Inflammatory Spinal Cord Lesions Research Articles

Clinical, Radiological, and Laboratory Features of Spinal Cord Involvement in Primary Sjögren's Syndrome.

Objective: To identify radiological and laboratory hallmarks in patients with primary Sjögren’s syndrome (pSS) presenting with spinal cord involvement. Methods: Clinical and laboratory routine parameters were analyzed in a retrospective multicenter case series of four patients who developed myelitis associated with pSS. Serological and cerebrospinal fluid (CSF) measurements of pSS associated anti-SSA(Ro)-antibodies were initiated, and CSF neurofilament light chain (NFL) levels were assessed. NFL values were compared with results from 15 sex- and age-matched healthy controls. Radiological assessment was performed using multi-sequence spinal cord magnetic resonance imaging. Results: Three of the four patients initially developed neurological signs suggestive of myelitis and were subsequently diagnosed with pSS. All patients presented a longitudinal spinal T2-hyperintense lesion in the cervical spinal cord, whereas only two patients showed pleocytosis and oligoclonal bands in the CSF. Median (range) CSF-NFL levels were significantly elevated in patients compared to controls (6672 pg/mL (621–50,000) vs. 585 pg/mL (357–729), p = 0.009). One patient showed sustained, highly increased NFL levels (50,000 pg/mL) in the initial assessment when radiological signs of axonal injury were still absent. Anti-SSA(Ro)-antibodies were found in the serum of three patients, while two patients additionally presented intrathecal anti-SSA(Ro)-antibody production. Elevated CSF-NFL levels and intrathecal synthesis of anti-SSA(Ro)-antibodies were associated with a relapsing and treatment-resistant disease course. Conclusion: Inflammatory spinal cord lesions associated with pSS are a rare but serious disease leading to severe disability. NFL and anti-SSA(Ro)-antibodies in CSF might serve as prognostic biomarkers and should be routinely assessed in patients with pSS.

Syringomyelia-like syndrome in neuromyelitis optica spectrum disorder complicated with Sjogren\u2019s syndrome: a case report

BackgroundBesides CSF-flow obstruction, syringomyelia is associated with inflammatory spinal cord lesions. However, syringomyelia-like syndrome concomitant with neuromyelitis optica spectrum disorder (NMOSD) and primary Sjogren’s syndrome (pSS) is extremely rare. Here, we would like to report a case of a patient with syringomyelia-like syndrome in NMOSD complicated with Sjogren’s Syndrome.Case presentationA 64-old male Han Chinese, presented with three episodes of acute demyelinating processes in the central nervous system within 5 years. Firstly, he presented with ascending left lower extremity weakness and numbness, and initially progressive loss of vision in the right eye before 5 years, and subsequently in the right eye 2 months later. High dose corticosteroid therapy was prescribed for this attack. Second, he suffered from refractory gastrointestinal symptoms.such as nausea, vomiting, abdominal pain and early satiety. After the second episode, he received long-term azathioprine and prednisone treatment in low dosages. Six months before admission, he developed the lower back pain and numbness in lower limbs, and urinary incontinence. This time, he complained of acute onset of right lower limb paralysis, paresthesia and urinary incontinence. MRI of the spine revealed a syringomyelia extending from the C7 to T4 levels with serum positive anti-aquaporin-4 antibodies (AQP4-Ab) (indirect immunofluorescence on AQP4 transfected cells). he was serologically positive for both anti-Sjögren’s syndrome-related antigen A and B antibodies and there was reduced salivary flow on scintigraphy. Lip salivary gland (LSG) biopsies were graded (grade four lymphocytic infiltration) according to the Chisholm and Mason classification system and by morphometric analysis. And finally, diagnosed as syringomyelia-like syndrome in NMOSD complicated with Sjogren’s syndrome.ConclusionsAlthough extremely rare, This index patient highlights that syringomyelia could be associated with underlying NMOSD and pSS, and autoimmune disorders should be considered in the initial differential diagnosis, This is very helpful for the therapeutic implications and evaluating curative effect.

