immunohistochemistry. Our findings suggest that diffusion basis spectrum imaging has great potential to provide non-invasive biomarkers for neuroinflammation, axonal injury and demyelination coexisting in multiple sclerosis.

Objective

To evaluate directional diffusivities within the optic nerve in a first event of acute optic neuritis to determine whether decreased axial diffusivity (AD) would predict 6-month visual outcome and optic nerve integrity measures.

Design

Cohort study.

Setting

Academic multiple sclerosis center.

Patients

Referred sample of 25 individuals who presented within 31 days after acute visual symptoms consistent with optic neuritis. Visits were scheduled at baseline, 2 weeks, and 1, 3, 6, and 12 months.

Main Outcome Measures

Visual acuity, contrast sensitivity, visual evoked potentials (VEPs), and thickness of the retinal nerve fiber layer (RNFL).

Results

An incomplete 6-month visual recovery was associated with a lower baseline AD (1.50 μm2/ms [95% confidence interval {CI}, 1.36–1.64 μm2/ms for incomplete recovery vs 1.75 μm2/ms [95% CI, 1.67–1.83 μm2/ms] for complete recovery). Odds of complete recovery decreased by 53% (95% CI, 27%–70%) for every 0.1-unit decrease in baseline AD. A lower baseline AD correlated with worse 6-month visual outcomes in visual acuity (r=0.40, P=.03), contrast sensitivity (r=0.41, P=.02), VEP amplitude (r=0.55, P<.01), VEP latency (r=−0.38, P=.04), and RNFL thickness (r=0.53, P=.02). Radial diffusivity increased between months 1 and 3 to become higher in those with incomplete recovery at 12 months than in those with complete recovery (1.45 μm2/ms [95% CI, 1.31–1.59 μm2/ms] vs 1.19 μm2/ms [95% CI, 1.10–1.28 μm2/ms]).

Conclusions

Decreased AD in acute optic neuritis was associated with a worse 6-month visual outcome and correlated with VEP and RNFL measures of axon and myelin injury. Axial diffusivity may serve as a marker of axon injury in acute white matter injury.

In multiple sclerosis (MS), the presence of B cells, plasma cells and excess immunoglobulins in central nervous system lesions and in the cerebrospinal fluid implicate the humoral immune system in disease pathogenesis. However, until the advent of specific B-cell-depleting therapies, the critical role of B cells and their products in MS was unproven. Rituximab, a monoclonal antibody that depletes B cells by targeting the CD20 molecule, has been shown to effectively reduce disease activity in patients with relapsing MS as a single agent. Our investigator-initiated phase II study is the only published clinical trial in which rituximab was used as an add-on therapy in patients with relapsing MS who had an inadequate response to standard injectable disease-modifying therapies (DMTs). The primary endpoint, magnetic resonance imaging (MRI) gadolinium-enhanced (GdE) lesion number before versus after rituximab, showed significant benefit of rituximab (74% of post-treatment MRI scans being free of GdE lesions compared with 26% free of GdE lesions at baseline; p < 0.0001). No differences were noted comparing patients on different DMTs. Several secondary clinical endpoints, safety and laboratory measurements (including B- and T-cell numbers in the blood and cerebrospinal fluid (CSF), serum and CSF chemokine levels, antibodies to myelin proteins) were assessed. Surprisingly, the decline in B-cell number was accompanied by a significant reduction in the number of T cells in both the peripheral blood and CSF. Rituximab therapy was associated with a significant decline of two lymphoid chemokines, CXCL13 and CCL19. No significant changes were observed in serum antibody levels against myelin proteins [myelin basic protein (MBP) and myelin/oligodendrocyte glycoprotein (MOG)] after treatment. These results suggest that B cells play a role in MS independent from antibody production and possibly related to their role in antigen presentation to T cells or to their chemokine/cytokine production.

Objective

Correlation of diffusion tensor imaging (DTI) with histochemical staining for demyelination and axonal damage in multiple sclerosis (MS) ex vivo human cervical spinal cords.

Background

In MS, demyelination, axonal degeneration, and inflammation contribute to disease pathogenesis to variable degrees. Based upon in vivo animal studies with acute injury and histopathologic correlation, we hypothesized that DTI can differentiate between axonal and myelin pathologies within humans.

