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1
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Cramer SP, Hamrouni N, Simonsen HJ, Vestergaard MB, Varatharaj A, Galea I, Lindberg U, Frederiksen JL, Larsson HBW. Insights from DCE-MRI: blood-brain barrier permeability in the context of MS relapses and methylprednisolone treatment. Front Neurosci 2025; 19:1546236. [PMID: 40182142 PMCID: PMC11966965 DOI: 10.3389/fnins.2025.1546236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Accepted: 03/03/2025] [Indexed: 04/05/2025] Open
Abstract
Background Detecting multiple sclerosis (MS) relapses remains challenging due to symptom variability and confounding factors, such as flare-ups and infections. Methylprednisolone (MP) is used for severe relapses, decreasing the number of contrast-enhancing lesions on MRI. The influx constant (Ki) derived from dynamic contrast-enhanced MRI (DCE-MRI), a marker of blood-brain barrier (BBB) permeability, has shown promise as a predictor of disease activity in relapsing-remitting MS (RRMS). Objectives To investigate the predictive value of Ki in relation to clinical MS relapses and MP treatment, comparing its performance with traditional MRI markers. Methods We studied 20 RRMS subjects admitted for possible relapse, using DCE-MRI on admission to assess Ki in normal-appearing white matter (NAWM) via the Patlak model. Mixed-effects modeling compared the predictive accuracy of Ki, the presence of contrast-enhancing lesions (CEL), evidence of brain lesions (EBL; defined as the presence of CEL or new T2 lesions), and MP treatment on clinical relapse events. Five models were evaluated, including combinations of Ki, CEL, EBL, and MP, to determine the most robust predictors of clinical relapse. Model performance was assessed using accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), with bootstrapped confidence intervals. Results Superior predictive accuracy was demonstrated with the inclusion of EBL and Ki, alongside MP treatment (AIC = 66.12, p = 0.006), outperforming other models with a classification accuracy of 83% (CI: 73-92%), sensitivity of 78% (CI: 60-94%), and specificity of 86% (CI: 74-97%). This model showed the highest combined PPV (78%, CI: 60-94%) and NPV (86%, CI: 74-98%) compared to models with EBL or CEL alone, suggesting an added value of Ki in enhancing predictive reliability. Conclusion These results support the use of Ki alongside conventional MRI imaging metrics, to improve clinical relapse prediction in RRMS. The findings underscore the utility of Ki as a marker of MS-related neuroinflammation, with potential for integration into relapse monitoring protocols. Further validation in larger cohorts is recommended to confirm the model's generalizability and clinical application.
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Affiliation(s)
- Stig P. Cramer
- Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark
| | - Nizar Hamrouni
- Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark
| | - Helle J. Simonsen
- Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark
| | - Mark B. Vestergaard
- Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark
| | - Aravinthan Varatharaj
- Clinical Neurosciences, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
- Wessex Neurological Centre, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom
| | - Ian Galea
- Clinical Neurosciences, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
- Wessex Neurological Centre, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom
| | - Ulrich Lindberg
- Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark
| | - Jette Lautrup Frederiksen
- Department of Neurology, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Henrik B. W. Larsson
- Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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Tatomir A, Anselmo F, Boodhoo D, Chen H, Mekala AP, Nguyen V, Cuevas J, Rus V, Rus H. Multiple sclerosis disease activity, a multi-biomarker score of disease activity and response to treatment in multiple sclerosis. Front Immunol 2024; 15:1338585. [PMID: 38994359 PMCID: PMC11236682 DOI: 10.3389/fimmu.2024.1338585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 06/17/2024] [Indexed: 07/13/2024] Open
Abstract
Regular assessment of disease activity in relapsing-remitting multiple sclerosis (RRMS) is required to optimize clinical outcomes. Biomarkers can be a valuable tool for measuring disease activity in multiple sclerosis (MS) if they reflect the pathological processes underlying MS pathogenicity. In this pilot study, we combined multiple biomarkers previously analyzed in RRMS patients into an MS disease activity (MSDA) score to evaluate their ability to predict relapses and treatment response to glatiramer acetate (GA). Response Gene to Complement 32 (RGC-32), FasL, IL-21, SIRT1, phosphorylated SIRT1 (p-SIRT1), and JNK1 p54 levels were used to generate cut-off values for each biomarker. Any value below the cutoff for RGC-32, FasL SIRT1, or p-SIRT1 or above the cutoff for IL-21 or JNK1 p54 was given a +1 value, indicating relapse or lack of response to GA. Any value above the cutoff value for RGC-32, FasL, SIRT1, p-SIRT1 or below that for IL-21 or JNK1 p54 was given a -1 value, indicating clinical stability or response to GA. An MSDA score above +1 indicated a relapse or lack of response to treatment. An MSDA score below -1 indicated clinical stability or response to treatment. Our results showed that the MSDA scores generated using either four or six biomarkers had a higher sensitivity and specificity and significantly correlated with the expanded disability status scale. Although these results suggest that the MSDA test can be useful for monitoring therapeutic response to biologic agents and assessing clinically challenging situations, the present findings need to be confirmed in larger studies.
