Pro-inflammatory activation of microglia in the brain of patients with sepsis.

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 (TMEM119), 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 CD163 or CD206 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.

Anti-contactin-associated protein-2 encephalitis: relevance of antibody titres, presentation and outcome.

BACKGROUND AND PURPOSE: To clarify the relevance of titres of IgG antibodies against contactin-associated protein-2 (CASPR2) in diagnosing anti-CASPR2 encephalitis and to describe features and outcomes. METHODS: This was a retrospective analysis of 64 patients with CASPR2 antibodies, categorized independently as 'autoimmune encephalitis' or 'other disease'. Logistic regression methods were performed to identify potential predictors of 'autoimmune encephalitis' in addition to CASPR2 antibodies. RESULTS: An upfront CASPR2 antibody serum titre cut-off at ≥1:200 had a diagnostic sensitivity of 85% and a specificity of 81%. Logistic regression analyses indicated that, in addition to titre, encephalitic magnetic resonance imaging (MRI) was a significant predictor of 'autoimmune encephalitis' (Nagelkerke's R2 = 0.81, P < 0.001) with high sensitivity (84%) and very high specificity (100%). Patients with CASPR2 antibodies and an estimated probability of >70% of having anti-CASPR2 encephalitis (n = 22) had limbic encephalitis (n = 18, one patient plus ataxia), Morvan syndrome (n = 2) or a hyperkinetic movement disorder (n = 2). Median modified Rankin score (mRS) at diagnosis was 3 (range 1-4). Twenty patients were male; median age was 64 (range 54-75) years; 5/15 patients with cerebrospinal fluid data had intrathecal CASPR2 antibody synthesis, and 12/19 with follow-ups >3 months (median 12 months, range 4-43 months) improved by ≥1 mRS point resulting in a median mRS of 2 (range 0-6; one death; all but one having received immunotherapy); and 2/15 patients with follow-up MRI developed hippocampal atrophy. CONCLUSIONS: 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.

Myotonic dystrophy 2 manifesting with non-alcoholic and non-hepatitic liver cirrhosis.

OBJECTIVE: Though the liver is frequently affected in myotonic dystrophy type 1 and 2 (DM1, DM2), non-alcoholic and non-hepatitic liver cirrhosis have not been reported as a manifestation of DM2. CLINICAL PRESENTATION AND INTERVENTION: In a 52-year-old Caucasian male with DM2, the disease manifested as myopathy, mild myotonia, cataract, diabetes, erectile dysfunction, gastrointestinal dysmotility, dysarthria, mild myocardial thickening and non-alcoholic and non-hepatitic liver cirrhosis with portal hypertension and oesophageal varicosities since age 48 years. His 69-year-old sister, who carried a CCTG expansion of >300 in intron 1 of the CNBP/ZNF9 gene, also manifested in the liver with hyperbilirubinaemia, hepatopathy and hyperlipidaemia since age 48 years. Liver cirrhosis in the index patient was complicated by hyperamonemia, hepatic encephalopathy and flapping tremor. CONCLUSION: Rarely, DM2 may also manifest in the liver with elevated transaminases, steatosis or non-alcoholic, non-hepatitic liver cirrhosis with its common complications. In patients with cryptogenic non-alcoholic, non-hepatitic liver cirrhosis or cataract before age 50 years, DM2 should be excluded.

Late-onset metachromatic leukodystrophy: genotype strongly influences phenotype.

BACKGROUND: P426L and I179S are the two most frequent mutations in juvenile and adult metachromatic leukodystrophy (late-onset MLD), which, in contrast to infantile MLD, show marked phenotypic heterogeneity. OBJECTIVE: To search for genotype-phenotype correlations in late-onset MLD. METHODS: The authors reviewed the clinical course of 22 patients homozygous for mutation P426L vs 20 patients heterozygous for mutation I179S, in which the second arylsulfatase A (ASA) mutation had also been determined. RESULTS: P426L homozygotes principally presented with progressive gait disturbance caused by spastic paraparesis or cerebellar ataxia; mental disturbance was absent or insignificant at the onset of disease but became more apparent as the disease evolved. In contrast, compound heterozygotes for I179S presented with schizophrenia-like behavioral abnormalities, social dysfunction, and mental decline, but motor deficits were scarce. Reduced peripheral nerve conduction velocities and less residual ASA activity were present in P426L homozygotes vs I179S heterozygotes. CONCLUSION: The characteristic clinical differences between homozygous P426L and compound heterozygous I179S patients establish a distinct genotype-phenotype correlation in late-onset metachromatic leukodystrophy.

Novel C59T leader peptide mutation in the MPZ gene associated with late-onset, axonal, sensorimotor polyneuropathy.

The objective of this study was to report a novel exon-1 mutation in the myelin protein zero (MPZ) gene, resulting in axonal Charcot-Marie-Tooth neuropathy with recurrent hyper-CK-emia. In a 64-year-old woman slowly progressive distal lower limb weakness, muscle cramps in the lower limb muscles, and stocking-type numbness had developed from the age of 61. Neurologic examination revealed discrete hip flexor weakness, weakness for foot extension, diffuse wasting of the distal lower limb muscles, reduced patella tendon reflexes, and absent Achilles tendon reflexes. There was recurrently elevated creatine kinase with a maximum of 607 U/l (n, <145 U/l). Stimulation of the peroneal and tibial nerves did not evoke a muscular response. Electromyography was neurogenic. Biopsy of the right sural nerve showed diffuse axonal degeneration and loss of axons of all diameters. Muscle biopsy showed increased fiber-size variability, angulated fibers, internalized nuclei, accumulations of nuclei, grouped atrophic muscle fibers, and fiber splitting. Molecular genetic analysis by PCR and direct nucleotide sequencing revealed the heterozygous C59T exon-1 MPZ gene mutation, resulting in the amino acid exchange S20F of the MPZ signal protein domain (leader peptide). The novel C59T mutation in the leader peptide of the MPZ gene is pathogenic and manifests as severe, late-onset, axonal, symmetric sensorimotor polyneuropathy (CMT2) and hyper-CK-emia.