Methods

DTI was performed at 4.7 Tesla on 9 MS and 5 normal control fixed cervical spinal cord blocks following autopsy. Sections were then stained for Luxol fast blue (LFB), Bielschowsky silver, and hematoxylin and eosin (H&E). Regions of interest (ROIs) were graded semi-quantitatively as normal myelination, mild (<50%) demyelination, or moderate-severe (>50%) demyelination. Corresponding axonal counts were manually determined on Bielschowsky silver. ROIs were mapped to co-registered DTI parameter slices. DTI parameters evaluated included standard quantitative assessments of apparent diffusion coefficient (ADC), relative anisotropy (RA), axial diffusivity and radial diffusivity. Statistical correlations were made between histochemical gradings and DTI parameters using linear mixed models. Results: Within ROIs in MS subjects, increased radial diffusivity distinguished worsening severities of demyelination. Relative anisotropy was decreased in the setting of moderate-severe demyelination compared to normal areas and areas of mild demyelination. Radial diffusivity, ADC, and RA became increasingly altered within quartiles of worsening axonal counts. Axial diffusivity did not correlate with axonal density (p=0.091).

Conclusions

Increased radial diffusivity can serve as a surrogate for demyelination. However, radial diffusivity was also altered with axon injury, suggesting that this measure is not pathologically specific within chronic human MS tissue. We propose that radial diffusivity can serve as a marker of overall tissue integrity within chronic MS lesions. This study provides pathologic foundation for on-going in vivo DTI studies in MS.

Experimental autoimmune encephalomyelitis (EAE), a model for the human disease multiple sclerosis (MS), is dependent upon the activation and effector functions of autoreactive CD4 T cells. Multiple interactions between CD4 T cells and major histocompatibility class II (MHCII)+ antigen presenting cells (APCs) must occur in both the periphery and central nervous system (CNS) to elicit autoimmunity. The identity of the MHCII+ APCs involved throughout this process remains in question. We investigated which APC in the periphery and CNS mediates disease using transgenic mice with MHCII expression restricted to dendritic cells (DCs). MHCII expression restricted to DCs results in normal susceptibility to peptide-mediated EAE. Indeed, radiation-sensitive bone marrow-derived DCs were sufficient for all APC functions during peptide-induced disease. However, DCs alone were inefficient at promoting disease after immunization with the myelin protein myelin oligodendrocyte glycoprotein (MOG), even in the presence of MHCII-deficient B cells. Consistent with a defect in disease induction following protein immunization, antigen presentation by DCs alone was incapable of mediating spontaneous optic neuritis. These results indicate that DCs are capable of perpetuating CNS-targeted autoimmunity when antigens are readily available, but other APCs are required to efficiently initiate pathogenic cognate CD4 T cell responses.

The exact role(s) of the cytokine IFN-γ in the demyelinating disease multiple sclerosis remain controversial, with evidence suggesting both detrimental and protective effects of the cytokine in MS and MS models such as EAE. The study by Lin and coworkers in this issue of the JCI produces evidence that protective effects of IFN-γ on mature oligodendrocytes during EAE induction are mediated via activation of the pancreatic ER kinase (PERK), resulting in induction of the endoplasmic reticular stress response pathway (see the related article beginning on page 448). Modulation of this stress pathway has what we believe to be novel therapeutic potential for MS.

Conventional MRI based on weighted spin-echo (SE) images aids in the diagnosis of multiple sclerosis (MS); however, MRI markers derived from SE sequences provide limited information about lesion severity and correlate poorly with patient disability assessed with clinical tests. In this study, we introduced a novel method [based on quantitative R2* (1/T2*) histograms] for estimating the severity of brain tissue damage in MS lesions. We applied at 1.5 T an advanced, multi-gradient-echo MRI technique [gradient echo plural contrast imaging (GEPCI)] to obtain images of the brains of healthy control subjects and subjects with MS. GEPCI is a simple yet robust technique allowing simultaneous acquisition of inherently co-registered quantitative T2* and FLAIR-like maps, along with T1-weighted images within a clinically acceptable time frame. Images obtained with GEPCI appear highly similar to standard scans; hence, they can be used in a reliable and conventional way for a clinical evaluation of the disease. Yet, the main advantage of GEPCI approach is its quantitative nature. Analysis of R2* histograms of white matter revealed a difference in the distribution between healthy subjects and subjects with MS. Based on this difference, we developed a new method for grading the severity of tissue damage [tissue-damage score (TDS)] in MS lesions. This method also provides a tissue damage load (TDL) assessing both lesion load and lesion severity, and a mean tissue damage score (MTDS) estimating the average MS lesion damage. We found promising correlations between the results derived from this method and the standard measure of clinical disability.

