BCAS1-positive oligodendrocytes enable efficient cortical remyelination in multiple sclerosis.

Remyelination is a crucial regenerative process in demyelinating diseases, limiting persisting damage to the central nervous system (CNS). It restores saltatory nerve conduction and ensures trophic support of axons. In multiple sclerosis (MS) patients, remyelination has been observed in both white and grey matter and found to be more efficient in the cortex. Brain-enriched myelin-associated protein 1 (BCAS1) identifies oligodendrocyte lineage cells in the stage of active myelin formation in development and regeneration. Other than in the white matter, BCAS1+ oligodendrocytes are maintained at high densities in the cortex throughout life. Here, we investigated cortical lesions in human biopsy and autopsy tissue from patients with MS in direct comparison to demyelinating mouse models and demonstrate that following a demyelinating insult BCAS1+ oligodendrocytes in remyelinating cortical lesions shift from a quiescent to an activated, internode-forming morphology co-expressing myelin-associated glycoprotein (MAG), necessary for axonal contact formation. Noteworthy, activated BCAS1+ oligodendrocytes are found at early time points of experimental demyelination amidst ongoing inflammation. In human tissue, activated BCAS 1+ oligodendrocytes correlate with the density of myeloid cells, further supporting their involvement in an immediate regenerative response. Furthermore, studying the microscopically normal appearing non demyelinated cortex in patients with chronic MS, we find a shift from quiescent BCAS1+ oligodendrocytes to mature, myelin-maintaining oligodendrocytes, suggesting oligodendrocyte differentiation and limited replenishment of BCAS1+ oligodendrocytes in long-standing disease. We also demonstrate that part of perineuronal satellite oligodendrocytes are BCAS1+ and contribute to remyelination in human and experimental cortical demyelination. In summary, our results provide evidence from human tissue and experimental models that BCAS1+ cells in the adult cortex represent a population of pre-differentiated oligodendrocytes that rapidly react after a demyelinating insult thus enabling immediate myelin regeneration. In addition, our data suggest that limited replenishment of BCAS1+ oligodendrocytes may contribute to the remyelination failure observed in the cortex in chronic MS.

Neurofilament Light Chain Serum Levels Mirror Age and Disability in Secondary Progressive Multiple Sclerosis: A Cross-Sectional Study.

OBJECTIVES: To assess neurofilament light chain serum (sNfL) levels in patients with secondary progressive multiple sclerosis (SP-MS). METHODS: Using a single molecule array, we analyzed sNfL levels in a cross-sectional cohort study of 153 patients with SP-MS hospitalized for rehabilitation in a clinic specialized in the care for patients with multiple sclerosis (MS). In addition, we investigated the correlation of disease activity with sNfL levels in 36 patients with relapsing-remitting MS (RR-MS). RESULTS: Mean sNfL levels in patients with SP-MS were consistently elevated when compared with age-matched controls and patients with RR-MS. In SP-MS, age dependency of sNfL levels was pronounced, whereas patients with RR-MS younger than 41 years without recent disease activity were not distinguishable from age-matched healthy controls. In a multivariate analysis, clinical disability was a risk factor for elevated sNfL levels in SP-MS, whereas no correlation with comorbidities, such as cardiovascular disease, diabetes mellitus, smoking status, or vitamin D serum levels, could be detected. DISCUSSION: These findings highlight that measurement of sNfL levels represents a useful tool to assess the extent of neuroaxonal damage as a surrogate for clinical progression in patients with SP-MS, when age and disease activity as major confounders are taken into account.

Progressive Multifocal Leukoencephalopathy: Pathogenesis, Diagnostic Tools, and Potential Biomarkers of Response to Therapy.

