Multiple Sclerosis: Polman CH

Polman CH, Reingold SC, Barkhof F, Calabresi PA, Clanet M, Cohen JA, Cutter GR, Freedman MS, Kappos L, Lublin FD, McFarland HF, Metz LM, Miller AE, Montalban X, O'Connor PW, Panitch H, Richert JR, Petkau J, Schwid SR, Sormani MP, Thompson AJ, Weinshenker BG, Wolinsky JS. · Department of Neurology, Free University Medical Center in Amsterdam, PO Box 4075, 1007 MB Amsterdam, The Netherlands. · Neurology. · Pubmed #18362273 No free full text.

Abstract: The increasing number of established effective therapies for relapsing multiple sclerosis (MS) and emerging consensus for early treatment raise practical concerns and ethical dilemmas for placebo-controlled clinical trials in this disease. An international group of clinicians, ethicists, statisticians, regulators, and representatives from the pharmaceutical industry convened to reconsider prior recommendations regarding the ethics of placebo-controlled trials in MS. The group concluded that placebo-controlled trials can still be done ethically, with restrictions. For patients with relapsing MS for which established effective therapies exist, placebo-controlled trials should only be offered with rigorous informed consent if the subjects refuse to use these treatments, have not responded to them, or if these treatments are not available to them for other reasons (e.g., economics). Suggestions are provided to protect subject autonomy and improve informed consent procedures. Recommendations are tighter than previously suggested for placebo-controlled trials in "resource-restricted" environments where established therapies may not be available. Guidance is also provided on the ethics of alternative trial designs and the balance between study subject burden and risk, scientific rationale and interpretability of trial outcomes.

Polman CH. · No affiliation provided · Mult Scler. · Pubmed #18089670 No free full text.

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Killestein J, Polman CH. · No affiliation provided · Int MS J. · Pubmed #17686340 links to  free full text

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Polman CH, Killestein J. · No affiliation provided · J Neurol Neurosurg Psychiatry. · Pubmed #16705192 links to  free full text

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Killestein J, Polman CH. · No affiliation provided · Can J Neurol Sci. · Pubmed #12945937 No free full text.

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Polman CH, Miller DH, McDonald WI, Thompson AJ. · No affiliation provided · J Neurol Neurosurg Psychiatry. · Pubmed #10519854 links to  free full text

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Rudick RA, Polman CH. · Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH 44195, USA. · Lancet Neurol. · Pubmed #19446274 No free full text.

Abstract: Disease-modifying drugs (DMDs) for relapsing-remitting multiple sclerosis (RRMS) are only partly effective -- breakthrough disease commonly occurs despite treatment. Breakthrough disease is predictive of continued disease activity and a poor prognosis. Availability of several DMDs offers the possibility of tailoring treatment to individual patients with RRMS and altering treatment in patients with breakthrough disease. However, no biological or imaging markers have been validated to guide initial treatment, markers of individual responsiveness to DMDs are scarce, and there is no class 1 evidence to guide alternative therapy in patients with breakthrough disease. In this Review, we discuss proposed strategies to monitor patients with RRMS being treated with DMDs, outline approaches to identifying therapeutic response in individual patients, review MRI and biological markers of treatment response, and summarise the role of antibodies in biological therapies. We also outline possible strategies for the management of patients with breakthrough disease and highlight areas in which research is needed.

Nielsen JM, Korteweg T, Polman CH. · Department of Neurology, VU Medical Centre, De Boelelaan 1117, 1007 MB Amsterdam, The Netherlands. · Int MS J. · Pubmed #17509251 links to  free full text

Abstract: Previous diagnostic guidelines for MS relied largely on clinical evidence and cerebrospinal fluid analysis. In 2001, guidelines were published that allowed partial substitution of the required clinical evidence by magnetic resonance imaging findings and defined primary progressive multiple sclerosis (PPMS). Recently, revised guidelines on MS diagnosis were published, mainly to improve definitions of dissemination in space (using spinal cord imaging) and in time (using T2 lesions), enabling a faster and more accurate MS diagnosis. Criteria for PPMS were also revised. Current research is concentrating on the definition of uniform clinical terms, to allow a more standardized diagnosis, and aims to simplify the criteria while improving diagnostic accuracy.

