The immunomodulatory properties of in vitro immunoglobulins are dose-dependent

OBJECTIVES: The mechanism by which intravenous immunoglobulins (immunoglobulin G, IgG) exert their beneficial effect on multiple sclerosis (MS) is unknown. Furthermore, there is uncertainty about the optimal dosage of IgG. Therefore, we investigated the influence of different IgG dosages on cytokine production in MS. MATERIALS AND METHODS: Twenty-five MS patients and 15 healthy controls were enrolled. We measured the production of interferon gamma (IFN-gamma), tumour necrosis factor alpha (TNF) and interleukin 10 (IL-10) in peripheral blood lymphocytes by flowcytometry after stimulation without and with IgG in different doses (1, 5 and 10 mg/ml). RESULTS: IFN-gamma and TNF were decreased significantly (P = 0.001) in the untreated and interferon beta (IFN-beta) treated patients after stimulation with IgG. In contrast, IL-10 production was significantly enhanced (P = 0.001) at least in the untreated patient group. The reduction of the pro-inflammatory cytokines IFN-gamma and TNF after stimulation with different IgG doses was clearly dose-dependent in all groups. CONCLUSION: Besides a suppression of the pro-inflammatory cytokines IFN-gamma and TNF, IgG enhances the anti-inflammatory cytokine IL-10. This effect is dose-dependent, speaking in favour of higher IgG doses in the treatment of MS.     

Impact of recently diagnosed multiple sclerosis on quality of life, anxiety, depression and distress of patients and partners

OBJECTIVES: Studies demonstrating reduced quality of life and psychological well-being in multiple sclerosis (MS) have typically investigated patients within more advanced stages of disease. The aim of the present paper was to evaluate the emotional burden and quality of life of recently diagnosed MS patients and their partners. METHODS: Data on health-related quality of life (SF-36), anxiety and depression (Hospital Anxiety and Depression Scale) and disease-related distress (Impact of Event Scale) were obtained in 101 patients and their partners (n=78). RESULTS: On average 8 months after diagnosis (range 0-24 months), 34% of the patients and 40% of the partners had clinically high levels of anxiety, and 36% of the patients and 24% of the partners had levels of severe distress. Scores of anxiety, depression and distress were higher in patients with more functional limitations (Expanded Disability Status Scale=3.0). Quality of life was significantly poorer in patients compared with controls, particularly among those with higher disability. CONCLUSIONS: Both patients and their partners demonstrated high levels of anxiety and distress in the early period after the diagnosis. These findings indicate careful attention by health care professionals to identify those who may benefit from further psychological support.     

Distribution of alpha and beta integrin subunits in the adult rat hippocampus after pilocarpine-induced neuronal cell loss,axonal reorganization and reactive astrogliosis

Integrins are –heterodimers that act as cell-extracellular matrix (ECM) and cell-cell adhesion molecules. During development, they are involved in axonal guidance, synaptogenesis, and in astrocytic maturation and migration. Here, we have examined the potential role of the integrin subunits 1–5 and 1–5 in axonal sprouting, synaptogenesis and reactive astrogliosis in the adult rat brain caused by pilocarpine-induced status epilepticus (SE). Strong hippocampal immunoreactivity of 1–5, 1, 3, 4, and 5 was observed in the pia mater, in vascular endothelia, and in astrocytes at the pial surface. 2 immunoreactivity was found exclusively in vascular endothelia. Pyramidal cells and interneurons of CA3–CA1, as well as hilar neurons revealed moderate 5 labeling in their cell bodies. Mossy fibers were immunoreactive for 2, 4, and 5. After pilocarpine-induced SE, strong immunoreactivity for 1, 2, 4, 5, 1, 3, and 4 was observed in reactive astrocytes. Our results show that members of the integrin family are differently distributed in cellular and subcellular compartments of the hippocampus and undergo specific patterns of regulation, which may be important for lesion-induced reactive changes in the adult brain.     