JC polyomavirus (JCV) establishes an asymptomatic latent and/or persistent infection in most of the adult population. However, in immunocompromised individuals, JCV can cause a symptomatic infection of the brain, foremost progressive multifocal leukoencephalopathy (PML). In the past 2 decades, there has been increasing concern among patients and the medical community because PML was observed as an adverse event in individuals treated with modern (selective) immune suppressive treatments for various immune-mediated diseases, especially multiple sclerosis. It became evident that this devastating complication also needs to be considered beyond the patient populations historically at risk, including those with hematologic malignancies or HIV-infected individuals. We review the clinical presentation of PML, its variants, pathogenesis, and current diagnostic approaches. We further discuss the need to validate JCV-directed interventions and highlight current management strategies based on early diagnosis and restoring JCV-specific cellular immunity, which is crucial for viral clearance and survival. Finally, we discuss the importance of biomarkers for diagnosis and response to therapy, instrumental in defining sensitive study end points for successful clinical trials of curative or preventive therapeutics. Advances in understanding PML pathophysiology, host and viral genetics, and diagnostics in conjunction with novel immunotherapeutic approaches indicate that the time is right to design and perform definitive trials to develop preventive options and curative therapy for JCV-associated diseases.

Long-term clinical, imaging and cognitive outcomes association with MS immunopathology.

OBJECTIVE: In this observational study on a cohort of biopsy-proven central nervous system demyelinating disease consistent with MS, we examined the relationship between early-active demyelinating lesion immunopattern (IP) with subsequent clinical course, radiographic progression, and cognitive function. METHODS: Seventy-five patients had at least one early-active lesion on biopsy and were pathologically classified into three immunopatterns based on published criteria. The median time from biopsy at follow-up was 11 years, median age at biopsy - 41, EDSS - 4.0. At last follow-up, the median age was 50, EDSS - 3.0. Clinical examination, cognitive assessment (CogState battery), and 3-Tesla-MRI (MPRAGE/FLAIR/T2/DIR/PSIR/DTI) were obtained. RESULTS: IP-I was identified in 14/75 (19%), IP-II was identified in 41/75 (56%), and IP-III was identified in 18/75 (25%) patients. Patients did not differ significantly by immunopattern in clinical measures at onset or last follow-up. The proportions of disease courses after a median of 11 years were similar across immunopatterns, relapsing-remitting being most common (63%), followed by monophasic (32%). No differences in volumetric or DTI measures were found. CogState performance was similar for most tasks. A slight yet statistically significant difference was identified for episodic memory scores, with IP-III patients recalling one word less on average. INTERPRETATION: In this study, immunopathological heterogeneity of early-active MS lesions identified at biopsy does not correlate with different long-term clinical, neuroimaging or cognitive outcomes. This could be explained by the fact that while active white matter lesions are pathological substrates for relapses, MS progression is driven by mechanisms converging across immunopatterns, regardless of pathogenic mechanisms driving the acute demyelinated plaque.

Neurofilament light chains in serum as biomarkers of axonal damage in early MS lesions: a histological-serological correlative study.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease associated with axonal injury, and neurofilament light chains in serum (sNfL) are considered a biomarker for this damage. We aimed to investigate the relationship between sNfL and the axonal damage in early MS lesions in a special cohort of biopsied patients. sNfL from 106 biopsied patients with 26 follow-up samples were analyzed using single-molecule array (SiMoA) technology. Findings were correlated with clinical parameters and histological findings of acute axonal damage (APP-positive spheroids) and axonal loss in different lesion stages. A median of 59 pg/ml sNfL was found (range 8-3101 pg/ml). sNfL levels correlated with APP-positive spheroids in early active demyelinating lesions that represent the earliest lesion stages (p < 0.01). A significant negative correlation between sNfL levels in follow-up blood samples and axonal density in normal-appearing white matter was also observed (p = 0.02). sNfL levels correlated with the Expanded Disability Status Score at biopsy (p < 0.01, r = 0.49) and at last clinical follow-up (p < 0.01, r = 0.66). In conclusion, sNfL likely represent a compound measure of recent and ongoing neuroaxonal damage. We found that sNfL in biopsied MS patients correlate with acute axonal damage in the earliest MS lesion stages. Determination of sNfL levels thus allows insight into brain pathology and underlines the relevance of relapse-associated lesional pathology. Axonal loss in normal-appearing white matter contributes to sNfL levels independent of relapses. Since sNfL levels correlate with clinical disability, they may predict the future disability of patients and help with individual treatment decisions.

Tissue donations for multiple sclerosis research: current state and suggestions for improvement.

