CIS Patients Research Articles

Antigen reactivity of B cells from patients at risk to develop Multiple Sclerosis demonstrates a specific somatic mutation pattern. (159.28)

Abstract Multiple Sclerosis (MS) is the leading disease of the central nervous system and a significant, costly cause of disability in young adults. Patients at risk for MS often present with a single demyelinating event, typically called a “clinically isolated syndrome” (CIS). A CIS can occur in the brain, spinal cord (Acute Partial Transverse Myelitis, APTM), or optic nerve (Optic Neuritis, ON). Our laboratory discovered a unique pattern of antibody gene mutation accumulation (i.e. antibody gene signature, or “AGS”) that is exclusive to B cells from the cerebrospinal fluid (CSF) and brain lesions of MS patients and CIS patients that develop MS in the future. Our goal for this study was to determine whether CIS and MS patient B cells that carry this pattern of somatic hypermutation accumulation in their antibody genes react to brain tissue. Thirty-four antibody genes of B cells isolated from the CSF of MS and CIS patients carrying this AGS pattern were cloned into antibody expression vectors to generate recombinant full-length human antibodies (rhAbs). Preliminary DAB staining using a subgroup of these rhAbs on cryo-sectioned mouse brain demonstrates binding to CNS tissue. Cortical staining of varied intensities was found among the rhAbs tested. Patterns of staining and details of antigen reactivity will be presented. This result provides promise in continuing to identify the auto-antigens that are recognized by the AGS B cells shared among patients at risk to convert to MS.

Cognitive Impairment Is Related to Cerebrospinal Fluid Neurofilament Levels in Clinically Isolated Syndrome Suggestive of Multiple Sclerosis. A Functional MRI Study (P04.104)

Objective: To investigate the interaction between of cerebrospinal fluid (CSF) neurofilament (NF) levels and fMRI pattern of activity during cognition in patients with clinically isolated syndromes suggestive of multiple sclerosis (CIS). Background fMRI suggests early adaptive changes of neuronal activation in CIS. Neuro-axonal damage is considered the main pathological contributor of cognitive impairment and CSF NF is demonstrated to be a suitable tool to assess in vivo neuro-axonal impairment. Design/Methods: fMRI was performed in 24 untreated CIS patients and 37 age and sex matched healthy controls (HCs) during N-Back and Variable Attentional Control (VAC) task. CSF NF light chain (NFL) was assessed by a standard ELISA. NFL levels above the median were considered high. SPM5 random-effects models were used for statistical analyses of fMRI data (p Results: Patients with high and low NFL levels did not differ in socio-demographic, clinical and MRI variables. Behavioral data demonstrated a better accuracy during both N-Back and VAC test in HCs in comparison to CIS patients and a significant interaction of WM and attentional performances with cognitive load. “High NFL” group showed a greater BOLD-fMRI response in DLPFC during both N-Back and VAC task in comparison to “low NFL” group and HCs. VAC fMRI analysis showed an interaction between NFL levels and cognitive load in bilateral Inferior Frontal Gyrus, right putamen and left DLPFC: HCs and “low NFL” group had a linear increase of cortical activity increasing attentional demand, whereas “high NFL” group has increased activity at the intermediate level and decreased activity at the high level of attentional demand. Conclusions: This analysis confirms an impairment of fMRI brain activity during WM and attention tasks in CIS and suggests a load related impairment of attentional processes. Brain recruitment abnormalities in CIS are related to CSF NFL levels suggesting a role of NFL as a surrogate outcome in neuroprotective trials. Disclosure: Dr. Tortorella has received personal compensation for activities with Biogen Idec, Sanofi-Aventis Pharmaceuticals and Novartis as a speaker. Dr. Romano has nothing to disclose. Dr. Ruggieri has nothing to disclose. Dr. Direnzo has nothing to disclose. Dr. Mastrapasqua has nothing to disclose. Dr. Iaffaldano has nothing to disclose. Dr. Taurisano has nothing to disclose. Dr. Fazio has nothing to disclose. Dr. Luciannatelli has nothing to disclose. Dr. Popolizio has nothing to disclose. Dr. Blasi has nothing to disclose. Dr. Bertolino has nothing to disclose. Dr. Trojano has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec and Sanofi-Aventis Pharmaceuticals, Inc. as a consultant and/or speaker. Dr. Trojano has received research support from Merck & Co., Inc.