Longitudinally extensive transverse myelitis: A retrospective analysis of sixty-four patients at tertiary care center of North-West India

ObjectivesTo evaluate the demographic profile, clinical presentations, laboratory parameters and etiologies of longitudinally extensive transverse myelitis (LETM) patients in Indian population. Patients and methodsLETM is characterized by contiguous inflammatory lesions of spinal cord extending to three or more vertebral segments. Neuromyelitis optica (NMO) is the most common cause of LETM. In clinical practice, both LETM and NMO are thought to be synonymous with each other because of their very frequent association. Other causes of LETM are infective, neoplastic, autoimmune diseases and connective tissue disorders. All other causes should be ruled out before making the diagnosis of NMO in LETM patients. We conducted a retrospective study from August 2010 to February 2016 and analyzed various demographic profile, clinical presentations, laboratory parameters and etiologies in sixty-four patients of LETM. ResultsIn our series, majority of the patients presented with acute bladder dysfunction and paraparesis. Twenty-one patients (32.81%) were clinically diagnosed as NMO, out of which thirteen patients were found to have positive serum NMO antibody. Other etiologies of LETM in our series were multiple sclerosis [9 patients], acute disseminated encephalomyelitis (ADEM) [6 patients], postinfectious [5 patient], subacute combined degeneration (SCD) [4 patient], tuberculous myelitis [4 patients], spinal arteriovenous malformation (AVM) [3 patient] and systemic lupus erythematosus (SLE) [3 patient], respectively. In nine patients, cause could not be ascribed despite thorough investigations. ConclusionLETM is a heterogeneous disorder with a varied clinical feature, etiologies and outcome. Even the LETM patients who presented with optic neuritis do not necessarily have NMO. Therefore, the diagnosis of NMO should be made only after excluding other causes of LETM. The presence of NMO-Ab (Aquaporin 4-Ab) predicts the increased risk of recurrence of LETM or conversion to NMO.

Transmembrane tumour necrosis factor is neuroprotective and regulates experimental autoimmune encephalomyelitis via neuronal nuclear factor-κB

Tumour necrosis factor mediates chronic inflammatory pathologies including those affecting the central nervous system, but non-selective tumour necrosis factor inhibitors exacerbate multiple sclerosis. In addition, TNF receptor SF1A, which encodes one of the tumour necrosis factor receptors, has recently been identified as a multiple sclerosis susceptibility locus in genome-wide association studies in large patient cohorts. These clinical data have emphasized the need for a better understanding of the beneficial effects of tumour necrosis factor during central nervous system inflammation. In this study, we present evidence that the soluble and transmembrane forms of tumour necrosis factor exert opposing deleterious and beneficial effects, respectively, in a multiple sclerosis model. We compared the effects, in experimental autoimmune encephalomyelitis, of selectively inhibiting soluble tumour necrosis factor, and of both soluble and transmembrane tumour necrosis factor. Blocking the action of soluble tumour necrosis factor, but not of soluble tumour necrosis factor and transmembrane tumour necrosis factor, protected mice against the clinical symptoms of experimental autoimmune encephalomyelitis. Therapeutic benefit was independent of changes in antigen-specific immune responses and focal inflammatory spinal cord lesions, but was associated with reduced overall central nervous system immunoreactivity, increased expression of neuroprotective molecules, and was dependent upon the activity of neuronal nuclear factor-κB, a downstream mediator of neuroprotective tumour necrosis factor/tumour necrosis factor receptor signalling, because mice lacking IκB kinase β in glutamatergic neurons were not protected by soluble tumour necrosis factor blockade. Furthermore, blocking the action of soluble tumour necrosis factor, but not of soluble tumour necrosis factor and transmembrane tumour necrosis factor, protected neurons in astrocyte-neuron co-cultures against glucose deprivation, an in vitro neurodegeneration model relevant for multiple sclerosis, and this was dependent upon contact between the two cell types. Our results show that soluble tumour necrosis factor promotes central nervous system inflammation, while transmembrane tumour necrosis factor is neuroprotective, and suggest that selective inhibition of soluble tumour necrosis factor may provide a new way forward for the treatment of multiple sclerosis and possibly other inflammatory central nervous system disorders.

