Search

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., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objectives: To compare clinical features and outcome, imaging characteristics, biopsy results and laboratory findings in a cohort of 69 patients with suspected or diagnosed primary central nervous system vasculitis (PCNSV) in adults; to identify risk factors and predictive features for PCNSV., Patients and Methods: We performed a case-control-study including 69 patients referred with suspected PCNSV from whom 25 were confirmed by predetermined diagnostic criteria based on biopsy (72%) or angiography (28%). Forty-four patients turned out to have 15 distinct other diagnoses. Clinical and diagnostic data were compared between PCNSV and Non-PCNSV cohorts., Results: Clinical presentation was not able to discriminate between PCNSV and its differential diagnoses. However, a worse clinical outcome was associated with PCNSV (p=0.005). Biopsy (p=0.004), contrast enhancement (p=0.000) or tumour-like mass lesion (p=0.008) in magnetic resonance imaging (MRI), intrathecal IgG increase (p=0.020), normal Duplex findings of cerebral arteries (p=0.022) and conventional angiography (p 0.010) were able to distinguish between the two cohorts., Conclusion: In a cohort of 69 patients with suspected PCNSV, a large number (64%) was misdiagnosed and partly received treatment, since mimicking diseases are very difficult to discriminate. Clinical presentation at manifestation does not help to differentiate PCNSV from its mimicking diseases. MRI and cerebrospinal fluid analysis are unlikely to be normal in PCNSV, though unspecific if pathological. Cerebral angiography and biopsy must complement other diagnostics when establishing the diagnosis in order to avoid misdiagnosis and mistreatment., Clinical Trial Registration: German clinical trials register: http://drks-neu.uniklinik-freiburg.de/drks_web/, Unique identifier: DRKS00005347., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an inflammatory disorder of the central nervous system; it has only recently been defined and to date has received only limited attention. Its cause is as yet unknown. The pathologic characteristics are infiltration of T lymphocytes into the perivascular spaces of the pons, responsiveness to immunotherapy, and gadolinium-enhancing punctiform lesions in the brainstem seen on magnetic resonance imaging (MRI)., Case Description: We report here on the clinical, MRI, and brain biopsy findings in a 68-year-old man who presented with dysphagia, numbness and paresthesia on the right side of his face, as well as progressive gait ataxia. Brain and spinal MRI showed lesions in the pons and in the cervical spinal cord. The pontine lesion became progressively larger extending to the middle cerebellar peduncle and a tumor was suspected. After repeated biopsy, the histopathologic diagnosis confirmed CLIPPERS., Conclusions: CLIPPERS syndrome may become manifest with a progressive tumor-like pontine lesion. This report adds clinical and radiologic aspects to the limited number of CLIPPERS cases reported to date, and underlines the importance of considering CLIPPERS in the differential diagnosis of tumor-like pontine processes., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Chronic muscular limb pain requires the adoption of motor patterns distinct from the classic ipsilateral flexion, crossed extension and corresponding reciprocal inhibitions to acute exteroceptive stimulation. Using selective chemical activation of group III/IV afferents in gastrocnemius-soleus (GS) muscles we investigated bilaterally their reflex responses conditioned by (a) acute 'myositis' induced by intramuscular carrageenan; and (b) sub-acute 'myositis' induced by infusion of complete Freund's adjuvant (CFA). Reflex transmission was detected by monosynaptic testing and c-fos staining used to identify increased neuronal activity. In all control experiments with chemical stimulation of group III/IV afferents, ipsilateral responses conformed to the flexor reflex pattern. However, the expected contralateral facilitation of GS motoneurones occurred in fewer than 50% trials while only 9% of trials induced contralateral inhibition of flexor posterior-biceps-semitendinosus (PBSt) motoneurones. During carrageenan acute myositis contralateral PBSt was transiently facilitated by selective activation of group III/IV afferents. During CFA-induced myositis, contralateral only inhibition of GS motoneurones occurred instead of any facilitation, while bidirectionally a crossed facilitation of PBST dominated. These reflex changes were mirrored in an enhanced number of neurones with enhanced c-fos expression. Muscle pain, particularly if chronically persistent, requires another behavioural response pattern than acute exteroceptive pain., (Copyright © 2015 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.)