Kappos L, Bates D, Hartung HP, Havrdova E, Miller D, Polman CH, Ravnborg M, Hauser SL, Rudick RA, Weiner HL, O'Connor PW, King J, Radue EW, Yousry T, Major EO, Clifford DB. · University Hospital, Basel, Switzerland. · Lancet Neurol. · Pubmed #17434098 No free full text.

Abstract: Natalizumab is a new treatment option for patients with active relapsing-remitting multiple sclerosis. In phase III studies, natalizumab was highly effective and well tolerated; however, three cases of progressive multifocal leucoencephalopathy (PML) were identified (estimated incidence of one per 1000; 95% CI 0.2-2.8; mean treatment period 17.9 months). In this Review we summarise the current information on PML, the three confirmed cases of PML, and the results of an extensive safety assessment of all patients treated with natalizumab. On the basis of these reviews, we make recommendations for appropriate selection of candidates for natalizumab and pretreatment assessments. In addition, a three-step diagnostic and management algorithm was developed to monitor natalizumab-treated patients with multiple sclerosis for PML and other opportunistic infections. The algorithm includes strategies for clinical, MRI, and laboratory assessments. Maintaining clinical vigilance allows for early suspension of natalizumab in potential cases of PML, thereby increasing the opportunity for immune reconstitution, which may improve prognosis if PML is confirmed.

Huijbregts SC, Kalkers NF, de Sonneville LM, de Groot V, Polman CH. · School of Psychology, Highfield, University of Southampton, SO17 1BJ, Southampton, UK. · J Neurol Sci. · Pubmed #16643951 No free full text.

Abstract: This paper presents results of two studies conducted to investigate cognition in different MS subtypes. First, the results of a study that has previously been published will be discussed. This was a cross-sectional study with 108 relapsing-remitting (RR), 71 secondary progressive (SP), 55 primary progressive (PP) MS patients, and 67 healthy controls [S.C.J. Huijbregts, N.F. Kalkers, L.M.J. de Sonneville, V. de Groot, I.E.W. Reuling, C.H. Polman, Differences in cognitive impairment of relapsing-remitting, secondary and primary progressive MS. Neurology 63 (2004) 335-339]. The second study involved a follow-up assessment after 2 years and included 30 SPMS patients, 25 PPMS patients, and 33 controls. The Brief Repeatable Battery of Neuropsychological Tests (BRB-N) was used for all cognitive assessments. All patient groups demonstrated cognitive deficits compared to healthy controls. RRMS patients were less affected compared to patients with progressive MS subtypes on the Paced Auditory Serial Addition Task (PASAT) and the Symbol Digit Modalities Test (SDMT). These differences were attenuated after control for physical disability level as measured by the Expanded Disability Status Scale. RRMS and SPMS patients were more severely impaired than PPMS patients on the 10/36 Spatial Recall Task and Word List Generation. Results of the follow-up study indicated that both progressive MS subtypes showed a lack of improvement compared to controls on the PASAT and the SDMT, but not on the other tasks of the BRB-N, indicating that performance on tasks requiring multiple abilities concurrently, i.e. visuo-spatial ability and processing speed (SDMT) or working memory and processing speed (PASAT), is most likely to decline across time.

Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, Lublin FD, Metz LM, McFarland HF, O'Connor PW, Sandberg-Wollheim M, Thompson AJ, Weinshenker BG, Wolinsky JS. · VU Medical Center Amsterdam, Free University, PO Box 7057, 1007 MB Amsterdam, the Netherlands. · Ann Neurol. · Pubmed #16283615 No free full text.

Abstract: New diagnostic criteria for multiple sclerosis integrating magnetic resonance image assessment with clinical and other paraclinical methods were introduced in 2001. The "McDonald Criteria" have been extensively assessed and used since 2001. New evidence and consensus now strengthen the role of these criteria in the multiple sclerosis diagnostic workup to demonstrate dissemination of lesions in time, to clarify the use of spinal cord lesions, and to simplify diagnosis of primary progressive disease. The 2005 Revisions to the McDonald Diagnostic Criteria for MS should simplify and speed diagnosis, whereas maintaining adequate sensitivity and specificity.