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Affiliation(s)
- Alexandru Tatomir
- Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD, United States
- Neurology Department, Baltimore Veterans Administration Hospital, Baltimore, MD, United States
| | - Freidrich Anselmo
- Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD, United States
| | - Dallas Boodhoo
- Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD, United States
| | - Hegang Chen
- Department of Epidemiology and Public Health, University of Maryland, School of Medicine, Baltimore, MD, United States
| | - Armugam P. Mekala
- Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD, United States
| | - Vinh Nguyen
- Department of Medicine, Division of Rheumatology and Clinical Immunology, University of Maryland, School of Medicine, Baltimore, MD, United States
| | - Jacob Cuevas
- Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD, United States
| | - Violeta Rus
- Department of Medicine, Division of Rheumatology and Clinical Immunology, University of Maryland, School of Medicine, Baltimore, MD, United States
| | - Horea Rus
- Department of Neurology, University of Maryland, School of Medicine, Baltimore, MD, United States
- Neurology Department, Baltimore Veterans Administration Hospital, Baltimore, MD, United States
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Yang B, Yu N. Glucocorticoid-dependent multiple sclerosis overlapping anti-NMDA receptor encephalitis: a case report and literature review update. Neurol Sci 2024; 45:83-92. [PMID: 37721572 PMCID: PMC10761549 DOI: 10.1007/s10072-023-07034-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 08/21/2023] [Indexed: 09/19/2023]
Abstract
BACKGROUND Previous studies suggest a relationship between central nervous system inflammatory demyelinating diseases and anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis. Also, the overlap between anti-NMDAR encephalitis and multiple sclerosis (MS) has been reported. However, the pathogenesis and clinical characteristics are still obscure. CASE PRESENTATION A 33-year-old woman presented with diplopia and sensory ataxia at the onset. The cerebrospinal fluid (CSF) anti-NMDAR antibodies were positive (1:3.2), and nuclear magnetic resonance imaging (MRI) showed bilateral centrum ovale and lateral ventricle demyelinating lesions. Therefore, she was diagnosed with anti-NMDAR encephalitis. After administering intravenous immunoglobulin and oral prednisone, her lesions disappeared, and symptoms were relieved. The condition was maintained with a low dose of prednisone, but her lesions reappeared on MRI. Consequently, immunomodulatory therapy of mycophenolate mofetil was initiated. However, she developed dysarthria and right limb ataxia after 10 months with a positive CSF anti-NMDAR antibody (1:1) and positive oligoclonal band. The MRI showed symmetrical multiple demyelinating lesions. Considering the MS diagnosis, her neurological dysfunction again improved significantly after intravenous methylprednisolone. Unfortunately, her symptoms aggravated for the second time when teriflunomide was started. Finally, her condition was controlled again with oral prednisone. CONCLUSIONS Consistent with previous cases of overlapping anti-NMDAR encephalitis and MS, patients often show atypical symptoms on MRIs and immunological tests. The overlap cannot be arbitrarily treated because of the recurrence of previous diseases. Long-term follow-up, dynamic antibody monitoring, and MRI examination are crucial for these patients. The special dependency of the patient on glucocorticoids in this study has been rarely reported, which may guide the treatment of insensitivity to disease-modifying therapy in recurrent overlapping anti-NMDAR encephalitis and MS.
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Affiliation(s)
- Bo Yang
- Department of Center for Psychosomatic Medicine, Sichuan Provincial Center for Mental Health, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Nengwei Yu
- Department of Neurology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, No. 32 West Second Section of First Loop, Qingyang District, Chengdu City, Sichuan Province, China.