Although major progress in multiple sclerosis research has been made during the last decades, key questions related to the cause and the mechanisms of brain and spinal cord pathology remain unresolved. These cover a broad range of topics, including disease aetiology, antigenic triggers of the immune response inside and/or outside the CNS and mechanisms of inflammation, demyelination neurodegeneration and tissue repair. Most of these questions can be addressed with novel molecular technologies in the injured CNS. Access to brain and spinal cord tissue from multiple sclerosis patients is, therefore, of critical importance. High-quality tissue is provided in part by the existing brain banks. However, material from early and highly active disease stages is limited. An initiative, realized under the patronage of the European Charcot Foundation, gathered together experts from different disciplines to analyse the current state of multiple sclerosis tissues collected post-mortem or as biopsies. Here, we present an account of what material is currently available and where it can be accessed. We also provide recommendations on how tissue donation from patients in early disease stages could be potentially increased and for procedures of tissue sampling and preservation. We also suggest to create a registry of the available tissues that, depending on the source (autopsy versus biopsy), could be made accessible to clinicians and researchers.

The neuroradiology of progressive multifocal leukoencephalopathy: a clinical trial perspective.

Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection of the CNS caused by the JC virus, which infects white and grey matter cells and leads to irreversible demyelination and neuroaxonal damage. Brain MRI, in addition to the clinical presentation and demonstration of JC virus DNA either in the CSF or by histopathology, is an important tool in the detection of PML. In clinical practice, standard MRI pulse sequences are utilized for screening, diagnosis and monitoring of PML, but validated imaging-based outcome measures for use in prospective, interventional clinical trials for PML have yet to be established. We review the existing literature regarding the use of MRI and PET in PML and discuss the implications of PML histopathology for neuroradiology. MRI not only demonstrates the localization and extent of PML lesions, but also mirrors the tissue destruction, ongoing viral spread, and resulting inflammation. Finally, we explore the potential for imaging measures to serve as an outcome in PML clinical trials and provide recommendations for current and future imaging outcome measure development in this area.

Clinical Correlation of Multiple Sclerosis Immunopathologic Subtypes.

BACKGROUND AND OBJECTIVES: The goal of this work was to compare clinical characteristics across immunopathologic subtypes of patients with multiple sclerosis. METHODS: Immunopathologic subtyping was performed on specimens from 547 patients with biopsy- or autopsy-confirmed CNS demyelination. RESULTS: The frequency of immunopathologic subtypes was 23% for pattern I, 56% for pattern II, and 22% for pattern III. Immunopatterns were similar in terms of age at autopsy/biopsy (median age 41 years, range 4-83 years, p = 0.16) and proportion female (54%, p = 0.71). Median follow-up after symptom onset was 2.3 years (range 0-38 years). In addition to being overrepresented among autopsy cases (45% vs 19% in biopsy cohort, p < 0.001), index attack-related disability was higher in pattern III vs II (median Expanded Disability Status Scale score 4 vs 3, p = 0.02). Monophasic clinical course was more common in patients with pattern III than pattern I or II (59% vs 33% vs 32%, p < 0.001). Similarly, patients with pattern III pathology were likely to have progressive disease compared to patients with patterns I or II when followed up for ≥5 years (24% overall, p = 0.49), with no differences in long-term survival, despite a more fulminant attack presentation. CONCLUSION: All 3 immunopatterns can be detected in active lesions, although they are found less frequently later into the disease due to the lower number of active lesions. Pattern III is associated with a more fulminant initial attack than either pattern I or II. Biopsied patients appear to have similar long-term outcomes regardless of their immunopatterns. Progressive disease is less associated with the initial immunopattern and suggests convergence into a final common pathway related to the chronically denuded axon.

CNS inflammation after natalizumab therapy for multiple sclerosis: A retrospective histopathological and CSF cohort study.

