Increased frequency of canine distemper virus-specific antibodies in multiple sclerosis.

BACKGROUND AND PURPOSE: Canine distemper virus (CDV) is a candidate agent in the etiology of multiple sclerosis (MS). Elevated anti-CDV levels were previously found in the sera from MS patients compared with controls. We now investigated whether there was an age-related association with the presence of antibodies specific to CDV-hemagglutinin (H) protein in MS. METHODS: Sera from patients with MS, other neurological diseases, and inflammatory and/or autoimmune diseases, and healthy individuals were screened for anti-CDV in an ELISA using linear peptides of the CDV-H protein as antigen. Antibody levels to measles and varicella-zoster virus were measured and served as controls. RESULTS: Analysis of the new cohort of MS patients and controls confirmed our initial finding of elevated anti-CDV-H levels in MS patients. An increase in measles but not varicella-zoster virus antibody levels was found in MS patients compared with healthy controls. Data from the new cohort of patients and controls were combined with data from the original study and analyzed with respect to age distribution of anti-CDV IgG. Mean CDV antibody levels were significantly elevated in each decade from 20 to 50 years of age in MS compared with healthy and disease controls. Antibody levels to measles virus were not consistently elevated during this age span. A striking relationship (p < .0001, odds ratio = 5.0) was observed between elevated anti-CDV-H levels and diagnosis of MS. CONCLUSIONS: The finding that anti-CDV levels are elevated in MS patients of all ages provides substantial evidence of a strong association between elevated anti-CDV and MS.

Gray Matter Nucleus Hyperintensity After Monthly Triple-Dose Gadopentetate Dimeglumine With Long-term Magnetic Resonance Imaging.

OBJECTIVES: Gadolinium deposition is widely believed to occur, but questions regarding accumulation pattern and permanence remain. We conducted a retrospective study of intracranial signal changes on monthly triple-dose contrast-enhanced magnetic resonance imaging (MRI) examinations from the previously published Betaseron vs. Copaxone in Multiple Sclerosis With Triple-Dose Gadolinium and 3-Tesla MRI Endpoints Trial (N = 67) to characterize the dynamics of gadolinium deposition in several deep brain nuclei and track persistence versus washout of gadolinium deposition on long-term follow-up (LTFU) examinations (N = 28) obtained approximately 10 years after enrollment in the Betaseron vs. Copaxone in Multiple Sclerosis With Triple-Dose Gadolinium and 3-Tesla MRI Endpoints Trial. MATERIALS AND METHODS: Using T2 and proton density images and using image analysis software (ITK-SNAP), manual regions of interest were created ascribing boundaries of the caudate nucleus, dentate nucleus, globus pallidus, pulvinar, putamen, white matter, and air. Intensity analysis was conducted on T1-weighted fat-saturated (fat-sat) images using the FSL package. A linear rigid-body transform was calculated from the fat-sat image at each target time point to the region of interest segmentation reference time point fat-sat image. Serial MRI signal was analyzed using linear mixed regression modeling with random intercept. Annual MRI signal changes including LTFU scans were assessed with t test. RESULTS: During monthly scanning, all gray matter structures demonstrated a significant (P < 0.0001) increase in contrast-to-noise ratio. Yearly changes in deposition showed distinctive patterns for the specific nucleus: globus pallidus showed complete retention, pulvinar showed partial washout, while dentate, caudate, and putamen returned to baseline (ie, complete washout). CONCLUSIONS: Monthly increased contrast-to-noise ratio in gray matter nuclei is consistent with gadolinium deposition over time. The study also suggests that some deep gray matter nuclei permanently retain gadolinium, whereas others demonstrate washout of soluble gadolinium.

Stability of visual outcome between 2 and 5 years following corneal transplantation in the UK.

