B Casanova

Hospital Universitari i Politècnic la Fe, Valenza, Valencia, Spain

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Publications (55)159.57 Total impact

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    ABSTRACT: The presence of oligoclonal IgM bands (OCMB) in cerebrospinal fluid (CSF) is an unfavourable prognostic marker in multiple sclerosis. There is no commercial test to investigate OCMB status. However, a sensitive and specific isoelectrofocusing (IEF) and western blot method was described. We aimed to study the inter-centre reproducibility of this technique, a necessary condition for a reliable test to be incorporated into clinical practice.
    Clinica Chimica Acta. 08/2014; 438.
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    ABSTRACT: To identify a biomarker distinguishing patients who, despite a primary progressive multiple sclerosis (PPMS) clinical course, may nonetheless benefit from immune therapy.
    Annals of Neurology 08/2014; 76(2). · 11.19 Impact Factor
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    ABSTRACT: Intrathecal oligoclonal bands of the cerebrospinal fluid are considered the most important immunological biomarkers of multiple sclerosis. They typically consist of clonally expanded IgG antibodies that underwent affinity maturation during sustained stimulation by largely unknown antigens. In addition, ∼40% of patients with multiple sclerosis have oligoclonal bands that consist of expanded IgM antibodies. We investigated the molecular composition of IgM- and IgG-chains from cerebrospinal fluid of 12 patients with multiple sclerosis, seven patients with other neurological diseases, and eight healthy control subjects by high-throughput deep-sequencing and single-cell PCR. Further, we studied the expression of activation-induced cytidine deaminase, the key enzyme for affinity maturation of antibodies, in cerebrospinal fluid samples of 16 patients. From the cerebrospinal fluid of two multiple sclerosis patients we isolated single B cells and investigated the co-expression of antibody chains with activation-induced cytidine deaminase. In striking contrast to IgM-chains from peripheral blood, IgM-chains from cerebrospinal fluid of patients with multiple sclerosis or neuroborreliosis showed a high degree of somatic hypermutation. We found a high content of mutations that caused amino acid exchanges as compared to silent mutations. In addition, more mutations were found in the complementarity determining regions of the IgM-chains, which interact with yet unknown antigens, as compared to framework regions. Both observations provide evidence for antigen-driven affinity maturation. Furthermore, single B cells from the cerebrospinal fluid of patients with multiple sclerosis co-expressed somatically hypermutated IgM-chains and activation-induced cytidine deaminase, an enzyme that is crucial for somatic hypermutation and class switch recombination of antibodies and is normally expressed during activation of B cells in germinal centres. Clonal tracking of particular IgM(+) B cells allowed us to relate unmutated ancestor clones in blood to hypermutated offspring clones in CSF. Unexpectedly, however, we found no evidence for intrathecal isotype switching from IgM to IgG. Our data suggest that the intrathecal milieu sustains a germinal centre-like reaction with clonal expansion and extensive accumulation of somatic hypermutation in IgM-producing B cells.
    Brain : a journal of neurology. 07/2014;
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    Neurology 04/2014; 82(10):P2.245. · 8.25 Impact Factor
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    ABSTRACT: Paraneoplastic myelitis is a rare inflammatory disorder most frequently associated with solid tumors or lymphoproliferative disorders. Patients often harbor onconeuronal antibodies and their prognosis is usually poor. Here we report a 42-year old woman with longitudinally extensive transverse myelitis and aquaporin-4 (AQP4) antibodies that led to the diagnosis of ovarian teratoma. After tumor removal and immune therapy (including corticosteroids, plasma exchange, intravenous immunoglobulins and rituximab) the patient progressively improved achieving complete recovery. Histological study of the teratoma demonstrated neural tissue containing AQP4 expressing cells and intense inflammatory infiltrates, providing evidence for a possible paraneoplastic link between both disorders.