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Vesic K, Gavrilovic A, Mijailović NR, Borovcanin MM. Neuroimmune, clinical and treatment challenges in multiple sclerosis-related psychoses. World J Psychiatry 2023; 13:161-170. [PMID: 37123101 PMCID: PMC10130959 DOI: 10.5498/wjp.v13.i4.161] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 02/16/2023] [Accepted: 03/23/2023] [Indexed: 04/18/2023] Open
Abstract
In recent years, epidemiological and genetic studies have shown an association between autoimmune diseases and psychosis. The question arises whether patients with schizophrenia are more likely to develop multiple sclerosis (MS) later in life. It is well known that the immune system plays an important role in the etiopathogenesis of both disorders. Immune disturbances may be similar or very different in terms of different types of immune responses, disturbed myelination, and/or immunogenetic predispositions. A psychotic symptom may be a consequence of the MS diagnosis itself or a separate entity. In this review article, we discussed the timing of onset of psychotic symptoms and MS and whether the use of corticosteroids as therapy for acute relapses in MS is unfairly neglected in patients with psychiatric comorbidities. In addition, we discussed that the anti-inflammatory potential of antipsychotics could be useful and should be considered, especially in the treatment of psychosis that coexists with MS. Autoimmune disorders could precipitate psychotic symptoms, and in this context, autoimmune psychosis must be considered as a persistent symptomatology that requires continuous and specific treatment.
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Affiliation(s)
- Katarina Vesic
- Department of Neurology, University of Kragujevac, Faculty of Medical Sciences, Kragujevac 34000, Sumadija, Serbia
| | - Aleksandar Gavrilovic
- Department of Neurology, University of Kragujevac, Faculty of Medical Sciences, Kragujevac 34000, Sumadija, Serbia
| | - Nataša R Mijailović
- Department of Pharmacy, University of Kragujevac, Faculty of Medical Sciences, Kragujevac 34000, Sumadija, Serbia
| | - Milica M Borovcanin
- Department of Psychiatry, University of Kragujevac, Faculty of Medical Sciences, Kragujevac 34000, Sumadija, Serbia
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Bellucci G, Rinaldi V, Buscarinu MC, Reniè R, Bigi R, Pellicciari G, Morena E, Romano C, Marrone A, Mechelli R, Salvetti M, Ristori G. Multiple Sclerosis and SARS-CoV-2: Has the Interplay Started? Front Immunol 2021; 12:755333. [PMID: 34646278 PMCID: PMC8503550 DOI: 10.3389/fimmu.2021.755333] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Accepted: 09/03/2021] [Indexed: 12/11/2022] Open
Abstract
Current knowledge on Multiple Sclerosis (MS) etiopathogenesis encompasses complex interactions between the host's genetic background and several environmental factors that result in dysimmunity against the central nervous system. An old-aged association exists between MS and viral infections, capable of triggering and sustaining neuroinflammation through direct and indirect mechanisms. The novel Coronavirus, SARS-CoV-2, has a remarkable, and still not fully understood, impact on the immune system: the occurrence and severity of both acute COVID-19 and post-infectious chronic illness (long COVID-19) largely depends on the host's response to the infection, that echoes several aspects of MS pathobiology. Furthermore, other MS-associated viruses, such as the Epstein-Barr Virus (EBV) and Human Endogenous Retroviruses (HERVs), may enhance a mechanistic interplay with the novel Coronavirus, with the potential to interfere in MS natural history. Studies on COVID-19 in people with MS have helped clinicians in adjusting therapeutic strategies during the pandemic; similar efforts are being made for SARS-CoV-2 vaccination campaigns. In this Review, we look over 18 months of SARS-CoV-2 pandemic from the perspective of MS: we dissect neuroinflammatory and demyelinating mechanisms associated with COVID-19, summarize pathophysiological crossroads between MS and SARS-CoV-2 infection, and discuss present evidence on COVID-19 and its vaccination in people with MS.