Synchronous (early) and metachronous (late) brain metastasis (BM) events of sporadic clear cell renal cell carcinoma (ccRCC) (n = 148) were retrospectively analyzed using comparative genomic hybridization (CGH). Using oncogenetic tree models and cluster analyses, chromosomal imbalances related to recurrence-free survival until BM (RFS-BM) were analyzed. Losses at 9p and 9q appeared to be hallmarks of metachronous BM events, whereas an absence of detectable chromosomal changes at 3p was often associated with synchronous BM events. Correspondingly, k-means clustering showed that cluster 1 cases generally exhibited low copy number chromosomal changes that did not involve 3p. Cluster 2 cases had a high occurrence of -9p/-9q (94-98%) deletions, whereas cluster 3 cases had a higher frequency of copy number changes, including loss at chromosome 14 (80%). The higher number of synchronous cases in cluster 1 was also associated with a significantly shorter RFS-BM compared with clusters 2 and 3 (P = 0.02). Conversely, a significantly longer RFS-BM was observed for cluster 2 versus clusters 1 and 3 (P = 0.02). Taken together, these data suggest that metachronous BM events of ccRCC are characterized by loss of chromosome 9, whereas synchronous BM events may form independently of detectable genetic changes at chromosomes 9 and 3p., (Copyright © 2014 Elsevier Inc. All rights reserved.)

A novel type of encephalomyelitis was first described as chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) in 2010 and few additional patients were reported since then. Partially due to its unknown aetiology and a lack of pathognomonic features some have suggested that CLIPPERS may not represent a distinct disease, but rather a syndrome with different underlying aetiologies. Here we report a 49-year-old German female who presented with a number of clinical and paraclinical features described as typical for CLIPPERS, while additionally showing symptoms and findings compatible with primary angiitis of the CNS (PACNS). This case may establish a previously unnoted link between two poorly understood autoimmune conditions of the CNS., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Laquinimod is a small, novel, orally active, well-tolerated molecule that significantly reduced gadolinium-enhancing lesions in patients with multiple sclerosis (MS). Orally administered laquinimod was found to be present within the central nervous system (CNS) in both healthy mice and mice with experimental autoimmune encephalomyelitis (EAE). Laquinimod inhibits development of both acute and chronic EAE. Furthermore, laquinimod minimizes inflammation, demyelination and axonal damage in MOG-induced EAE in mice treated at disease induction and following clinical disease onset. In vitro, laquinimod down-regulates secretion of pro-inflammatory cytokines and enhances production of anti-inflammatory cytokines from peripheral blood mononuclear cells (PBMCs) derived from healthy subjects and untreated relapsing remitting (RR) MS patients. Additionally, patients treated with laquinimod demonstrate up-regulation of brain-derived neurotrophic factor (BDNF) in the serum. In conclusion, treatment with laquinimod is effective in reducing inflammation, demyelination and axonal damage., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Toll-like receptor (TLR) 4 responds to a range of agonists in infection and injury, but is best known for the recognition of bacterial lipopolysaccharides (LPS). Assembly in heterologous receptor complexes as well as signaling through both MyD88 and TRIF adaptor proteins, as unmatched by other TLRs, could underlie its versatile response options, probably also in a cell type-dependent manner. We show that microglia, the CNS macrophages, react to diverse LPS variants, including smooth (S) and rough (R) LPS chemotypes, with cytokine/chemokine induction, MHC I expression and suppression of myelin phagocytosis. The TLR4 co-receptor CD14 was shown in peritoneal macrophages to be essential for S-LPS effects and the link of both S- and R-LPS to TRIF signaling. In contrast, cd14(-/-) microglia readily respond to S- and R-LPS, suggesting an a priori high(er) sensitivity to both chemotypes, while CD14 confers increased S- and R-LPS potencies and compensates for their differences. Importantly, CD14 controls the magnitude and shapes the profile of cyto/chemokine production, this influence being itself regulated by critical LPS concentrations. Comparing reactive phenotypes of microglia with deficiencies in CD14, MyD88 and TRIF (cd14(-/-), myd88(-/-), and trif(lps2)), we found that distinct signaling routes organize for individual functions in either concerted or non-redundant fashion and that CD14 has contributions beyond the link to TRIF. Modulation of response profiles by key cytokines finally reveals that the microglial TLR4 can differentiate between the class of LPS structures and a self-derived agonist, fibronectin. It thus proves as a sophisticated decision maker in infectious and non-infectious CNS challenges., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Inflammatory processes are considered to play an important role in the progression of neurodegenerative changes in Alzheimer's disease (AD). In the present study, we performed a systematic expression analysis of various inflammatory and oxidative stress markers in pre-symptomatic and diseased APP/PS1KI mice. This mouse model has been previously shown to harbor severe pathological alterations, including behavioral deficits, axonal degeneration and hippocampal neuron loss starting at the age of 6 months. While the expression levels of most markers remained unchanged in 2-month-old APP/PS1KI mice, at the age of 6 months different astro- and microglia markers including GFAP, Cathepsin D, members of the Toll-like receptor (Tlr) family, TGFbeta-1 and osteopontin were up-regulated. In addition, oxidative stress markers, including the metallothioneins, were also significantly elevated at that time point. As expected, both brain and spinal cord were affected, the latter showing early activation of GFAP-positive astrocytes and Iba1-positive microglia in white matter fiber tracts, which might contribute to the previously reported axonal defects in this mouse model. These data add further evidence to the assumption that inflammatory processes are tightly associated with axonal degeneration and neuron loss, as is evident in the APP/PS1KI mouse model.