Restrictive cardiomyopathy in dermatomyositis.

The association between dermatomyositis and restrictive cardiomyopathy has not been reported before. We present here the clinical, echocardiographic and muscle biopsy data for a patient with dermatomyositis and restrictive cardiomyopathy. In a 78-year-old male with a history of arterial hypertension, recurrent episodes of atrial fibrillation and syncopes, rupture of an infra-renal aortic aneurysm with complications (recurrent QT-prolongation, lumbo-sacral plexopathy, transient ischaemic attack, peripheral embolism), monoclonal gammopathy, subdural haematoma, focal seizures, megaloblastic anaemia, leucopenia, eosinophilia, elevated muscle enzymes and increasing tiredness, dermatomyositis was diagnosed upon clinical presentation, muscle enzyme and muscle biopsy findings. Cardiological examination revealed atrial fibrillation, left anterior hemiblock and restrictive cardiomyopathy. After the exclusion of various differentials for restrictive cardiomyopathy, a causative relationship between restrictive cardiomyopathy and dermatomyositis was assumed. This case suggests the need for suspecting restrictive cardiomyopathy in patients with dermatomyositis. Patients with dermatomyositis should undergo a comprehensive cardiological investigation as soon as the neurological diagnosis is established.

Guillain-Barré syndrome with marked pleocytosis or a significant proportion of polymorphonuclear granulocytes in the cerebrospinal fluid: neuropathological investigation of five cases and review of differential diagnoses.

In cases with otherwise clinically typical Guillain-Barré syndrome (GBS), pronounced cerebrospinal fluid (CSF) pleocytosis or the mere presence of CSF-polymorphonuclear granulocytes should alert the physician to consider alternative diagnoses. Therefore, we retrospectively studied the neuropathology of central and peripheral nervous system in two cases with a CSF cell count of more than 50/microl and in three cases with a significant proportion of polymorphonuclear granulocytes in the CSF sediment. All cases fulfilled the required criteria for the diagnosis of GBS, the duration from onset to death ranged from 4 to 100 days. Neuropathological investigations included routine staining procedures and immunohistochemistry for antigens of glial and haematopoetic cells as well as for products of relevant neurotropic viruses. Demyelinating polyradiculitis was present in four cases, in one patient with a survival time of 4 days the type of damage to myelinated fibres was unclassifiable. In the central nervous system a consistent finding was diffuse activation of microglia, only one case showed mild meningeal and lower brainstem inflammation. Viral products were generally absent. In summary, the neuropathological findings confirm that marked CSF pleocytosis or the presence of polymorphonuclear granulocytes does not rule out the diagnosis of GBS.

Inflammation in the nervous system: the human perspective.

Many basic aspects of brain inflammation, recently disclosed in experimental models, are reflected in the pathology of human inflammatory brain diseases. Examples include the key role of T lymphocytes in immune surveillance and in the regulation of the inflammatory response, the essential contributions of adhesion molecules, proinflammatory cytokines, chemokines, and proteases in the recruitment of inflammatory cells into the nervous tissue, the modulating effect of glia cells on the inflammatory process and the termination of T-cell-mediated inflammation by apoptotic cell death. Despite this progress in our understanding of the pathogenesis of brain inflammation, there are still major unresolved questions. Because of technical constraints, most of our knowledge on central nervous system inflammation so far relates to the role of a specific T-cell subset, the so-called T-helper-1 cells. Other T-cell subsets, in particular cytotoxic class I MHC-restricted T lymphocytes, however, appear to be of major importance in human disease. Furthermore, the detailed mechanisms, which are responsible for the profound differences in the patterns of tissue damage in different human inflammatory brain diseases, such as multiple sclerosis or various forms of virus encephalitis, are largely unresolved. We discuss the open questions to be addressed in the future, which, when answered, may help to design novel therapeutic strategies.

Rolipram does not normalize very long-chain fatty acid levels in adrenoleukodystrophy protein-deficient fibroblasts and mice.

In its severe form, X-linked adrenoleukodystrophy (X-ALD) is a lethal neurodegenerative disorder with inflammatory demyelination, in which defective peroxisomal beta-oxidation causes accumulation of very long-chain fatty acids (VLCFA) in tissues and plasma, in particular in the nervous system and adrenal glands. Recently, several drugs have been reported to reduce VLCFA in cultured human fibroblasts of X-ALD patients, and therefore to be potential candidates for novel therapeutic treatments in X-ALD. Among the most promising of these substances is the antidepressant rolipram, because of favourable adverse event profile in clinical studies and its additionally reported anti-inflammatory action. To further elucidate the effects of rolipram on peroxisomal beta-oxidation and VLCFA accumulation, we administered rolipram orally in the diet to ALD protein-deficient mice and ALD protein-deficient cultured human and mouse fibroblasts and assayed the accumulation of VLCFA. In contrast to the previously reported reduction of VLCFA, our data did not demonstrate a decrease in VLCFA content either in vivo or in vitro. NMR spectroscopic analysis verified the structural integrity and purity of the rolipram used here, thus excluding inauthenticity as a reason for the discrepancy. We therefore suggest that rolipram should be excluded from the current list of potential therapeutic agents for X-ALD.