    Journal of neuroimmunology 07/2013; · 2.84 Impact Factor
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    ABSTRACT: This study aimed to correlate body mass index or biomarkers with the frequency of common adverse events (AEs) with subcutaneous IFN beta-1a during treatment titration in patients with remitting-relapsing multiple sclerosis previously naive to IFN beta. Eighty-four patients (66.3% females) were followed up during 8 weeks, 25.3% were overweight and 14.5% were obese. Biomarkers steadily increased during all study period by 45.3% for beta2-microglobulin, 262.8% for olygoadenylate synthetase-1, and 92.8% for neopterin. Overall AE reporting did not vary with the dose or treatment duration. BMI was not predictive of increased risk for AEs. Biomarkers did not discriminate on the frequency of any AE either.
    BMC Neurology 07/2013; 13(1):82. · 2.56 Impact Factor
  • M.J. Magraner, F. Coret, B. Casanova
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    ABSTRACT: Objective Evaluate safety and tolerance levels for intravenous immunoglobulins (IVIG) as treatment for neuromyelitis optica (NMO).Methods Eight patients meeting Wingerchuk's revised diagnostic criteria were treated with IVIG every 2 months (0.7 g per kg body weight per day for 3 days). The primary outcome measure was the occurrence of serious adverse effects, defined according to NIH guidelines for clinical trials. Secondary outcome measures were changes in the yearly rate of attacks and in the degree of neurological disability measured with the Expanded Disability Status Scale (EDSS).ResultsAll 8 patients were treated; 5 had relapsing optic neuritis with or without myelitis and 3 had recurrent longitudinally extensive transverse myelitis. The mean age of onset was 20.5 years (range, 7-31 years) and 87,5% were female. The mean duration of the disease before beginning treatment was 9.0 years (range, 3-17 years). Following 83 infusions (range, 4-21 per patient) and a mean follow-up time of 19.3 months (range, 6-39 months), minor adverse events had occurred (headache in 3 patients and a mild cutaneous eruption in a single patient). The relapse rate decreased from 1.8 in the previous year to 0.006 during follow-up (z= 2,5, P=.01). The EDSS score fell from 3.3 ± 1.3 to 2.6 ± 1.5 (z = −2.0, P=.04).Conclusions Treatment with IVIG is safe and well-tolerated, and it may be used as a treatment alternative for NMO spectrum disorders.
    Neurología. 03/2013; 28(2):65–72.
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    ABSTRACT: An abnormal pattern of brain activations has been shown in patients with multiple sclerosis during the performance of several cognitive tasks. The aim of this study is to investigate abnormalities of the patterns of activation/deactivation in the functional networks related to "task-positive" and "task-negative" events during the execution of the Symbol Digit Modalities Test (SDMT) in patients with clinically isolated syndromes (CIS) and preserved cognitive abilities. Eighteen CIS patients within 3 months from their first clinical attack and 15 healthy controls (HC) underwent neuropsychological assessment and performed an adapted functional magnetic resonance imaging (fMRI) version of the SDMT. "Task-positive" responses to task execution and "task-negative" activity of the default mode network were compared between groups. A regression analysis was performed to investigate the correlation between fMRI results and T2 lesion load (T2 LL) and brain atrophy. Neuropsychological performance did not differ between groups. Compared to HC, CIS patients exhibited an enhanced deactivation of the "task-negative" network at the level of the posterior cingulate cortex, whereas no differences between groups were found when the patterns of "task-positive" events were compared. A regression analysis detected a correlation (p < 0.001,r ranging from 0.62 to 0.73) between T2 LL and "task-positive" activations of areas that are part of the attention network, comprising the anterior cingulate gyrus, left prefrontal gyrus and inferior parietal lobe. No correlation was found between patterns of functional modifications and brain atrophy. CIS patients experience an enhanced pattern of brain deactivations during cognitive performances, which might contribute to their normal neuropsychological status.