A Voxel-Based Assessment of Cervical Cord Atrophy in MS Patients (P03.061)

Objective: To apply a voxel-based method to assess the regional distribution of atrophy in the cervical cord of multiple sclerosis (MS) patients with different clinical phenotypes. Background Cervical cord atrophy in MS, measured at a single anatomical level, has been correlated with clinical disability, especially in the progressive forms of the disease. Design/Methods: Brain dual-echo and sagittal 3D T1-weighted cervical cord scans were acquired from 31 healthy controls (HC) and 77 MS patients (15 clinically isolated syndrome [CIS], 15 relapsing remitting [RR] MS, 19 benign MS [BMS], 15 primary progressive MS [PPMS] and 13 secondary progressive [SPMS]). T2 lesion volume (T2LV) was assessed on dual-echo scans. Cervical cord images were analyzed using an active surface (AS) method, which segmented the cord surface from C1 to C7 and created output images reformatted in planes perpendicularly to the estimated cord centre line. Unfolded cervical cord images were co-registered into a common standard space, and smoothed cord binary masks were used as input images for spatial statistics. Between-group comparisons of regional cervical cord atrophy as well as and correlations with clinical and structural MRI variables were assessed (SPM8). Results: Compared to HC, CIS patients showed no cord atrophy, while PPMS had a diffuse cord atrophy. Several clusters of cord atrophy were found in BMS vs. RRMS, SPMS vs. RRMS, BMS and PPMS patients. Atrophy mainly involved the posterior and lateral cord segments at different levels. In PPMS, regional cord atrophy was correlated (p Conclusions: Voxel-based assessment of cervical cord atrophy allows a precise localization of regional cord tissue loss and may contribute to a better characterization of the clinical heterogeneity of MS patients. Disclosure: Dr. Damjanovic has nothing to disclose. Ms. Rocca has received personal compensation for activities with Bayer Schering Pharma and Biogen Idec as a consultant. Dr. Valsasina has nothing to disclose. Dr. Mesaros has received personal compensation for activities with Merck-Serono and Bayer Schering Pharma. Dr. Horsfield has received compensation for serving as a Director of Xinapse Systems Ltd.Dr. Horsfield holds stock and/or stock options in Xinapsse Systems Ltd. Dr. Stosic-Opincal has nothing to disclose. Dr. Drulovic has received personal compensation for activities with Bayer Schering Pharma and Merck Serono S.A. Dr. Comi has received personal compensation for activities with Novartis, Teva Neuroscience, Sanofi-Aventis Pharmaceuticals, Inc., Merck Serono, Bayer Schering, and Biogen Dompe. Dr. Filippi has received personal compensation for activities with ECTRIMS, MSIF, MS Ireland, US NMSS, Bayer-Schering, Biogen-Dompe AG, Genmab, Merck Serono, Pepgen Corporation, Teva, and Sanofi-Aventis. Dr. Filippi has received research support from Teva, Bayer-Schering and Genmab.

Iron Deposition on SWI-Filtered Phase in the Subcortical Deep Gray Matter of Patients with Clinically Isolated Syndrome May Precede Structure-Specific Atrophy