Teunissen CE, van Boxtel MP, Jolles J, de Vente J, Vreeling F, Verhey F, Polman CH, Dijkstra CD, Blom HJ. · Department of Molecular Cell Biology and Immunology, Amsterdam, and VUmc Medical Center Amsterdam, Amsterdam, The Netherlands. · Clin Chem Lab Med. · Pubmed #16197303 No free full text.

Abstract: Elevated serum homocysteine has been associated with increased risk of Alzheimer's disease. Furthermore, elevated homocysteine levels are related to cognitive dysfunction in the elderly. The aim of the present study was to explore the disease specificity of the relation between serum total homocysteine levels and cognitive function. For this, we summarize data from several studies on homocysteine levels in both normal and pathological conditions performed in our laboratories and evaluate possible mechanisms of effects of elevated homocysteine levels in the central nervous system. Total homocysteine levels were measured in serum of: 1) healthy aging individuals; 2) patients with Alzheimer's and Parkinson's disease and patients with other cognitive disorders; and 3) patients with multiple sclerosis. Increased serum homocysteine concentration was related to worse cognitive performance over a 6-year period in the normal aging population (r=-0.36 to -0.14, p<0.01 for the Word learning tests; r=0.76, p<0.05 for the Stroop Colored Word test). Homocysteine was only increased in patients with Parkinson's disease on L-Dopa therapy (18.9 vs. 16.5 micromol/L in healthy controls), and not in dementia patients. Homocysteine was elevated in patients with progressive multiple sclerosis (15.0 micromol/L, n=39, compared to 12.0 micromol/L in 45 controls) and correlated to both cognitive and motor function (r=-0.33 and -0.33, p<0.05, respectively). The relationship between homocysteine and cognitive function in non-pathological and pathological situations indicates that changes in its levels may play a role in cognitive functioning in a broad spectrum of conditions.

Killestein J, Polman CH. · Department of Neurology, MS Centre, VU Medical Centre Amsterdam, Amsterdam, The Netherlands. · Curr Opin Neurol. · Pubmed #15891408 No free full text.

Abstract: PURPOSE OF REVIEW: The aim of the present report is to briefly review multiple sclerosis therapeutic trials published or presented in 2004 to provide an up-to-date overview of the established evidence and new insights. RECENT FINDINGS: New data have come available that help us understand how currently approved disease modifying drugs can best be used. Nonetheless, their limited effectiveness - especially in progressive forms of multiple sclerosis - as well as the inconvenience and toxicity associated with their use, emphasize the need for new treatment strategies. A substantial number of reports on new emerging treatment modalities were published in 2004, and one of these modalities was newly approved by the US Food and Drug Administration for the treatment of relapsing forms of multiple sclerosis. SUMMARY: Further advances have been made in the treatment of multiple sclerosis patients. On the one hand, we know better how and in whom to use existing medications. On the other hand, it is exciting to witness how increased insight in the pathophysiology of the disease and its symptoms has led to a series of new, innovative treatment modalities.

Polman CH, Wolinsky JS, Reingold SC. · Department of Neurology, VU Medical Centre, Amsterdam, The Netherlands. · Mult Scler. · Pubmed #15732260 No free full text.

Abstract: New diagnostic criteria for multiple sclerosis (MS) were developed by an International Panel in 2001 and have had wide distribution and discussion since publication. These provided the first formal incorporation of magnetic resonance imaging (MRI) in a diagnosis work-up for patients suspected of having MS. The so-called McDonald criteria have been studied in retrospective and prospective analyses for sensitivity, specificity and utility, and have been proven to compare favourably or to be an improvement upon prior MS diagnostic criteria. The purpose of the current review is to present and evaluate the key studies that have been performed using the McDonald criteria since 2001 and to set the stage for an upcoming re-evaluation of the new criteria based on data-driven information gathered since their development.

Killestein J, Bet PM, van Loenen AC, Polman CH. · VU Medisch Centrum, Postbus 7057, 1007 MB, Amsterdam. · Ned Tijdschr Geneeskd. · Pubmed #15615271 No free full text.

