Corpus callosum volumetrics and clinical progression in early multiple sclerosis.

OBJECTIVE: Corpus callosum (CC) is commonly affected in multiple sclerosis (MS), with known association between CC atrophy and MS clinical activity. In this study, we assessed the association of callosal atrophy, lesions volume and residual CC volume with the clinical disability of early MS patients. SUBJECTS AND METHODS: Thirteen MS subjects (9 female, mean age 36.9 years), studied with magnetic resonance imaging (MRI) were selected. MRI scans were performed at baseline (T0), at 6 (T1), 12 (T2), and 24 months (T3) from baseline. CC was segmented into three sections (genu, body, and splenium); callosal boundaries were outlined and all CC lesions were manually traced. Normal CC and CC lesion volumes were measured using a semiautomatic software. RESULTS: From January 2014 to December 2016, all selected patients had confluent lesions on MRI at T3 with a significant increase in the size of confluent lesions compared to baseline (p=0.0007). At T1, a significant increase in the size of confluent (p=0.02) and single lesions located in the callosal body (p=0.04) was detected in patients with EDSS ≥1.5. Also, CC residual volume (CCR) rather than the whole CC volume (CCV) significantly correlated (p=0.03) with the clinical progression of MS in the whole cohort. CONCLUSIONS: In early MS patients with higher EDSS at baseline, a significant increase in confluent CC lesions size is evident, particularly in the callosal body. Also, median CCR is significantly associated with MS progression in the whole MS group, regardless of initial EDSS. Given their significant association with disability, we encourage measuring CC body lesions and residual CC size for therapeutic decisions and prognostic planning in early MS.

Natalizumab therapy of multiple sclerosis: recommendations of the Multiple Sclerosis Study Group--Italian Neurological Society.

Three years after the introduction of natalizumab (NA) therapy for the second line treatment of relapsing-remitting multiple sclerosis (MS), Italian MS centers critically reviewed the scientific literature and their own clinical experience. Natalizumab was shown to be highly efficacious in the treatment of MS. However, the risk of progressive multifocal leukoencephalopathy was confirmed and defined better. This article summarizes the MS-SIN Study Group recommendations on the use of NA in MS, with particular reference to the appropriate selection and monitoring of patients as well as to the management of adverse events.

Multiple sclerosis-associated retrovirus and progressive disability of multiple sclerosis.

Retrovirus-like particles containing the multiple sclerosis-associated retrovirus RNA, significantly found in the cerebrospinal fluid of patients with multiple sclerosis, have been preliminarily associated with a short-term poor clinical and radiological prognosis of the disease. We asked whether these prognostic indications are still measurable after a long-term clinical evaluation (10 years). Our 10-year blind observational study confirms that the presence of multiple sclerosis-associated retrovirus in the cerebrospinal fluid of early multiple sclerosis patients is associated with a significantly greater rate of relapse-unrelated unremitting disability and secondary progression of the disease.

Variation within the CLEC16A gene shows consistent disease association with both multiple sclerosis and type 1 diabetes in Sardinia.

Variation within intron 19 of the CLEC16A (KIAA0350) gene region was recently found to be unequivocally associated with type 1 diabetes (T1D) in genome-wide association (GWA) studies in Northern European populations. A variant in intron 22 that is nearly independent of the intron 19 variant showed suggestive evidence of association with multiple sclerosis (MS). Here, we genotyped the rs725613 polymorphism, representative of the earlier reported associations with T1D within CLEC16A, in 1037 T1D cases, 1498 MS cases and 1706 matched controls, all from the founder, autoimmunity-prone Sardinian population. In these Sardinian samples, allele A of rs725613 is positively associated not only with T1D (odds ratio=1.15, P one-tail=5.1 x 10(-3)) but also, and with a comparable effect size, with MS (odds ratio=1.21, P one-tail 6.7 x 10(-5)). Taken together these data provide evidence of joint disease association in T1D and MS within CLEC16A and underline a shared disease pathway.

Multiple sclerosis: reduced proportion of circulating plasmacytoid dendritic cells expressing BDCA-2 and BDCA-4 and reduced production of IL-6 and IL-10 in response to herpes simplex virus type 1.

