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X‐linked adrenoleukodystrophy (X‐ALD) and metachromatic leukodystrophy (MLD) are two relatively common examples of hereditary demyelinating diseases caused by a dysfunction of peroxisomal or lysosomal lipid degradation. In both conditions, accumulation of nondegraded lipids leads to the destruction of cerebral white matter. Because of their high lipid content, oligodendrocytes are considered key to the pathophysiology of these leukodystrophies. However, the response to allogeneic stem cell transplantation points to the relevance of cells related to the hematopoietic lineage. In the present study, we aimed to better characterize the pathogenetic role of microglia in the above‐mentioned diseases. Applying recently established microglia markers to human autopsy cases of X‐ALD and MLD we were able to delineate distinct lesion stages in evolving demyelinating lesions. The immune‐phenotype of microglia was altered already early in lesion evolution, and microglia loss preceded full‐blown myelin degeneration both in X‐ALD and MLD. DNA fragmentation indicating phagocyte death was observed in areas showing microglia loss. The morphology and dynamics of phagocyte decay differed between the diseases and between lesion stages, hinting at distinct pathways of programmed cell death. In summary, the present study shows an early and severe damage to microglia in the pathogenesis of X‐ALD and MLD. This hints at a central pathophysiologic role of these cells in the diseases and provides evidence for an ongoing transfer of toxic substrates primarily enriched in myelinating cells to microglia.

Monocytes represent a heterogeneous population of primary immune effector cells. At least three different subsets can be distinguished based on expression of the low-affinity FcγRIII: CD14++CD16− classical monocytes, CD14++CD16+ intermediate monocytes, and CD14+CD16++ non-classical monocytes. Whereas CD16− classical monocytes are considered key players in multiple sclerosis (MS), little is known on CD16+ monocytes and how they contribute to the disease. In this study, we examined the frequency and phenotype of monocyte subpopulations in peripheral blood, cerebrospinal fluid (CSF), and brain biopsy material derived from MS patients and controls. Furthermore, we addressed a possible monocyte dysfunction in MS and analyzed migratory properties of monocyte subsets using human brain microvascular endothelial cells. Our ex vivo studies demonstrated that CD16+ monocyte subpopulations are functional but numerically reduced in the peripheral blood of MS patients. CD16+ monocytes with an intermediate-like phenotype were found to be enriched in CSF and dominated the CSF monocyte population under noninflammatory conditions. In contrast, an inversed CD16+ to CD16− CSF monocyte ratio was observed in MS patients with relapsing-remitting disease. Newly infiltrating, hematogenous CD16+ monocytes were detected in a perivascular location within active MS lesions, and CD16+ monocytes facilitated CD4+ T cell trafficking in a blood–brain barrier model. Our findings support an important role of CD16+ monocytes in the steady-state immune surveillance of the CNS and suggest that CD16+ monocytes shift to sites of inflammation and contribute to the breakdown of the blood–brain barrier in CNS autoimmune diseases.

Remyelination capacity decreases with age in adult mice, but data comparing remyelination capacity after toxic demyelination in developing mice versus adult mice are not available. We treated 3-week-old and adult C57BL/6 mice with cuprizone for 1 to 5 weeks and studied demyelination/remyelination and cellular reactions in the corpus callosum and motor cortex by histology, immunohistochemistry, and electron microscopy. We compared results between the 2 treated groups and age-matched controls. In juvenile mice, significant demyelination was detectable in the corpus callosum on Week 2 and in the motor cortex on Week 5. Oligodendrocyte loss, microglial activation, and acute axonal damage peaked on Week 2. Increased numbers of oligodendrocyte precursor cells were evident on Week 1, and remyelination was detectable on Week 3. Juvenile mice showed more rapid demyelination than adult mice, which may be related to greater vulnerability of oligodendrocytes, lower myelin content, or dose-dependent cuprizone effects. Earlier activation of microglia and proliferation of oligodendrocyte precursor cells probably contributed to accelerated remyelination and less pronounced axonal damage. Our data indicate that oligodendroglial regeneration and remyelination are enhanced in the maturing rodent brain compared with the young-adult rodent brain.

