Background An extensive analysis of white matter plaques in a large sample of MS autopsies provides insights into the dynamic nature of MS pathology. Methods 120 MS cases (1220 tissue blocks) were included. Plaque types were classified according to demyelinating activity based on stringent criteria. Early-active, late-active, smoldering, inactive, and shadow plaques were distinguished. 2476 MS white matter plaques were identified. Plaque type distribution was analyzed in relation to clinical data. Findings Active plaques were most often found in early disease, whereas at later stages, smoldering, inactive and shadow plaques predominated. The presence of early-active plaques rapidly declined with disease duration. Plaque type distribution differed significantly by clinical course. The majority of plaques in acute-monophasic and RRMS were active. Among SPMS cases with attacks, all plaque types could be distinguished including active plaques, in contrast to SPMS without attacks in whom inactive plaques predominated. Smoldering plaques were frequently and almost exclusively found in progressive MS. At 47-years of age, an equilibrium was observed between active and inactive plaques, whereas smoldering plaques began to peak. Men displayed a higher proportion of smoldering plaques. Interpretation Disease duration, clinical course, age and gender contribute to the dynamic nature of white matter MS pathology. Active MS plaques predominate in acute and early RRMS and are the likely substrate of clinical attacks. Progressive MS transitions to an accumulation of smoldering plaques characterized by microglial activation and slow expansion of pre-existing plaques. Whether current MS therapeutics impact this pathological driver of disease progression remains uncertain.

Background It is unclear if all patients with RRMS ultimately develop progressive MS. Onset of progressive disease course seems to be age- rather than disease duration dependent. Some forms of progressive MS (e.g. PPMS) are uncommon in population-based studies. Ascertainment of patients with PPMS from clinic-based populations can facilitate a powerful comparison of age-of-progression-onset between SPMS and PPMS but may introduce unclear biases. Objective To confirm that onset of progressive disease course is more relevant to patient's age than the presence or duration of a pre-progression relapsing disease course in MS. Methods We studied a population-based MS cohort (n=210, relapsing-remitting MS n=109, progressive MS n=101) and a clinic-based progressive MS cohort (n=754). Progressive course was classified as primary- (PPMS; n=322), single attack- (SAPMS; n=112) and secondary-progressive (SPMS; n=421). We studied demographics (chi2 or t-test), age-of-progression-onset (t-test) and time-to-EDSS6 (Kaplan-Meier analyses). Results Sex-ratio (p=0.58), age-of-progression-onset (p=0.37) and time-to-EDSS6 (p=0.16) did not differ between the cohorts. Progression had developed before age 75 in 99% of patients with known progressive disease course; 38% with RRMS did not develop progression by age 75. Age-of-progression-onset did not differ between SPMS (44.9±9.6), SAPMS (45.5±9.6) and PPMS (45.7±10.8). In either cohort, only 2% of patients had reached EDSS6 before onset of progression. Conclusions Patients with RRMS do not inevitably develop progressive disease course. Onset of progression is more dependent on age than the presence or duration of a pre-progression symptomatic disease course. Moderate disability is sustained predominantly after the onset of a progressive disease course in MS.

Objective: We examined the effect of relapses-before and after progression onset-on the rate of postprogression disability accrual in a progressive multiple sclerosis (MS) cohort. Methods:We studied patients with primary progressive MS (n 5 322) and bout-onset progressive MS (BOPMS) including single-attack progressive MS (n 5 112) and secondary progressive MS (n 5 421). The effect of relapses on time to Expanded Disability Status Scale (EDSS) score of 6 was studied using multivariate Cox regression analysis (sex, age at progression, and immunomodulation modeled as covariates). Kaplan-Meier analysis was performed using EDSS 6 as endpoint. Conclusions: Pre-and postprogression relapses accelerate time to severe disability in progressive MS. Continuing immunomodulation for 5 years after the onset of progressive disease or until 55 years of age may be reasonable to consider in patients with BOPMS who have ongoing relapses. Results: Preprogression relapses (hazard ratioNeurology ® 2015;84:81-88 GLOSSARY BOPMS 5 bout-onset progressive multiple sclerosis; CI 5 confidence interval; EDSS 5 Expanded Disability Status Scale; HR 5 hazard ratio; MS 5 multiple sclerosis; PPMS 5 primary progressive multiple sclerosis; RRMS 5 relapsing-remitting multiple sclerosis; SAPMS 5 single-attack progressive multiple sclerosis; SPMS 5 secondary progressive multiple sclerosis.

Optic neuritis (ON) is an acute inflammatory demyelinating disorder of the optic nerve. The general characteristics of isolated ON include unilateral, subacute, and painful visual loss without systemic or other neurological symptoms. The etiology for ON varies including demyelinating disorders or infections, inflammation, toxic reasons, and genetic disorders. In most cases the responsible etiology may not be known for ON and in this case, it is termed idiopathic ON. When a patient presents with an initial episode of ON, patients should undergo further tests. Assessing the patient with routine blood work, magnetic resonance imaging, cerebrospinal fluid tests, and visual evoked potentials provide further insight. In this review, we aimed to provide a review of ON as an initial symptom of multiple sclerosis and present clinical characteristics, therapy options, and recent literature.

We systematically evaluated the frequency of neurological disorders and muscle and neural autoantibodies in 177 patients with neuromyelitis optica (NMO) and in 250 control subjects (173 healthy; 77 multiple sclerosis, MS, patients). An excess of myasthenia gravis (MG, 2%), and muscle-type acetylcholine receptor antibody (11%) was detected among NMO patients. The presence of neural or muscle autoantibodies was more common in NMO patients (34%) than in MS patients or healthy controls (7%), P < 0.0001. The coexistence of NMO and MG should be considered in atypical or refractory presentations of either disorder.

Patients with MS with poor recovery from early relapses will develop progressive disease course earlier than those with good recovery.

Further research is warranted concerning the immunogenetics of GCA. Further treatment trials are also needed to develop more specific and sensitive diagnostic tests and new corticosteroid-sparing treatment modalities.

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