Focal demyelinated plaques in white matter, which are the hallmark of multiple sclerosis pathology, only partially explain the patient's clinical deficits. We thus analysed global brain pathology in multiple sclerosis, focusing on the normal-appearing white matter (NAWM) and the cortex. Autopsy tissue from 52 multiple sclerosis patients (acute, relapsing-remitting, primary and secondary progressive multiple sclerosis) and from 30 controls was analysed using quantitative morphological techniques. New and active focal inflammatory demyelinating lesions in the white matter were mainly present in patients with acute and relapsing multiple sclerosis, while diffuse injury of the NAWM and cortical demyelination were characteristic hallmarks of primary and secondary progressive multiple sclerosis. Cortical demyelination and injury of the NAWM, reflected by diffuse axonal injury with profound microglia activation, occurred on the background of a global inflammatory response in the whole brain and meninges. There was only a marginal correlation between focal lesion load in the white matter and diffuse white matter injury, or cortical pathology, respectively. Our data suggest that multiple sclerosis starts as a focal inflammatory disease of the CNS, which gives rise to circumscribed demyelinated plaques in the white matter. With chronicity, diffuse inflammation accumulates throughout the whole brain, and is associated with slowly progressive axonal injury in the NAWM and cortical demyelination.

Some recent studies suggest that in progressive multiple sclerosis, neurodegeneration may occur independently from inflammation. The aim of our study was to analyse the interdependence of inflammation, neurodegeneration and disease progression in various multiple sclerosis stages in relation to lesional activity and clinical course, with a particular focus on progressive multiple sclerosis. The study is based on detailed quantification of different inflammatory cells in relation to axonal injury in 67 multiple sclerosis autopsies from different disease stages and 28 controls without neurological disease or brain lesions. We found that pronounced inflammation in the brain is not only present in acute and relapsing multiple sclerosis but also in the secondary and primary progressive disease. T- and B-cell infiltrates correlated with the activity of demyelinating lesions, while plasma cell infiltrates were most pronounced in patients with secondary progressive multiple sclerosis (SPMS) and primary progressive multiple sclerosis (PPMS) and even persisted, when T- and B-cell infiltrates declined to levels seen in age matched controls. A highly significant association between inflammation and axonal injury was seen in the global multiple sclerosis population as well as in progressive multiple sclerosis alone. In older patients (median 76 years) with long-disease duration (median 372 months), inflammatory infiltrates declined to levels similar to those found in age-matched controls and the extent of axonal injury, too, was comparable with that in age-matched controls. Ongoing neurodegeneration in these patients, which exceeded the extent found in normal controls, could be attributed to confounding pathologies such as Alzheimer's or vascular disease. Our study suggests a close association between inflammation and neurodegeneration in all lesions and disease stages of multiple sclerosis. It further indicates that the disease processes of multiple sclerosis may die out in aged patients with long-standing disease.

Although spontaneous remyelination does occur in multiple sclerosis lesions, its extent within the global population with this disease is presently unknown. We have systematically analysed the incidence and distribution of completely remyelinated lesions (so-called shadow plaques) or partially remyelinated lesions (shadow plaque areas) in 51 autopsies of patients with different clinical courses and disease durations. The extent of remyelination was variable between cases. In 20% of the patients, the extent of remyelination was extensive with 60-96% of the global lesion area remyelinated. Extensive remyelination was found not only in patients with relapsing multiple sclerosis, but also in a subset of patients with progressive disease. Older age at death and longer disease duration were associated with significantly more remyelinated lesions or lesion areas. No correlation was found between the extent of remyelination and either gender or age at disease onset. These results suggest that the variable and patient-dependent extent of remyelination must be considered in the design of future clinical trials aimed at promoting CNS repair.

Neocortical demyelination in the forebrain has recently been identified as an important pathological feature of multiple sclerosis (MS). Here we describe that the cerebellar cortex is a major predilection site for demyelination, in particular in patients with primary and secondary progressive MS. In these patients, on average, 38.7% of cerebellar cortical area is affected, reaching in extreme examples up to 92%. Cerebellar cortical demyelination occurs mainly in a band-like manner, affecting multiple folia. The lesions are characterized by primary demyelination with relative axonal and neuronal preservation, although some axonal spheroids and a moderate reduction of Purkinje cells are present. Although cortical demyelination sometimes occurs together with demyelination in the adjacent white matter (leukocortical lesions), in most instances, the cortex was affected independently from white matter lesions. We found no correlation between demyelination in the cortex and the white matter, and in some cases, extensive cortical demyelination was present in the near absence of white matter lesions. Our data identify cortical demyelination as a potential substrate of cerebellar dysfunction in MS. Brain Pathol 2007;17:38-44. INTRODUCTIONMultiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system, which leads to large confluent demyelinated plaques in the white matter (15). However, recent studies show that in addition to focal white matter plaques, there is also widespread damage in the gray matter and a diffuse and global injury in the normal appearing white matter (6,9,11). With the introduction of new and sensitive staining techniques for myelin, extensive cerebral cortical demyelination in MS brains recently became apparent (2,17). Cortical lesions are prominent in patients with primary and secondary progressive MS (PPMS and SPMS, respectively) (11), and the majority of cortical demyelination occurs in the form of widespread and band-like subpial lesions, which appear to be related to an inflammatory process within the meninges (3, 11). Cortical demyelination has so far only been investigated in the forebrain. Here we describe that cortical demyelination is even more prominent in the cerebellum. PATIENTS AND METHODSAutopsy material. The study was performed on autopsy material from 40 MS patients, eight neurologically normal patients without cerebellar pathology and 34 patients with focal or diffuse cerebellar hypoxia (Tables 1 and 2). The MS cohort consisted of patients with acute MS (AMS; Marburg's type, n = 5), relapsing/remitting MS (RRMS; n = 3), SPMS (n = 19), PPMS (n = 10) and progressive MS, where clinical records were insufficient to differentiate between SPMS and PPMS (UPMS; n = 3). Patient demographics are given in Table 1. Clinical courses were determined by retrospective chart reviews, performed by a neurologist (PSS, CFL, HR and MS) blinded to the outcome of the neuropathological analysis.Neuropathological evaluation. Autopsy material was fixed in buffered formalin. ...

