Defining high, medium and low impact prognostic factors for developing multiple sclerosis.

Prognostic Factors Stratification in Multiple Sclerosis

CIS diagnostics and predictors of conversion to CDMS

To study the relationship between retinal nerve fiber layer (RNFL) thickness and brain atrophy using magnetic resonance imaging (MRI) with bicaudate ratio (BCR) in patients with multiple sclerosis (MS) with different levels of disease severity. We also assessed whether RNFL thickness correlated with Expanded Disability Status Scale (EDSS) score. The participants consisted of 88 patients with MS and 59 age- and sex-matched healthy control subjects. Eleven patients had clinically isolated syndrome (CIS), 68 patients had relapsing-remitting MS (RR-MS), and 9 patients had secondary progressive MS. Patients and controls were evaluated using optical coherence tomography (OCT, Cirrus) and scanning laser polarimetry with variable corneal compensation (GDx VCC). Patients underwent the same brain MRI scanning protocol. Disability was evaluated according to the EDSS. The BCR was calculated by dividing the minimum intercaudate distance by brain width along the same level. The BCR was higher in patients with MS (0.12 ± 0.03) than in controls (0.08 ± 0.009) (P < 0.001). OCT average RNFL thickness in patients with MS was significantly lower (84.51 ± 14.27 μm) than in control subjects (98.44 ± 6.83 μm). BCR was correlated with OCT average RNFL thickness (r = -0.48, P = 0.002) in patients with MS without optic neuritis. Significant correlations were found between average RNFL thickness and EDSS (r = -0.43, P = 0.003). Additionally, there were correlations between BCR with GDx parameters in patients with MS without optic neuritis. This study shows that RNFL thickness correlates with BCR and with MS subtypes. Additionally, our study indicates that OCT is better suited for MS assessment than GDx. We conclude that the damage of retinal axons appears related to brain damage in patients with MS.

Multiple sclerosis (MS) is a common demyelinating disease of the central nervous system (1–86), with substantial long-term neurologic consequences (1,4,9,25,34, 52,54,55,57,60,63,65). After 10 years with MS, 50% of patients are unable to perform household and occupational responsibilities; after 15 to 20 years, 50% are unable to walk without assistance; after 25 years, 50% are unable to ambulate. The average annual cost of MS in the United States is greater than 6.8 billion dollars (1). There are three main subtypes of the disease: relapsing remitting (RR), secondary progressive (SP), and primary progressive (PP). This update reviews the current status of MS therapy (1–86). We have chosen to focus on the new and emerging immunomodulatory therapies for disease relapses and the treatments to prevent disease progression. We do not review the treatments for common MS-related sensory and motor symptoms, fatigue, or depression (35).

The 58th Annual Meeting of the American Academy of Neurology (AAN) was held in San Diego, California, April 1-8, 2006. There were 1,580 scientific abstracts presented and a very full educational program. Neuro-ophthalmology and neuro-otology courses and scientific presentations were very well attended this year in part as a result of a recent innovation at the AAN: the enhanced vertical integration (EVI) program. This program comprises a day that integrates many aspects of select subspecialties, allowing an AAN attendee the ability to concentrate on that subspecialty for the entire day. In addition to a cluster of courses, the day included a private poster session and a scientific session followed by a more in-depth session and panel discussion. The scientific portion of EVI began with a neuro-otology poster blitz with discussion of the posters by Michael Halmagyi, MD (Sydney, Australia), David Zee, MD (Baltimore, MD), and John Leigh, MD (Cleveland, OH). The scientific platform session, chaired by Kathleen Digre, MD (Salt Lake City, UT) and Mark Moster, MD (Philadelphia, PA), consisted of a presentation of 6 abstracts focused mainly on mitochondrial disorders. This was followed by a session devoted to the mechanisms of optic nerve injury and neuronal death and featured Valerio Carelli, MD (Bologna, Italy) speaking on hereditary optic neuropathies, Leonard Levin, MD (Montreal, Quebec, Canada) speaking on mechanisms of axonal injury, and Robert Weinreb, MD (San Diego, CA) speaking on mechanisms of cell injury in glaucoma. Nancy Newman, MD (Atlanta, GA) chaired the session. Elizabeth Engle, MD (Boston, MA) delivered the Sydney Carter Award Lecture at the presidential plenary session on the subject of ocular motility disorders arising from errors in brainstem motor neuron development. She discussed a classification of these entities as congenital cranial dysinnervation disorders (CCDDs). She described the conditions that primarily affect horizontally acting extraocular muscles, including Duane syndrome, horizontal gaze palsy with