BACKGROUND AND AIMS: Many studies of corneal transplantation focus on graft failure or rejection as endpoints, or report visual outcomes at one postoperative time point. We aimed to study the stability of visual outcomes between 2 and 5 years following corneal transplantation. METHODS: All patients with keratoconus (868) or Fuchs endothelial dystrophy (FED) (569) receiving their first corneal transplant for visual purposes in the UK between January 2003 and December 2009 were included. The probability of visual improvement or deterioration (gain or loss of ≥2 Snellen lines, respectively) between 2 and 5 years after keratoplasty was modelled by multivariable logistic regression. RESULTS: The majority of keratoconus patients with a penetrating keratoplasty (PK) or deep anterior lamellar keratoplasty maintained their visual acuity (651/868; 75%) while 15% (133/868) improved and 10% (84/868) deteriorated. Similarly, most patients with FED who received a PK maintained their vision (395/569; 70%) while 18% (105/569) improved and 12% (68/569) deteriorated.

Long-Term Outcomes of High-Risk Keratoplasty in Patients Receiving Systemic Immunosuppression.

PURPOSE: Immunological graft rejection after corneal transplantation remains the leading cause of graft failure. Systemic immunosuppression is used for keratoplasty at a high risk of rejection to improve graft survival. We examined the long-term outcomes of high-risk corneal grafts in patients receiving systemic immunosuppression. METHODS: Thirty-five corneal transplants with a high risk of rejection were identified from 29 patients within a regional immunosuppression service in the United Kingdom. Definition of keratoplasty at "high risk" of rejection included one or more of the following: a history of ipsilateral graft rejection and/or failure, 2 or more quadrants of stromal vascularization, perforation or ocular inflammation at the time of surgery, presence of atopy, and a large-diameter (≥9 mm) graft. Median follow-up duration was 5 years after transplantation. RESULTS: Graft survival at 5 years in patients receiving systemic immunosuppression was 73.5%. Rejection episodes occurred in 14 grafts (40%); these episodes were reversible in 10 grafts (71%). Indications for transplantation were mostly visual (n = 19; 54%) and tectonic (n = 14; 40%). Eighteen grafts (51%) had 2 or more high-risk characteristics. Most patients (n = 20; 69%) received monotherapy, commonly with tacrolimus (n = 15; 52%) or mycophenolate mofetil (n = 8; 28%). Three patients (10%) experienced severe systemic side effects. Median "day-to-day" logMAR visual acuity was 0.5 in grafts for all indications and 0.2 for visual indications. CONCLUSIONS: Systemic immunosuppression in patients with high-risk keratoplasty seems to improve graft survival with a median follow-up duration of 5 years and is tolerated by most patients. Despite rejection episodes occurring in 40% of grafts, these were mostly reversible.

Hypophosphatemia is Associated with the Serial Administration of Triple-Dose Gadolinium to Patients for Brain MRI.

BACKGROUND AND PURPOSE: The purpose of this study is to report a metabolic abnormality associated with frequent, triple-dose Gadolinium (TdGd) use in MS patients during BECOME trial. METHODS: Potential clinical adverse events and lab abnormalities were monitored at each monthly MRI visit. Hypophosphatemia was defined as phosphate <2.5 mg/dL. Statistical analysis included McNemar's test for pairwise comparisons across visits and generalized estimating equations (GEE) to fit models over time. RESULTS: Eight hundred seventy seven phosphate values were analyzed from the first 12 months. Compared with 4% of subjects at screening, an average of 15.1% (95% confidence interval (CI): 11.4%-19.7%) of patients had hypophosphatemia at visits from months 1 to 12, during which subjects received serial TdGd. Forty four of seventy five (59%) patients developed hypophosphatemia at least once. We also found a significant increasing trend in hypophosphatemia by visit when treatment groups were evaluated together or separately (p < .001). There was a statistically significant decrease in frequency to 9.8% (95% CI: 4.6-19.8%) by month 24 (p = .005) coinciding with a period of less frequent gadolinium administration. CONCLUSIONS: Serial TdGd in MS patients, unrelated to immunomodulatory treatment, was associated with increased frequency of hypophosphatemia that progressed with cumulative triple-dose and markedly decreased in second year, with less frequent triple-dose administration.