Increasing evidence suggests that iron deposition is present in the later stages of MS. In this study we examined abnormal phase values, indicative of increased iron content on SWI-filtered phase images of the SDGM in CIS patients and HC. We also examined the association of abnormal phase with conventional MR imaging outcomes at first clinical onset. Forty-two patients with CIS (31 female, 11 male) and 65 age and sex-matched HC (41 female, 24 male) were scanned on a 3T scanner. Mean age was 40.1 (SD = 10.4) years in patients with CIS, and 42.8 (SD = 14) years in HC, while mean disease duration was 1.2 years (SD = 1.3) in patients with CIS. MP-APT, NPTV, and normalized volume measurements were derived for all SDGM structures. Parametric and nonparametric group-wise comparisons were performed, and associations were determined with other MR imaging metrics. Patients with CIS had significantly increased MP-APT (P = .029) and MP-APT volume (P = .045) in the pulvinar nucleus of the thalamus compared with HC. Furthermore, the putamen (P = .004), caudate (P = .035), and total SDGM (P = .048) displayed significant increases in MP-APT volume, while MP-APT was also significantly increased in the putamen (P = .029). No global or regional volumetric MR imaging differences were found between the study groups. Significant correlations were observed between increased MP-APT volumes of total SDGM, caudate, thalamus, hippocampus, and substantia nigra with white matter atrophy and increased T2 lesion volume (P < .05). Patients with CIS showed significantly increased content and volume of iron, as determined by abnormal SWI-phase measurement, in the various SDGM structures, suggesting that iron deposition may precede structure-specific atrophy.

Comparison of two methods for the detection of oligoclonal bands in a large number of clinically isolated syndrome and multiple sclerosis patients

ObjectiveA novel oligoclonal band (OB) assay which consists of isoelectric focusing (IEF) and IgG immunodetection by alkaline phosphatase-labeled anti IgG antibody was reported to be very sensitive. It also accurately predicted conversion to MS in patients with CIS. The aim of our study was to compare sensitivity of a novel and the standard procedure with peroxidase immunodetection in a large number of CIS and MS patients. MethodsOB were determined in serum and CSF samples in 161 patients (104 females), 47 with CIS and 114 with MS with median age 38 years (range 19–68) using both methods. ResultsEighty-three percent of patients had CSF OB with the standard and 89% with the novel method. Median number of OB was 5 (range 0–17) with the peroxidase and 8 (range 0–18) with the alkaline phosphatase method; p=0.001. Twenty-one percent of patients had ≥10 OB with the standard and 37% with the novel method of the detection; p=0.021. Subjective impression of band clarity showed that 20% of patients had sharper and stronger bands when the peroxidase and 65% when the alkaline phosphatase method was used; p<0.0001. ConclusionThe alkaline phosphatase method is more sensitive than the peroxidase method and at the same time cheaper, easy to perform and less time consuming.

Upregulation of IL-17, but not of IL-9, in circulating cells of CIS and relapsing MS patients. Impact of corticosteroid therapy on the cytokine network

The concomitant production of IL-17A and IL-9, both Th17 cytokines, has not been compared in MS patients. We show that IL-17A but not IL-9 expression by CD3+ cells was increased during a MS relapse. Co-expression of IL-17A and IL-9 was marginal. In addition to Th1 and Th2 cytokines, IL-17A, IL-6 and IL-23p19 were down-regulated by ivMP, but Foxp3 was not, while an increase in IL-10, TGF-β1 and IL-27p28 mRNA was observed. This change in the Th17, Treg and IL-10 balance could be an additional mechanism by which corticosteroids shorten the duration of a MS relapse and promote recovery.

Pathological Assessment of Brain White Matter in Relapsing-Remitting MS Patients using Quantitative Magnetization Transfer Imaging

Introduction: Multiple sclerosis (MS) is characterized by lesions in the white matter (WM) of the central nervous system. Magnetic resonance imaging is the most specific and sensitive method for diagnosis of multiple sclerosis. However, the ability of conventional MRI to show histopathologic heterogeneity of MS lesions is insufficient. Quantitative magnetization transfer imaging (qMTI) is a relatively new method to investigate pathologic processes of the brain tissue occurring in MS patients. Material and Methods: Voxel-based analyses allow regional comparisons between groups to be made for the whole brain in a single analysis. This is done by coregistering data from all individual subjects to a reference brain, generally referred to as the standard space, and then comparing them on a voxel-by-voxel basis. This study aimed to analyze whole-brain quantitative T1 maps, not to find global changes or changes in selected regions, but specifically to investigate the spatial distribution throughout the brain of T1 increases in MS WM with respect to control WM. In this study, 11 healthy controls, 10 relapsing-remitting (RR) MS patients and 13 CIS patients were studied using MT-MRI imaging. MT parameters, including magnetization transfer ratio (MTR), magnetization transfer rate between free protons and restricted macromolecular protons, Ksat and longitudinal relaxation times (with and without MT saturation pulse), T1sat and T1free values were evaluated. Results: The results showed that, at a group level, there is widespread involvement of WM throughout the brain in CIS MS and especially in RRMS, where a significant T1 increase was found in 15.58% of WM voxels (normals < RR). Discussion and Conclusion: This study demonstrates that WM in large parts of the brain is susceptible to disease processes in RR and CIS MS