progressive scoliosis, and Möbius syndrome. Of the many scientific abstracts presented, the following had particular interest to neuro-ophthalmologists. OPTIC NEURITIS AND MULTIPLE SCLEROSIS Three studies of optical coherence tomography (OCT) in optic neuritis and multiple sclerosis (MS) were reported. A measurement of macular volume and retinal nerve fiber layer (RNFL) thickness with OCT-3 was performed in patients with MS (n = 70 [140 eyes]) and in disease-free controls (n = 29 [58 eyes]). Visual function was tested with low-contrast letter acuity (Sloan charts, 1.25%) and Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity. Total macular volume and RNFL thickness were lower in MS compared with controls (6.48 mm3 vs 6.86 mm3 for macular volume, 88 μm vs 98 μm for RNFL thickness; P < 0.0005) and were reduced even in eyes with no history of optic neuritis (ON). Lower vision scores were associated with reduced macular volumes and RNFL thickness. Measurements of macular volume and RNFL thickness were able to distinguish patients from controls and separate MS eyes with and without an ON history. However, direct correlations of overall RNFL thickness and total macular volume were only within the moderate range (rs = 0.60, P < 0.0001), suggesting to the authors that these two parameters may capture different aspects of the disease (Osborne B, Philadelphia, PA, EV5.006). A study of RNFL thickness using OCT-3 compared 60 patients with a single episode of ON (nonrecurrent ON), 10 patients with recurrent ON, and 27 patients with relapsing-remitting MS (RRMS). Those with recurrent ON had the thinnest RNFL (66 μm), those with RRMS 93 μm, and those with nonrecurrent ON 81 microns in the affected eye and 100 μm in the unaffected eye. Decreased RNFL measurements correlated with poorer visual acuity and worse visual fields (Costello F, Ottawa, Ontario, Canada, EV4.013). Another prospective study found a reduced RNFL thickness, as measured by OCT, in patients with MS with or without a history of ON. This small prospective study evaluated 61 patients with MS and 20 controls every 6 months over an 18-month period. RNFL thickness and the presence of retinal periphlebitis were associated with disease activity in MS as measured by T2 and enhanced T1 MRI. Six (9.8%) of 61 patients developed retinal periphlebitis, which was associated with clinical relapses (P < 0.05). These findings suggest that RNFL thickness and the presence of retinal periphlebitis could be used as substitute markers of disease activity in MS (Villoslada P, Pamplona, Spain, S22.003). A study looked at mitochondrial function in animals with experimental allergic encephalomyelitis, an animal model used to study MS. Oxidative injury to the mitochondrion began 3 days after antigenic sensitization, even before any inflammatory cell infiltration. Reductions in adenosine triphosphate (ATP) synthesis of 94% in retinal ganglion cells were even greater than those associated with mitochondrial diseases. Mice that received intravitreal recombinant AAV-SOD2 to suppress oxidative injury had a rescue of ATP synthesis by 55%, a suppression of myelin fiber injury by 51%, and a fourfold increase in retinal ganglion cell survival 1 year later. This study implicates a mitochondrial process in the axonal and neuronal loss in MS (Qi X, Gainesville, FL, EV5.005). A study of 117 brain biopsies in patients with pathologically proven MS and sufficient cortical tissue for analysis were reviewed for evidence of cortical demyelination. The biopsies were performed for diagnostic purposes within days to weeks of clinical presentation. Cortical demyelination was present in 21% of biopsies. Perivascular T-lymphocyte density was similar in cortical and white matter plaques, but parenchymal T cell density was less. Microglia predominated in all cortical plaques. Early active cortical demyelination characterized by myelin degradation products within macrophages was present in a subset of cases. MS cortical plaques were present in the subpial cortex, within the cortex, and in subcortical white matter. The lesions showed dramatic evidence of inflammation and tissue destruction. These findings contrast with prior reports emphasizing the noninflammatory nature of cortical plaques, but the prior reports may be biased toward patients with longstanding disease (Roemer S, Gottingen, Germany, P02.080). An MRI study of newly enhancing lesions was performed as part of the BECOME study, which compares interferon beta-1b (INFB-1b; Betaseron) with glatiramer acetate (Copaxone) for RRMS and clinically isolated syndromes (CIS). In that study, 406 newly enhancing lesions were identified with a mean of 0.6 per patient per month using a 3-Tesla MRI and triple-dose gadolinium. In 62% of lesions, the enhancement lasted less than 1 month, in 34% for 1 to 3 months, and in 4% for longer than 3 months. Twenty lesions were hypointense on T1 MRI at 3 months. Nineteen of these 20 lesions fulfilled criteria for black holes at 6 months. Larger