Abstract: --In 1996, the Netherlands Health Council issued a negative recommendation regarding the use of medication on the basis of cannabis (marihuana). However, interest in medicinal cannabis has certainly not waned since. --The neurological diseases for which cannabis could presently be used therapeutically are: multiple sclerosis, chronic (neuropathic) pain and the syndrome of Gilles de la Tourette. --Since September 2003, the Dutch Ministry of Health, Welfare and Sport delivers medicinal cannabis to Dutch pharmacies, so that now for the first time, medicinal cannabis can be given to patients on a prescription basis within the framework of the Opium Law. The result of this is that doctors and patients now assume that this is a medication for which the efficacy and safety have been established. --The question arises whether new scientific data have become available since 1996 that provide scientific support for the current Governmental policy. --In a recent clinical trial that has aroused much discussion, patients with multiple sclerosis and problematic spasticity were treated with oral cannabis or a placebo. There was no significant effect of treatment on the primary outcome measure, i.e. objectively determined spasticity. Nevertheless, it was concluded that the mobility was improved and that the pain was subjectively decreased. --Until now, convincing scientific evidence that cannabinoids are effective in neurological conditions is still lacking. --However, it is also not possible to conclude definitely that cannabinoids are ineffective; still, this is no basis for official stimulation of their use.

Miller DH, Filippi M, Fazekas F, Frederiksen JL, Matthews PM, Montalban X, Polman CH. · NMR Research Unit, Department of Neuroinflammation, Institute of Neurology, University College London, London, United Kingdom. · Ann Neurol. · Pubmed #15293279 No free full text.

Abstract: The diagnosis of multiple sclerosis (MS) has been improved in recent decades with the incorporation of paraclinical investigations in diagnostic workup. In the last 15 years, magnetic resonance imaging (MRI) has become an especially valuable tool for supporting MS diagnosis, and specific imaging criteria became fundamental to the guidelines for the diagnosis of MS published in 2001 by an international panel (IP). The new IP criteria include MRI evidence of dissemination in space and time, making it possible to diagnose MS after a single clinical episode. This review considers current evidence concerning the reliability of the new IP criteria for the diagnosis of relapsing-onset MS, discusses strengths and weaknesses of the criteria, and outlines areas which may need modification or should be the focus of future research directed toward improving diagnostic accuracy. It also makes practical recommendations when using MRI and the IP criteria in MS diagnosis, especially in patients with clinically isolated syndromes or atypical presentations. The IP criteria are timely and concrete and introduce an important concept to MS diagnosis. Future modifications, based on emerging evidence, should further facilitate their implementation and improve their accuracy.

VanAmerongen BM, Dijkstra CD, Lips P, Polman CH. · Department of Molecular Cell Biology and Immunology, VU Medical Center, Amsterdam, The Netherlands. · Eur J Clin Nutr. · Pubmed #15054436 No free full text.

Abstract: MS is a chronic, immune-mediated inflammatory and neurodegenerative disease of the central nervous system (CNS), with an etiology that is not yet fully understood. The prevalence of MS is highest where environmental supplies of vitamin D are lowest. It is well recognized that the active hormonal form of vitamin D, 1,25-dihydroxyvitamin D (1,25-(OH)(2)D), is a natural immunoregulator with anti-inflammatory action. The mechanism by which vitamin D nutrition is thought to influence MS involves paracrine or autocrine metabolism of 25OHD by cells expressing the enzyme 1 alpha-OHase in peripheral tissues involved in immune and neural function. Administration of the active metabolite 1,25-(OH)(2)D in mice and rats with experimental allergic encephalomyelitis (EAE, an animal model of MS) not only prevented, but also reduced disease activity. 1,25-(OH)(2)D alters dendritic cell and T-cell function and regulates macrophages in EAE. Interestingly, 1,25-(OH)(2)D is thought to be operating on CNS constituent cells as well. Vitamin D deficiency is caused by insufficient sunlight exposure or low dietary vitamin D(3) intake. Subtle defects in vitamin D metabolism, including genetic polymorphisms related to vitamin D, might possibly be involved as well. Optimal 25OHD serum concentrations, throughout the year, may be beneficial for patients with MS, both to obtain immune-mediated suppression of disease activity, and also to decrease disease-related complications, including increased bone resorption, fractures, and muscle weakness.