OBJECTIVE: We hypothesized that autoaggressive immune responses observed in multiple sclerosis (MS) could be associated with an imbalance in proportion of immune cell subsets and in cytokine production in response to infection, including viruses. METHODS: We collected blood mononuclear cells (MNC) from 23 patients with MS and 23 sex- and age-matched healthy controls (HC) from the island of Sardinia, Italy, where the prevalence of MS is extraordinarily high. Using flow cytometry, we studied MNC for expression of blood dendritic cell antigens (BDCA)-2 and BDCA-4 surface markers reflecting the proportion of plasmacytoid dendritic cells (pDC) that produce type I interferons (IFNs) after virus challenge and promote Th2/anti-inflammtory cytokine production. In parallel, pro-inflammatory (interleukin [IL]-2, IL-12, IFN-gamma), anti-inflammatory (IL-4, IL-10), and immuno-regulatory/pleiotropic cytokines (type I IFNs including IFN-alpha and beta, IL-6) were measured before and after an in vitro exposure to herpes simplex virus type 1 (HSV-1). RESULTS: The subset of lineage negative (lin(-)), BDCA-2(+) cells was lower in patients with MS compared with HC (0.08 + or - 0.02% vs 0.24 + or - 0.02%; P < 0.001). A similar pattern was observed for lin(-)BDCA-4(+) cells (0.08 + or - 0.02% vs 0.17% + or - 0.03; P < 0.01). Spontaneous productions of IL-6 (45 + or - 10 pg/mL vs 140 + or - 26 pg/mL; P < 0.01) and IL-10 (17 + or - 0.4 pg/mL vs 21 + or - 1 pg/mL; P < 0.05) by MNC were lower in patients with MS compared with HC. Spontaneous production of IL-6 (6.5 + or - 0.15 pg/mL vs 21 + or - 5 pg/mL; P < 0.01 and IL-10 (11 + or - 1 pg/mL vs 14 + or - 3 pg/mL; P < 0.05) by pDC was also lower in patients with MS compared with HC. Exposure of MNC to HSV-1 showed, in both patients with MS and HC, increased production of IFN-alpha, IL-6, and IL-10 but decreased production of IL-4. In response to HSV-1 exposure, productions of IL-6 (165 +or - 28 pg/mL vs 325 + or - 35 pg/mL; P < 0.01) and IL-10 (27 +or - 3 vs 33 + or - 3 P < 0.05) by MNC as well as by pDC (IL-6: 28 + or - 7 vs 39 + or - 12 P < 0.05; IL-10: 14 + or - 1 vs 16 + or - 3 P < 0.05) were lower in patients with MS compared with HC. CONCLUSION: The results implicate a new evidence for altered immune cells and reduced immune responses in response to viral challenge in MS.

An extremes of outcome strategy provides evidence that multiple sclerosis severity is determined by alleles at the HLA-DRB1 locus.

Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpassed for variability in disease outcome. A cohort of sporadic MS cases (n = 163), taken from opposite extremes of the distribution of long-term outcome, was used to determine the role of the HLA-DRB1 locus on MS disease severity. Genotyping sets of benign and malignant MS patients showed that HLA-DRB1*01 was significantly underrepresented in malignant compared with benign cases. This allele appears to attenuate the progressive disability that characterizes MS in the long term. The observation was doubly replicated in (i) Sardinian benign and malignant patients and (ii) a cohort of affected sibling pairs discordant for HLA-DRB1*01. Among the latter, mean disability progression indices were significantly lower in those carrying the HLA-DRB1*01 allele compared with their disease-concordant siblings who did not. The findings were additionally supported by similar transmission distortion of HLA-DRB1*04 subtypes closely related to HLA-DRB1*01. The protective effect of HLA-DRB1*01 in sibling pairs may result from a specific epistatic interaction with the susceptibility allele HLA-DRB1*1501. A high-density (>700) SNP examination of the MHC region in the benign and malignant patients could not identify variants differing significantly between the two groups, suggesting that HLA-DRB1 may itself be the disease-modifying locus. We conclude that HLA-DRB1*01, previously implicated in disease resistance, acts as an independent modifier of disease progression. These results closely link susceptibility to long-term outcome in MS, suggesting that shared quantitative MHC-based mechanisms are common to both, emphasizing the central role of this region in pathogenesis.