Intraocular lens opacification after descemet stripping automated endothelial keratoplasty.

PURPOSE: Intraocular lens (IOL) opacification is a rare but serious complication that may necessitate its exchange. The use of intraocular gases is a known precipitant. Descemet stripping endothelial keratoplasty (DSAEK) involves injecting air into the anterior chamber. IOL opacification has been described after this procedure; however its incidence is currently unknown. METHODS: A retrospective review of case notes from a single center of all patients undergoing DSAEK, who were either already pseudophakic or had simultaneous cataract surgery. Cases with IOL opacification were analyzed, and any risk factors were identified. RESULTS: One hundred sixty-eight DSAEK were performed on 154 eyes of 137 patients. Fifty-four cases had simultaneous cataract surgery with implantation of an IOL. Fifteen (9.7%) eyes developed IOL opacification. This had a distinctive pattern, being limited to the anterior lens surface, in the pupillary zone. Median time interval from keratoplasty to the first observation of IOL opacification was 17 months (range, 4-34 months). The only statistically significant risk factor was rebubbling of detached endothelial grafts. Rebubbling was performed in 62.5% (10/15) of cases with IOL opacification, compared with 23% (32/139) with no opacification (P = 0.0009). CONCLUSIONS: This is the first study to report the incidence of IOL opacification after undergoing DSAEK. Although the mechanism is unknown, multiple injections of air into the anterior chamber statistically increase the risk of IOL opacification.

Peripheral ulcerative keratitis and corneal melt: a 10-year single center review with historical comparison.

PURPOSE: Management of noninfectious ulcerative keratitis (UK) and associated systemic disorders has changed over recent years. This study aimed to analyze a recent cohort of patients with UK in this context. METHODS: The case notes of all the patients attending a specialist corneal immunosuppression clinic between June 2002 and July 2012 were reviewed. A subgroup comparison of those with rheumatoid arthritis (RA) was made with those included in an earlier report from this same center (Malik et al. Eur J Ophthalmol. 2006;16:791-797). The Fisher exact test was used for statistical comparison, and a Bonferroni correction was applied. RESULTS: Seventy patients, whose mean age was 65.0 years (median, 64 years), were included. Fifteen (21%) had bilateral disease, and forty-six had RA (66%). At presentation, the mean (median) visual acuity (VA) was 0.59 (0.18) logarithm of the minimum angle of resolution equivalent to 6/24 (6/9) Snellen. All the patients were prescribed systemic corticosteroids, which were later stopped in 45 (64%) patients. All but 2 were treated with steroid-sparing immunosuppressive agents, with each patient being prescribed a mean of 1.5 medications (range, 0-4), including prednisolone. These included prednisolone (70, 100%), methotrexate (47, 67%), mycophenolate (15, 21%), tacrolimus (5, 7%), and azathioprine (4, 6%). No irreversible side effects occurred. After perforation, 12 eyes of 11 patients (16%) underwent a corneal transplantation, and 10 (83%) of these remained clear. The mean (median) VA of the affected eyes when last seen was 0.34 (0.18) logarithm of the minimum angle of resolution equivalent to 6/13 (6/9) Snellen. The subset of patients with RA had significantly lower rates of corneal perforation and a VA ≤ 6/60 when last seen (P < 0.05) compared with that of the earlier cohort. CONCLUSIONS: Ocular morbidity associated with UK has fallen, possibly because of a move toward more aggressive systemic antiinflammatory therapy.

MRI outcomes with cladribine tablets for multiple sclerosis in the CLARITY study.