Corticotropin-releasing factor (CRF) can directly affect brain microvessel endothelial cells

Stress activates the hypothalamic-pituitary-adrenal (HPA) axis through release of corticotropin releasing factor (CRF), leading to production of glucocorticoids that down regulate immune responses. However, acute stress via CRF also has pro-inflammatory effects. We previously showed that acute stress increases rat blood-brain barrier (BBB) permeability, an effect involving brain mast cells and CRF, as it was absent in W/W(v) mast cell-deficient mice and was blocked by the CRF-receptor antagonist, Antalarmin. We investigated if CRF could also have a direct action on brain microvessel endothelial cells (BMEC) isolated from rat and bovine brain. BMEC were cultured and identified by electron microscopy. Western blot analysis of cultured BMEC identified CRF receptor protein; stimulation with CRF, or it structural analogue urocortin (Ucn) showed that the receptor is functionally coupled to adenylate cyclase as it increased cyclic AMP (cAMP) levels by 2-fold. These findings suggest that CRF could affect BMEC structure or function, as reported for increased cAMP levels by other studies. It is, therefore, possible that CRF may directly regulate BBB permeability, in addition to any effect mediated via brain mast cells.     

Epilepsy and multiple sclerosis in Sicily: a population-based study

PURPOSE: To evaluate the association between epilepsy and multiple sclerosis (MS), we analyzed the incidence of epilepsy in a population-based incidence cohort of MS in Catania, Sicily. METHODS: According to Poser's diagnostic criteria, 170 incident cases of MS have been identified from 1975 to 1994 in the city of Catania. All these subjects underwent a complete neurological examination to confirm the diagnosis of MS and to identify those patients with a history of seizures. Diagnosis of epilepsy was based on the criteria proposed by the International League Against Epilepsy (ILAE) in 1993, and seizures were classified according to the classification of the ILAE, 1981. RESULTS: From 1975 to 1994, 170 subjects with MS had the clinical onset of the disease. The mean annual incidence of MS was 2.3/100,000 (95% CI, 2.0-2.6). Of the 170 defined MS patients, four developed epilepsy after the onset and also diagnosis of MS, giving an incidence rate of epilepsy of 285/100,000 person years at risk (95% CI, 119-684) and 147.8/100,000 when age adjusted to the world standard population. The cumulative risk of developing epilepsy after the onset of MS, evaluated by using the life-table methods, was zero at 1 year and 1.76% at 5 years. Of these four patients, three were classified as having partial seizures with secondary generalization and one with tonic-clonic seizures. CONCLUSIONS: Our data are consistent with those reported in literature suggesting that the risk of developing epilepsy is threefold higher among MS patients than in the general population.     

Major vault protein, a marker of drug resistance, is upregulated in refractory epilepsy

PURPOSE: The molecular basis of drug resistance in epilepsy is being explored. Two proteins associated with drug resistance in cancer, P-glycoprotein and multidrug resistance-associated protein 1, are upregulated in human epileptogenic pathologies. Other proteins associated with resistance in cancer include major vault protein (MVP) and breast cancer resistance protein (BCRP). We hypothesized that these proteins would also be upregulated in human epileptogenic pathologies. METHODS: Hippocampal sclerosis (HS), focal cortical dysplasia (FCD), and dysembryoplastic neuroepithelial tumor (DNT) were studied by using immunohistochemistry for MVP and BCRP. Nonepileptogenic control and histologically normal brain adjacent to epileptogenic tissue were used for comparison. RESULTS: MVP and BCRP were expressed ubiquitously in brain capillary endothelium. Ectopic upregulation of MVP was seen in hilar neurons in HS, dysplastic neurons in FCD, and lesional neurons in DNT. Only in HS cases were rare extralesional neurons immunoreactive. Glial upregulation was not seen. There was no qualitative upregulation of BCRP. CONCLUSIONS: These results show that more than one resistance protein may be upregulated in a given epileptogenic pathology and may contribute to drug resistance. Determination of the types, amounts, and distribution of such proteins will be necessary for rational treatment for drug resistance in epilepsy.     

The role of hippocampal sclerosis in topiramate-related depression and cognitive deficits in people with epilepsy

PURPOSE: To clarify the role of hippocampal sclerosis (HS) in developing psychiatric and cognitive adverse events during therapy with topiramate (TPM) in patients with temporal lobe epilepsy (TLE). METHODS: We analyzed the data of 70 patients with TLE and HS and 128 patients with cryptogenic TLE matched for age, sex, starting dose, and titration schedule of TPM. They were selected from the first consecutive 431 patients started on TPM between 1995 and 1999. RESULTS: Patients with HS were more likely to develop cognitive adverse events (CAEs; p = 0.002) and depression (p = 0.018) and to be receiving a polytherapy regimen (p = 0.007). However, regression analysis demonstrated that only HS was a predictive factor for the occurrence of CAEs (OR = 2.4; p < 0.001) and depression (OR = 2.3; p = 0.02). CONCLUSIONS: Patients with TLE and HS were more prone to develop CAEs and depression than were patients with cryptogenic TLE, during TPM therapy, despite the same titration schedule. The presence of HS and not duration of epilepsy or polytherapy regimen represented the main risk factor.     