    Experimental Brain Research 01/2013; · 2.22 Impact Factor
  • M J Magraner, F Coret, B Casanova
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    ABSTRACT: OBJECTIVE: Evaluate safety and tolerance levels for intravenous immunoglobulins (IVIG) as treatment for neuromyelitis optica (NMO). METHODS: Eight patients meeting Wingerchuk's revised diagnostic criteria were treated with IVIG every 2 months (0,7 g per kg body weight per day for 3 days). The primary outcome measure was the occurrence of serious adverse effects, defined according to NIH guidelines for clinical trials. Secondary outcome measures were changes in the yearly rate of attacks and in the degree of neurological disability measured with the Expanded Disability Status Scale (EDSS). RESULTS: All 8 patients were treated; 5 had relapsing optic neuritis with or without myelitis and 3 had recurrent longitudinally extensive transverse myelitis. The mean age of onset was 20.5 years (range, 7-31 years) and 87.5% were female. The mean duration of the disease before beginning treatment was 9.0 years (range, 3-17 years). Following 83 infusions (range, 4-21 per patient) and a mean follow-up time of 19.3 months (range, 6-39 months), minor adverse events had occurred (headache in 3 patients and a mild cutaneous eruption in a single patient). The relapse rate decreased from 1.8 in the previous year to 0.006 during follow-up (z=2,5, P=.01). The EDSS score fell from 3.3±1.3 to 2.6±1.5] (z=-2.0, P=.04). CONCLUSIONS: Treatment with IVIG is safe and well-tolerated, and it may be used as a treatment alternative for NMO spectrum disorders.
    Neurologia 07/2012;
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    ABSTRACT: Axonal injury is the major cause of disability in patients with multiple sclerosis (MS), but the mechanisms leading to axonal damage are poorly understood. Oligoclonal IgM against lipids predicts an aggressive disease course in MS; however, the antigen that elicits the immune response has not yet been identified. We screened the CSF of 12 patients with MS, 7 patients with neuromyelitis optica (NMO), and 5 controls with non-inflammatory neurological disease (NIND) for the presence of IgM-type antibodies (IgM-Ab) against neuronal surface antigens, and analyzed the relationship between IgM-Ab level and the extent of brain atrophy. The CSF of MS patients displayed significantly higher levels of IgM-Ab compared to NIND or NMO patients. Furthermore, we document for the first time that these IgM-Ab recognize neuronal surface antigens, and that the levels of neuronal-bound IgM-Ab were independent of the IgM concentration and correlate with brain atrophy. Our findings suggest a role for the CSF IgM-Ab in the development of MS pathophysiology.
    Journal of neuroimmunology 04/2012; 247(1-2):63-9. · 2.84 Impact Factor
  • M Magraner, F Coret, B Casanova
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    ABSTRACT: To assess the evolution of brain atrophy and its relationship with inflammatory activity in RRMS patients treated with natalizumab. Eighteen RRMS patients were prospectively followed up for 18 months after starting natalizumab therapy. Patients were monitored monthly and assessed for signs of relapses, adverse events or disability increase. MRI scans were performed before starting natalizumab and every six months. Cross-sectional T2 lesion volume (T2LV) and the normalized brain volume (NBV) at baseline and 18 months MRI scans were calculated using the Steronauta(®) and SIENAx softwares, respectively. Longitudinal Percentage of Brain Volume Change (PBVC) was estimated with SIENA. Linkage between inflammatory activity and brain atrophy was studied. Natalizumab reduced ARR by 67% and cumulative CEL by 87.5%. T2 lesion volume decreased from 1000mm(3), to 960mm(3) (p=0.006) and NBV decreased from 1.55×10(5)mm(3) to 1.42×10(5) mm(3) (p=0.025). Global PBVC from baseline to 18 months was -2.5%, predominantly during the first six months (0-6 months PBVC -1.7%; 6-12 months PBVC -0.74%; 12-18 months PBVC -0.50%). The number of relapses before treatment was correlated to the PBVC during the first semester (Pearson's coefficient -0.520, p=0.003), while the number of basal CEL or baseline T2LV did not correlate with brain atrophy rate. During follow-up, nine patients had clinical or radiological inflammatory activity. Their PBVC was significantly higher in the first semester (-2.3% to -1.1%, p=0.002). Natalizumab reduced relapse rate and CEL in MRI. Brain atrophy predominated in the first semester and was related to previous inflammatory activity.