Multiple sclerosis (MS) lesions are histopathologically characterized by inflammation, demyelination/remyelination, axonal damage and gliosis. Animal experimental and in vitro studies suggest that sex hormones influence the immune system and contribute to the increased likelihood in women of developing MS. However, a variety of studies have also shown that remyelination is more marked in female rodents or that female sex hormones are beneficial for myelin repair. To determine whether gender influences the histopathology of MS lesions, we compared the extent of inflammation, axonal damage and remyelination in MS lesions of female and male MS patients. We observed no differences in the composition of inflammatory infiltrates, axonal damage or cortical pathology. Similar numbers of oligodendroglial progenitor cells and mature oligodendrocytes were present in MS lesions. Remyelination is slightly, but not significantly, more extensive in women than men in early MS lesions. The absence of significant differences in lesion pathology between female and male MS patients might be explained by a lack of a gender influence, but also might be due to the limited number of tissue samples available for histopathological analysis.

Early, active multiple sclerosis lesions show four immunopathological patterns of demyelination. Although these patterns differ between patients, multiple active lesions from a given patient have an identical pattern, which suggests pathogenic heterogeneity. Therapeutic plasma exchange (TPE) has been successfully used to treat fulminant demyelinating attacks unresponsive to steroids. We postulated that patients with pattern II would be more likely to improve after TPE than those with other patterns since pattern II lesions are distinguished by prominent immunoglobulin deposition and complement activation. We retrospectively studied 19 patients treated with TPE for an attack of fulminant CNS inflammatory demyelinating disease. All patients with pattern II (n=10), but none with pattern I (n=3) or pattern III (n=6), achieved moderate to substantial functional neurological improvement after TPE (p<0.0001). Patients with multiple sclerosis with pattern II pathology are more likely to respond favourably to TPE than are patients with patterns I or III.