We herein provide a comprehensive assessment of magnetic resonance imaging (MRI) outcomes from CLARITY, a 96-week, double-blind study demonstrating significant clinical and MRI improvements in patients with relapsing-remitting multiple sclerosis (RRMS) treated with cladribine tablets. Patients with RRMS were randomized 1:1:1 to annual short-course therapy with cladribine tablets cumulative dose 3.5 or 5.25 mg/kg or placebo. MRI endpoints included mean number of T1 gadolinium-enhancing (Gd+), active T2 and combined unique (CU) lesions/patient/scan. MRI-measured disease activity was significantly reduced in both cladribine tablets groups versus placebo. The proportion of patients with no active lesions at study end was: T1 Gd+ lesions: 86.8 and 91.0 versus 48.3 % (p < 0.001); active T2 lesions: 61.7 and 62.5 versus 28.4 % (p < 0.001); CU lesions: 59.6 and 60.7 versus 26.1 % (p < 0.001). Clinically meaningful and significant reductions in active lesion counts and increases in proportions of active lesion-free patients were achieved consistently in cladribine tablet groups when data were stratified by baseline disease characteristics. For example, the percentage of patients who remained lesion-free over the study was significantly greater in cladribine tablet groups than in the placebo group for all lesion types regardless of relapse category at baseline (p < 0.001 for all analyses of patients with ≤1 or 2 relapses; p ≤ 0.022 for analyses of patients with ≥3 relapses). MRI-measured disease activity was greatly reduced by both doses of cladribine tablets, with consistent effect across clinically relevant patient populations. These findings add to our scientific understanding of the neurological impact of this therapeutic modality in patients with RRMS.

Cause of death in MS: long-term follow-up of a randomised cohort, 21 years after the start of the pivotal IFNß-1b study.

OBJECTIVES: Compared with controls, multiple sclerosis (MS) patients die, on average, 7-14 years prematurely. Previously, we reported that, 21 years after their participation in the pivotal randomised, controlled trial (RCT) of interferon ß-1b, mortality was reduced by 46-47% in the two groups who received active therapy during the RCT. To determine whether the excessive deaths observed in placebo-treated patients was due to MS-related causes, we analysed the causes-of-death (CODs) in these three, randomised, patient cohorts. DESIGN: Long-term follow-up (LTF) of the pivotal RCT of interferon ß-1b. SETTING: Eleven North American MS-centres participated. PARTICIPANTS: In the original RCT, 372 patients participated, of whom 366 (98.4%) were identified after a median of 21.1 years from RCT enrolment. INTERVENTIONS: Using multiple information sources, we attempted to establish COD and its relationship to MS in deceased patients. PRIMARY OUTCOME: An independent adjudication committee, masked to treatment assignment and using prespecified criteria, determined the likely CODs and their MS relationships. RESULTS: Among the 366 MS patients included in this LTF study, 81 deaths were recorded. Mean age-at-death was 51.7 (±8.7) years. COD, MS relationship, or both were determined for 88% of deaths (71/81). Patients were assigned to one of nine COD categories: cardiovascular disease/stroke; cancer; pulmonary infections; sepsis; accidents; suicide; death due to MS; other known CODs; and unknown COD. Of the 69 patients for whom information on the relationship of death to MS was available, 78.3% (54/69) were adjudicated to be MS related. Patients randomised to receive placebo during the RCT (compared with patients receiving active treatment) experienced an excessive number of MS-related deaths. CONCLUSIONS: In this long-term, randomised, cohort study, MS patients receiving placebo during the RCT experienced greater all-cause mortality compared to those on active treatment. The excessive mortality in the original placebo group was largely from MS-related causes, especially, MS-related pulmonary infections.

Impact of inflammation on brain volume in multiple sclerosis.