Natalizumab, a recombinant humanized monoclonal antibody directed against the α4 subunit of the integrins α4ß1 and α4ß7, has been approved for the treatment of active relapsing-remitting MS. Although natalizumab is a highly beneficial drug that effectively reduces the risk of sustained disability progression and the rate of clinical relapses, some patients do not respond to it, and some are at higher risk of developing progressive multifocal leukoencephalopathy (PML). The histopathological effects after natalizumab therapy are still unknown. We, therefore, performed a detailed histological characterization of the CNS inflammatory cell infiltrate of 24 brain specimens from natalizumab treated patients, consisting of 20 biopsies and 4 autopsies and 21 MS controls. To complement the analysis, immune cells in blood and cerebrospinal fluid (CSF) of 30 natalizumab-treated patients and 42 MS controls were quantified by flow cytometry. Inflammatory infiltrates within lesions were mainly composed of T cells and macrophages, some B cells, plasma cells, and dendritic cells. There was no significant difference in the numbers of T cells or macrophages and microglial cells in lesions of natalizumab-treated patients as compared to controls. A shift towards cytotoxic T cells of a memory phenotype was observed in the CSF. Plasma cells were significantly increased in active demyelinating lesions of natalizumab-treated patients, but no correlation to clinical disability was observed. Dendritic cells within lesions were found to be reduced with longer ongoing therapy duration. Our findings suggest that natalizumab does not completely prevent immune cells from entering the CNS and is associated with an accumulation of plasma cells, the pathogenic and clinical significance of which is not known. As B cells are considered to serve as a reservoir of the JC virus, the observed plasma cell accumulation and reduction in dendritic cells in the CNS of natalizumab-treated patients may potentially play a role in PML development.

TSPO PET imaging of natalizumab-associated progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is a severe infection of the CNS caused by the polyomavirus JC that can occur in multiple sclerosis patients treated with natalizumab. Clinical management of patients with natalizumab-associated PML is challenging not least because current imaging tools for the early detection, longitudinal monitoring and differential diagnosis of PML lesions are limited. Here we evaluate whether translocator protein (TSPO) PET imaging can be applied to monitor the inflammatory activity of PML lesions over time and differentiate them from multiple sclerosis lesions. For this monocentre pilot study we followed eight patients with natalizumab-associated PML with PET imaging using the TSPO radioligand 18F-GE-180 combined with frequent 3 T MRI. In addition we compared TSPO PET signals in PML lesions with the signal pattern of multiple sclerosis lesions from 17 independent multiple sclerosis patients. We evaluated the standardized uptake value ratio as well as the morphometry of the TSPO uptake for putative PML and multiple sclerosis lesions areas compared to a radiologically unaffected pseudo-reference region in the cerebrum. Furthermore, TSPO expression in situ was immunohistochemically verified by determining the density and cellular identity of TSPO-expressing cells in brain sections from four patients with early natalizumab-associated PML as well as five patients with other forms of PML and six patients with inflammatory demyelinating CNS lesions (clinically isolated syndrome/multiple sclerosis). Histological analysis revealed a reticular accumulation of TSPO expressing phagocytes in PML lesions, while such phagocytes showed a more homogeneous distribution in putative multiple sclerosis lesions. TSPO PET imaging showed an enhanced tracer uptake in natalizumab-associated PML lesions that was present from the early to the chronic stages (up to 52 months after PML diagnosis). While gadolinium enhancement on MRI rapidly declined to baseline levels, TSPO tracer uptake followed a slow one phase decay curve. A TSPO-based 3D diagnostic matrix taking into account the uptake levels as well as the shape and texture of the TSPO signal differentiated >96% of PML and multiple sclerosis lesions. Indeed, treatment with rituximab after natalizumab-associated PML in three patients did not affect tracer uptake in the assigned PML lesions but reverted tracer uptake to baseline in the assigned active multiple sclerosis lesions. Taken together our study suggests that TSPO PET imaging can reveal CNS inflammation in natalizumab-associated PML. TSPO PET may facilitate longitudinal monitoring of disease activity and help to distinguish recurrent multiple sclerosis activity from PML progression.

Leukoencephalopathy with calcifications and cysts: Genetic and phenotypic spectrum.