Comparison of antibody gene mutation patterns in first attack optic neuritis and transverse myelitis leading to Multiple Sclerosis (47.18)

Abstract Multiple Sclerosis (MS) is the leading disease of the central nervous system and a significant, costly cause of disability in young adults. Patients at risk for MS often present with a single demyelinating event, typically called a “clinically isolated syndrome” (CIS). A CIS can occur in the brain, spinal cord (Acute Partial Transverse Myelitis, APTM), or optic nerve (Optic Neuritis, ON) at similar rates and present a challenging diagnostic and therapeutic dilemma. Stratifying CIS patients most likely to develop MS is a complicated process, but desirable since treatment with the appropriate immunomodulatory agents early in the disease course can delay long-term disability. Thus, a primary focus of our laboratory has been to develop a completely novel type of biomarker that can identify CIS patients that will develop MS. This unique biomarker is based on a pattern of antibody gene mutations (i.e. antibody gene signature or “AGS”) that is exclusive to B cells from the cerebrospinal fluid and brain lesions of MS patients that initially presented with either TM or ON. In fact, the AGS is consistently elevated in patients with one attack of ON that go on to develop definite MS, and can predict conversion to MS with 91% accuracy. More recently, we are testing the hypothesis that the AGS serves as a predictor for conversion to MS in CIS patients that present with TM. Preliminary data demonstrate that the AGS is also prevalent in CIS patients presenting with TM.

Fluoreszenzdiagnostik bei Patienten mit nicht muskelinvasivem Harnblasenkarzinom: Ergebnisse einer Metaanalyse

Heterogeneous results of single studies with photodynamic diagnosis (PDD) in bladder cancer have been reported. A metaanalysis of prospective studies has now been performed. The effect of PDD in addition to WLC on a) the diagnosis and b) the therapeutic outcome of primary or recurrent non-muscle invasive bladder cancer (NMIBC) investigated by cystoscopy or transurethral resection was analysed. An electronic database search was performed. Trials were included if they prospectively compared WLC with PDD in bladder cancer. Primary endpoints were additional detection rate, residual tumour at second resection and recurrence-free survival. Significantly more tumour-positive patients were detected with PDD in all patients with non-muscle invasive tumours (= 20 %) [95 % confidence interval (CI): 8 to 35 %] and in CIS patients (= 39 %) (CI: 23 to 57 %). Residual tumour was significantly less often found after PDD (odds ratio 0.28, CI: 0.15 to 0.52, p < 0.0001). Recurrence-free survival was significantly higher at 12 and 24 months in the PDD groups than in WLC only groups. More bladder tumour-positive patients are detected by PDD. Best results were found in CIS patients. Diagnosis with PDD results in a more complete resection and a longer recurrence-free survival.

Oligoclonal bands and MRI in clinically isolated syndromes: predicting conversion time to multiple sclerosis

The objective of the study was to evaluate whether the presence of oligoclonal bands (OB) adds information in predicting CIS conversion to clinical definite multiple sclerosis (CDMS) and conversion time to CDMS. From 1998 to 2006, CIS patients were included in a prospective study. Patients underwent brain MRI and OB determination within 2 months of the first demyelinating event. We analyzed conversion to CDMS and time to conversion to CDMS according to abnormal MRI and the presence of OB. Forty patients were included. Fifteen patients (37%) converted to CDMS; 14 of them (93.3%) had abnormal baseline MRI (P = 0.01, RR = 5.9; 95% CI 1.3-10.1) and 13 (86.7%) had positive OB in CSF (P = <0.01, RR = 5.3; 95% CI 1.6-9.5). The risk of conversion to CDMS in patients with positive OB and abnormal baseline MRI was significantly higher compared to patients negative for both tests or with only one positive (RR = 9.1; 95% CI 3.5-14.6). Time to conversion to CDMS was 6.8 +/- 3.5 months for patients with OB and abnormal baseline MRI and 19 +/- 14 months for patients with only one abnormal test. CIS patients with abnormal baseline OB in CSF have a higher risk for developing CDMS. Regarding conversion time to CDMS, when abnormal MRI was added to positive OB, patients converted faster (mean time, 6 vs. 19 months). This information may be useful when considering treatment in CIS patients.