The role of hereditary spastic paraplegia related genes in multiple sclerosis. A study of disease susceptibility and clinical outcome.

Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpassed for its variability in disease outcome. It has been observed that axonal loss in MS is significant and that irreversible clinical disability relates to such axonal loss. The clinical similarities between Hereditary Spastic Paraplegia (HSP) and progressive MS, along with their analogous profiles of axonal loss in the long tracts, make the genes known to cause HSP biologically relevant candidates for the study of clinical outcome in MS. A cohort of sporadic MS cases and a set of unaffected controls were used to determine the role of HSP genes on MS susceptibility and disease severity. The MS cases were taken from opposite extremes of the putative distribution of long-term outcome using the most stringent clinical criteria to date. Genotyping the two sets of MS patients and controls could not provide any evidence to suggest that genes involved in the pathogenesis of HSP (Paraplegin, NIPA1, KIF5A, HSPD1, Atlastin, Spartin, Spastin, PLP1, L1CAM, Maspardin and BSCL2) play a role in susceptibility to, or modifying the course of, MS, although small effects of these genes cannot be ruled out.

No effect of APOE and PVRL2 on the clinical outcome of multiple sclerosis.

Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpassed for its variability in disease outcome. Apolipoprotein E (APOE) is involved in neuronal remodelling and several studies have attempted to examine the effect of APOE on MS disease severity, but its function in modifying the course of MS is controversial. It has been suggested recently that PVRL2, not APOE, is the locus on chromosome 19 which influences clinical outcome of MS. A cohort of sporadic MS cases, taken from opposite extremes of the putative distribution of long-term outcome using the most stringent clinical criteria to date, was used to determine the role of APOE and PVRL2 on MS disease severity. The MS cases selected represent the prognostic best 5% (benign MS) and worst 5% (malignant MS) of cases in terms of clinical outcome assessed by the EDSS. Genotyping the two sets of MS patients (112 benign and 51 malignant) and a replication cohort from Sardinia provided no evidence to suggest that APOE or PVRL2 have any outcome modifying activity. We conclude that APOE and PVRL2 have little or no effect on the clinical outcome of MS.

Intrathecal chitotriosidase and the outcome of multiple sclerosis.

Activated macrophages are major effectors at all stages of lesion formation in multiple sclerosis (MS) brain. Here, we report that the macrophage enzyme chitotriosidase (Chit) is significantly elevated both in plasma and cerebrospinal fluid (CSF) of patients with MS as compared to healthy controls and other neurological patients (P<0.001). Furthermore, the Chit activity in blood significantly associates with the MS clinical course (higher in secondary progressive relative to relapsing-remitting, P=0.01) and the clinical severity as measured by Kurtkze's Expanded Disability Status Scale (P<0.001). Also, we found that Chit activity is compartmentalized in the central nervous system of early MS patients and that its CSF/plasma quotient, in the presence of a preserved albumin quotient, correlates with the extent of future clinical deterioration (r=0.91; P<0.001). These findings confirm that innate immunity, here represented by Chit, is clinically relevant in MS and allows, if confirmed, reconsidering novel MS therapeutic strategies specifically aimed at this branch of the immune response.

Multiple sclerosis-associated retrovirus and optic neuritis.

One prognostic factor for early multiple sclerosis (MS) patients to develop a definite MS may be the presence of the MS-associated retrovirus (MSRV) in the cerebrospinal fluid (CSF). We designed a specific study on a cohort of optic neuritis (ON) patients to evaluate the MSRV-dependent conversion to MS relative to the prediction conferred by magnetic resonance imaging (MRI) and CSF abnormalities. At follow-up, 33.3% MSRV+ and 0% MSRV- ON patients developed MS (P = 0.03). The prediction value is lower than that given by CSF and MRI abnormalities (42.3%). This intriguing finding is discussed in the light of the abundant discrepancies observed in the MSRV literature. Multiple Sclerosis 2006; 12: 357-359. www.multiplesclerosisjournal.com

Inflammatory biomarkers in blood of patients with acute brain ischemia.