Biallelic mutations in SNORD118, encoding the small nucleolar RNA U8, cause leukoencephalopathy with calcifications and cysts (LCC). Given the difficulty in interpreting the functional consequences of variants in nonprotein encoding genes, and the high allelic polymorphism across SNORD118 in controls, we set out to provide a description of the molecular pathology and clinical spectrum observed in a cohort of patients with LCC. We identified 64 affected individuals from 56 families. Age at presentation varied from 3 weeks to 67 years, with disease onset after age 40 years in eight patients. Ten patients had died. We recorded 44 distinct, likely pathogenic, variants in SNORD118. Fifty two of 56 probands were compound heterozygotes, with parental consanguinity reported in only three families. Forty nine of 56 probands were either heterozygous (46) or homozygous (three) for a mutation involving one of seven nucleotides that facilitate a novel intramolecular interaction between the 5' end and 3' extension of precursor-U8. There was no obvious genotype-phenotype correlation to explain the marked variability in age at onset. Complementing recently published functional analyses in a zebrafish model, these data suggest that LCC most often occurs due to combinatorial severe and milder mutations, with the latter mostly affecting 3' end processing of precursor-U8.

Case Report: A Case of Severe Clinical Deterioration in a Patient With Multiple Sclerosis.

Tumefactive multiple sclerosis (MS) is a rare variant of MS that may lead to a rapidly progressive clinical deterioration requiring a multidisciplinary diagnostic workup. Our report describes the diagnostic and therapeutic approach of a rare and extremely severe course of MS. A 51-year-old man with an 8-year history of relapsing-remitting MS (RRMS) was admitted with a subacute progressive left lower limb weakness and deterioration of walking ability. After extensive investigations including repeated MRI, microbiological, serological, cerebrospinal fluid (CSF) studies, and finally brain biopsy, the diagnosis of a tumefactive MS lesion was confirmed. Despite repeated intravenous (IV) steroids as well as plasma exchanges and IV foscarnet and ganciclovir owing to low copy numbers of human herpesvirus 6 (HHV-6) DNA in polymerase chain reaction (PCR) analysis, the patient did not recover. The clinical presentation of tumefactive MS is rare and variable. Brain biopsy for histopathological workup should be considered in immunocompromised patients with rapidly progressive clinical deterioration with brain lesions of uncertain cause.

Dimethyl fumarate impairs differentiated B cells and fosters central nervous system integrity in treatment of multiple sclerosis.

In multiple sclerosis (MS), the effect of dimethyl fumarate (DMF) treatment is primarily attributed to its capacity to dampen pathogenic T cells. Here, we tested whether DMF also modulates B cells, which are newly recognized key players in MS, and to which extent DMF restricts ongoing loss of oligodendrocytes and axons in the central nervous system (CNS). Therefore, blood samples and brain tissue from DMF-treated MS patients were analyzed by flow cytometry or histopathological examination, respectively. Complementary mechanistic studies were conducted in inflammatory as well as non-inflammatory CNS demyelinating mouse models. In this study, DMF reduced the frequency of antigen-experienced and memory B cells and rendered remaining B cells less prone to activation and production of pro-inflammatory cytokines. Dissecting the functional consequences of these alterations, we found that DMF ameliorated a B cell-accentuated experimental autoimmune encephalomyelitis model by diminishing the capacity of B cells to act as antigen-presenting cells for T cells. In a non-inflammatory model of toxic demyelination, DMF limited oligodendrocyte apoptosis, promoted maturation of oligodendrocyte precursors and reduced axonal damage. In a CNS biopsy of a DMF-treated MS patient, we equivalently observed higher numbers of mature oligodendrocytes as well as a reduced extent of axonal damage when compared to a cohort of treatment-naïve patients. In conclusion, we showed that besides suppressing T cells, DMF dampens pathogenic B cell functions, which probably contributes to its clinical effectiveness in relapsing MS. DMF treatment may furthermore limit chronically ongoing CNS tissue damage, which may reduce long-term disability in MS apart from its relapse-reducing capacity.

Rebound After Fingolimod and a Single Daclizumab Injection in a Patient Retrospectively Diagnosed With NMO Spectrum Disorder-MRI Apparent Diffusion Coefficient Maps in Differential Diagnosis of Demyelinating CNS Disorders.

