Cerebrospinal fluid biomarkers for predicting development of multiple sclerosis in acute optic neuritis: a population-based prospective cohort study.

BACKGROUND: Long-term outcome in multiple sclerosis (MS) depends on early treatment. In patients with acute optic neuritis (ON), an early inflammatory event, we investigated markers in cerebrospinal fluid (CSF), which may predict a diagnosis of MS. METHODS: Forty patients with acute ON were recruited in a prospective population-based cohort with median 29 months (range 19-41) of follow-up. Paired CSF and serum samples were taken within 14 days (range 2-38), prior to treatment. Prospectively, 16/40 patients were by a uniform algorithm diagnosed with MS (MS-ON) and 24 patients continued to manifest isolated ON (ION) during follow-up. Levels of cytokines and neurofilament light chain (NF-L) were measured at the onset of acute ON and compared to healthy controls (HC). Significance levels were corrected for multiple comparisons ("q"). The predictive value of biomarkers was determined with multivariable prediction models using nomograms. RESULTS: CSF TNF-α, IL-10, and CXCL13 levels were increased in MS-ON compared to those in ION patients (q = 0.021, 0.004, and 0.0006, respectively). MS-ON patients had increased CSF pleocytosis, IgG indices, and oligoclonal bands (OCBs) compared to ION (q = 0.0007, q = 0.0058, and q = 0.0021, respectively). CSF levels of IL-10, TNF-a, IL-17A, and CXCL13 in MS-ON patients correlated with leukocyte counts (r > 0.69 and p < 0.002) and IgG index (r > 0.55, p < 0.037). CSF NF-L levels were increased in ON patients compared to those in HC (q = 0.0077). In MS-ON, a progressive increase in NF-L levels was observed at 7 to 14 days after disease onset (r = 0.73, p < 0.0065). Receiver-operating characteristic (ROC) curves for two multivariable prediction models were generated, with IL-10, CXCL13, and NF-L in one ("candidate") and IgG index, OCB, and leukocytes in another ("routine"). Area under the curve was 0.89 [95% CI 0.77-1] and 0.86 [0.74-0.98], respectively. Predictions of the risk of MS diagnosis were illustrated by two nomograms. CONCLUSIONS: CSF TNF-α, IL-10, CXCL13, and NF-L levels were associated with the development of MS, suggesting that the inflammatory and neurodegenerative processes occurred early. Based on subsequent diagnosis, we observed a high predictive value of routine and candidate biomarkers in CSF for the development of MS in acute ON. The nomogram predictions may be useful in the diagnostic work-up of MS.

A population-based prospective study of optic neuritis.

BACKGROUND: Optic neuritis (ON) is often associated with multiple sclerosis (MS). Early diagnosis is critical to optimal patient management. OBJECTIVE: To estimate the incidence of acute ON and the rates of conversion to MS and antibody-mediated ON. METHOD: Population-based prospective study was performed in patients with ON from three ophthalmological departments and 44 practicing ophthalmologists from 2014 to 2016. Ophthalmological and neurological examination, magnetic resonance imaging (MRI), determination of aquaporin-4(AQP4)-IgG and myelin-oligodendrocyte glycoprotein (MOG)-IgG were investigated blindly. RESULTS: In all, 63 patients were evaluated and 51 fulfilled the criteria for ON. All were Caucasian, with female:male ratio of 2.2:1 and a median age of 38 years (16-66); 44 (86%) had a single episode of ON (four bilateral), while 7/51 (14%) had recurrent ON. The overall age-specific incidence was 3.28 (2.44-4.31) per 100,000 person years, 2.02 for men and 4.57 for women. At follow-up, 20 patients met the diagnostic criteria for MS, MRI lesions disseminated in space and time in 17/20 patients. AQP4-IgG was detected in none, MOG-IgG was detected in two patients. CONCLUSION: The prospective incidence of ON was estimated. MRI enabled a diagnosis of MS in a subgroup of patients. Antibody-mediated ON with specificity for MOG was detected in 4% of cases.

Highly sensitive quantification of optic neuritis intrathecal biomarker CXCL13.

BACKGROUND: Elevation of CXCL13, a key regulator of B-cell recruitment in cerebrospinal fluid (CSF) is implicated in multiple sclerosis (MS). OBJECTIVE: to evaluate if measurement of CXCL13 using a highly sensitive assay is of value in acute optic neuritis (ON) patients for the prediction of later MS. METHOD: CXCL13 was measured by Simoa in two independent treatment-naïve ON cohorts, a training cohort (TC, n = 33) originating from a population-based cohort, a validation cohort (VC, n = 30) consecutively collected following principles for population studies. Prospectively, 14/33 TC and 12/30 VC patients progressed to MS (MS-ON) while 19/33 TC and 18/30 VC patients, remained as isolated ON (ION). RESULTS: CXCL13 was detectable in all samples and were higher in ON compared with healthy controls (HC) (p = 0.012). In the TC, CSF levels in MS-ON were higher compared with ION patients and HC (p = 0.0001 and p<0.0001). In the VC, we confirmed the increase of CXCL13 in MS-ON compared to ION (p = 0.0091). Logistic regression analysis revealed an area under receiver operating characteristic curve of 0.83 [95% C.I: 0.73-0.93]. CONCLUSIONS: The highly sensitive CXCL13 Simoa assay demonstrated ability to identify ON patients and separate MS-ON from ION, and predictive diagnostic values indicates a promising potential of this assay.

Autoimmune and immunogenetic profile of patients with optic neuritis in a population-based cohort.