Human glial-restricted progenitors survive, proliferate, and preserve electrophysiological function in rats with focal inflammatory spinal cord demyelination

Transplantation of glial progenitor cells results in transplant-derived myelination and improved function in rodents with genetic dysmyelination or chemical demyelination. However, glial cell transplantation in adult CNS inflammatory demyelinating models has not been well studied. Here we transplanted human glial-restricted progenitor (hGRP) cells into the spinal cord of adult rats with inflammatory demyelination, and monitored cell fate in chemically immunosuppressed animals. We found that hGRPs migrate extensively, expand within inflammatory spinal cord lesions, do not form tumors, and adopt a mature glial phenotype, albeit at a low rate. Human GRP-transplanted rats, but not controls, exhibited preserved electrophysiological conduction across the spinal cord, though no differences in behavioral improvement were noted between the two groups. Although these hGRPs myelinated extensively after implantation into neonatal shiverer mouse brain, only marginal remyelination was observed in the inflammatory spinal cord demyelination model. The low rate of transplant-derived myelination in adult rat spinal cord may reflect host age, species, transplant environment/location, and/or immune suppression regime differences. We conclude that hGRPs have the capacity to myelinate dysmyelinated neonatal rodent brain and preserve conduction in the inflammatory demyelinated adult rodent spinal cord. The latter benefit is likely dependent on trophic support and suggests further exploration of potential of glial progenitors in animal models of chronic inflammatory demyelination.

Diffusion-weighted imaging in noncompressive myelopathies: a 33-patient prospective study

Diffusion-weighted imaging (DWI) is frequently used to differentiate cerebral lesions. The aim of our study was to evaluate the diagnostic value of DWI and the measurement of the apparent diffusion coefficient (ADC) in noncompressive myelopathy explorations. Thirty-three patients presenting a spinal cord syndrome due to a noncompressive myelopathy underwent spinal cord MRI between September 2005 and November 2008. For each patient, the ADC was calculated in the pathological spinal cord. ADC values were also measured in the healthy spinal cord of ten control subjects. Statistical analysis was based on the Student's t test. Twenty-one patients presented an inflammatory myelopathy: Nine patients presented multiple sclerosis, three patients presented a parainfectious myelopathy, two patients acute disseminated encephalomyelitis, one patient neuromyelitis optica, one patient systemic lupus erythematosus, and five patients a myelopathy of unknown aetiology. Six patients presented a spinal cord infarction. ADC values were significantly lower in spinal cord infarct (mean ADC = 0.81 +/- 0.08 x 10(-3) mm(2)/s) than in inflammatory spinal cord lesions (mean ADC = 1.37 +/- 0.23 x 10(-3) mm(2)/s) and in healthy control spinal cord (mean ADC = 0.93 +/- 0.07 x 10(-3) mm(2)/s). These results are important to differentiate ischaemic from inflammatory myelopathies, especially at the acute phase when clinical presentation and extensive work-up are not able to show an aetiologic diagnosis. Although these results are similar to those described in cerebral explorations, ADC measurements remain technically limited for the moment.

Patient with neuromyelitis optica and inflammatory demyelinating lesions comprising whole spinal cord from C2 level till conus: case report

BackgroundNeuromyelitis optica (NMO) is an idiopathic, severe, inflammatory demyelinating disease of the central nervous system, that causes severe optic neuritis and myelitis attacks. Early discrimination between multiple sclerosis (MS) and NMO is important, as optimum treatment for both diseases may differ considerably.Case PresentationWe report a case of a patient who initially presented as longitudinally extensive transverse myelitis (LETM), having spastic upper extremities diparesis and spastic paraplegia, C2/C3 sensory level and urinary incontinence, as well as extensive inflammatory spinal cord lesions from C2 level to conus. After 5 months the patient had another attack of transverse myelitis, had electrophysiological findings consistent with optic neuritis, was seropositive for NMO-IgG (aquaporin-4 IgG) and thus fulfilled NMO diagnostic criteria. Following treatment of disease attacks with pulse corticosteroid therapy and intravenous immunoglobulins, we included oral azathioprine in a combination with oral prednisone in the therapy. Since there was no significant clinical improvement, we decided to use cyclophosphamide therapy, which resulted in good clinical improvement and gradual decrease of cord swelling.ConclusionIn this NMO case report we wanted to emphasize the extensiveness of inflammatory spinal cord changes in our patient, from C2 level to conus. In the conclusion it is important to say that accurate, early diagnosis and distinction from MS is critical to facilitate initiation of immunosuppressive therapy for attack prevention.