Objective: Differential diagnosis of neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS) or mimics can be challenging, especially in patients with atypical presentations and negative serostatus for aquaporin-4 antibodies (AQP4-Ab). This brief research report describes magnetic resonance imaging (MRI) findings focusing on quantitative apparent diffusion coefficient (ADC) histogram analysis as a potential tool to differentiate NMOSD from MS. Methods: Longitudinal MRI data obtained during routine clinical examinations were retrospectively analyzed in a patient with histologically determined cerebral NMOSD, a patient with an acute tumefactive MS lesion, and a patient with ischemic stroke. Histogram analyses of ADC maps were evaluated. Results: A patient diagnosed with MS experienced a severe rebound after fingolimod withdrawal and a single daclizumab injection. Cerebral NMOSD manifestation was confirmed by brain biopsy. However, the patient did not fulfill consensus criteria for NMOSD and was AQP4-Ab negative. Comparison of ADC histogram analyses of this patient with those from a patient with MS and one with ischemic stroke revealed differential ADC characteristics: namely a more pronounced and prolonged ADC leftward shift in inflammatory than in ischemic pathology, even more accentuated in NMOSD versus MS. Conclusion: ADC map histograms and ADC threshold values for different conditions may be useful for differentiation of large inflammatory brain lesions and further studies are merited.

Differences in the Reponses to Apheresis Therapy of Patients With 3 Histopathologically Classified Immunopathological Patterns of Multiple Sclerosis.

Importance: Plasma exchange and immunoadsorption are second-line apheresis therapies for patients experiencing multiple sclerosis relapses. Early active multiple sclerosis lesions can be classified into different histopathological patterns of demyelination. Pattern 1 and 2 lesions show T-cell- and macrophage-associated demyelination, and pattern 2 is selectively associated with immunoglobulin and complement deposits, suggesting a humoral immune response. Pattern 3 lesions show signs of oligodendrocyte degeneration. Thus it is possible that pathogenic heterogeneity might predict therapy response. Objective: To evaluate the apheresis response in relation to histopathologically defined immunopathological patterns of multiple sclerosis. Design, Setting and Participants: This single-center cohort study recruited 69 patients nationwide between 2005 and 2016. All included patients had a diagnosis of early active inflammatory demyelination consistent with multiple sclerosis; were classified into patterns 1, 2, or 3 based on brain biopsy analysis; and underwent apheresis treatments. Patients who had concomitant severe disease, neuromyelitis optica, or acute disseminated encephalomyelitis were excluded. Main Outcomes and Measures: The primary therapy outcome was a functionally relevant improvement of the relapse-related neurological deficit. Radiological and Expanded Disability Status Scale changes were secondary outcome parameters. Results: The mean (SD) age of patients was 36.6 (13.3) years; 46 of the 69 participants (67%) were female. Overall, 16 patients (23%) exhibited pattern 1 lesions, 40 (58%) had pattern 2 lesions, and 13 (19%) had pattern 3 lesions. A functional therapy response was observed in 5 of the 16 patients with pattern 1 disease (31%) and 22 of the 40 patients with pattern 2 disease (55%), but none of the 13 patients with pattern 3 disease exhibited improvement (pattern 2 vs 3 P < .001). Radiological improvements were found in 4 (25%), 22 (56%), and 1 (11%) of patients with patterns 1, 2, and 3, respectively. The respective rates of response measured by changes in Expanded Disability Status Scale scores were 25%, 40%, and 0%. Brainstem involvement was a negative predictive factor for the functional therapy response (logarithmic odds ratio [logOR], -1.43; 95% CI, -3.21 to 0.17; P = .03), while immunoadsorption (as compared with plasma exchange) might be a positive predictive factor (logOR, 3.26; 95% CI, 0.75 to 8.13; P = .01). Conclusions and Relevance: This cohort study provides evidence that the response to apheresis treatment is associated with immunopathological patterns. Patients with both patterns 1 and 2 improved clinically after apheresis treatment, but pattern 2 patients who showed signs of a humoral immune response benefited most. Apheresis appears unlikely to benefit patients with pattern 3 lesions.

Diagnostic red flags: steroid-treated malignant CNS lymphoma mimicking autoimmune inflammatory demyelination.