Non-invasive assessment of the progression of axon damage is important for evaluating disease progression and developing neuroprotective interventions in multiple sclerosis (MS) patients. We examined the cellular responses correlated with diffusion tensor imaging (DTI)-derived axial (λ||) and radial (λ⊥) diffusivity values throughout acute (4 weeks) and chronic (12 weeks) stages of demyelination and after 6 weeks of recovery using the cuprizone demyelination of the corpus callosum model in C57BL/6 and Thy1-YFP-16 mice. The rostro-caudal progression of pathologic alterations in the corpus callosum enabled spatially and temporally defined correlations of pathological features with DTI measurements. During acute demyelination, microglial/macrophage activation was most extensive and axons exhibited swellings, neurofilament dephosphorylation, and reduced diameters. Axial diffusivity values decreased in the acute phase but did not correlate with axonal atrophy during chronic demyelination. In contrast, radial diffusivity increased with the progression of demyelination but did not correlate with myelin loss or astrogliosis. Unlike other animals models with progressive neurodegeneration and axon loss, the acute axon damage did not progress to discontinuity or loss of axons even after a period of chronic demyelination. Correlations of reversible axon pathology, demyelination, microglia/macrophage activation, and astrogliosis with regional axial and radial diffusivity measurements will facilitate the clinical application of DTI in MS patients.

Objective

Describe the clinical and imaging characteristics of spinal cord ring enhancement in multiple sclerosis (MS).

Design

Clinical case series.

Setting

Academic referral center.

Patients

Twenty MS subjects with spinal cord ring enhancement were retrospectively identified from 322 cervical and thoracic spinal cord MRI studies over a 3 year period.

Main Outcome Measures

Demographics, disability, pattern of enhancement on spinal cord imaging, and concomitant brain magnetic resonance imaging (MRI) were determined.

Results

Ring enhancement was seen in 20 subjects with spinal cord enhancement, most commonly in the cervical cord. Incomplete or ‘open’ ring enhancement was the dominant pattern in 19 of 20 (95%) subjects. Concurrent ring enhancing brain lesions were present in 40% of subjects. At the time of the MRI, the Expanded Disability Status Scale (EDSS) ranged from 1.0–7.0 (median 3.0).

Conclusion

Ring enhancement is not an uncommon pattern for MS spinal cord lesions, occurring with a prevalence of 6.2% (20/322). The most common pattern was incomplete ring enhancement in the cervical spinal cord. Recognition of this pattern may improve and expedite the diagnosis of MS and preclude need for invasive diagnostic interventions.

Objective

Evaluate antibodies (Ab) to myelin oligodendrocyte glycoprotein (MOG) in the serum and cerebrospinal fluid (CSF) of multiple sclerosis (MS) subjects and controls.

Design

Prospective case control series.

Setting

Academic referral center.

Subjects

Twenty-six controls with non-inflammatory neurologic disease (NIND) and 35 MS subjects donated serum and CSF for rMOG Ab determination.

Main Outcome Measures

Serum and CSF rMOG Ab and albumin levels were used to calculate an “rMOG index”. Clinical disability, CSF markers, and magnetic resonance (MR) metrics were correlated to rMOG index.

Results

rMOG index was elevated in MS subjects compared to controls (p=0.012). Progressive MS subjects exhibited elevated rMOG indices compared to relapsing remitting MS (RRMS) (p=0.041). rMOG index was inferior to IgG index in differentiating MS subjects from controls. However, 7 of 16 MS subjects with normal IgG indices had an elevated rMOG index. rMOG index did not correlate with clinical disability, other CSF markers, or radiographic outcome measures.

Conclusions

rMOG index, a marker of intrathecal MOG Ab production, may provide complementary information to routine CSF testing in the diagnosis of MS. Furthermore, intrathecal anti-MOG Ab production may be more pronounced in progressive than relapsing forms of MS.