    European journal of radiology 03/2012; 81(11):3485-90. · 2.65 Impact Factor
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    ABSTRACT: To assess whether abnormalities on functional magnetic resonance imaging (fMRI) are related to cognitive function in patients at presentation with clinically isolated syndrome (CIS) suggestive of multiple sclerosis. Eighteen patients with CIS and 15 healthy controls (HCs) performed an adapted fMRI version of the Paced Auditory Serial Addition Test (PASAT). According to their PASAT performance, CIS patients were divided into two groups: 10 with a low PASAT performance (<1 SD from the mean value of HCs) were considered 'cognitive impairment' (CI); eight patients were defined as 'cognitively preserved' (CP). Between-group differences in the patterns of brain activations and effective connectivity were assessed. During PASAT, compared to HCs, CIS patients showed increased activations of the bilateral inferior parietal lobe (IPL), bilateral precuneus, bilateral middle frontal gyrus (MFG), left anterior cingulate cortex (ACC), left claustrum, right thalamus and right caudate nucleus. When CIS patients were analyzed, the CI group had a more significant activation of the bilateral IPL than HCs and CP patients. Compared to CP patients, they also had more significant recruitment of the right superior parietal lobe, right cerebellum, left MFG and left ACC. The analysis of effective connectivity showed stronger connections between several regions of the right hemisphere involved in working memory function in CI patients versus CP and HC. During performance of the PASAT, CIS patients show abnormalities in the patterns of cortical recruitment and connectivity related to the level of their cognitive impairment.
    Multiple Sclerosis 08/2011; 18(2):153-63. · 4.47 Impact Factor
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    ABSTRACT: An early and accurate diagnosis of multiple sclerosis (MS) is very important, since it allows early treatment initiation, which reduces the activity of the disease. Oligoclonal IgG band (OCGB) detection is a good ancillary tool for MS diagnosis. However, it was argued that its usefulness was limited by the high interlaboratory variability. In the last years, different techniques for OCGB detection have appeared. We performed a blinded aleatorized multicenter study in 19 Spanish hospitals to assess the accuracy and reproducibility of OCGB detection in this new scenario. We studied cerebrospinal fluid (CSF) and serum samples from 114 neurological patients. Every hospital contributed to the study with triplicated pairs of CSF and serum samples of six patients and analyzed 18 different samples. Global analysis rendered a sensitivity of 92.1%, a specificity of 95.1% and a Kappa value of 0.81. This shows that current techniques for OCGB detection have good accuracy and a high interlaboratory reproducibility and thus, represent a good tool for MS diagnosis. When we analyzed separately the different techniques used for OCGB detection, the highest concordance was observed in western blot with alkaline phosphatase detection (kappa=0.91). This indicates that high sensitivity techniques improve the reproducibility of this assay.
    Journal of immunological methods 06/2011; 371(1-2):170-3. · 2.35 Impact Factor
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    ABSTRACT: In this study, the tolerability and safety of treatment with pulsed steroids and glatiramer acetate and the occurrence of clinical and radiological activity after natalizumab (NTZ) cessation in multiple sclerosis (MS) patients were assessed. MS patients with NTZ were discontinued after 2 years of treatment, or if adverse events or disease progressed during NTZ. They were offered as alternative treatment 1 g methylprednisolone per month during 3 months followed by daily 20 mcg glatiramer acetate and were prospectively studied. Adverse events, occurrence of immune reconstitution inflammatory syndrome, clinical exacerbations, and gadolinium-enhancing lesions in MRI performed at 3 and 6 months after NTZ cessation were recorded. EDSS change during follow-up was also recorded. A total of 18 MS patients entered the study and were followed up for a mean of 10 months (range 6-18 months). There were no significant adverse events. At month 3, no patient had clinical or radiological disease activity. At month 6, 16.6% of patients had had a relapse and 55.5% of patients showed gadolinium-enhancing lesions in the MRI. After 6 months, 33.3% of patients had a further relapse. There was no IRIS, severe relapses, or significant difference between EDSS at NTZ discontinuation and after follow-up. The alternative treatment with monthly prednisolone followed by GA prevents the development of IRIS, but not the return to previous inflammatory activity, which occurs between 5 and 6 months after NTZ withdrawal.