Multiple sclerosis (MS) is an autoimmune, inflammatory demyelinating disease of the central nervous system (CNS) and the most common disabling neurological disease in young adults.1,2 Pediatric MS with a clinical onset before the age of 18 years occurs in about 3–10% of MS patients.3 More than 90% of pediatric MS patients have a relapsing–remitting disease course.3,4 The clinical course differs between pediatric and adult MS patients. First, children more often present with an acute disease onset associated with disabling clinical symptoms.3–8 A polyfocal presentation at disease onset is more common in children (48.9%) than in adults (12%).5 Second, children show a significantly higher relapse rate early in the disease.4,9–12 Third, the remission after a severe relapse is better in children than in adults,4,5,7,8 with 62 to 66% of pediatric patients13,14 recovering completely from initial relapses compared to 46% of adult patients.14 Furthermore, the mean time of recovery after a relapse is shorter in pediatric MS (4.3 weeks) than in adult MS (6–8 weeks).11 Finally, children show a slower rate of disease progression7,15 and take approximately 10 years longer to reach the secondary progressive disease phase compared to adults. However, given their younger age at disease onset, they are approximately 10 years younger when they enter this phase of the disease.16 Overall, children develop irreversible physical disability more slowly than adults.9,13 Defining the factors that are associated with the clinical differences between pediatric and adult MS is of special interest. Pathological studies in particular represent a promising way of gaining more insight. To date, there has been no comprehensive histological study of pediatric MS available in the literature. This study investigates axonal pathology in pediatric inflammatory demyelinating lesions consistent with MS. Axonal loss, one of the hallmarks of MS lesions, is an important pathological correlate of nonremitting clinical disability and disease progression.17–19 Hence, there may be differences in axonal damage between pediatric and adult MS patients. Various histological and immunohistochemical staining methods are available to assess axonal damage. The classical methods for visualizing the axonal network are silver impregnation20 and immunohistochemistry for neurofilaments.21 Irreversible loss of axons may be determined by analyzing the reduction in axonal density, whereas the presence of axonal spheroids is a reflection of impaired axonal transport associated with acute and possibly reversible axonal injury. Immunostaining with the precursor of the beta-amyloid protein (amyloid precursor protein [APP]) or other anterogradely transported proteins, such as synuclein, are good markers to evaluate the extent of acute axonal damage, because anterograde transport is interrupted and APP and/or synuclein accumulate focally as spheroids.22–24 These APP-positive spheroids may persist for up to 30 days.22 The accumulation of APP may be reversible24 and in part account for the improvement of neurological symptoms observed after a relapse. In the present study, we analyzed axonal pathology in pediatric MS lesions and compared the findings with data from adult MS patients to determine whether differences contribute to different clinical outcomes.

Objective Intraoperative ultrasound displays dynamic processes intraoperatively. Performing burr-hole biopsies under a real-time visual control is an interesting option for the neurosurgeon. However, the percentage of conclusive diagnoses obtained by this technique and the rate of complications must be evaluated in a larger series. Methods One hundred consecutive intracranial biopsies were analyzed. Through a burr hole, the lesion was localized by ultrasonography, and the planned needle trajectory was superimposed onto the image. Intracranial vessels were imaged by Doppler flow signals. Biopsies were taken in a mean depth of 41 mm (maximal 65 mm) from different parts of each tumor. Results Thirty-six lesions involved the corpus callosum, 16 lesions were located deeply within the white matter, five in the internal capsule, and one in the upper brainstem. There were three cerebellar and 17 temporal lesions. Ten tumors did not exceed a diameter of 15 mm in any plane. The mean time interval from skin incision to the end of suturing was 45 minutes, and the mean time from the surgeons entering the operating theater to leaving the theater was 63 minutes. In 95% of the lesions, a diagnosis could be established. Transient neurologic deficits occurred in five patients, which were permanent in three. In 42 patients without postoperative neurological symptoms, postoperative computed tomography scans were obtained within 24 hours; a visible hemorrhage occurred in eight (19%), six of which were seen intraoperatively. Conclusion When intraoperative ultrasound−navigated biopsies were used they obtained a similar percentage of conclusive diagnoses as stereotactic biopsies. The complication rate is comparable as well. Emerging intracranial complications such as hemorrhages can be observed. However, their incidence cannot be decreased.

Impaired remyelination in multiple sclerosis (MS) might be due to the failure of oligodendrocyte precursor cells (OPC) to differentiate into myelinating oligodendrocytes. Animal experimental data have shown that p57kip2 inhibits oligodendroglial differentiation, indicating that this factor could contribute to remyelination failure. This study investigates oligodendroglial p57kip2 expression and its association with remyelination in MS lesions. To analyze the potential association of p57kip2 expression with human oligodendroglial maturation, double immunofluorescence staining was performed on brain tissue from 30 MS patients and 20 controls. Anti-p57kip2 antibody was combined with either anti-Nogo-A to label mature oligodendrocytes or anti-Olig2 antibodies to identify immature OPCs. We evaluated MS lesions with or without remyelination, the periplaque white matter (PPWM) as well as control white matter (WM). p57kip2-expressing cells were assessed and correlated with the extent of remyelination. Most Nogo-A-positive oligodendrocytes (range, 87-98%) and all Olig2strong-positive OPCs expressed p57kip2 in MS lesions, in the PPWM and in control WM. p57kip2 expression in oligodendrocytes and OPCs were similar in MS lesions with remyelination compared to MS lesions lacking remyelination. Interestingly, all oligodendroglial lineage cells showed nuclear p57kip2 expression only, with mature oligodendrocytes expressing p57kip2 at low or intermediate levels and OPCs featuring strong expression levels, indicating that this factor may be dynamically expressed during maturation processes. Therefore, p57kip2 appears to be widely expressed in the human oligodendroglial lineage, and potential beneficial effects on remyelination in the MS brain are not based on subcellular p57kip2 localization shifts, as suggested by previous animal experiments.