Multiple sclerosis (MS) is characterized as an autoimmune demyelinating disease. Numerous family studies have confirmed a strong genetic component underlying its etiology. After several decades of frustrating research, the advent and application of affordable genotyping of dense SNP maps in large datasets has ushered in a new era in which rapid progress is being made in our understanding of the genetics underlying many complex traits. For MS, one of the first discoveries to emerge in this new era was the association with rs6897932[T244I] in the interleukin-7 receptor alpha chain (IL7RA) gene (Gregory et al. 2007; International Multiple Sclerosis Genetics Consortium 2007; Lundmark 2007), a discovery that was accompanied by functional data that suggest this variant is likely to be causative rather than a surrogate proxy (Gregory et al. 2007). We hypothesized that variations in other genes functionally related to IL7RA might also influence MS. We investigated this hypothesis by examining genes in the extended biological pathway related to IL7RA to identify novel associations. We identified 73 genes with putative functional relationships to IL7RA and subsequently genotyped 7,865 SNPs in and around these genes using an Illumina Infinium BeadChip assay. Using 2,961 case-control dataset, two of the gene regions examined, IL7 and SOCS1, had significantly associated single-nucleotide polymorphisms (SNPs) that further replicated in an independent case-control dataset (4,831 samples) with joint p-values as high as 8.29×10-6 and 3.48×10-7, respectively, exceeding the threshold for experiment-wise significance. Our results also implicate two additional novel gene regions that are likely to be associated with MS: PRKCE with p-values reaching 3.47×10-4 and BCL2 with p-values reaching 4.32×10-4. The TYK2 gene, which also emerged in our analysis, has recently been associated with MS (Ban et al. 2009). These results help to further delineate the genetic architecture of MS and validate our pathway approach as an effective method to identify novel associations in a complex disease.

Recent clinical trials have established B cell depletion by the anti-CD20 chimeric antibody Rituximab as a beneficial therapy for patients with relapsing-remitting multiple sclerosis (MS). The impact of Rituximab on T cell responses remains largely unexplored. In the experimental autoimmune encephalomyelitis (EAE) model of MS in mice that express human CD20, Rituximab administration rapidly depleted peripheral B cells and strongly reduced EAE severity. B cell depletion was also associated with diminished Delayed Type Hypersensitivity (DTH) and a reduction in T cell proliferation and IL-17 production during recall immune response experiments. While Rituximab is not considered a broad immunosuppressant, our results indicate a role for B cells as a therapeutic cellular target in regulating encephalitogenic T cell responses in specific tissues.

Multiple sclerosis (MS) is an autoimmune demyelinating disease characterized by complex genetics and multifaceted gene-environment interactions. Compared to whites, African Americans have a lower risk for developing MS, but African Americans with MS have a greater risk of disability. These differences between African Americans and whites may represent differences in genetic susceptibility and/or environmental factors. SNPs from 12 candidate genes have recently been identified and validated with MS risk in white populations. We performed a replication study using 918 cases and 656 unrelated controls to test whether these candidate genes are also associated with MS risk in African Americans. CD6, CLEC16a, EVI5, GPC5, and TYK2 contained SNPs that are associated with MS risk in the African American dataset. EVI5 showed the strongest association outside the MHC (rs10735781, OR = 1.233, 95% CI = 1.06–1.43, P value = 0.006). In addition, RGS1 appears to affect age of onset whereas TNFRSF1A appears to be associated with disease progression. None of the tested variants showed results that were statistically in-consistent with the effects established in whites. The results are consistent with shared disease genetic mechanisms among individuals of European and African ancestry.

A challenge for the clinician treating patients with multiple sclerosis (MS) is to determine the most effective treatment while weighing the benefits and risks. Results of the phase 2 and phase 3 studies on natalizumab were received with great interest, in part due to the “improved” risk reduction for relapse rate, disease progression, and MRI metrics observed in comparison to results in trials of beta-interferon and glatiramer acetate. However, comparison across trials is invalid, in large part due to differences in the study populations. The increased efficacy observed in more recent trials has also been attributed to a fundamental change in subjects with MS enrolled in recent trials compared with the prior decade. In this article, we debate the relative efficacy of natalizumab vs the older injectable therapies.

GLOSSARY

= absolute risk reduction;

= clinically isolated syndrome;

= disease-modulating therapy;

= Expanded Disability Status Scale;

= Food and Drug Administration;

= glatiramer acetate;

= interferon;

= multiple sclerosis;

= number needed to treat;

= progressive multifocal leukoencephalopathy;

= relapsing-remitting MS;

= relative risk reduction.