lesions were more likely to show prolonged enhancement and to progress to black holes (Gomez-Choco MJ, Canary Islands, Spain, P02.093). Eleven patients with diplopia as part of a CIS were reported. Seven patients had sixth cranial nerve palsy, 3 had internuclear ophthalmoplegia, and 1 had partial third cranial nerve palsy. All had MRI lesions consistent with demyelination and negative diffusion-weighted studies but 4 had initially negative reports by the radiologist. All 9 patients followed up for at least 6 months had significant improvement. Three have progressed to clinically definite MS (CDMS) (Pula J, Peoria, IL, P01.027). Prior studies of antimyelin antibodies as a predictor for developing CDMS have had conflicting results. In a study reported here of 51 patients with CIS, 28 (54.9%) had either double or single positivity for antimyelin (anti-MOG or anti-MBP) antibodies. Antibody status significantly predicted development of MS based on Poser (but not McDonald) criteria (P = 0.004) with a higher proportion of patients converting to MS in the antibody-positive group (P = 0.027). However, patients who were anti-MBP-positive developed a significantly higher number of T2-hyperintense lesions than did patients who were anti-MBP-negative (anti-MBP+ 9.28 ± 10.45 vs anti-MBP- 3.96 ± 5.12, P = 0.03) (Tomassini V, Rome, Italy, P02.107). The BENEFIT trial reported the results of 250 μg IFNB1b administered subcutaneously every other day in patients with a clinical demyelinating event and 2 clinically silent MRI lesions. Primary efficacy end points were time to CDMS and time to diagnosis of MS according to the McDonald criteria. IFNB-1b significantly delayed the progression from the first clinical event to CDMS (log-rank test P < 0.0001) and McDonald criteria-defined MS (P < 0.00001). According to proportional hazards regression analysis adjusted for standard baseline covariates, the risk of CDMS in the IFNB-1b group was reduced by 50% (hazard ratio with 95% confidence interval [CI]: 0.50; 0.36-0.70) and for McDonald criteria-defined MS by 46% (0.54; 0.43-0.67), respectively. The Kaplan-Meier estimates of the percentage of patients who fulfilled the criteria for CDMS within 24 months were 45% in the placebo group and 28% in the IFNB-1b group. IFNB-1b prolonged the time to CDMS by 363 days based on the 25th percentiles. The BENEFIT study demonstrates that IFNB-1b administered according to that regimen significantly delays progression to definite MS in patients with a first clinical demyelinating event suggestive of MS (Freedman M, Ottawa, Ontario, Canada, S02.001). Twenty patients with RRMS with acute exacerbations were included in a study of intravenous immunoglobulin (IVIg) vs intravenous methylprednisolone (IVMP). Ten patients received 0.4 g/kg IVIg per day for 5 days and ten patients received 1,000 mg IVMP per day for 3 days. In both groups, the Expanded Disability Status Scale score improved significantly after the treatment of relapse with no difference seen between the two groups. Brain MRI showed significant reduction of T2, FLAIR, and enhanced T1 lesion volumes in the IVIg group, whereas no such finding was observed in the IVMP group. The authors conclude that IVIg is effective and well tolerated in the treatment of acute MS relapses. However, there was no untreated control group in this study (Kuusisto H, Tampere, Finland, P01.069). New sensitive measures of visual function in MS have been evaluated over the past year. Low-contrast letter acuity was used in 2 clinical trials of natalizumab to measure the drug's potential to preserve visual function in patients with MS. The AFFIRM (natalizumab vs placebo) and SENTINEL (natalizumab plus interferon beta 1a vs placebo plus interferon beta 1a) were multicenter, randomized, double-blind trials in patients with RRMS. Although high-contrast letter acuity was not able to show a treatment effect after 24 months, low-contrast letter acuity testing (1.25% and 2.5% Sloan charts) showed sustained reductions in vision loss in the AFFIRM (hazard ratio: 0.73, CI: 0.58-0.91, P = 0.006) and SENTINEL (hazard ratio: 0.75, CI: 0.61-0.92, P = 0.007) trials (Balcer LJ, Philadelphia, PA, S32.004). Another aim of the AFFIRM and SENTINEL trials was to measure the effect of the medications on quality of life in patients with MS. The Multiple Sclerosis Quality of Life Inventory (MSQLI) and Visual Analog Scale (VAS) were used to measure quality of life and well-being, respectively. Patients on natalizumab therapy over 2 years in both the AFFIRM and SENTINEL trials demonstrated statistically significant improvement in quality of life and well-being compared to those on placebo or 30 mcg interferon β-1a intramuscularly weekly (Rudick RA, Cleveland, OH, S52.005). The incidence of neutralizing antibodies and their potential clinical effect were investigated in the AFFIRM and SENTINEL trials. Nataluzimab is a humanized monoclonal antibody against VLA-4, an integrin receptor that blocks T cell egress