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Affiliation(s)
- Gianmarco Bellucci
- Centre for Experimental Neurological Therapies (CENTERS), Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University of Rome, Rome, Italy
| | - Virginia Rinaldi
- Centre for Experimental Neurological Therapies (CENTERS), Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University of Rome, Rome, Italy
| | - Maria Chiara Buscarinu
- Centre for Experimental Neurological Therapies (CENTERS), Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University of Rome, Rome, Italy
- Neuroimmunology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, Rome, Italy
| | - Roberta Reniè
- Centre for Experimental Neurological Therapies (CENTERS), Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University of Rome, Rome, Italy
| | - Rachele Bigi
- Centre for Experimental Neurological Therapies (CENTERS), Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University of Rome, Rome, Italy
| | - Giulia Pellicciari
- Centre for Experimental Neurological Therapies (CENTERS), Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University of Rome, Rome, Italy
| | - Emanuele Morena
- Centre for Experimental Neurological Therapies (CENTERS), Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University of Rome, Rome, Italy
| | - Carmela Romano
- Centre for Experimental Neurological Therapies (CENTERS), Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University of Rome, Rome, Italy
| | - Antonio Marrone
- Centre for Experimental Neurological Therapies (CENTERS), Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University of Rome, Rome, Italy
| | - Rosella Mechelli
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Pisana, Rome, Italy
- San Raffaele Roma Open University, Rome, Italy
| | - Marco Salvetti
- Centre for Experimental Neurological Therapies (CENTERS), Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University of Rome, Rome, Italy
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Neurologico Mediterraneo Neuromed, Pozzilli, Italy
| | - Giovanni Ristori
- Centre for Experimental Neurological Therapies (CENTERS), Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University of Rome, Rome, Italy
- Neuroimmunology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Santa Lucia, Rome, Italy
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Wicks CR, Sloan R, DiMauro S, Thompson EL, Billington S, Webb M, Pepper G. Patients' experiences of self-identification, seeking support, and anticipation of potential relapse in multiple sclerosis. Mult Scler Relat Disord 2021; 56:103259. [PMID: 34628265 DOI: 10.1016/j.msard.2021.103259] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 08/17/2021] [Accepted: 09/06/2021] [Indexed: 11/26/2022]
Abstract
BACKGROUND Multiple sclerosis (MS) relapses are associated with increased disability, reduced quality of life and negative psychosocial impacts. However, they often go unrecognised; people with MS (MSers) may face barriers to self-identification of relapses or seeking support for them. The charity Shift.ms sought to better understand 1) MSers' challenges in self-identifying potential relapses, 2) where MSers' seek support for potential relapses, and 3) the impact of the anticipation of relapses on MSers' wellbeing and daily living. METHODS Shift.ms developed a patient perspective 8-question pilot survey (included likert-style, multiple-choice, and optional free-text responses) and shared it with Shift.ms' international online community (n = 20,052). Descriptive quantitative analysis, and content analysis and thematic analysis of qualitative free-text responses were used. RESULTS 1,737 MSers responded. Just under one third (29.9%) of MSers reported that it takes them 24 h or less to self-identify a potential relapse, while more than half (54.5%) reported that identification occurs within 48 h; 55% MSers felt that the "at least 24 h" clinical criterion of relapse classification was appropriate. Challenges to relapse self-identification included confounding background symptoms or infection, variability of relapse symptoms, and individualistic nature of MS. Fatigue was reported to be the most common symptom of relapse (75%), however fatigue was also the symptom most commonly mistaken for relapse (40%). Barriers to relapse self-identification were a shorter duration since MS diagnosis and a perceived lack of consensus around relapse classification. Respondents reported they most often seek relapse support/advice from healthcare professionals (HCPs) (37.1%), family/friends (32.1%), or not at all (16.9%). Rather than temporal criteria (i.e. the 24 h criterion), participants felt that severity of symptoms could play a more critical role in whether to seek support for a potential relapse. Barriers to seeking support/advice included variability in HCP advice and feelings of invalidation. Anticipation of relapses negatively impacted MSers wellbeing; led to reduced participation in activities, and the development of adjustment/coping strategies. Relapse triggers included stress, reduced self-care, infection/illness; 78.5% reported stress or anxiety had triggered relapse. CONCLUSIONS These findings highlight difficulties MSers face in self-identifying relapses, barriers to accessing support, and impact of anticipation of relapses. They also highlight opportunities for improved MSer and HCP communication, dialogue and two-way education to help optimise patient access to relapse support and intervention.
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Affiliation(s)
| | - Rob Sloan
- Shift.ms, Platform, New Station Street, Leeds, LS1 4JB, UK
| | - Sophie DiMauro
- Shift.ms, Platform, New Station Street, Leeds, LS1 4JB, UK
| | | | - Sam Billington
- Shift.ms, Platform, New Station Street, Leeds, LS1 4JB, UK
| | - Mark Webb
- Shift.ms, Platform, New Station Street, Leeds, LS1 4JB, UK
| | - George Pepper
- Shift.ms, Platform, New Station Street, Leeds, LS1 4JB, UK.