    Journal of Neurology 04/2011; 258(10):1805-11. · 3.58 Impact Factor
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    ABSTRACT: The objective of this work is to study the relationship between the presence of lipid-specific oligoclonal IgM bands (LS-OCMB) in CSF, with both T2 lesion volume (T2LV) accumulation and brain atrophy (percentage change of brain volume-PCBV-and brain parenchyma fraction-BPF) in patients with clinically isolated syndromes (CIS) suggestive of demyelination. Twenty-four CIS patients were included in this prospective study. IgG oligoclonal bands (OCGB) and LS-OCMB were determined in paired serum and CSF samples within 3 months since clinical onset. Brain MRI studies were scheduled at baseline, 3 months, first and second years after CIS onset. Differences in T2LV, PCBV and BPF between CIS patients according to the type of OCB were studied. Nine patients had no OCB; 15 had only OCGB, and seven had OCGB + LS-OCMB present in the CSF. LS-OCMB were associated with greater T2LV in all scheduled MRI studies. At the end of follow-up (year 2), it was threefold higher in patients with these antibodies than in those without LS-OCMB (3.95 cm(3) vs. 1.36 cm(3), p = 0.001). At that point, brain atrophy was also higher in patients with LS-OCMB (BPF, 0.73 in LS-OCMB+ patients vs. 0.76 in negative ones, p = 0.03). The rate in brain atrophy was higher in the first group of patients as well. Considering only patients with OCGB, the presence of LS-OCMB was also related to greater T2LV, T2LV increase and a trend towards higher atrophy rate. The presence of LS-OCMB in the first event suggestive of demyelination is related to an early increase in lesion load and brain atrophy. These data are in line with prospective studies showing the clinical prognostic value of LS-OCMB.
    Neuroradiology 02/2011; 54(1):5-12. · 2.70 Impact Factor
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    ABSTRACT: Objective Assessing the effectiveness and safety of natalizumab for treating relapsing-remitting multiple sclerosis in a tertiary hospital.
    Farmacia Hospitalaria. 01/2011; 35(2):75-79.
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    ABSTRACT: We prospectively assessed the risk of second relapse in 192 patients with clinically isolated syndromes (CIS) divided into three groups: patients lacking oligoclonal IgG bands (OC-IgG, 25.7%), those showing OC-IgG (52.4%), and those with both OC-IgG and lipid-specific IgM bands (LS-OC-IgM, 22%). OC-IgG increased 9.3-fold the risk compared to lacking OC-IgG; OC-IgG+LS-OC-IgM increased the risk 39.6-fold compared to not having OC-IgG and 4.4-fold compared to having only OC-IgG. Median time to second relapse was 0.7 years for patients with OC-IgG+LS-OC-IgM and 3.3 years for those with only OC-IgG. Therefore, CSF analysis identifies CIS patients at risk of second relapse.
    Journal of neuroimmunology 09/2010; 226(1-2):143-6. · 2.84 Impact Factor
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    ABSTRACT: To study the long-term outcome and persistence of two patterns of cervical spinal cord abnormality in early relapsing-remitting multiple sclerosis (RRMS). RRMS patients with a spinal cord MRI performed during the first 3 years of the disease, a control MRI 5 years later and who have been followed up at least 10 years were included. Patients were grouped according the T2 spinal cord MRI into: (A) nodular pattern, if one or more focal lesions were present; and (B) diffuse pattern, defined as a poorly demarcated high signal area. The end point was defined as the time to reach an Expanded Disability Status Score (EDSS) of 4.0. Twenty-five patients were included; 12 in group A and 13 in group B. Three patients in group A and 9 in group B reached EDSS 4, in a mean time of 11 years in group A and 7 years in group B (log rank 10.3, p = 0.001). Multivariate Cox regression analysis assessing the risk of EDSS 4.0 including sex, age, number of relapses in the first 2 years, number of T2 brain lesions and spinal cord pattern showed higher risk for the diffuse pattern (hazard ratio 7.2, 95% confidence interval 1.4-36.4). Control MRI showed the persistence of the diffuse pattern in all patients, and the development of diffuse pattern in two patients with basal nodular lesions. The diffuse abnormality in cervical spinal cord at the beginning of the disease is persistent and predicts a worse prognosis in RRMS patients.