OBJECTIVE: To study changes in brain volume measured monthly in patients treated for relapsing multiple sclerosis due to loss of tissue and the appearance of inflammation. DESIGN AND PATIENTS: The results from T2/fluid-attenuated inversion recovery axial images from 13 consecutive monthly 3-T brain magnetic resonance imaging tests conducted on 74 patients diagnosed with relapsing multiple sclerosis in the BECOME study were used to calculate whole brain volumes using automated software analysis tools. The patients had been randomized to receive treatment with interferon beta-1b or glatiramer acetate. Ongoing inflammation was studied by counting the number of combined active lesions and measuring the volume of gadolinium enhancement. A mixed-effects model was used to analyze brain volumes over time. RESULTS: There was a significant decrease in brain volume over time but there was no difference in its rate of change by age, sex, frequency of ongoing inflammation, multiple sclerosis type, or randomized treatment assignment. The mean rate of brain volume change per month from multivariable models was -1.1 cm(3) (95% CI, -1.5 to -0.6) and during times of magnetic resonance imaging activity, it increased transiently by an average of 1.2 cm(3)/lesion (95% CI, 0.7 to 1.7) and 7.1 cm(3)/1 cm(3 )of gadolinium volume. In a model with both measures, combined active lesions were independent predictors of brain volume but gadolinium volume was not. CONCLUSION: Two major changes in brain volume occur in patients with relapsing multiple sclerosis, a steady decrease likely due to tissue loss with overlapping transient increases due to the appearance of inflammation.

Use of Magnetic Resonance Imaging as Well as Clinical Disease Activity in the Clinical Classification of Multiple Sclerosis and Assessment of Its Course: A Report from an International CMSC Consensus Conference, March 5-7, 2010.

It has recently been suggested that the Lublin-Reingold clinical classification of multiple sclerosis (MS) be modified to include the use of magnetic resonance imaging (MRI). An international consensus conference sponsored by the Consortium of Multiple Sclerosis Centers (CMSC) was held from March 5 to 7, 2010, to review the available evidence on the need for such modification of the Lublin-Reingold criteria and whether the addition of MRI or other biomarkers might lead to a better understanding of MS pathophysiology and disease course over time. The conference participants concluded that evidence of new MRI gadolinium-enhancing (Gd+) T1-weighted lesions and unequivocally new or enlarging T2-weighted lesions (subclinical activity, subclinical relapses) should be added to the clinical classification of MS in distinguishing relapsing inflammatory from progressive forms of the disease. The consensus was that these changes to the classification system would provide more rigorous definitions and categorization of MS course, leading to better insights as to the evolution and treatment of MS.

A second case of Marburg's variant of multiple sclerosis with vasculitis and extensive demyelination.

Marburg's variant of multiple sclerosis is a rapidly progressive and malignant form of multiple sclerosis (MS) that usually leads to severe disability or death within weeks to months without remission. Few cases have been described in the literature since the original description by Marburg. The classic pathological findings usually include highly destructive zones of extensive demyelination, necrosis with dense cellular infiltrate, and giant reactive astrocytes. We report a case of a 31-year-old woman with Marburg's variant of MS who, over a period of eight months, became totally disabled, blind, and quadriplegic, with vocal cord paralysis, requiring a tracheostomy. The patient underwent diagnostic stereotactic brain biopsy. Clinical findings, magnetic resonance imaging (MRI), serologic and cerebrospinal fluid (CSF) findings, and neuropathology are discussed. MRI showed extensive white matter involvement in the brain and spinal cord that continuously progressed over time. A diagnostic stereotactic brain biopsy revealed extensive active demyelination with unexpected finding of active vasculitis and fibrinoid necrosis with a vascular inflammatory cell infiltrate, including polymorphonuclear neutrophils and rare eosinophils. Serologic work-up for vasculitis and neuromyelitis optica was unremarkable and the CSF showed only one oligoclonal band (OCB) not present in serum. This is the second case of Marburg's variant of MS that demonstrated both demyelination and vasculitis. In our case these features were demonstrated simultaneously, even though the demyelination was the predominant pathological finding. Since vasculitis is not a feature of classic MS, these findings pose the question as to whether Marburg's variant of MS is a true variant or different entity altogether.

Clinical consequences of MRI activity in treated multiple sclerosis.