Multiple sclerosis is characterized by widespread primary demyelination and progressive degeneration, driven by heterogeneous mechanisms. Haider et al. provide a topographic map of the frequency with which different brain regions are affected by these processes, and show that demyelination and neurodegeneration involve inflammatory as well as vascular changes., Multiple sclerosis is a chronic inflammatory disease with primary demyelination and neurodegeneration in the central nervous system. In our study we analysed demyelination and neurodegeneration in a large series of multiple sclerosis brains and provide a map that displays the frequency of different brain areas to be affected by these processes. Demyelination in the cerebral cortex was related to inflammatory infiltrates in the meninges, which was pronounced in invaginations of the brain surface (sulci) and possibly promoted by low flow of the cerebrospinal fluid in these areas. Focal demyelinated lesions in the white matter occurred at sites with high venous density and additionally accumulated in watershed areas of low arterial blood supply. Two different patterns of neurodegeneration in the cortex were identified: oxidative injury of cortical neurons and retrograde neurodegeneration due to axonal injury in the white matter. While oxidative injury was related to the inflammatory process in the meninges and pronounced in actively demyelinating cortical lesions, retrograde degeneration was mainly related to demyelinated lesions and axonal loss in the white matter. Our data show that accumulation of lesions and neurodegeneration in the multiple sclerosis brain does not affect all brain regions equally and provides the pathological basis for the selection of brain areas for monitoring regional injury and atrophy development in future magnetic resonance imaging studies.

We report the clinical course and pathological features of a 52-year-old woman with fulminant acute disseminated encephalomyelitis (ADEM). She presented with subacute tetraparesis, which developed over 2 days, and progressive loss of consciousness. CCT showed pronounced bihemispherical and periventricular edema. Multifocal glioma was suspected, and the patient was referred for brain biopsy to the neurosurgery department at our hospital. On admission, the patient presented with progressive tetraparesis and aphasia. Subsequently, she developed epileptic seizures. Cranial magnetic resonance imaging (MRI) revealed confluent bihemispherical and periventricular white matter edema (Fig. 1a) with abnormal patchy gadolinium enhancement, compatible with progressive multifocal leukoencephalopathy (PML), multifocal brain tumor or ADEM. Cerebrospinal fluid (CSF) analysis revealed mild pleocytosis (11 cells/ll) with increased protein levels, and normal glucose and lactate levels. No intrathecal IgG and IgM synthesis or oligoclonal bands (OCB) were observed in CSF. Antiviral and antibiotic treatment was initiated. Stereotactic brain biopsy from right frontal periventricular white matter (Fig. 1b) was performed 5 days after disease onset. Histopathology ruled out malignant brain tumor but showed acute perivascular inflammation.

Background: Because of the emergence of novel therapies for multiple sclerosis (MS) and the associated increased risk of progressive multifocal leukoencephalopathy, John Cunningham (JC) virus infection has become a focus of interest for neurologists. However, little is known about JC virus infection in pediatric MS to date. Objective: We aimed to analyze the prevalence of anti-JC virus antibodies, the conversion rate and the influence of the anti-JC virus antibody status on the clinical course in a large pediatric MS cohort. Methods: Anti-JC virus antibodies were analyzed in serum samples within six months of disease onset and during the course of the disease. Clinical data were extracted from a pediatric MS databank. Results: A total of 51.6% of 256 patients were found to be positive for anti-JC virus antibodies at onset of disease. No correlation between antibody status and clinical course was seen. Analyzing 693 follow-up serum samples revealed high titer stability, and an annual conversion rate of 4.37% was seen. Conclusion: No evidence was found that seropositivity for anti-JC virus antibodies influences the clinical course. Surprisingly, seroprevalence for anti-JC virus antibodies was more than twice as high as anticipated in this age group, raising the question of whether the infection increases the risk of MS development.