Killestein J, Uitdehaag BM, Polman CH. · Department of Neurology, VU Medical Center, Amsterdam 1007 MB, The Netherlands. · Drugs. · Pubmed #14723555 No free full text.

Abstract: This is an exciting time for cannabinoid research. Evidence suggests that cannabis (marijuana) can alleviate symptoms like muscle spasticity and pain in patients with multiple sclerosis (MS). Interest in the field of cannabinoids has been strengthened by the identification and cloning of cannabinoid receptors located in the central nervous system and the peripheral immune organs, and by the discovery of the endogenous cannabinoid ligands. Cannabinoids are also efficacious in animal models of MS. However, there have been only ten published clinical reports on the use of cannabis in MS, involving 78 individuals worldwide, and the results have been equivocal. Researchers encounter a number of difficulties in designing clinical studies that use cannabinoids. From the studies reporting the use of cannabinoids in MS patients with spasticity, the somewhat better designed studies failed to demonstrate objective improvement. Therefore, convincing evidence that cannabinoids are effective in MS is still lacking.

Polman CH, Uitdehaag BM. · Department of Neurology, VU Medical Center, Amsterdam, Netherlands. · Lancet Neurol. · Pubmed #12941579 No free full text.

Abstract: BACKGROUND: The use of interferon beta and glatiramer acetate for the treatment of multiple sclerosis (MS) has, to some extent, changed the course of the disease. The annual relapse rate of patients treated with these drugs is lower than that in placebo-treated patients, and more treated patients remain relapse-free compared with untreated patients. In addition, these compounds reduce the development of new lesions, as detected by MRI. RECENT DEVELOPMENTS: The limited effectiveness of approved treatments for MS, as well as reports of adverse events and toxicity, emphasise the need for the development of new therapies with improved efficacy and fewer side-effects. Clinical observations, increased understanding of the underlying pathophysiology of the disease, and advances in biotechnology have led to several new therapeutic approaches to the treatment of MS that are currently under investigation. WHERE NEXT? Mitoxantrone has recently been shown to produce benefit when used to treat patients with progressive MS; it may also be an effective second-line treatment for patients who do not respond to interferon beta or glatiramer acetate. Over the past few years, several studies have drawn attention to the potential of natalizumab, alemtuzumab, statins, and oestrogens as effective treatments for MS. These drugs are at different stages of clinical development and additional clinical data are needed to support their use and devise dosage regimens. However, they are important and attractive candidates for several reasons: they counteract a fundamental and well-defined pathophysiological process; they have a less cumbersome route of administration than interferon beta and glatiramer acetate; or they have a remarkable safety record.

Polman CH, Uitdehaag BM. · Department of Neurology, Academic Hospital Vrije Universiteit, PO Box 7057, 1007 MB Amsterdam, Netherlands. · BMJ. · Pubmed #10948033 links to  free full text

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McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, McFarland HF, Paty DW, Polman CH, Reingold SC, Sandberg-Wollheim M, Sibley W, Thompson A, van den Noort S, Weinshenker BY, Wolinsky JS. · Royal College of Physicians, London, United Kingdom. · Ann Neurol. · Pubmed #11456302 No free full text.

Abstract: The International Panel on MS Diagnosis presents revised diagnostic criteria for multiple sclerosis (MS). The focus remains on the objective demonstration of dissemination of lesions in both time and space. Magnetic resonance imaging is integrated with dinical and other paraclinical diagnostic methods. The revised criteria facilitate the diagnosis of MS in patients with a variety of presentations, including "monosymptomatic" disease suggestive of MS, disease with a typical relapsing-remitting course, and disease with insidious progression, without clear attacks and remissions. Previously used terms such as "clinically definite" and "probable MS" are no longer recommended. The outcome of a diagnostic evaluation is either MS, "possible MS" (for those at risk for MS, but for whom diagnostic evaluation is equivocal), or "not MS."