Texture analysis of hippocampal sclerosis

Mesial temporal lobe epilepsy (MTLE) is frequently associated with refractory seizures and pathologic features of hippocampal sclerosis (HS). Quantitative magnetic resonance imaging (MRI) techniques can improve the detection and quantification of HS. The objective of this study was to evaluate whether MRI texture analysis can detect hippocampal abnormalities in patients with pathologically proven HS. METHODS: Nineteen consecutive patients who underwent surgery for refractory unilateral MTLE and had HS diagnosed on histopathology (12 right and seven left) had their preoperative MRIs evaluated. We performed texture analysis in 3-mm coronal T1-IR MRIs, focusing on the hippocampal head, by using the software MAZDA. Data were compared with those of a group of 78 normal hippocampi from 39 healthy adult volunteers through multivariate analysis of variance and selection of the most significant texture parameters. RESULTS: Overall, almost all parameters of texture could discriminate the group of hippocampi with HS and the group of contralateral hippocampi from the group of normal hippocampi, but the post hoc comparison showed no differences between HS and contralateral hippocampi. CONCLUSIONS: These results provide evidence of texture alteration in MRIs of hippocampi with HS and corroborate the hypothesis of bilaterality of hippocampal damage in patients with MTLE, but further studies are needed to investigate the lateralization power of texture analysis.     

More severe neurologic deficits in SJL/J male than female mice following Theiler's virus-induced CNS demyelination

Although multiple sclerosis (MS) is more prevalent in women than men, male MS patients develop more severe clinical symptoms and deteriorate faster than female patients. We investigated the differences in CNS demyelinating disease between SJL/J male and female mice following Theiler's murine encephalomyelitis virus (TMEV) infection. Infected female mice had consistently higher serum levels of virus-specific IgG at 14 and 21 days and and 7 months postinfection, which resulted in less infectious virus in CNS. All male mice infected for 6 to 7 months developed paralysis, with 50% displaying bilateral posterior limb paralysis, whereas 77% of age-matched female mice were paralyzed, all displaying unilateral posterior limb paralysis. Male mice infected for 6 to 7 months performed up to threefold fewer spontaneous horizontal and vertical movements (activity box test) compared to infected age-matched females. In addition, infected male mice performed the coordination and balance (Rotarod) test at 27 +/- 4% of the expected level (expressed as a percentage of that of uninfected age-matched mice), whereas infected female mice performed at 41 +/- 5% of the expected level. Male mice had a small increase in the extent of spinal cord white matter demyelination analyzed at both 45 days and between 6 and 7 months postinfection. For individual male and female mice, the extent of demyelination had a negative linear relationship with the neurologic performances. The emergence of a disease paradigm similar to MS supports using the TMEV model to investigate molecular and genetic factors responsible for the gender dimorphism in MS and other autoimmune diseases.     

Tau haplotype frequency in frontotemporal lobar degeneration and amyotrophic lateral sclerosis

It has been reported that the H1 haplotype of the tau gene, located on chromosome 17q21, is associated with progressive supranuclear palsy. Recently, it has also been claimed that the H1 haplotype could also be a risk factor for frontotemporal dementia. However, these claims are variable and the involvement of the apolipoprotein E gene as well as the H1 haplotype has been suggested. In light of this we assessed the frequency of tau gene haplotypes in 113 cases of frontotemporal lobar degeneration and 168 control samples. We found a positive association between the H1 haplotype and frontotemporal dementia, but not with any of the other disease groupings (P = 0.029, odds ratio 1.81). We did not observe any affect on age at onset and tau haplotype or apolipoprotein E alleles, nor were any deviation from control frequencies of apolipoprotein E alleles observed. These data are consistent with the hypothesis that the tau gene, or nearby gene on the H1 haplotype, is a risk factor for frontotemporal dementia.