from the circulation into the central nervous system. Over a 2-year period, 6% of patients in the AFFIRM trial were found by enzyme-linked immunosorbent assay to have positive antinataluzimab antibodies at more than 2 time points separated by at least 6 weeks (“persistently positive”). Patients with persistent antibodies demonstrated a reduced clinical benefit by 6 months and a higher incidence of adverse reactions from infusion (Calabresi PA, Baltimore, MD, S42.007). The most severe adverse reaction associated with natalizumab is the development of progressive multifocal leukoencephalopathy (PML). To find predictors of which treated patients are at risk for developing PML, investigators compared the cerebrospinal fluid (CSF) cell counts in patients with MS treated with natalizumab, untreated patients with MS, patients with HIV, and patients with other neurologic diseases. Also, PCR for JC virus DNA was performed on the CSF and peripheral blood. The patients with MS on natalizumab therapy had a low CD4:CD8 ratio in the CSF similar to the patients with HIV, whereas untreated patients with MS and patients with other neurologic diseases had normal CD4:CD8 ratios. The CSF CD4:CD8 ratio returned to normal in the treated patients with MS 6 months after discontinuing therapy with nataluzimab. These results suggest that the lowered CSF CD4:CD8 ratio in treated patients was the result of the natalizumab giving a similar immunologic profile as patients with HIV. The effect of natalizumab on the CD4:CD8 ratio may be a risk factor for developing PML, but further research is necessary to test this hypothesis (Stuve O, Dallas, TX, S32.001). A study of how glatiramer acetate dosing affects MRI included a randomization of 90 patients with RRMS to 40 mg subcutaneously per day or 20 mg subcutaneously per day. At 7, 8, and 9 months after treatment was begun, the 40-mg dose demonstrated a 38% reduction in enhancing MRI lesions compared with the 20-mg dose; this difference did not, however, reach statistical significance (P = 0.0898). The adverse reactions were similar in both groups (Cohen JA, Cleveland, OH, S61.001). Mitoxantrone treatment for progressive MS has been associated with the development of acute myelogenous leukemia. In one clinical center, among 111 patients with MS treated with mitoxantrone, 3 developed acute myelogenous leukemia. This was a higher incidence than the 0.25% previously reported (Lynn DJ, Columbus, OH, P01.074). The mechanisms of action of FTY720, a new medication to treat MS, were demonstrated in several papers. FTY720 is an oral agent that binds with high affinity to sphingosine 1-phosphate receptors. The drug has already shown effectiveness in reducing MRI activity and relapse rate over a 6-month period in a phase II trial of 281 patients with RRMS. Patients in another study demonstrated decreases in their peripheral lymphocyte counts at both tested doses (1.25 mg and 5 mg orally per day) beginning at week 1 and lasting until week 24 (Schmidli H, Basel, Switzerland, S32.003). In a murine model, FTY720 prevented peripheral lymphocytes from leaving lymphoid tissue, decreasing their transit into other tissues and into the central nervous system. In addition, the murine model showed that FTY720 prevented vascular endothelial growth factor-induced leakage across the blood-brain barrier (Brinkmann V, Basel, Switzerland, P03.175). Another study of FTY720 administered 2 to 4 weeks after onset of experimental allergic encephalomyelitis in mice showed normalization of somatosensory evoked potentials within 2 weeks. Neurologic deficits in the animals were improved by 4 weeks and histopathologic studies at autopsy showed no active inflammatory lesions. If it shows significant efficacy in its phase III trial, FTY720 could potentially be the first oral immunomodulatory agent for MS (Foster CA, Vienna, Austria, P05.193). NEUROMYELITIS OPTICA Neuromyelitis optica (NMO) is a syndrome consisting of (usually bilateral) ON and transverse myelitis. According to the most recent diagnostic criteria, the brain MRI should be normal. However, recent studies have shown that patients with NMO may have some typical abnormalities on brain MRI. MRI abnormalities in the hypothalamus and periventricular area have been shown to colocalize with areas of aquaporin-4 (AQP4), the predominant water channel protein in the central nervous system. The NMO-IgG antibody binds selectively to AQP4. Studies have shown that AQP4 i s most highly concentrated in the astrocytic foot processes forming the blood-brain barrier around the hypothalamus and the periventricular areas. A study looked at 130 patients clinically diagnosed with NMO whose serum was positive for the NMO antibody. Nine of these patients had abnormal T2 signal in the hypothalamic and periventricular areas corresponding the localization of AQP4, although no autopsy studies were performed to verify this histologically. Future studies will be needed to further elaborate the relationship of