Havrdova E, Galetta S, Hutchinson M, Stefoski D, Bates D, Polman CH, O'Connor PW, Giovannoni G, Phillips JT, Lublin FD, Pace A, Kim R, Hyde R. · Charles University in Prague, Department of Neurology, First Faculty of Medicine, Prague, Czech Republic. · Lancet Neurol. · Pubmed #19201654 No free full text.

Abstract: BACKGROUND: The efficacy of natalizumab on clinical and radiological measures in the phase III Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study has prompted the investigation of whether natalizumab can increase the proportion of patients with relapsing-remitting multiple sclerosis who do not have disease activity. METHODS: Post-hoc analyses of data from the AFFIRM study were done to determine the effects of natalizumab compared with placebo on the proportion of patients who were free of disease activity over 2 years. Absence of disease activity was defined as no activity on clinical measures (no relapses and no sustained disability progression), radiological measures (no gadolinium-enhancing lesions and no new or enlarging T2-hyperintense lesions on cranial MRI), or a composite of the two. FINDINGS: 383 (64%) of 596 patients taking natalizumab and 117 (39%) of 301 taking placebo were free of clinical disease activity (absolute difference 25.4%, 95% CI 18.7-32.1%, p<0.0001); 342 (58%) of 593 and 42 (14%) of 296 were free of radiological disease activity (43.5%, 37.9-49.1%, p<0.0001); and 220 (37%) of 600 and 22 (7%) of 304 were free of combined activity (29.5%, 24.7-34.3%, p<0.0001) over 2 years. The effect of natalizumab versus placebo was consistent across subgroups of patients with highly active or non-highly active disease at baseline. INTERPRETATION: Disease remission might become an increasingly attainable goal in multiple sclerosis treatment with the use of newer, more effective therapies.

Kappos L, Gold R, Miller DH, Macmanus DG, Havrdova E, Limmroth V, Polman CH, Schmierer K, Yousry TA, Yang M, Eraksoy M, Meluzinova E, Rektor I, Dawson KT, Sandrock AW, O'Neill GN, Anonymous00017. · University Hospital Basel, Basel, Switzerland. · Lancet. · Pubmed #18970976 No free full text.

Abstract: BACKGROUND: Oral fumarate (BG00012) might have dual anti-inflammatory and neuroprotective effects. Our aim was to assess the efficacy and safety of BG00012 in patients with relapsing-remitting multiple sclerosis. METHODS: 257 patients, aged 18-55 years, with relapsing-remitting multiple sclerosis were randomly assigned to receive 120 mg once daily (n=64), 120 mg three times daily (n=64), or 240 mg three times daily (n=64) BG00012, or placebo (n=65) for 24 weeks. During an extension period of 24 weeks for safety assessment, patients treated with placebo received BG00012 240 mg three times daily. The primary endpoint was total number of new gadolinium enhancing (GdE) lesions on brain MRI scans at weeks 12, 16, 20, and 24. Additional endpoints included cumulative number of new GdE lesions (weeks 4-24), new or enlarging T2-hyperintense lesions, new T1-hypointense lesions at week 24, and annualised relapse rate. Analysis was done on the efficacy-evaluable population. Safety and tolerability were also assessed. This study is registered with ClinicalTrials.gov, number NCT00168701. FINDINGS: Treatment with BG00012 240 mg three times daily reduced by 69% the mean total number of new GdE lesions from week 12 to 24 compared with placebo (1.4 vs 4.5, p<0.0001). It also reduced number of new or enlarging T2-hyperintense (p=0.0006) and new T1-hypointense (p=0.014) lesions compared with placebo. BG00012 reduced annualised relapse rate by 32% (0.44 vs 0.65 for placebo; p=0.272). Adverse events more common in patients given BG00012 than in those given placebo included abdominal pain, flushing, and hot flush. Dose-related adverse events in patients on BG00012 were headache, fatigue, and feeling hot. INTERPRETATION: The anti-inflammatory effects and favourable safety profile of BG00012 warrant further long-term phase III studies in large patient groups.

van der Voort LF, Kok A, Visser A, Oudejans CB, Caldano M, Gilli F, Bertolotto A, Polman CH, Killestein J. · Department of Neurology, VU University Medical Center, Amsterdam, The Netherlands. · Mult Scler. · Pubmed #18805837 No free full text.