CNS inflammation and neuronal degeneration is aggravated by impaired CD200–CD200R-mediated macrophage silencing

Multiple sclerosis is a chronic disabling CNS disorder, characterized by autoimmune inflammatory demyelination and neurodegeneration. CD200, broadly expressed on neurons and endothelial cells, mediates inhibitory signals through its receptor, CD200R, on cells of myeloid origin. Antibody-mediated blockade of CD200R leads to an aggravated clinical course of rodent experimental autoimmune encephalomyelitis in vivo, accompanied by profoundly augmented cellular infiltrates consisting of T cells and activated iNOS+ macrophages in inflammatory spinal cord lesions. In vitro blockade of CD200R on macrophages leads to enhanced IFN-γ-induced release of IL6 and neuronal cell death in co-cultures with hippocampal neurons expressing CD200. CD200 and its receptor could also be detected on neurons and macrophages in human MS plaques. Therefore the CD200–CD200R pathway seems of critical relevance for macrophage-mediated damage in autoimmune inflammation of the CNS.

Inflammatory Myelopathies and Traumatic Spinal Cord Lesions: Comparison of Functional and Neurological Outcomes

Outcomes knowledge is essential to answer patients' questions regarding function, to plan the use of resources, and to evaluate treatments to enhance recovery. The purpose of this study was to compare the outcomes of patients with traumatic spinal cord injury (SCI) with those of patients with inflammatory spinal cord lesions (ISCLs). The authors evaluated 181 subjects with traumatic SCI and 67 subjects with ISCLs. Using a matching cohorts procedure, 38 subjects were selected from each group. The measures used were the American Spinal Injury Association (ASIA) Impairment Scale (motor function), the Barthel Index (BI), the Rivermead Mobility Index (RMI), and the Walking Index for Spinal Cord Injury (WISCI). The subjects in the ISCL group were older than those in the SCI group, with a longer interval from onset of lesion to rehabilitation admission and more incomplete lesions. In the matching cohorts, at admission, the traumatic SCI group had RMI and WISCI scores comparable to those of the ISCL group, but the traumatic SCI group had lower scores on the BI (greater dependence on assistance for activities of daily living). At discharge, the 2 groups had comparable functional outcomes. The neurological status of the 2 groups was comparable at admission and discharge. The results indicate that, at admission, patients with SCI have a greater physical dependence for assistance with activities of daily living than patients with ISCLs who have comparable neurological status. Such a difference depends on factors not related to the spinal cord lesion, such as the presence of associated lesions, the need to wear an orthotic device, or the sequelae of surgery. The outcomes of patients with SCI are determined more by factors such as lesion level and severity and age than by etiology. This finding could have implications for health care planning and rehabilitation research.