    Multiple Sclerosis 08/2010; 16(8):935-41. · 4.47 Impact Factor
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    ABSTRACT: The objective of this study was to investigate whether the presence of lipid-specific oligoclonal IgM bands (LS-OCMB) in cerebrospinal fluid (CSF) influences the response to treatment with beta-interferon in relapsing-remitting multiple sclerosis (RRMS) patients. We performed a collaborative prospective study including RRMS patients with brain MRI and LS-OCMB studies performed before starting interferon treatment. The primary endpoint was the risk of having a relapse after treatment initiation. Secondary endpoints included relapse rate, relapse-rate reduction, proportion of relapse-free patients and proportion of patients with sustained disability increase during follow-up. One-hundred and two patients were included. After a mean follow-up of 37.4 months, the risk of suffering a relapse was two-fold higher in patients with LS-OCMB (hazard ratio 2.0, 95% confidence interval 1.1-3.8). LS-OCMB+ patients showed lower reduction in relapse rate (51.8% versus 80.8%; p < 0.0001), higher relapse rate in the first year (0.8 versus 0.2; p = 0.001), lower proportion of relapse-free patients (25% versus 61.3%; p = 0.003), and higher proportion of patients with sustained 1.0 increase in the Expanded Disability Status Score (45% versus 12.9%; p = 0.0003). In conclusion, LS-OCMB can have an influence on the response to interferon treatment in RRMS patients. They could be used as a biological marker to predict high inflammatory activity after treatment.
    Multiple Sclerosis 07/2010; 16(7):810-5. · 4.47 Impact Factor
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    ABSTRACT: The objective in this paper is to compare the cumulative incidence and incidence density of therapy-related acute myeloid leukaemia in two cohorts of patients with multiple sclerosis treated with mitoxantrone, and with previously reported data in the literature. Six new cases of acute myeloid leukaemia were observed by prospectively following two Spanish series of 142 and 88 patients with worsening relapsing multiple sclerosis and secondary-progressive disease treated with mitoxantrone. A literature review shows 32 further cases of acute myeloid leukaemia reported, 65.6% of which are therapy-related acute promyelocytic leukaemia. Five cases in the cohorts fulfilled the diagnostic criteria for acute promyelocytic leukaemia, and one patient was diagnosed with pre-B-acute lymphoblastic leukaemia. Acute myeloid leukaemia latency after mitoxantrone discontinuation was 1 to 45 months. The accumulated incidence and incidence density was 2.82% and 0.62%, respectively, in the Valencian cohort, and 2.27% and 0.44% in the Catalonian cohort. In the only seven previously reported series, the accumulated incidence varied from 0.15% to 0.80%. The real incidence of acute myeloid leukaemia after mitoxantrone therapy in the multiple sclerosis population could be higher as evidenced by the growing number of cases reported. Haematological monitoring should continue for at least 5 years after the last dose of mitoxantrone. These data stress the necessity of re-evaluating this risk.
    Multiple Sclerosis 10/2009; 15(11):1303-10. · 4.47 Impact Factor

Publication Stats

409 Citations
159.57 Total Impact Points

Institutions

  • 1991–2014
    • Hospital Universitari i Politècnic la Fe
      • Department of Neurology
      Valenza, Valencia, Spain
  • 2009–2010
    • Hospital Clínico Universitario de Valencia
      Valenza, Valencia, Spain
    • University of Valencia
      • Departamento de Psicobiología
      Valencia, Valencia, Spain