the aquaporin water channel protein with the MRI abnormalities and the clinical manifestations of NMO (Pittock SJ, Rochester, MN, S22.004). The NMO antibody was studied in two small cohorts of children with clinical NMO. In one cohort, all 4 children (girls) were positive for the NMO antibody. Three of the patients had ON followed by transverse myelitis and 3 also had supratentorial lesions on MRI. One of the patients had lupus (Moein M, Dallas, TX, P05.045). In the second cohort, a retrospective analysis of patients with MS who presented between 2002 and 2005 found 3 who met the diagnostic criteria for NMO. All 3 were women; 2 tested positive for the NMO antibody with the serology on the third patient pending. Common findings were an initial presentation suggestive of acute disseminated encephalomyelitis and a significant clinical response to rituximab without significant side effects (McClinskey N, Huntington, NY, P05.198). INTRACRANIAL HYPERTENSION A small prospective trial of endovascular venous sinus stenting was reported in patients with intracranial hypertension secondary to dural venous sinus obstruction. Ten patients had papilledema, elevated CSF pressures ranging from 270 to 450 mm H2O, and venous sinus obstruction demonstrated by retrograde cerebral venography and manometry. After stent placement, all patients had reduced sinus pressures and normalized CSF pressures at 3 months. Four patients became asymptomatic, 5 improved, and 1 remained unchanged. At 6 months after the procedure, 7 patients had repeat venography that showed no stent thrombosis. Future larger trials of this intervention may validate it as another treatment option besides optic nerve sheath fenestration and ventricular for patients who have dural venous sinus obstruction and whose elevated intracranial is to therapy The of test is a measure of visual that has been used mainly to the area from which one visual from visual using a without or eye The of this area are reduced by and A study of the of compared normal with patients who had lesions in the or the groups performed compared with normal but the test did not distinguish between the two patient groups City, were presented on the of vision therapy for patients with different of In one study, patients with from brain injury, optic were evaluated by after 6 months of patients were able to more within their at the end of the 6 month period (P < and were seen in of patients of such as the or of the visual Germany, Another study reported the of visual improvement after patients with visual from or brain injury for 6 or months and had and standard an of months after of the initial on either 6-month or were at This correlated with of their on of Germany, A presented results to and in of visual The study and on their reviewed and and reviewed on a The and on the of this and on of The of visual fields by the found by the on 2 patients were not by the A more study of how are visual fields to be A of with retinal was In a of patients with clinical of cerebral or retinal and a found on had retinal with no other than the was years patients had vascular risk Seven patients had retinal of which 2 were Six patients had patients had prior or cerebral One episode was present on and the patients had at the time of The authors that retinal may be by by a for this an of vascular risk in some and activity have been associated with of patients with MS treated with with one with were reported to have consisting of within 4 to 6 months of beginning One was therapy with of the reports are needed to the findings are or New NY, have reported visual loss in retinal This and other in prior reports a of the on to reported the criteria of least two of visual associated with within of the visual 7 had clinical manifestations consistent with and only 3 met the criteria of The authors that as a of is This is an many patients have visual loss diagnosed as other should be In a study of patients with a presentation hereditary optic who had no history of only 6 had the patients had of patients had evidence of mitochondrial study will the of these A patient with and was found to have a in not present in and The an in all and in all to The is in from the This an to and as of this syndrome J, CA, A study of mitochondrial ATP synthesis in of patients with optic with or without the was reported. the were studied at and in the were associated with deficits in ATP but patients without were similar to These the of mitochondrial in Italy, Nine patients with with visual loss for less than 6 months and normal visual function in the eye were followed for up to 2 years in an study of as treatment after first eye in normal visual acuity at baseline in all 7 patients had in the central visual of the eye. All patients had of visual visual mean and in the eye. The of visual was a to a central with a or The visual in the two eyes of any patient were may be a at onset more than Although retinal ganglion cell loss is seen in and the are is by in