Background

B cells are implicated in the pathogenesis of multiple sclerosis (MS). A beneficial effect of B cell depletion using rituximab has been shown, but the complete mechanism of action for this drug is unclear.

Objective

To determine the relationship between T cells, B cells, and changes in CSF chemokines with rituximab, a monoclonal antibody that targets CD20.

Design

Phase II trial of rituximab as an add-on therapy.

Setting

The John L. Multiple Sclerosis Center, Washington University, St. Louis, Missouri.

Patients

Thirty relapsing-remitting MS subjects with clinical and MRI activity despite treatment with an immunomodulatory drug received four weekly doses of 375mg/m2 rituximab.

Main Outcome Measures

Lumbar puncture was performed before and after rituximab infusions in 26 subjects. CSF B and T lymphocytes were enumerated by flow cytometry, and chemoattractants were measured by ELISA.

Results

After rituximab administration, CSF B cells were decreased or undetectable in all subjects and CSF T cells were reduced in 81% of subjects. The mean reduction in CSF cellularity was 95% for B cells and 50% for T cells. After rituximab infusion, CSF CXCL13 and CCL19 decreased (P= 0.002, P=0.03, respectively). The proportional decline in CSF T cells correlated with the proportional decrease in CXCL13 (r=0.45;P=0.03), suggesting a possible relationship. CSF IgG index, IgG concentration, and oligoclonal band number were unchanged following treatment.

Conclusions

B cells are critical for T cell trafficking into the CNS in MS patients, and may alter T cell trafficking by influencing chemokine production within the CNS.

In this study, axial (λ∥) and radial (λ⊥) diffusivities derived from diffusion tensor imaging (DTI) were used to evaluate white matter injury in brains of mice affected by experimental autoimmune encephalomyelitis (EAE). Sixteen female C57BL/6 mice were immunized with amino acids 35-55 of myelin oligodendrocyte glycoprotein (MOG35-55). Three months after immunization, optic nerve and tract were severely affected with 19% and 18% decrease in λ∥ respectively, suggesting the presence of axonal injury. In addition, a 156% and 86% increase in λ⊥ was observed in optic nerve and tract respectively, suggestive of myelin injury. After in vivo DTI, mice were perfusion fixed and immunohistochemistry for the identification of myelin basic protein (MBP) and phosphorylated neurofilament (pNF) was performed to verify the presence of axonal and myelin injury. The present study demonstrated that the visual pathway is selectively affected in MOG35-55 induced murine EAE and these injuries are non-invasively detectable using λ∥ and λ⊥.

Background

Acquired copper deficiency in adults is associated with a subacute to chronic progressive myeloneuropathy and optic neuropathy.

Objective

To describe an individual after gastric bypass surgery who developed a chronic progressive myeloneuropathy, an acute optic neuropathy, along with anemia and leukopenia.

Design

Case report.

Setting

Academic center.

Patient

A 55-year-old woman, following gastric bypass surgery 22 years earlier, developed progressive numbness, weakness, and sphincter disturbance over 6 years. She awoke one morning with bilateral blindness. Examination findings showed evidence of severe myelopathy and peripheral neuropathy.

Main Outcome Measures

Magnetic resonance imaging, optical coherence tomography, electrophysiologic studies, nerve and muscle biopsy specimens, and vision testing.

Results

Over 1 year of follow-up, copper infusion therapy seemed to stabilize the progressive myeloneuropathy and improved leukopenia and anemia. It had no effect on the optic neuropathy. Optic nerve tissue injury was observed on magnetic resonance diffusion tensor imaging and on optical coherence tomography.

Conclusions

Copper deficiency should be considered in cases of atypical optic neuropathy. Serum copper levels should be monitored in patients with a compatible neurologic syndrome who have undergone gastric bypass surgery. Although visual acuity did not improve after copper infusion in our patient, prompt recognition of copper deficiency may prevent further deterioration.