BACKGROUND: Optic neuritis (ON) is an inflammatory optic neuropathy, where the genetic and autoimmune dependency remains poorly characterized. OBJECTIVE: To investigate autoimmune and immunogenetic aspects of ON. METHOD: In a prospective population-based cohort 51 patients with ON were included. At follow up 20 patients had progressed to multiple sclerosis (MS-ON). All patients were screened for neuronal and systemic autoantibodies. HLA genotypes and allele and genotype frequencies of the PTPN22 C1858T and the PD-1.3 single-nucleotide polymorphisms (SNPs) were determined and compared to a cohort of Danish blood donors, acting as healthy controls. RESULTS: Median follow-up was 366 days (301-430) for MS-ON patients and 375 (range 50-436) for isolated ON (ION). Autoantibodies against myelin oligodendrocyte glycoprotein (MOG-IgG), were positive in two patients, no patients had anti-aquaporin-4 antibodies. Coexisting neural autoantibodies were detected in two patients and in 12 patients other systemic autoantibodies were found. Four (8%) had other autoimmune disorders. A family history of autoimmunity was observed in 12 (24%) and of demyelinating disease in six patients (12%). In MS-ON patients the frequencies of HLA-DQB1*06:02 and HLA-DRB1*15:01 tended to be higher compared to controls (p = 0.08). Stratification of patients with presence of oligoclonal bands (OCB) showed an association to the HLA-DQB1*06:02-HLA-DRB1*15:01 haplotype in ION (HLA-DQB1*06:02 and HLA-DRB1*15:01 (p = 0.03)), and in MS-ON patients (HLA-DQB1*06:02 and HLA-DRB1*15:01 (p = 0.03)). No significant associations to PTPN22 1858C/T or PD-1.3 G/A were found in any group comparison. CONCLUSIONS: ON patients had a general susceptibility to autoimmunity and two were MOG-IgG positive. HLA-DQB1*06:02 and HLA-DRB1*15:01 were associated with the presence of OCB in ON patients.

Magnetic resonance imaging findings at the first episode of acute optic neuritis.

BACKGROUND: Optic neuritis (ON) is a focal demyelinating event, which may evolve into multiple sclerosis (MS). OBJECTIVE: To study MRI characteristics in the acute phase of the first ON episode. METHODS: A prospective population-based study was performed on 31 patients with a first episode of acute ON with a one year follow-up. MRI, clinical evaluation, and detection of aquaporin-4 (AQP4)-IgG and myelin oligodendrocyte glycoprotein (MOG)-IgG was undertaken. For lesion characterization on MRI the optic nerves were divided into three segments: intra-orbital (IO), canalicular (CAN) and chiasmal (CHI). RESULTS: Lesions of the optic nerve were observed in 80.6%(25/31), with IO location in 48%(12/25), CAN in 8% (2/25) and both IO and CAN in 44%(11/25). Patients who converted to MS had lesions located at IO in 77%(10/13), whereas the group with isolated ON had IO and CAN in 73% (8/11), p = 0.003. Brain lesions were observed in 84% (21/25) at onset of ON; 62%(13/25) progressed to MS with more frequent location in brainstem (p = 0.030) and lesions in periventricular areas (p = 0.015). Spinal cord lesions were detected only in patients who progressed to MS (p = 0.002). MOG-IgG was detected in one patient with an optic nerve lesion located at IO and CAN. Serum AQP4-IgG was detected in none. Follow-up MRI showed progression in optic nerve lesions in 55% (11/20) patients. CONCLUSIONS: Specific location of optic nerve and brain lesions and the presence of spinal cord lesions in the acute phase of the first ON episode facilitated an MS diagnosis. The extension of optic nerve lesions following ON suggests a long-term progressive degeneration as an important element of ON pathology.

Direct and indirect pulp capping.

Cavity disinfection, indirect pulp capping, and direct pulp capping have been discussed in light of present day knowledge of the biology of the pulp. A format has been presented to the restorative dentist which has had long-standing clinical acceptance based on some scientific data and clinical evidence to substantiate the treatment radionale.

Evaluation of the apical sealing ability of apatite root canal sealer.

The apical sealing ability of a tricalcium phosphate sealer was compared with that of three other sealers. Seventy roots of human incisors were cleansed and shaped and randomly assigned to one of seven groups of ten roots each. The root canal systems were obturated with gutta-percha and one sealer using the lateral-vertical condensation technique. The canal was sealed with Roth's sealer, Sealapex, Kerr root canal sealer, or Sankin apatite root sealer (Type I, II, or III). One group was filled with gutta-percha without sealer to serve as a control. After the roots were immersed in silver nitrate, the degree of dye penetration was measured under a dissecting microscope. Results indicated that Sealapex had the best sealing ability, followed by Sankin apatite root sealer, Type II. Roth's cement showed the most dye penetration. Canals that were obturated without sealer showed significantly greater apical leakage.

Human blood pressure and pulse rate response to racemic epinephrine retraction cord.

1. The pulse rate of patients after application of racemic epinephrine-impregnated retraction cords depends more on the level of anxiety and stress than on the level of the epinephrine. 2. Blood pressure is elevated by placement of racemic epinephrine-impregnated retraction cords upon an exposed vascular bed or lacerated tissue. 3. Four percent racemic epinephrine-impregnated retraction cords cause less elevation of blood pressure than 8% racemic epinephrine cords. 4. Although the elevations in blood pressure from 8% cord occur within a narrow range, this range may be hazardous to cardiac patients. Therefore, 4% racemic epinephrine cord should be used. 5. A desirable amount of tissue retraction is produced by 4% racemic epinephrine cord. 6. Dry cords do not provide adequate retraction of tissue and are contraindicated for tissue-retraction purposes.