Pathogenetic role of myelitis for syringomyelia

Background CSF-flow obstruction is regarded as a mandatory factor for the development of syringomyelia. However, there are conditions in which syringomyelia is not associated with evident persistent CSF-flow obstruction, as in the case of inflammatory spinal cord lesions. In these instances we hypothesize that the accumulation of vasogenic edema may play a role in the development of the syrinx. Recently proposed theories underline, even in the event of CSF-flow obstructions, a major role for the accumulation and final coalescence of interstitial spinal fluid, rather than CSF penetration through the spinal cord. Aim To clarify the relationship between syrinx development and spinal cord inflammation, through the analysis of the role of intrinsic medullary factors versus CSF-flow block. Methods A prospective case series including patients with transient syringomyelia associated with different examples of non-infectious myelitis: sarcoidosis, post-infectious transverse myelitis, Devic's disease and multiple sclerosis. Cavitations resulting from cystic myelomalacia were excluded. CSF-flow block was assessed by structural MRI. Results Syringes associated with myelitis shared some common features: they developed during the acute phase of myelitis and disappeared after steroids, were all non-communicating cavitations involving the central canal, and occurred in the same spinal segment affected by myelitis. CSF-flow obstruction was detected in one patient (Chiari I malformation), while in the other three patients we could not detect anatomical predispositions. Conclusion Only one patient had structural abnormalities, though without evidence of a pathogenetic role in itself: however, CSF space obstruction and reduced CSF compliance could have accelerated the development of syringomyelia triggered by intramedullary inflammation. The clinical and radiological features in this patient are consistent with the label “presyringomyelia”. The absence of any anatomical predisposition in the other patients suggests a major pathophysiological role for intrinsic medullary mechanisms, including blood–spinal cord barrier breakdown, impairment of extracellular fluid drainage, and leakage of subarachnoidal CSF into the nervous tissue.

TREM2-Transduced Myeloid Precursors Mediate Nervous Tissue Debris Clearance and Facilitate Recovery in an Animal Model of Multiple Sclerosis

BackgroundIn multiple sclerosis, inflammation can successfully be prevented, while promoting repair is still a major challenge. Microglial cells, the resident phagocytes of the central nervous system (CNS), are hematopoietic-derived myeloid cells and express the triggering receptor expressed on myeloid cells 2 (TREM2), an innate immune receptor. Myeloid cells are an accessible source for ex vivo gene therapy. We investigated whether myeloid precursor cells genetically modified to express TREM2 affect the disease course of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis.Methods and FindingsEAE was induced in mice by immunization with a myelin autoantigen. Intravenous application of TREM2-transduced bone marrow–derived myeloid precursor cells at the EAE peak led to an amelioration of clinical symptoms, reduction in axonal damage, and prevention of further demyelination. TREM2-transduced myeloid cells applied intravenously migrated into the inflammatory spinal cord lesions of EAE-diseased mice, showed increased lysosomal and phagocytic activity, cleared degenerated myelin, and created an anti-inflammatory cytokine milieu within the CNS.ConclusionsIntravenously applied bone marrow–derived and TREM2-tranduced myeloid precursor cells limit tissue destruction and facilitate repair within the murine CNS by clearance of cellular debris during EAE. TREM2 is a new attractive target for promotion of repair and resolution of inflammation in multiple sclerosis and other neuroinflammatory diseases.

Treatment of Passive Experimental Autoimmune Encephalomyelitis in SJL Mice with a Recombinant TCR Ligand Induces IL-13 and Prevents Axonal Injury

The major goal of this study was to evaluate the efficacy and mechanism of a rTCR ligand (RTL) construct (I-A(s)/proteolipid protein (PLP)-139-151 peptide = RTL401) for treatment of SJL/J mice developing passive experimental autoimmune encephalomyelitis (EAE) that did not involve coimmunization with the highly inflammatory CFA. Our results demonstrated clearly that RTL401 was highly effective in treating passive EAE, with kinetics of recovery from disease very similar to treatment of actively induced EAE. The potent RTL401 treatment effect was reflected by a partial reduction of infiltrating mononuclear cells into CNS, minimal inflammatory lesions in spinal cord, and preservation of axons injured in vehicle-treated mice during the progression of EAE. Interestingly, in the absence of CFA, RTL401 treatment strongly enhanced production of the Th2 cytokine, IL-13, in spleen, blood, and spinal cord tissue, with variable effects on other Th1 and Th2 cytokines, and no significant effect on the Th3 cytokine, TGF-beta1, or on FoxP3 that is expressed by regulatory T cells. Moreover, pretreatment of PLP-139-151-specific T cells with RTL401 in vitro induced high levels of secreted IL-13, with lesser induction of other pro- and anti-inflammatory cytokines. Given the importance of IL-13 for protection against EAE, these data strongly implicate IL-13 as a dominant regulatory cytokine induced by RTL therapy. Pronounced IL-13 levels coupled with marked reduction in IL-6 levels secreted by PLP-specific T cells from blood after treatment of mice with RTL401 indicate that IL-13 and IL-6 may be useful markers for following effects of RTL therapy in future clinical trials in multiple sclerosis.