Abstract: BACKGROUND: Neutralising antibodies (NAb) to interferon beta (IFN beta) are associated with a reduced bioactivity and efficacy of IFN beta in multiple sclerosis (MS). Unclear is how to apply IFN beta bioactivity measurements (quantification of Myxovirus resistance protein A (MxA) mRNA) in clinical practice. OBJECTIVES: To evaluate value and feasibility of IFN beta bioactivity measurement with a single MxA mRNA measurement for screening and a second measurement before and after IFN beta administration for definite confirmation of IFN beta bioactivity status. METHODS: In 79 MS patients MxA mRNA expression was determined 4 hours after IFN beta administration. If inadequate, MxA mRNA expression testing was repeated 3 months afterwards, comparing post- and pre injection samples to determine whether IFNb bioactivity was persistently lacking. MxA mRNA expression was compared to NA beta titres, determined by the cytopathic effect assay (CPE). RESULTS: NAb titres correlated significantly with MxA mRNA expression and MxA mRNA induction. Of all screened patients, only one patient had adequate MxA mRNA expression and high NAb titres simultaneously. Of the biological non-responders at second measurement (21/55), 17 (81%) were high-titre NAb positive, 1 (5%) was low-titre NAb positive and 3 (14%) were NAb negative. Without considering the pre-injection measurement, two more NAb negative patients would have tested negative for IFN beta bioactivity, emphasizing the need of a pre-injection sample. CONCLUSIONS: Our data suggest that for IFN beta bioactivity screening a single post-injection measurement seems reasonable. However, MxA induction measurement based on both pre- and post-IFN beta injection samples at second measurement is somewhat more precise in determining ultimate IFN beta bioactivity status.

Vellinga MM, Oude Engberink RD, Seewann A, Pouwels PJ, Wattjes MP, van der Pol SM, Pering C, Polman CH, de Vries HE, Geurts JJ, Barkhof F. · Department of Neurology, University Medical Centre, Amsterdam, The Netherlands. · Brain. · Pubmed #18245785 links to  free full text

Abstract: Gadolinium-DTPA (Gd-DTPA) is routinely used as a marker for inflammation in MRI to visualize breakdown of the blood-brain barrier (BBB) in multiple sclerosis. Recent data suggest that ultra-small superparamagnetic particles of iron oxide (USPIO) can be used to visualize cellular infiltration, another aspect of inflammation. This project aimed to compare the novel USPIO particle SHU555C to the longitudinal pattern of Gd-DTPA enhancement in multiple sclerosis. Nineteen relapsing-remitting patients were screened monthly using Gd-enhanced MRI. In case of new enhancing lesions, USPIO were injected and 24 h later, MRI was performed and blood was collected to confirm USPIO loading of circulating monocytes. Lesion development was monitored by 3 monthly Gd-DTPA-enhanced scans and a final scan 7-11 months after injection. USPIO-enhancement was observed as hyperintensity on T1-weighted images, whereas no signal changes were observed on T2-weighted-gradient-echo images. In 14 patients with disease activity, 188 USPIO-positive lesions were seen, 144 of which were Gd-negative. By contrast, there were a total of 59 Gd-positive lesions, 15 of which were USPIO negative. Three patterns of USPIO-enhancement were seen: (i) focal enhancement; (ii) ring-like enhancement and (iii) return to isointensity of a previously hypointense lesion. The latter pattern was most frequently observed for lesions that turned out to be transiently hypointense on follow-up scans, and ring-enhancing lesions were less likely to evolve into black holes at follow-up than lesions without ring-like USPIO-enhancement; we speculate this to be associated with repair. In 4% of the USPIO-positive/Gd negative lesions, USPIO-enhancement preceded Gd-enhancement by 1 month. USPIO-enhancement remained visible for up to 3 months in 1.5% of all USPIO-positive lesions. In 29% of the lesions enhancing with both contrast agents, USPIO-enhancement persisted whereas Gd-enhancement had already resolved. In conclusion, the new nano-particle SHU555C provides complementary information to Gd-enhanced MRI, probably related to monocyte infiltration. The use of USPIO-enhanced MRI is likely to lead to more insight in the pluriformity of inflammation in multiple sclerosis.