which a mitochondrial in of the mitochondrial is by function and mitochondrial were studied in from patients with and patients with mitochondrial in to loss of ATP and to cell A mitochondrial as seen in was also in The cell of in from mainly characterized by of mitochondrial and of cell V, Italy, In a of patients with at and had These included an and other There was no or for any and no in serum was a in of 2 or more with the was of patients with were Italy, gaze palsy with progressive is a syndrome of horizontal gaze and severe progressive in The and the to in the in patients with to in the with an abnormal patients have from In a study of 3 were found highly or in a All newly identified are in the of as are the of previously reported Ontario, Canada, A new for disease was in the for is a mitochondrial protein in which has previously been in progressive and syndrome. were found to have a syndrome consisting of action and did not have either or any evidence of This to the of clinical manifestations of New NY, is associated with A MRI study the between 7 and 7 an test of and the on Although the scores were not significantly the had of secondary visual a

Novel Imaging Techniques in Detection of Progressive Multiple Sclerosis

Disease-modifying therapies in managing disability worsening in paediatric-onset multiple sclerosis: a longitudinal analysis of global and national registries

Should Spinal MRI Be Routinely Performed in Patients With Clinically Isolated Optic Neuritis?

Locally produced oligoclonal IgG bands (OCB) are present in the cerebrospinal fluid (CSF) of 95% patients with multiple sclerosis (MS) [2,3]. The most sensitive method for the detection of OCB is isoelectric focusing (IEF) [1]. Occasional patients with clinically definite MS lack evidence for intrathecal IgG synthesis [2,9]. This study was designed to compare brain magnetic resonance imaging (MRI) findings between CSF OCB positive and negative MS patients. The study comprised 22 OB negative patients with clinically definite MS and 22 OCB positive controls matched for age, disease duration, activity and course of MS. In the both groups clinical assessment was performed by using Expanded Disability Status Scale (EDSS) score. T2 weighted MRI of the brain was performed on a Siemens Magnetom (1.0T). Lesions were counted and sized for 15 anatomically defined locations: 7 periventricular (PV) and 8 non-periventricular (NPV) regions. An arbitrary scoring system weighted for lesions size was used to estimate total and regional lesions loads: a) 1 point was given for each lesion with a diameter 1-5 mm, b) 2 points for one lesion with a diameter 6-10 mm, c) 3 points for one over 10 mm, and confluent lesions scored one extra point [16]. Atrophy were scored as follows: 0-normal size, 1-mild atrophy, 2-moderate atrophy and 3-severe atrophy. Mean score of total brain MRI loads was lower in OCB negative than in OCB positive MS patients (44 vs. 50) but the difference was not statistically significant. Mean periventricular (32 vs. 23), non-periventricular (26 vs. 19) and infratentorial (11 vs. 9) scores were higher in OCB positive MS group in comparison with OCB negative patients, but non-significant (figure 1). There was no correlation between EDSS score and total MRI lesions load in OCB negative MS patients, while in OCB positive group we detected significant correlation between EDSS score and total MRI lesions load (p = 0.026) (figure 2). The results of this study demonstrate that by using conventional brain MRI the extent end severity of the pathological process seems to be similar in OCB negative and OCB positive MS patients. On the other hand, we found statistically significant correlation between brain MRI total lesion load and EDSS in the OCB positive MS patients, while this correlation was not detected in OCB negative MS patients. Differences in brain MRI findings between OCB positive nad OCB negative MS patients have been already analyzed [9,12]. In the first, Zeman et al. reported that OCB negative MS patients have lower total MRI brain lesion loads in comparison to OCB positive group, but the differences was not statistically significant [9]. In accordance with these findings, Fukazawa et al. also failed to show differences in the distribution, extent, shape and number of brain MRI lesions between OCB positive and negative MS patients. [12]. On the other hand, it has been demonstrated that the rate of intrathecal IgG synthesis apparently correlates with plaque volume in the brain, as demonstrated on MRI, in MS patients [17]. However, our results along with those from two above-mentioned previous studies do not support this notion. In conclusion, trend towards lesser MRI lesion load and lack of its correlation with EDSS in OCB negative MS patients, warrants further investigations with new MRI techniques (magnetic resonance spectroscopy and magnetisation transfer), including the thorough exploration of normal-appearing while matter, in OCB negative MS patients.