Progranulin has recently attracted attention due to the discovery of mutations in its encoding gene (GRN) in several cases of frontotemporal lobar degeneration, but also for a possible role in inflammatory processes. In adult central nervous system, GRN mRNA is expressed in forebrain, olfactory bulbs and spinal cord. Progranulin cerebrospinal fluid (CSF) levels were evaluated in 55 patients with multiple sclerosis (MS) as well as in 35 subjects with non-inflammatory neurological diseases (NIND), 7 individuals with other inflammatory neurological disease (OIND) and 8 controls (CON), matched for ethnic background, gender and age. No statistically significant differences were found in patients compared with either NIND, OIND or CON (P > 0.05), even stratifying according to disease subtype or gender. A positive correlation between progranulin CSF levels and age was observed in patients (ρ = 0.29, P = 0.03). According to these data, progranulin does not likely play a major role in the pathogenesis of MS.

Triggering receptor expressed on myeloid cells 2 (TREM-2) is a membrane-bound receptor expressed by microglia and macrophages. Engagement of TREM-2 on these cells has been reported to reduce inflammatory responses and, in microglial cells, to promote phagocytosis. TREM-2 function is critical within the CNS, as its genetic deficiency in humans causes neurodegeneration with myelin and axonal loss. Blockade of TREM-2 worsened the mouse model for multiple sclerosis. In the present study, a soluble form of TREM-2 protein has been identified by immunoprecipitation and by ELISA. Soluble TREM-2 protein (sTREM-2) was detected in human CSF, and was compared among subjects with relapsing-remitting multiple sclerosis (RR-MS; n = 52), primary progressive multiple sclerosis (PP-MS; n = 21), other inflammatory neurologic diseases (OIND; n = 19), and non-inflammatory neurologic diseases (NIND; n = 41). Compared to NIND subjects, CSF sTREM-2 levels were significantly higher in RR-MS (P = 0.004 by ANOVA) and PP-MS (P < 0.001) subjects, as well as in OIND (P < 0.001) subjects. In contrast, levels of sTREM-2 in blood did not differ among the groups. Furthermore, TREM-2 was detected on a subset of CSF monocytes by flow cytometry, and was also highly expressed on myelin-laden macrophages in eight active demyelinating lesions from four autopsied multiple sclerosis subjects. The elevated levels of sTREM-2 in CSF of multiple sclerosis patients may inhibit the anti-inflammatory function of the membrane-bound receptor suggesting sTREM-2 to be a possible target for future therapies.

Background

Demyelinating polyneuropathy is a debilitating, poorly understood disease that can exist in acute (Guillain-Barré syndrome) or chronic forms. Interleukin-10 (IL-10), although traditionally considered an anti-inflammatory cytokine, has also been implicated in promoting abnormal angiogenesis in the eye and in the pathobiology of autoimmune diseases such as lupus and encephalomyelitis.

Principal Findings

Overexpression of IL-10 in a transgenic mouse model leads to macrophage-mediated demyelinating polyneuropathy. IL-10 upregulates ICAM-1 within neural tissues, promoting massive macrophage influx, inflammation-induced demyelination, and subsequent loss of neural tissue resulting in muscle weakness and paralysis. The primary insult is to perineural myelin followed by secondary axonal loss. Infiltrating macrophages within the peripheral nerves demonstrate a highly pro-inflammatory signature. Macrophages are central players in the pathophysiology, as in vivo depletion of macrophages using clodronate liposomes reverses the phenotype, including progressive nerve loss and paralysis. Macrophage-mediate demyelination is dependent on Fas-ligand (FasL)-mediated Schwann cell death.

Significance

These findings mimic the human disease chronic idiopathic demyelinating polyneuropathy (CIDP) and may also promote further understanding of the pathobiology of related conditions such as acute idiopathic demyelinating polyneuropathy (AIDP) or Guillain-Barré syndrome.

The dissociation between MRI and permanent disability in Multiple Sclerosis (MS), termed the clinicoradiological paradox, can largely be attributed to the lack of specificity of conventional, relaxivity-based MRI measurements in detecting axonal damage, the primary pathological correlate of long-term impairment in MS. Diffusion tensor imaging (DTI) has shown promise in specifically detecting axonal damage and demyelination in MS and its animal model, experimental autoimmune encephalomyelitis (EAE). In order to quantify the specificity of DTI in detecting axonal injury, in vivo DTI maps from the spinal cords of mice with EAE and quantitative histological maps were both registered to a common space. A pixelwise correlation analysis between DTI parameters, histological metrics, and EAE scores revealed a significant correlation between the water diffusion parallel to the white matter fibers, or axial diffusivity, and EAE score. Furthermore, axial diffusivity was the primary correlate of quantitative staining for neurofilaments (SMI31), markers of axonal integrity. Both axial diffusivity and neurofilament staining were decreased throughout the entire white matter, not solely within the demyelinated lesions seen in EAE. In contrast, although anisotropy was significantly correlated with EAE score, it was not correlated with axonal damage. The results demonstrate a strong, quantitative relationship between axial diffusivity and axonal damage and show that anisotropy is not specific for axonal damage following inflammatory demyelination.

