Increased IL-2 and Reduced TGF-ß Upon T-Cell Stimulation are Associated with GM-CSF Upregulation in Multiple Immune Cell Types in Multiple Sclerosis.

Granulocyte macrophage colony stimulating factor (GM-CSF) is a pro-inflammatory cytokine produced by immune cells. Recent evidence suggests that GM-CSF plays an important role in multiple sclerosis (MS) pathogenesis. We investigated the expression and regulation of GM-CSF in different immune cells in MS. We also investigated the differentiation and frequency of GM-CSF-producing Th cells that do not co-express interferon (IFN)-γ or interleukin-17 (IL-17) (Th-GM cells) in MS. We found a significant increase in the percentage of GM-CSF-expressing Th cells, Th1 cells, Th-GM cells, cytotoxic T (Tc) cells, monocytes, natural killer (NK) cells, and B cells in PBMC from MS patients stimulated with T cell stimuli. Stimulated PBMC culture supernatants from MS patients contained significantly higher levels of IL-2, IL-12, IL-1ß, and GM-CSF and significantly lower levels of transforming growth factor (TGF-)ß. Blocking IL-2 reduced the frequency of Th-GM cells in PBMC from MS patients. The frequency of Th-GM cells differentiated in vitro from naïve CD4+ T cells was significantly higher in MS patients and was further increased in MS with IL-2 stimulation. These findings suggest that all main immune cell subsets produce more GM-CSF in MS after in vitro stimulation, which is associated with defective TGF-ß and increased IL-2 and IL-12 production. Th-GM cells are increased in MS. GM-CSF may be a potential therapeutic target in MS.

Single Test to ARrive at Multiple Sclerosis (STAR-MS) diagnosis: A prospective pilot study assessing the accuracy of the central vein sign in predicting multiple sclerosis in cases of diagnostic uncertainty.

BACKGROUND: Misdiagnosis is common in multiple sclerosis (MS) as a proportion of patients present with atypical clinical/magnetic resonance imaging (MRI) findings. The central vein sign has the potential to be a non-invasive, MS-specific biomarker. OBJECTIVE: To test the accuracy of the central vein sign in predicting a diagnosis of MS in patients with diagnostic uncertainty at disease presentation using T2*-weighted, 3 T MRI. METHODS: In this prospective pilot study, we recruited individuals with symptoms unusual for MS but with brain MRI consistent with the disease, and those with a typical clinical presentation of MS whose MRI did not suggest MS. We calculated the proportion of lesions with central veins for each patient and compared the results to the eventual clinical diagnoses. The optimal central vein threshold for diagnosis was established. RESULTS: Thirty-eight patients were scanned, 35 of whom have received a clinical diagnosis. Median percentage of lesions with central veins was 51% in MS and 28% in non-MS. A threshold of 40.7% lesions with central veins resulted in 100% sensitivity and 73.9% specificity. CONCLUSION: The central vein sign assessed with a clinically available T2* scan can successfully diagnose MS in cases of diagnostic uncertainty. The central vein sign should be considered as a diagnostic biomarker in MS.

The MRI central vein marker; differentiating PPMS from RRMS and ischemic SVD.

OBJECTIVE: To determine whether the assessment of brain white matter lesion (WML) central veins differentiate patients with primary progressive MS (PPMS) from relapsing-remitting MS (RRMS) and ischemic small vessel disease (SVD) using 3T MRI. METHODS: In this cross-sectional study, 71 patients with PPMS, RRMS, and SVD were imaged using a T2*-weighted sequence. Two blinded raters identified the total number of WMLs, proportion of WMLs in periventricular, deep white matter (DWM) and juxtacortical regions, and proportion of WMLs with central veins in all patient groups. The proportions were compared between disease groups, including effect sizes. MS or SVD was categorized using a threshold of ≥40% WMLs with central veins as indicative of MS. Interrater and intrarater reproducibility was calculated. RESULTS: The mean proportion of WMLs with central veins was 68.4% in PPMS, 74.3% in RRMS, and 4.7% in SVD. The difference in proportions between PPMS and SVD groups was significant (p < 0.0005; effect size: 3.8) but not significant between MS subtypes (p = 0.3; effect size: 0.29). Distribution of WMLs was similar across both MS groups, but despite SVD patients having more DWM lesions than PPMS patients, proportions of WMLs with central veins remained low (2.75% in SVD; 62.5% in PPMS). Interrater and intrarater reproducibility comparing proportions of WMLs with central veins across all patients was 0.86 and 0.90, respectively. Level of agreement between the proportion of WML central veins and established diagnosis was 0.84 and 0.82 for each rater. CONCLUSIONS: WML central veins could be used to differentiate PPMS from SVD but not between MS subtypes.

The Central Vein Sign in Multiple Sclerosis Lesions Is Present Irrespective of the T2* Sequence at 3 T.