BACKGROUND: Inflammation on brain MRI is the most sensitive marker of disease activity in multiple sclerosis (MS) but its clinical consequences remain controversial. OBJECTIVE: Here we investigated the clinical consequences of MRI activity in MS subjects treated with two different first line disease modifying agents. METHODS: Seventy-five treatment-naïve subjects with relapsing-remitting MS (N = 61) or clinically isolated syndromes at risk of MS (N = 14) from the BECOME study that had been randomized to interferon beta-1b (N = 39) or glatiramer acetate (N = 36) and followed for up to two years by monthly brain MRI optimized to detect inflammatory activity were studied for the clinical consequences of lack of MRI remission. RESULTS: MRI remission occurred in 46.4% of participants transiently and in 23.2% completely while it was never achieved in 30.4%. There was no difference by treatment in MRI remission, progression of physical disability, or cognitive function. The percentage of relapse-free subjects was 87.5% for the group in complete MRI remission, 47.6% in the group never in remission and 59.4% in the group in transient remission (p = 0.017). Similar differences were observed for six-month-confirmed worsening of ambulatory function as measured by the timed 25 foot walk (p = 0.026) and by Expanded Disability Status Scale (EDSS) (p = 0.10). Cognitive function was lowest at baseline for the group that never reached MRI remission on treatment; this group improved the least upon repeated cognitive testing during the two years of treatment (p < 0.001). CONCLUSIONS: Lack of MRI remission during treatment with interferon beta-1b or glatiramer acetate is associated with higher relapse rate and worsening of physical and cognitive function.

A case-control study of risk factors for multiple sclerosis in Iran.

BACKGROUND: Numerous studies have assessed risk factors for multiple sclerosis (MS), although none have been conducted previously in Iran. OBJECTIVE: The objective of this study was to study lifestyle and environmental risk factors of MS in the Iranian population. METHODS: A case-control study, including 394 MS cases and 394 matched controls, was conducted in MS clinics in different Iranian cities. Information on lifestyles, environmental exposures, and past medical history was obtained from medical charts and phone interviews. RESULTS: In multivariable analysis, sunlight exposure was associated with a lower risk of MS: the odds ratio (OR) and 95% confidence interval (CI) of MS associated with a 1-h increment in daily sunlight was 0.62 (0.53-0.73). Smoking was associated with MS risk in women (OR: 6.48, 95% CI: 1.46-28.78), but not in men (OR: 0.72, 95% CI: 0.31-1.68) (p=0.002 for interaction). Finally, past history of common surgical procedures, infectious disorders, or exposure to pets and farm animals was not associated with MS risk. CONCLUSIONS: Different modifiable lifestyles, including sunlight exposure and smoking, were associated with lower MS risk in Iran. Interventions aimed at promoting smoking cessation and, more importantly, at increasing exposure to sunlight might contribute to the prevention of MS.

Serum levels of CXCL13 are elevated in active multiple sclerosis.

There is increasing recognition of the important role that B cells play in the pathogenesis of multiple sclerosis (MS). Recently it was reported that the B cell chemokine CXCL13 is elevated in MS serum and cerebrospinal fluid. Here we study whether serum levels of CXCL13 are associated with active MS. We measured serum levels of CXCL13 by enzyme-linked immunosorbent assay in 74 patients with relapsing MS randomized to interferon beta 1b or glatiramer acetate and examined with monthly 3 T brain MRI scans optimized for detection of gadolinium-enhancement for up to 2 years. The median (range) serum levels of CXCL13 pre-treatment were 40 (3-171) pg/ml. Serum levels of CXCL13 were significantly higher at times of active brain MRI scans (p < 0.01). Furthermore, serum levels were higher in patients who never reached MRI remission compared with those in complete (p < 0.01) or partial (p = 0.01) remission. There was a significant positive correlation between the pattern of serum levels of CXCL13 and MRI activity during the first (r = 0.33, p < 0.05) and the full 2 years (r = 0.35, p < 0.01) of the study. Treatment with interferon beta 1b or glatiramer acetate did not affect serum CXCL13. We conclude that the serum levels of the B cell chemokine CXCL13 are associated with active MS.