Although many failed surrogate markers are provided in the literature, inflammation may contribute to the outcome of ischemic stroke. In 50 consecutive patients with acute ischemic stroke, in the absence of symptoms and signs of concomitant infection, we evaluated a panel of biomarkers reported to be variably associated with brain ischemia, and correlate their serum level with the brain lesion volume and clinical outcome. Infarct size was calculated on computed tomography (CT) scans by means of the Cavalieri's method. Neurological impairment was scored by using the Glasgow Coma Scale, Glasgow Outcome Scale and National Institutes of Health (NIH) scales at stroke onset and 3-month follow-up. Some markers showed a direct significant correlation with both initial and final NIH scale and with infarct size, particularly tumor necrosis factor alpha (TNF-alpha) (P=0.002), intercellular adhesion molecule-1 (P<0.01) and matrix metalloproteinase-2/9 (P=0.001). In contrast to previous reports, interleukin-6 (IL-6) serum level showed a significant inverse correlation with both final neurological impairment and infarct size (P<0.001). This novel finding allows us suggesting that IL-6, in the context of a complex pro-inflammatory network occurring during stroke, is associated with neuroprotection rather than neurotoxicity in patients with ischemic brain injury.

Glatiramer acetate reduces lymphocyte proliferation and enhances IL-5 and IL-13 production through modulation of monocyte-derived dendritic cells in multiple sclerosis.

Dendritic cells (DC), as the most effective antigen presenting cells, are protagonists of the complex immune network involved in multiple sclerosis (MS) lesion formation. Glatiramer acetate (GA), a synthetic random copolymer, is thought to exert its therapeutical effect in MS by favouring both Th2 cell development and IL-10 production from peripheral lymphocytes as well as by systemically affecting the antigen presenting cells. In the present study we further analysed the mechanisms of action of GA by using an autologous DC-lymphocytes (Ly) coculture system from 11 MS patients and 12 matched healthy controls (HC). We found that, in MS patients, pretreatment with GA significantly decreases the in vitro proliferative effect of DC on lymphocytes as compared to HC and to unpulsed or myelin basic protein (MBP)-pulsed DC from MS patients (P < 0.05). In addition, GA-treated DC from both MS patients and HC significantly increase the lymphocyte production of IL-5 and IL-13 as compared to MBP-treated DC (P < 0.05). In conclusion our in vitro study may provide new therapeutical mechanisms of GA on lymphocytes, antiproliferative and Th2-favouring effects, which are mediated by monocyte-derived DC.

Multiple sclerosis-associated retrovirus in early multiple sclerosis: a six-year follow-up of a Sardinian cohort.

The human endogenous retroviruses (HERV)-W family contains an extracellular particle detected in multiple sclerosis (MS) patients and designated as MS-associated retrovirus (MSRV). Through nested RT-PCR assays specific for pol MSRV gene, we preliminary reported that its presence in the cerebrospinal fluid (CSF) of early MS patients could be indicative of a poor prognosis upon a three-year follow-up. In the present clinical study, we enlarged our blind observation up to six years. At study entry, 10 MS patients were MSRV+ and eight were MSRV- in the CSF, both groups having a similar mean age and Expanded Disability Status Scale (EDSS) score. After six year follow-up, the mean EDSS significantly differed between the MSRV+ and MSRV- cohorts (4.3 versus 2.2; P = 0.004), as did the annual relapse rate (0.5 in the MSRV+ versus 0.3 in the MSRV-; P = 0.01). Finally, two MSRV+ patients entered the progressive phase, whilst none of the MSRV- group entered this phase, and 9/10 MSRV+ versus 2/8 MSRV patients were treated with immunomodulatory or immunosuppressive drugs (P = 0.009). In conclusion, we found that the presence of MSRV virions in the CSF at the onset of MS is associated, not only with disability accumulation, but also with a higher rate of clinical re-exacerbations. With the known potential pathogenic effects of MSRV given in the literature, further investigations on MSRV are warranted.

Immunomodulation of fucosyl-lactose and lacto-N-fucopentaose on mononuclear cells from multiple sclerosis and healthy subjects.