Axonal damage occurs early in multiple sclerosis (MS) and contributes to the degree of clinical disability. Children with MS more often show disabling and polyfocal neurological symptoms at disease onset than adults with MS. Thus, axonal damage may differ between pediatric and adult MS patients.We analyzed axonal pathology in archival brain biopsy and autopsy samples from 19 children with early MS. Lesions were classified according to demyelinating activity and presence of remyelination. Axonal density and extent of acute axonal damage were assessed using Bielschowsky silver impregnation and immunohistochemistry for amyloid precursor protein (APP), respectively. Axonal injury was correlated with the inflammatory infiltrate as well as clinical characteristics. Results were compared with data from adult MS patients.Acute axonal damage was most extensive in early active demyelinating (EA) lesions of pediatric patients and correlated positively with the Expanded Disability Status Scale at attack leading to biopsy/autopsy. Comparison with 12 adult patients showed a 50% increase in the extent of acute axonal damage in EA lesions from children compared to adults, with the highest number of APP-positive spheroids found prior to puberty. The extent of acute axonal damage correlated positively with the number of lesional macrophages. Axonal density was reduced in pediatric lesions irrespective of the demyelinating activity or the presence of remyelination. Axonal reduction was similar between children and adults.Our results provide evidence for more pronounced acute axonal damage in inflammatory demyelinating lesions from children compared to adults.

Impaired remyelination in multiple sclerosis (MS) might be due to the failure of oligodendrocyte precursor cells (OPC) to differentiate into myelinating oligodendrocytes. Animal experimental data have shown that p57kip2 inhibits oligodendroglial differentiation, indicating that this factor could contribute to remyelination failure. This study investigates oligodendroglial p57kip2 expression and its association with remyelination in MS lesions. To analyze the potential association of p57kip2 expression with human oligodendroglial maturation, double immunofluorescence staining was performed on brain tissue from 30 MS patients and 20 controls. Anti-p57kip2 antibody was combined with either anti-Nogo-A to label mature oligodendrocytes or anti-Olig2 antibodies to identify immature OPCs. We evaluated MS lesions with or without remyelination, the periplaque white matter (PPWM) as well as control white matter (WM). p57kip2-expressing cells were assessed and correlated with the extent of remyelination. Most Nogo-A-positive oligodendrocytes (range, 87-98%) and all Olig2strong-positive OPCs expressed p57kip2 in MS lesions, in the PPWM and in control WM. p57kip2 expression in oligodendrocytes and OPCs were similar in MS lesions with remyelination compared to MS lesions lacking remyelination. Interestingly, all oligodendroglial lineage cells showed nuclear p57kip2 expression only, with mature oligodendrocytes expressing p57kip2 at low or intermediate levels and OPCs featuring strong expression levels, indicating that this factor may be dynamically expressed during maturation processes. Therefore, p57kip2 appears to be widely expressed in the human oligodendroglial lineage, and potential beneficial effects on remyelination in the MS brain are not based on subcellular p57kip2 localization shifts, as suggested by previous animal experiments.

Pediatric MS tends to present more often with an acute onset and a polysymptomatic form of the disease, possibly with encephalopathy and large tumefactive lesions similar to those observed in some cases of acute disseminated encephalomyelitis (ADEM), which makes it more difficult to differentiate between an explosive and severe onset of MS vs. ADEM. An ADEM-like first demyelinating event can be the first attack of pediatric MS, but international consensus definitions require two or more non-ADEM demyelinating events for diagnosis of MS. In our patient KIDMUS MRI criteria for MS (Mikaeloff et al. J Pediatr 144:246–252, 2004a; Mikaeloff et al. Brain 127:1942–1947, 2004b) were negative at first attack, but Barkhof criteria for lesion dissemination in space in adults (Barkhof et al. 120:2059–2069, 1997), Callen modified MS-criteria and Callen MS-ADEM criteria for children (Callen et al. Neurology 72:961–967, 2009a; Callen et al. Neurology 72:968–973, 2009b) were positive suggesting pediatric MS. As the clinical course was devastating with non-responsiveness upon high-dose immune modulatory therapy and due to the absence of an alternative diagnosis other than demyelinating disease brain biopsy was performed. Brain biopsy studies or autopsy case reports of fulminant pediatric MS patients are extremely rare. Histopathology revealed an inflammatory demyelinating CNS process with confluent demyelination, indicating the likelihood of a relapsing disease course compatible with an acute to subacute demyelinating inflammatory disease. This pattern was corresponding to the early active multiple sclerosis subtype I of Lucchinetti et al. (Ann Neurol 47(6):707–717, 2000). peerReviewed

A 32-year-old man presented with generalized epileptic seizures and right homonymous hemianopia. MRI detected a left parieto-occipital lesion suspicious for lymphoma ([figure 1][1]); biopsy showed inflammatory demyelinating white matter lesions suggestive of multiple sclerosis ([figure 2][2], A–C

e13016 Background: Ets-1 regulates migration & angiogenesis and is active in malignomas. Methods: We investigated Ets-1 in 60 glioblastomas WHO IV° & 40 astrocytomas WHO II° and evaluated its progn...