In multiple sclerosis (MS) the structural damage to axons determines the persistent clinical deficit patients acquire during the course of the disease. It is therefore important to test therapeutic strategies that can prevent or reverse this structural damage. The conventional animal model of MS, experimental autoimmune encephalomyelitis (EAE), typically shows disseminated inflammation in the central nervous system, which leads to a clinical deficit that cannot be directly attributed to a defined tract system. For this reason we have developed a localized EAE model, in which large inflammatory lesions are targeted to the dorsal columns of the spinal cord, an area including the corticospinal tract. These lesions show the pathological hallmarks of MS plaques and lead to reproducible and pronounced deficits in hindlimb locomotion. Because of the anatomical specificity of this technique we can now use highly sensitive behavioral tests that assess the functional integrity of specific axonal tracts. We show that these tests are predictive of the site and extent of a given lesion and are more sensitive for assessing the clinical course than the scales commonly used for disseminated EAE models. We believe that this targeted EAE model will become a helpful new tool for the evaluation of therapeutic approaches for MS that attempt to protect axons or support their repair.

Remyelination in multiple sclerosis (MS) lesions has been described in several studies. It depends on the presence of myelinating oligodendrocytes and a functional interaction between these myelinating cells and axons. The imaging signal of remyelination in magnetic resonance imaging or spectroscopy is not yet defined. The present review will focus on the morphological appearance of remyelinating MS lesions, their correlation with oligodendrocyte pathology, and possible markers for remyelination in imaging.

Neuronal loss is prominent in Alzheimer's disease (AD), and its mechanisms remain unresolved. Apoptotic cell death has been implicated on the basis of studies demonstrating DNA fragmentation and an up-regulation of proapoptotic proteins in the AD brain. However, DNA fragmentation in neurons is too frequent to account for the continuous neuronal loss in a degenerative disease extending over many years. Furthermore, the typical apoptotic morphology has not been convincingly documented in AD neurons with fragmented DNA. We report the detection of the activated form of caspase-3, the central effector enzyme of the apoptotic cascade, in AD and Down's syndrome (DS) brain using an affinity-purified antiserum. In AD and DS, single neurons with apoptotic morphology showed cytoplasmic immunoreactivity for activated caspase-3, whereas no neurons were labeled in age-matched controls. Apoptotic neurons were identified at an approximate frequency of 1 in 1100 to 5000 neurons in the cases examined. Furthermore, caspase-3 immunoreactivity was detected in granules of granulovacuolar degeneration. Our results provide direct evidence for apoptotic neuronal death in AD with a frequency compatible with the progression of neuronal degeneration in this chronic disease and identify autophagic vacuoles of granulovacuolar degeneration as possible means for the protective segregation of early apoptotic alterations in the neuronal cytoplasm.

Wallerian degeneration of the peripheral nervous system was studied in ICAM-1-deficient mice and compared with the phenomena observed in C57BL wild-type animals. There was a decrease in myelin density in both mice strains 4 and 6 days after transection of the sciatic nerve. The degenerating nerves were invaded by Mac-1-, LFA-1-, and F4/80-positive macrophages; significantly lower numbers of macrophages were present in ICAM-1-deficient nerves. Myelin loss decreased after nerve transection with a more prominent loss in ICAM-1-deficient animals. Schwann cells revealed a much higher myelin load in these animals when compared with wild-type nerves, and there was an increased proliferation of endoneurial cells in ICAM-1-deficient mice. These data indicate that ICAM-1 is involved in macrophage recruitment to injured peripheral nerves as well as in the proliferative and phagocytic response of Schwann cells after peripheral nerve transection.