Destruction of myelin and oligodendrocytes leading to the formation of large demyelinated plaques is the hallmark of multiple sclerosis (MS) pathology. In a subset of MS patients termed pattern III, actively demyelinating lesions show preferential loss of myelin-associated glycoprotein (MAG) and apoptotic-like oligodendrocyte destruction, whereas other myelin proteins remain well preserved. MAG is located in the most distal periaxonal oligodendrocyte processes and primary "dying back" oligodendrogliopathy may be the initial step of myelin degeneration in pattern III lesions. In the present study, various human white matter pathologies, including acute and chronic white matter stroke, virus encephalitis, metabolic encephalopathy, and MS were studied. In addition to a subset of MS cases, a similar pattern of demyelination was found in some cases of virus encephalitis as well as in all lesions of acute white matter stroke. Brain white matter lesions presenting with MAG loss and apoptotic-like oligodendrocyte destruction, irrespective of their primary disease cause, revealed a prominent nuclear expression of hypoxia inducible factor-1alpha in various cell types, including oligodendrocytes. Our data suggest that a hypoxia-like tissue injury may play a pathogenetic role in a subset of inflammatory demyelinating brain lesions.

Only higher CASPR2 serum antibody titres indicate anti-CASPR2 encephalitis, and diagnostic accuracy increases if MRI findings are considered. Anti-CASPR2 encephalitis has characteristic features and a favourable outcome with immunotherapy.

BackgroundIn 2008 the Austrian Task Force for Neuromyelitis Optica (NMO) started a nation-wide network for information exchange and multi-centre collaboration. Their aim was to detect all patients with NMO or NMO spectrum disorders (NMO-SD) in Austria and to analyse their disease courses and response to treatment.Methods(1) As of March 2008, 1957 serum samples (of 1557 patients) have been tested with an established cell based immunofluorescence aquaporin-4 antibody (AQP4-ab) assay with a high sensitivity and specificity (both >95%). All tests were performed in a single reference laboratory (Clinical Dept. of Neurology of the Innsbruck Medical University). (2) A nation-wide survey with several calls for participation (via email newsletters, articles in the official journal of the Austrian Society of Neurology, and workshops) was initiated in 2008. All collected data will be presented in a way that allows that every individual patient can be traced back in order to ensure transparency and to avoid any data distortion in future meta-analyses. The careful and detailed presentation allows the visualization and comparison of the different disease courses in real time span. Failure and response to treatment are made visible at one glance. Database closure was 31 December 2011. All co-operators were offered co-authorship.ResultsAll 71 NMO- or NMO-SD patients with AQP4-ab positivity (age range 12.3 to 79.6 years) were analysed in detail. Sex ratio (m:f = 1:7) and the proportion of patients without oligoclonal bands in cerebrospinal fluid (86.6%) were in line with previously published results. All identified patients were Caucasians.ConclusionsA nationwide collaboration amongst Austrian neurologists with good network communications made it possible to establish a database of 71 AQP4-ab positive patients with NMO/NMO-SD. This database is presented in detail and provides the basis for further studies and international cooperation in order to investigate this rare disease.

Aims Experimental data suggest that systemic immune activation may create a pro‐inflammatory environment with microglia activation in the central nervous system in the absence of overt inflammation, which in turn may be deleterious in conditions of neurodegenerative disease. The extent to which this is relevant for the human brain is unknown. The central aim of this study is to provide an in‐depth characterization of the microglia and macrophage response to systemic inflammation. Methods We used recently described markers to characterize the origin and functional states of microglia/macrophages in white and grey matter in patients who died under septic conditions and compared it to those patients without systemic inflammation. Results We found pro‐inflammatory microglia activation in septic patients in the white matter, with very little activation in the grey matter. Using a specific marker for resident microglia ( TMEM 119), we found that parenchyma microglia were activated and that there was additional recruitment of perivascular macrophages. Pro‐inflammatory microglia activation occurred in the presence of homeostatic microglia cells. In contrast to inflammatory or ischaemic diseases of the brain, the anti‐inflammatory microglia markers CD 163 or CD 206 were not expressed in acute sepsis. Furthermore, we found pronounced upregulation of inducible nitric oxide synthase not only in microglia, but also in astrocytes and endothelial cells. Conclusion Our results demonstrate the pronounced effects of systemic inflammation on the human brain and have important implications for the selection of control populations for studies on microglia activation in human brain disease.