PO10-TU-18 Non-invasive brain mapping of motor related areas of four limbs in CIS patients compared with normal subjects

PO10-TU-18 Non-invasive brain mapping of motor related areas of four limbs in CIS patients compared with normal subjects

Prospective combined brain and spinal cord MRI in clinically isolated syndromes and possible early multiple sclerosis: impact on dissemination in space and time

The diagnosis of multiple sclerosis (MS) is based on dissemination in space (DIS) and time (DIT). The aim of the study was to assess the impact of spinal cord (SC) imaging on the evidence of DIS and DIT. Thirty-five treatment-naive patients with a first clinical symptom suggestive of MS were examined in a 2-year prospective longitudinal follow-up assessment. Brain and SC magnetic resonance imaging (MRI), Expanded Disability Status Scale and multiple sclerosis functional composite were analysed at baseline and after 1 and 2 years. At study entry, 21 patients were classified as clinically isolated syndrome suggestive of MS (CIS) and 14 patients as possible early MS. SC lesions were detected at baseline in 14 CIS patients (67%, median: 1.0, enhancing 29%) and in 11 patients with possible early MS (79%, median: 2.0, enhancing 29%). DIS as depicted by additive SC imaging was detected in two additional individuals according to the revised versus the 2001 McDonald criteria. All patients with emerging cord lesions showed new brain lesions. Five individuals developed clinically asymptomatic cord lesions. Spinal cord abnormalities are frequent in CIS patients and in patients with possible early MS. SC imaging slightly improved the establishment of DIS, but had no impact on the evidence of DIT.

Preserved decision making ability in early multiple sclerosis

The purpose of this study was to assess decision making in patients with multiple sclerosis (MS) at the earliest clinically detectable time point of the disease. Patients with definite MS (n = 109) or with clinically isolated syndrome (CIS, n = 56), a disease duration of 3 months to 5 years, and no or only minor neurological impairment (Expanded Disability Status Scale [EDSS] score 0-2.5) were compared to 50 healthy controls using the Iowa Gambling Task (IGT). The performance of definite MS, CIS patients, and controls was comparable for the two main outcomes of the IGT (learning index: p = 0.7; total score: p = 0.6). The IGT learning index was influenced by the educational level and the co-occurrence of minor depression. CIS and MS patients developing a relapse during an observation period of 15 months dated from IGT testing demonstrated a lower learning index in the IGT than patients who had no exacerbation (p = 0.02). When controlling for age, gender and education, the difference between relapsing and non-relapsing patients was at the limit of significance (p = 0.06). Decision making in a task mimicking real life decisions is generally preserved in early MS patients as compared to controls. A possible consequence of MS relapsing activity in the impairment of decision making ability is also suspected in the early phase of MS.

Regional grey matter atrophy in clinically isolated syndromes at presentation

Background:The presence and degree of neuronal degeneration already existing in patients at their initial presentation with a clinically isolated syndrome suggestive of multiple sclerosis (CIS) is unclear, and whole brain...

Interferon Beta-1a Modulates the Innate Immune-response-mediated Regulation of Adaptive Immunity in Early Multiple Sclerosis (131.15)