Progress in Multiple Sclerosis Research

Clinicians' experience and findings from recent natural history studies suggest that multiple sclerosis (MS) may now be running a more slowly progressing course than before. To investigate whether the risk of reaching MS disability milestones has changed over the last decade in Sweden. A nationwide population-based retrospective cohort study. By April 2017, 12 512 patients with available information on demographics, MS phenotype, and date of MS onset and diagnosis were registered in the Swedish MS Registry of which 7331 patients with at least 2 recorded Expanded Disability Status Scale scores (EDSS) and diagnosed between January 1995 and December 2010 were included. No further exclusion criteria were applied. Patients were followed up until December 2016 with a median duration follow-up of 8.5 (interquartile range, 4.7-13.8) years. Statistical analysis began in April 2017. Patients were followed up from MS onset date to the date of sustained EDSS 3.0, 4.0, and 6.0. To handle interval-censored observations, a Weibull model was fit, and the change in the risk of EDSS 3.0, 4.0, and 6.0 over calendar years was estimated and hazard ratios (HRs) with corresponding CIs were calculated. Of 7331 patients, 5196 (70.9%) were women, and the mean (SD) age at diagnosis was 38.3 (11.7) years. Adjusting for sex, number of clinic visits, diagnostic delay, and onset age, a 3% decrease per calendar year of diagnosis for the risk of sustained EDSS 3.0 (HR, 0.97; 95% CI, 0.96-0.97), a 6% decrease for the risk of EDSS 4.0 (HR, 0.94; 95% CI, 0.93-0.95), and a 7% decrease for the risk of EDSS 6.0 (HR, 0.93; 95% CI, 0.91-0.94) among patients with relapsing-onset MS was found. The trends were not significant for patients with progressive-onset MS (EDSS 3.0: HR, 1.01; 95% CI, 0.98-1.03; EDSS 4.0: HR, 1.00; 95% CI, 0.98-1.02; EDSS 6.0: HR, 1.00; 95% CI, 0.98-1.02). Risk of reaching major disability milestones has significantly decreased over the last decade in patients with relapsing-onset MS in Sweden. Several factors could potentially be responsible for this observation. However, given that no change was seen in disability accrual of patients with progressive-onset MS and the absence of efficacious treatment option in this group, increased use of more efficacious disease-modifying treatments could be a possible driver of this change.