BACKGROUND AND PURPOSE: Previous T2*-weighted magnetic resonance imaging (MRI) studies have used white matter lesion (WML) central veins to distinguish multiple sclerosis (MS) from its mimics. To be clinically applicable, the "central vein sign" needs to be detectable across different T2* sequences. Our objective was to determine if the central vein sign is reliably present in MS and absent in patients with ischemic small vessel disease (SVD) across different T2* sequences at 3T MRI. METHODS: Ten patients with MS and 10 with SVD were each scanned on a 3 T Philips and GE scanner. The MRI protocol included 3-dimensional (3D) T2* GRE, T2* with high echo planar imaging (EPI) factor and susceptibility-weighted angiography (SWAN). Total WML numbers, central vein numbers, and proportion of WMLs with central veins were calculated using each sequence. Three blinded raters identified a subset of six WMLs with central veins to diagnose MS or SVD. RESULTS: Irrespective of the sequence, MS patients were identified based on a higher proportion of WMLs with central veins. This proportion was dependent on the T2* sequence used. T2* with high EPI allowed the highest median proportion (69.6%) in MS patients; 6.1% in SVD patients (P < .0004). Rater reproducibility varied depending on the T2* sequence used. T2* with high EPI produced good agreement with the clinical diagnosis (Cohen's kappa range; .78-.89), as did SWAN imaging with some raters; ĸ = .69. CONCLUSIONS: The central vein sign can diagnose MS in the clinical setting of modern 3T scanners. However, variations in the T2* sequences need to be considered when defining a threshold for diagnosis.

The central vein sign and its clinical evaluation for the diagnosis of multiple sclerosis: a consensus statement from the North American Imaging in Multiple Sclerosis Cooperative.

Over the past few years, MRI has become an indispensable tool for diagnosing multiple sclerosis (MS). However, the current MRI criteria for MS diagnosis have imperfect sensitivity and specificity. The central vein sign (CVS) has recently been proposed as a novel MRI biomarker to improve the accuracy and speed of MS diagnosis. Evidence indicates that the presence of the CVS in individual lesions can accurately differentiate MS from other diseases that mimic this condition. However, the predictive value of the CVS for the development of clinical MS in patients with suspected demyelinating disease is still unknown. Moreover, the lack of standardization for the definition and imaging of the CVS currently limits its clinical implementation and validation. On the basis of a thorough review of the existing literature on the CVS and the consensus opinion of the members of the North American Imaging in Multiple Sclerosis (NAIMS) Cooperative, this article provides statements and recommendations aimed at helping radiologists and neurologists to better understand, refine, standardize and evaluate the CVS in the diagnosis of MS.

Imaging central veins in brain lesions with 3-T T2*-weighted magnetic resonance imaging differentiates multiple sclerosis from microangiopathic brain lesions.

BACKGROUND: White matter lesions are frequently detected using brain magnetic resonance imaging (MRI) performed for various indications. Most are microangiopathic, but demyelination, including multiple sclerosis (MS), is an important cause; conventional MRI cannot always distinguish between these pathologies. The proportion of lesions with a central vein on 7-T T2*-weighted MRI prospectively distinguishes demyelination from microangiopathic lesions. OBJECTIVE: To test whether 3-T T2*-weighted MRI can differentiate MS from microangiopathic brain lesions. METHODS: A total of 40 patients were studied. Initially, a test cohort of 10 patients with MS and 10 patients with microangiopathic white matter lesions underwent 3-T T2*-weighted brain MRI. Anonymised scans were analysed blind to clinical data, and simple diagnostic rules were devised. These rules were applied to a validation cohort of 20 patients (13 with MS and 7 with microangiopathic lesions) by a blinded observer. RESULTS: Within the test cohort, all patients with MS had central veins visible in >45% of brain lesions, while the rest had central veins visible in <45% of lesions. By applying diagnostic rules to the validation cohort, all remaining patients were correctly categorised. CONCLUSION: 3-T T2*-weighted brain MRI distinguishes perivenous MS lesions from microangiopathic lesions. Clinical application of this technique could supplement existing diagnostic algorithms.

Lymphomatoid papulosis: A cutaneous lymphoproliferative disorder in a patient on fingolimod for multiple sclerosis.

BACKGROUND: Fingolimod was the first oral disease-modifying treatment for relapsing-remitting multiple sclerosis. It has previously been associated with the development of lymphoma. OBJECTIVE: To describe a case of lymphomatoid papulosis, a CD30+ cutaneous lymphoproliferative disorder, in a patient taking fingolimod. METHODS: Case study. RESULTS: Our patient developed lymphomatoid papulosis 2 months after starting fingolimod. Histology confirmed the diagnosis. The drug was withdrawn. Resolution began only 2 days later. CONCLUSIONS: Lymphomatoid papulosis is a benign subtype of cutaneous T-cell lymphoma, but up to 20% of cases can transform to a malignant course. Patients on fingolimod and physicians caring for them should be mindful of the need to monitor the skin.

Thyrotoxic periodic paralysis: correct hypokalemia with caution.

BACKGROUND: Thyrotoxic periodic paralysis is rare in Caucasian populations, but affects approximately 2% of East Asians with thyrotoxicosis (13% of males, 0.17% of females). The presentation is characterized by abrupt-onset hypokalemia and profound proximal muscular weakness, and commonly occurs after carbohydrate loading or exercise. OBJECTIVES: To raise awareness of this condition through the description of a typical case of thyrotoxic periodic paralysis; to remind readers that, despite intravascular hypokalemia, total body potassium is normal and that correction must be done with caution; to highlight the differences in treatment compared to familial hypokalemic periodic paralysis. CASE REPORT: We describe the presentation of a 36-year-old Filipino man with a background history of Graves disease. Over-administration of intravenous potassium was narrowly averted in this case. CONCLUSION: It may be important to check thyroid function in patients presenting with acute paralysis, especially those of Asian origin. In patients with thyrotoxic periodic paralysis, administration of potassium, with cardiac monitoring and a total dose of <50 mmol, limits the dysrhythmia risk. Patients are likely to benefit from the prescription of non-selective beta-blockers until they become euthyroid. In contrast to familial periodic paralysis, regular oral potassium supplementation is ineffective in thyrotoxic periodic paralysis, and acetazolamide precipitates, rather than prevents, attacks.