When in situ hybridization was used for the detection of mRNA for the beta-trace protein (beta-trace; prostaglandin-D-synthase) in sections of rat and porcine brains, unspecific binding reactions of sense and antisense probes to neurons were observed. The beta-trace fragment which served as a template for the synthesis of cRNA probes was blunt end-cloned in the vector pCR-Script SK (+). It was demonstrated that the unspecific signals were caused by artifactual binding of two portions of the cRNA which correspond to sequences of the multicloning site of this vector. These sequences are localized between the SrfI restriction site (or the insert) and the promoter for the T7 RNA polymerase. Thus, artifactual binding could be prevented using riboprobes synthesized by T3 RNA polymerase instead of T7 RNA polymerase. Because of the relatively weak transcription efficiency of T3 RNA polymerase, as compared with T7 RNA polymerase, a blocking procedure was established which allowed successful in situ hybridization with T7 RNA polymerase-synthesized probes. Blocking was performed using synthetic oligonucleotides deduced from the two sequences of the multicloning site which were found to be responsible for artifactual binding.

A 38 year-old woman with a solitary intracerebral Langerhans cell histocytosis (LCH) lesion is presented, in whom, cerebral magnetic resonance imaging (MRI) revealed a non-enhancing mass in the right parieto-occipital lobe. The surgical specimen consisted of a nodular polymorphic infiltrate of mononuclear histiocytic cells, macrophages, eosinophilic granulocytes, lymphocytes and Langerhans giant cells involving leptomeninges, cerebral cortex and white matter. The histiocytes displayed features of Langerhans cells such as CD1a and S-100 immunopositivity, and of reticulum cells such as Ki-M4P and X-12 immunopositivity. This case as well as ten other cases from the literature are reviewed.

Macrophages are important effector cells involved in the pathogenesis of demyelination in multiple sclerosis (MS). Macrophage differentiation was studied in a series of 158 MS plaques from 43 patients obtained at different stages of the disease. Macrophages were identified by immunocytochemistry using a panel of antibodies recognizing different formalin- and paraffin-resistant macrophage activation antigens. The number of cells stained with each antibody was related to the demyelinating activity of the lesions as detected by the presence of myelin degradation products as well as to the category of MS tissue. Highest numbers of macrophages were observed in actively demyelinating and early remyelinating lesions using immunocytochemistry for the panmacrophage marker Ki-M1P. Lower numbers were encountered in inactive, demyelinated or late remyelinated lesions. The acute stage inflammatory macrophage markers MRP14 and 27E10 were selectively expressed in early and late active lesions, thus allowing the identification of actively demyelinating lesions. The chronic stage inflammatory macrophage marker 25F9, in contrast, showed a continuous expression also in inactive lesions. The different types of MS tissue revealed significant differences in their macrophage response. The most intense macrophage infiltration was seen in acute MS cases whereas lesions of early and late chronic MS showed lower macrophage levels. These findings indicate a differentiated pattern of macrophage activation in MS depending on the stage of the demyelinating activity as well as on the category of MS tissue. Furthermore, these macrophage markers give new parameters for staging the inflammatory and demyelinating activity of MS lesions.

Myelin removal in nerves undergoing wallerian degeneration mainly depends on invading, non-resident macrophages. The present study clarifies the role of serum complement components in this process in vitro and in vivo. Macrophages cocultured with degenerating nerves in vitro were unable to invade these nerves in the presence of C3-deficient serum. Application of C3-deficient serum subsequent to cellular invasion abolished the myelin phagocytic capacity of the invaded macrophages. This indicates that opsonization of myelin by complement components is necessary in myelin ingestion via macrophage receptors. In vivo, a monoclonal antibody to the macrophage complement receptor type 3 (CR3) significantly reduced myelin phagocytosis. Immunohistochemistry with anti-C3 antibodies showed a marked reaction in degenerating nerves. Immunoelectron microscopy localized C3 particles at the degenerating myelin sheaths. Haematogenous cells, invading the degenerating nerves, also showed a strong reaction for C3 in their cytoplasm. These results indicate that complement components play a critical role both in macrophage invasion of degenerating nerves and in the ingestion of myelin by these cells.