The 1,2-fucosyl-oligosaccharides, and among these the 2'-fucosyl-lactose (2'-FL) and lacto-N-fucopentaose (LNFP)-I, are quantitatively the most represented oligosaccharides of human milk. They are also seen to represent an important immune device to prevent nursing infants from severe infectious diarrhoea. Recent evidences show that the appearance of 2'-FL and LNFP-I in human colostrums is synchronised with the macrophage inhibition and that LNFP-III induces a Th2 response from the mouse peripheral immune system. Since mannosyl-fucosyl receptors are described on the macrophage surface, all these evidences allow us to investigate on the possible immune function of human 2'-FL and LNFP-I in vitro on LPS-activated mononuclear cells (MNC) from 12 patients with multiple sclerosis (MS) and 20 matched health controls (HC). We found that 2'-FL and LNFP-I significantly decrease, to a different extent, the MNC proliferation from both HC and MS patients, in a linear and dose-dependent manner. 2'-FL and LNFP-I also reduce the production of IL-12 and IFN-γ, particularly in MS patients as compared to HC (p=0.01 and p<0.001, respectively), while increasing that of IL-10. The overall immunomodulatory effect of 2'-FL and LNFP I here presented may represent a future therapeutic option for the abnormal immune response found in some monocyte-mediated diseases.

Chronic subdural collection after endoscopic third ventriculostomy.

Endoscopic third ventriculostomy (ETV) is considered a safe technique for the treatment of obstructive hydrocephalus. We describe a case of chronic subdural haematoma (CSDH) after ETV, revealed by MRI four weeks after the procedure, and requiring surgical evacuation, in a 69 y.o. asymptomatic male patient. In our opinion, overdrainage may evolve also in endoscopic treatment of obstructive hydrocephalus. This complication could be the starting point of the subdural collection. We review the literature and discuss the causes that may lead to CSDH after ETV procedure.

Neuroendoscopy: one year of experience--personal results, observations and limits.

After reading reports of successful neuroendoscopic treatment of hydrocephalus, colloid cysts and arachnoid cysts as well as tumor biopsy, we started using endoscopic procedures in our Department, one year ago. One surgeon (E.S.) skilled in the Decq Endoscope, performed a series of sixteen procedures, from January 2001 to March 2002 (in patients aged 28 to 69 years). The most common pathology was obstructive hydrocephalus (14 cases), one was colloid cyst, and the last case was tumor biopsy. The surgical treatment consisted of third ventriculostomy, cyst opening and shrinking and tumor biopsy. In fourteen patients treated for hydrocephalus with third ventriculostomy (ETV), one required a definitive shunt. Complication occurred in one case with chronic subdural collection. We further report one case of aqueductal restoration after third ventriculostomy. Our results, with no neurological deficits or deaths, confirmed our opinion that neuroendoscopy is a safe surgical technique in well-selected patients and we believe it is the ideal treatment in obstructive hydrocephalus.

Alpha B-crystallin is not a dominant peripheral T-cell autoantigen in multiple sclerosis amongst Sardinians.

The heat shock protein alpha B-crystallin appears to be the dominantly recognized autoantigen in the early demyelinative process of multiple sclerosis (MS) in brain of patients. In Sardinia, MS is linked to human leucocyte antigen (HLA)-DR alleles that might influence the production of cytokines from peripheral lymphocytes. We tested the nature of peripheral anti-alpha B-crystallin-specific T-cell response in the context of predisposing HLA haplotypes both in MS patients and healthy controls. The alpha B-crystallin specific T-cell lines were generated by using the 'split-well' technique. The results indicate that the presence of short-term T-cell lines towards alpha B-crystallin is numerically comparable between the two groups and not restricted to MS-predisposing HLA-DR alleles. As for the T-cell characterization, CD4+ anti-alpha B-crystallin T cells secreting high levels of interferon-gamma are similarly identified in MS and healthy donors. In conclusion, the peripheral response towards the myelin antigen alpha B-crystallin is neither quantitatively nor qualitatively peculiar to MS, in contrast to the theoretical paradigm suggesting peripheral activation of myelin-reactive T cells to be the prerequisite for MS induction.