The role of B cells and antibody in Experimental Autoimmune Encephalomyelitis (EAE) appears to differ based on the identity and state (protein vs. encephalitogenic peptide) of the inducing antigen and the strain of mouse utilized. The involvement of B cells in the induction of EAE by peptides of proteolipid protein (PLP) in BALB/c mice was investigated. Wild-type and B cell-deficient (B cell−/−) mice on the BALB/c background were immunized with overlapping PLP peptides, and the disease course was followed. Although incidence and onset of PLP180–199-induced EAE was similar in WT and B cell−/− mice, the clinical course was more severe in B cell−/− mice. During acute disease, proliferation and interferon-γ production by lymphoid cells from both strains were similar and were elicited predominantly in response to the immunizing antigen. However, during chronic disease lymphoid cells isolated from B cell−/− mice proliferated to a greater extent and produced more interferon-γ in response to the overlapping peptide PLP185–206 and to the smaller internal peptide PLP185–199 than did WT mice. These data suggest that B cells regulate PLP-induced EAE in BALB/c mice through control of epitope spreading.

Wallerian degeneration plays a significant role in many central nervous system (CNS) diseases. Tracking the progression of Wallerian degeneration may provide better understanding of the evolution of many CNS diseases. In this study, a 28-day longitudinal in vivo DTI of optic nerve (ON) and optic tract (OT) was conducted to evaluate the temporal and spatial evolution of Wallerian degeneration resulting from the transient retinal ischemia. At 3 − 28 days after ischemia, ipsilateral ON and contralateral OT showed significant reduction in axial diffusivity (32 − 40% and 21 − 29% respectively) suggestive of axonal damage. Both ON and OT showed significant increase in radial diffusivity, 200 − 290% and 58 − 65% in ON and OT respectively, at 9 − 28 days suggestive of myelin damage. Immuohistochmistry of phosphorylated neurofilament (pNF) and myelin basic protein (MBP) was performed to assess axonal and myelin integrities validating the DTI findings. Both DTI and immunohistochemistry detected that transient retinal ischemia caused more severe damage to ON than to OT. The current results suggest that axial and radial diffusivities are capable of reflecting the severity of axonal and myelin damage in mice as assessed using immunohistochemistry.

Optic nerve is often affected in patients with glaucoma and multiple sclerosis (MS). Conventional MRI can detect nerve damage but it does not accurately assess the underlying pathologies. Mean diffusivity and diffusion anisotropy indices derived from diffusion tensor imaging (DTI) have been shown to be sensitive to a variety of central nervous system (CNS) white matter pathologies. Despite being sensitive, the lack of specificity limits the ability of these measures to differentiate the underlying pathology in CNS white matter tissues. Directional (axial and radial) diffusivities, measuring water diffusion parallel and perpendicular to the axonal tracts, have been shown to be specific to axonal and myelin damages in mouse models of optic nerve injury, including retinal ischemia and experimental autoimmune encephalomyelitis (EAE). The progression of Wallerian degeneration has also been detected using directional diffusivities after retinal ischemia. However, translating these findings to human optic nerve is technically challenging. The current status of human optic nerve diffusion MRI, including the imaging sequences and protocols, are summarized herein. Despite lacking a consensus of the optimal sequence or protocol among different groups, increased mean diffusivity and decreased diffusion anisotropy has been observed in injured optic nerve from chronic optic neuritis patients. Decreased λ∥, correlating with visual function and recovery, was observed recently in acute optic neuritis patients in a pilot study, suggesting the specificity of λ∥ to axonal injury. From different mouse models of optic nerve injuries to the emerging studies on optic neuritis patients, directional diffusivities demonstrate great potential to be specific biomarkers for axonal and myelin injury.