The presence of inflammation and demyelination in a central nervous system (CNS) biopsy points towards a limited, yet heterogeneous group of pathologies, of which multiple sclerosis (MS) represents one of the principal considerations. Inflammatory demyelination has also been reported in patients with clinically suspected primary central nervous system lymphoma (PCNSL), especially when steroids had been administered prior to biopsy acquisition. The histopathological changes induced by corticosteroid treatment can range from mild reduction to complete disappearance of lymphoma cells. It has been proposed that in the absence of neoplastic B cells, these biopsies are indistinguishable from MS, yet despite the clinical relevance, no histological studies have specifically compared the two entities. In this work, we analyzed CNS biopsies from eight patients with inflammatory demyelination in whom PCNSL was later histologically confirmed, and compared them with nine well defined early active multiple sclerosis lesions. In the patients with steroid-treated PCNSL (ST-PCNSL) the interval between first and second biopsy ranged from 3 to 32 weeks; all of the patients had received corticosteroids before the first, but not the second biopsy. ST-PCNSL patients were older than MS patients (mean age: ST-PCNSL: 62 ± 4 years, MS: 30 ± 2 years), and histological analysis revealed numerous apoptoses, patchy and incomplete rather than confluent and complete demyelination and a fuzzy lesion edge. The loss of Luxol fast blue histochemistry was more profound than that of myelin proteins in immunohistochemistry, and T cell infiltration in ST-PCNSL exceeded that in MS by around fivefold (P = 0.005). Our data indicate that in the presence of extensive inflammation and incomplete, inhomogeneous demyelination, the neuropathologist should refrain from primarily considering autoimmune inflammatory demyelination and, even in the absence of lymphoma cells, instigate close clinical follow-up of the patient to detect recurrent lymphoma.

Association of primary central nervous system vasculitis with the presence of specific human leucocyte antigen gene variant.

OBJECTIVES: The etiology and genetic susceptibility of primary central nervous system vasculitis (PCNSV) are still unclear. PATIENTS AND METHODS: We analyzed the DNA of 25 Caucasian patients with PCNSV for human leucocyte antigen genes HLA-A, HLA-B, HLA-DRB1, and HLA-DQB1, respectively. HLA-frequencies of the 25 patients with PCNSV were compared with HLA-frequencies of matched Caucasian controls. RESULTS: No statistically significant associations were found for HLA-B, HLA-DR1 and HLA-DQB1 variant. In the PCNSV group, only the HLA-A*69 variant was found more often than expected statistically. CONCLUSION: The results of this study indicate a potential association of HLA marker with PCNSV in Caucasian patients. Further studies are needed to elucidate the role of genes within the human major histocompatibility complex in the pathogenesis of this angiopathy.

Pathogenic implications of distinct patterns of iron and zinc in chronic MS lesions.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) in which oligodendrocytes, the CNS cells that stain most robustly for iron and myelin are the targets of injury. Metals are essential for normal CNS functioning, and metal imbalances have been linked to demyelination and neurodegeneration. Using a multidisciplinary approach involving synchrotron techniques, iron histochemistry and immunohistochemistry, we compared the distribution and quantification of iron and zinc in MS lesions to the surrounding normal appearing and periplaque white matter, and assessed the involvement of these metals in MS lesion pathogenesis. We found that the distribution of iron and zinc is heterogeneous in MS plaques, and with few remarkable exceptions they do not accumulate in chronic MS lesions. We show that brain iron tends to decrease with increasing age and disease duration of MS patients; reactive astrocytes organized in large astrogliotic areas in a subset of smoldering and inactive plaques accumulate iron and safely store it in ferritin; a subset of smoldering lesions do not contain a rim of iron-loaded macrophages/microglia; and the iron content of shadow plaques varies with the stage of remyelination. Zinc in MS lesions was generally decreased, paralleling myelin loss. Iron accumulates concentrically in a subset of chronic inactive lesions suggesting that not all iron rims around MS lesions equate with smoldering plaques. Upon degeneration of iron-loaded microglia/macrophages, astrocytes may form an additional protective barrier that may prevent iron-induced oxidative damage.