Abstract We performed Affymetrix gene arrays (HU133, ~38,500 genes) using RNA from the in vitro activated PBMCs from patients with clinically isolated syndrome suggestive of multiple sclerosis (CIS) (n=15) and matched healthy controls (HC) (n=8). Results were confirmed and further supported by RT-PCR and RayBio Cytokine Arrays. Affymetrix data revealed that IFNB-1a induced significant (p&amp;lt;0.05) up-regulation of 711, and down-regulation of 587 genes in CIS patients, and 446 and 543 in HC, respectively. CXCL11 and CXCL10, the ligands of CXCR3 were significantly increased in CIS patients and HC, whereas proinflammatory chemokines CXCL2, CXCL3 and CXCL5 were decreased in CIS patients. CCL18 and CCL19 were increased in CIS, while CCL22 and CCL17 were decreased in CIS and HC. Those chemokine gene changes reflect the complex effects of IFNB-1a that likely affect differentiation/ maturation and chemotaxis of DCs and other cells bridging the innate and adaptive immune response. The anti-inflammatory cytokine IL-10 was increased in CIS, consistent with the previous findings in multiple sclerosis, while IL1A, IL1R1 and IL-16 were decreased in CIS and HC. IL-1 is an acute inflammatory phase cytokine whose inhibition may decrease differentiation of IL-17 secreting T-cells that is critical in the development of autoimmune response. SOCS7 and SCOS5 were decreased in CIS and HC that may result in impaired Th1 responses. TLR7 and its signal adapter MYD88 were increased in CIS and HC. IRAK4 and TRAF6, the components of MYD88-dependent pathway were also increased in CIS. IRF2 and IRF7 that may be involved in MYD88-independent TLR signaling pathway were increased in CIS and HC. Such effects on TLRs signaling pathways may inhibit DCs maturation and alter the innate immune response mediated regulation of adaptive immunity.

Antimyelin antibodies in clinically isolated syndromes correlate with inflammation in MRI and CSF

We investigated the correlation of antimyelin oligodendrocyte glycoprotein-(anti-MOG) and anti-myelin basic protein antibodies (anti-MBP) in serum of CIS patients with inflammatory signs in MRI and in CSF and, as previously suggested,the incidence of more frequent and rapid progression to clinically definite MS (CDMS). 133CIS patients were analysed for anti-MOG and anti-MBP (Western blot). Routine CSF and cranial MRI (quantitatively and qualitatively) measures were analyzed. 55 patients had a follow-up of at least 12 months or until conversion to CDMS. Patients with anti-MOG and anti-MBP had an increased intrathecal IgG production and CSF white blood cell count(p = 0.048 and p = 0.036). When anti-MBP alone, or both antibodies were present the cranial MRI showed significantly more T2 lesions (p = 0.007 and p = 0.01,respectively). There was a trend for more lesion dissemination in anti-MBP positive patients (p = 0.076).Conversely, anti-MOG- and/or anti-MBP failed to predict conversion to CDMS in our follow-up group (n = 55). Only in female patients with at least one MRI lesion (n = 34) did the presence of anti-MOG correlate with more frequent (p = 0.028) and more rapid (p = 0.0209) transition to CDMS. Presence of anti-MOG or anti-MBP or both was not significantly associated with conversion to CDMS in our CIS cohort. However, patients with anti-MOG and anti-MBP had higher lesion load and more disseminated lesions in cranial MRI as well as higher values for CSF leucocytes and intrathecal IgG production. Our data support a correlation of anti-MOG and anti-MBP to inflammatory signs in MRI and CSF. The prognostic value of these antibodies for CDMS, however, seems to be less pronounced than previously reported.

Inpatient and Community Ischemic Strokes in a University Hospital

Background: Previous studies have shown that inpatient strokes are common and severe. We sought to characterize the risk factors, stroke subtypes, timing of acute stroke evaluation and frequency of thrombolytic therapy in inpatient ischemic strokes compared with community ischemic strokes. Design/Methods: The hospital records of patients admitted for acute ischemic stroke between 1996 and 2002 were reviewed. Acute stroke was defined as occurrence of stroke symptoms within 72 h, and in-hospital status was assigned if the patient was currently admitted for another illness at the time of the stroke. Patient demographics such as medical versus surgical service, admission diagnoses, clinical features including stroke risk factors, access to thrombolytic therapy and immediate outcome were analyzed. Results: Of 947 patients with acute ischemic stroke, 161 (17.0%) had strokes occurring while already in the hospital (IHIS), compared to 786 (83%) that occurred in the outpatient community (CIS). Approximately two thirds of IHIS occurred on medical services (102, 63.4%) and one third on surgical services (59, 36.7%). Mean age, male gender, atherothrombotic etiology and risk factors including hypertension, diabetes and smoking history were of similar frequencies in IHIS and CIS, but penetrating artery disease was the cause of only 5.6% of IHIS compared to 21.8% of CIS (p < 0.0001). The mean modified Rankin scale for IHIS at presentation was 4.33 ± 0.74, compared to 3.67 ± 1.03 for CIS (p < 0.0001). Of 161 IHIS patients, 21 (13.0%) had neurological assessment within 3 h of symptom onset, compared to 16.0% of CIS patients (p = 0.403, n.s.), and the rate of thrombolytic therapy was not significant between IHIS (3.7%) and CIS (5.6%) patients. Conclusions: IHIS are common and severer than CIS. The use of thrombolytic therapy in IHIS patients was limited because of time of recognition and inpatient-associated conditions. Increased vigilance for timely neurological assessment of these patients is warranted.