The type IV phosphodiesterase specific inhibitor mesopram inhibits experimental autoimmune encephalomyelitis in rodents

Experimental autoimmune encephalomyelitis (EAE) is an autoimmune disease with pathological features reminiscent of those seen in multiple sclerosis and thus serves as an animal model for this disease. Inhibition of type IV phosphodiesterase (PDE IV) in animals with this disease has been shown to result in amelioration of disease symptoms. Here we describe the immunomodulatory activity of the novel potent and selective PDE IV inhibitor mesopram. In vitro, mesopram selectively inhibits the activity of type 1 helper T (Th1) cells without affecting cytokine production or proliferation of type 2 helper T (Th2) cells. Administration of mesopram to rodents inhibits EAE in various models. Clinically, EAE is completely suppressed by mesopram in Lewis rats. This is accompanied by a reduction of inflammatory lesions in spinal cord and brain. RT-PCR analysis revealed a marked reduction in the expression of interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) in the brains of these animals. Furthermore, the ex vivo production of Th1 cytokines by activated spleen cells derived from mesopram-treated animals is significantly reduced compared to vehicle-treated controls. Amelioration of the clinical symptoms is also observed during chronic EAE in mesopram-treated SJL mice as well as in relapsing–remitting EAE in SWXJ mice using a therapeutic treatment regimen. These data demonstrate the anti-inflammatory activity of mesopram and provide a rationale for its clinical development.

Presence of T cells with activated and memory phenotypes in inflammatory spinal cord lesions.

The phenotypic and functional characteristics of activated T cells and recruited unactivated T cells at an inflammatory site were examined using a V beta 4+ myelin basic protein-specific T cell clone in a passively transferred model of experimental allergic encephalomyelitis. A high percentage of the T cells isolated from the central nervous system (CNS) were V beta 4+. This population exhibited the characteristics of activated T cells based on the proportion of cells in the blast state, their ability to proliferate in response to IL-2 or CNS Ag, and their expression of activation/memory cell markers. Activated V beta 4+ T cells were also observed in the periphery. Large numbers of V beta 4- T cells, which are entirely host-recruited, were also found in the CNS, where they demonstrated the properties of memory cells. There were differences in adhesion molecule expression between CNS V beta 4+ T cells and peripheral V beta 4+ T cells, although both populations were in activated state. V beta 4+ T cells at the site of Ag expression (the spinal cord) demonstrated higher levels of LFA-1 and CD44, but lower levels of VLA-4 and intercellular adhesion molecule-1, than did V beta 4+ T cells in the spleen. In contrast, the levels of all of these adhesion molecules on recruited V beta 4- T cells were higher in the CNS than in the periphery. This experimental model allows the detailed characterization of different T cell populations isolated from the same inflammatory site.

Identification and quantitation of T lymphocyte subsets found in the spinal cord of the Lewis rat during acute experimental allergic encephalomyelitis.

Monoclonal antibodies specific for different rat T cell subsets and Ia-positive cells were used in a quantitative morphologic study of the cellular infiltrates in the spinal cords of Lewis rats during acute, actively induced experimental allergic encephalomyelitis (EAE). The predominant cell types in the inflammatory spinal cord lesions are W3/25-positive and Ia-positive cells. The relative percentages represented by each cell type remain quite constant regardless of the degree of clinical illness exhibited by the rat. These data demonstrate a quantitative profile of the infiltrating cells in acute, active EAE, and suggest that the principal inflammatory cells in these lesions are T helper cells and Ia-bearing cells (macrophages, B cells, or activated T helper cells).