Mitoxantrone: a review of its use in multiple sclerosis.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system. Optic neuritis (ON) is common clinical manifestation of MS. Spectral domain optical coherence tomography (SD-OCT) has been used as a useful tool to quantify the neuronal damage in the eyes of MS patients. The study aimed to evaluate the lamina cribrosa thickness (LCT) and lamina cribrosa depth (LCD) in patients with MS and their relationship with Expanded Disability Status Scale (EDSS) score. Fifty-two eyes of 26 relapsing-remitting MS patients and 39 eyes of 39 healthy age- and sex- matched participants were evaluated in this prospective, cross-sectional, observational study. There were two MS subgroups: 38 MS eyes without an ON history (MS&#8722;ON), and 14 MS eyes with an ON history (MS+ON). The LCT and LCD were measured with SD-OCT. Of the 26 participants with MS, 14 (53.8%) were female and the mean (SD) age was 35.1 (6.2) years; of the 39 healthy controls, 26 (66.7%) were female and the mean (SD) age was 36.7 (8.2) years (P=0.19 for sex and P=0.27 for age). The mean LCT was not significantly different between MS patients and healthy controls (272.66 ± 33.52 &#956;m and 272.58 ± 35.97 &#956;m, respectively, P=0.992). The mean LCD was 325.15 ± 67.07 &#956;m for the MS+ON group, 409.71 ± 93.18 &#956;m for the MS&#8722;ON group, and 427.64 ± 91.65 &#956;m for the healthy control group. The LCD was significantly decreased in MS+ON group compared to MS&#8722;ON group (P=0.011) and healthy controls (P=0.002). EDSS score was negatively correlated with LCD in MS patients (r= -0.313, P=0.025). This study revealed decreased LCD in MS eyes particularly with optic neuritis, and its relationship with increased disease severity. Additional longitudinal studies are needed to confirm the use of LCD as an imaging biomarker in patients with MS. [Med-Science 2018; 7(4.000): 867-72]

To investigate the influence of cigarette smoking on progression and disability accumulation in multiple sclerosis (MS). Information on past and present smoking of 364 patients with MS was obtained through a structured questionnaire survey. We used Kaplan-Meier analyses and Cox regression models to evaluate the influence of smoking on the development and age at onset of secondary progression, on the age at onset of progression in patients with primary progressive MS, and on the time from disease onset to Expanded Disability Status Scale (EDSS) scores 4.0 and 6.0 in all patients. We also investigated the correlation between smoked pack-years and EDSS scores and the rate of progression as measured with the Multiple Sclerosis Severity Score. We found no significant associations between cigarette smoking and any of the used measures. Our data suggest that cigarette smoking has no influence on disease progression or accumulation of disability in multiple sclerosis.

The ability to better predict disease progression represents a major unmet need in multiple sclerosis (MS), and would help to inform therapeutic and management choices. To develop multilevel models using longitudinal data on disease progression in patients with relapsing-remitting MS (RRMS) or secondary-progressive MS (SPMS); and to use these models to estimate the association of disease-modifying therapy (DMT) with progression. Secondary analysis of three MS cohorts. Two natural history cohorts: University of Wales Multiple Sclerosis (UoWMS) cohort, UK, and British Columbia Multiple Sclerosis (BCMS) cohort, Canada. One observational DMT-treated cohort: UK MS risk-sharing scheme (RSS). The UoWMS database has > 2000 MS patients and the BCMS database (as of 2009) has > 5900 MS patients. All participants who had definite MS (RRMS/SPMS), who reached the criteria set out by the Association of British Neurologists (ABN) for eligibility for DMT [i.e. age ≥ 18 years, Expanded Disability Status Scale (EDSS) score of ≤ 6.5, occurrence of two or more relapses in the previous 2 years] and who had at least two repeated outcome measures were included: 404 patients for the UoWMS cohort and 978 patients for the BCMS cohort. Through the UK MS RSS scheme, 5583 DMT-treated patients were recruited, with the analysis sample being the 4137 who had RRMS and were eligible and treated at baseline, with at least one valid EDSS score post baseline. EDSS score observations post ABN eligibility. We used multilevel models in the development cohort (UoWMS) to develop a model for EDSS score with time since ABN eligibility, allowing for covariates and appropriate transformation of outcome and/or time. These methods were then applied to the BCMS cohort to obtain a 'natural history' model for changes in the EDSS score with time. We then used this natural history model to predict the trajectories of EDSS score in treated patients in the UK MS RSS database. Differences between the progression predicted by the natural history model and the progression observed at 6 years' follow-up for the UK MS RSS cohort were used as indicators of the effectiveness of the DMTs. Previously developed utility scores were assigned to each EDSS score, and differences in utility also examined. The model best fitting the UoWMS data showed a non-linear increase in EDSS score over time since ABN eligibility. This model fitted the BCMS cohort data well, with similar coefficients, and the BCMS model predicted EDSS score in UoWMS data with little evidence of bias. Using the natural history model predicts EDSS score in a treated cohort (UK MS RSS) higher than that observed [by 0.59 points (95% confidence interval 0.54 to 0.64 points)] at 6 years post treatment. Only two natural history cohorts were compared, limiting generalisability. The comparison of a treated cohort with untreated cohorts is observational, thus limiting conclusions about causality. EDSS score progression in two natural history cohorts of MS patients showed a similar pattern. Progression in the natural history cohorts was slightly faster than EDSS score progression in the DMT-treated cohort, up to 6 years post treatment. Long-term follow-up of randomised controlled trials is needed to replicate these findings and examine duration of any treatment effect. The National Institute for Health Research Health Technology Assessment programme.