Differences in cerebral activation patterns in idiopathic inflammatory demyelination using the paced visual serial addition task: An fMRI study

We performed a functional MRI (fMRI) study during the execution of the Paced Visual Serial Addition Task (PVSAT) in 9 patients with a clinically isolated syndrome suggestive of multiple sclerosis (CIS), 9 patients with clinically definite multiple sclerosis (CDMS), and 18 matched healthy control subjects. In controls, the PVSAT elicited a fronto-parietal network with cerebellar activation which we expected for this kind of working memory test and which indicates that this PVSAT version is an appropriate tool for measuring functional changes during a cognitive task. Although there were no significant differences in the actual test results of patients vs. controls, CDMS and CIS patients activated distinct cerebral networks in their attempt to solve the fMRI-PVSAT. Compared to CIS patients, CDMS patients showed increased hippocampal and parahippocampal activation, suggesting the need to additionally support their working memory. In contrast, compared to CDMS patients and healthy controls, CIS patients demonstrated stronger activation of the anterior cingulate cortex, which might indicate focused involvement of executive processes. On the PASAT (Paced Auditory Serial Addition Task) patients also performed similarly to controls but they showed decreased scores on most of the sub-tests of the Wechsler Memory Scale. Based on our observations using the fMRI-PVSAT, we hypothesize that distinct differences in cognitive processing occur with the evolution of MS and that, at these early stages of the disease, they cannot be detected with sufficient sensitivity using only the PASAT.

Is Autofluorescence Bronchoscopy Needed to Diagnose Early Bronchogenic Carcinoma?

Is Autofluorescence Bronchoscopy Needed to Diagnose Early Bronchogenic Carcinoma?

Analyses of the effects of intravesical Bacillus Calmette-Guerin (Tokyo 172 strain) therapy of superficial bladder cancer

In this paper, we summarize the results of a multicentric controlled study of induction treatment with intravesical BCG in patients with superficial bladder cancer (Ta, T1) or CIS. The BCG Tokyo 172 strain (Japan BCG K.K.) was given for 8 weeks, as a rule, in a dose of either 80 mg or 120 mg in 40 ml of saline instilled into the bladder. Sixty-six (90.5%) of the 73 patients registered in the study were evaluable for response. High response rates were obtained in the patients with Ta or T1 tumors, irrespective of the treatment dose; 65.4% CR, 27.3% PR and 7.3% NC for all. The number of CIS patients is too small to draw any conclusions, but 54.5% CR, 36.4% PR and 9.1% NC were obtained. Several factors were evaluated in relation to the tumor ablative effects. The CR rate was significantly higher for tumors less than 1 cm in size compared with tumors 1-3 or larger in size, although the response rates, including CR and PR, were very similar irrespective of the size. Other factors did not contribute to provoke a significant difference. Japanese elder people show a high positive rate of PPD reaction. Thus, in our study, 78% of the patients showed positive PPD reaction. In this situation, no significant relation between PPD reaction and BCG efficacy was obtained. In addition, OKT8, OKT7, OKT4, OKT4/OKT8 ratio, Leu7, ADCC activity and NK activity did not show any correlation with tumor ablative effect of BCG.(ABSTRACT TRUNCATED AT 250 WORDS)