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Segamarchi C, Silva B, Saidon P, Garcea O, Alonso R. Would it be recommended treating multiple sclerosis relapses with high dose oral instead intravenous steroids during the COVID-19 pandemic? Yes. Mult Scler Relat Disord 2020; 46:102449. [PMID: 32853893 PMCID: PMC7440146 DOI: 10.1016/j.msard.2020.102449] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 08/10/2020] [Accepted: 08/12/2020] [Indexed: 01/08/2023]
Abstract
The emergence of novel Coronavirus 2019 and the subsequent pandemic are presenting a challenge to neurologists managing patients with multiple sclerosis (MS). The clinical management has dramatically altered and it was necessary to change and/or adapt it to the new situation. Regarding relapses management, the use of intravenous corticosteroids and hospitalization during MS relapses increase the risk of viral exposure. OBJECTIVE To review the efficacy and safety of high dose oral corticosteroids in acute relapses treatment compared to intravenous corticosteroids. METHODS Descriptive review of the utility of high dose oral corticosteroids for MS relapses treatment was performed. We searched the literature available on PubMed and Scientific Electronic Library Online (Scielo). We focused on different trials comparing the use of high dose intravenous vs oral corticosteroids. RESULTS Five studies were selected. One hundred and eighty two patients receiving treatment with high dose oral corticosteroids were included. The most frequent schedule was oral methylprednisolone 1000 mg (over three days). There were no significant differences between both routes of corticosteroids administration. CONCLUSION Neurologists should be aware of the current evidence on the similar efficacy of both oral and intravenous corticosteroids for MS relapses. Using oral steroids during the pandemic would be a safe option for patients.
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Affiliation(s)
- Constanza Segamarchi
- Servicio de Neurología. Hospital Ramos Mejía, Urquiza 609, Buenos Aires, Argentina
| | - Berenice Silva
- Centro Universitario de Esclerosis Múltiple, Hospital Ramos Mejía, Buenos Aires, Argentina
| | - Patricia Saidon
- Servicio de Neurología. Hospital Ramos Mejía, Urquiza 609, Buenos Aires, Argentina
| | - Orlando Garcea
- Centro Universitario de Esclerosis Múltiple, Hospital Ramos Mejía, Buenos Aires, Argentina
| | - Ricardo Alonso
- Centro Universitario de Esclerosis Múltiple, Hospital Ramos Mejía, Buenos Aires, Argentina; Hospital Universitario. Sanatorio Güemes, Buenos Aires, Argentina.
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Koudriavtseva T, Stefanile A, Fiorelli M, Lapucci C, Lorenzano S, Zannino S, Conti L, D'Agosto G, Pimpinelli F, Di Domenico EG, Mandoj C, Giannarelli D, Donzelli S, Blandino G, Salvetti M, Inglese M. Coagulation/Complement Activation and Cerebral Hypoperfusion in Relapsing-Remitting Multiple Sclerosis. Front Immunol 2020; 11:548604. [PMID: 33193314 PMCID: PMC7655134 DOI: 10.3389/fimmu.2020.548604] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 08/25/2020] [Indexed: 01/08/2023] Open
Abstract
Introduction Multiple sclerosis (MS) is a demyelinating disease of the central nervous system with an underlying immune-mediated and inflammatory pathogenesis. Innate immunity, in addition to the adaptive immune system, plays a relevant role in MS pathogenesis. It represents the immediate non-specific defense against infections through the intrinsic effector mechanism “immunothrombosis” linking inflammation and coagulation. Moreover, decreased cerebral blood volume (CBV), cerebral blood flow (CBF), and prolonged mean transit time (MTT) have been widely demonstrated by MRI in MS patients. We hypothesized that coagulation/complement and platelet activation during MS relapse, likely during viral infections, could be related to CBF decrease. Our specific aims are to evaluate whether there are differences in serum/plasma levels of coagulation/complement factors between relapsing-remitting (RR) MS patients (RRMS) in relapse and those in remission and healthy controls as well as to assess whether brain hemodynamic changes detected by MRI occur in relapse compared with remission. This will allow us to correlate coagulation status with perfusion and demographic/clinical features in MS patients. Materials and Methods This is a multi-center, prospective, controlled study. RRMS patients (1° group: 30 patients in relapse; 2° group: 30 patients in remission) and age/sex-matched controls (3° group: 30 subjects) will be enrolled in the study. Patients and controls will be tested for either coagulation/complement (C3, C4, C4a, C9, PT, aPTT, fibrinogen, factor II, VIII, and X, D-dimer, antithrombin, protein C, protein S, von-Willebrand factor), soluble markers of endothelial damage (thrombomodulin, Endothelial Protein C Receptor), antiphospholipid antibodies, lupus anticoagulant, complete blood count, viral serological assays, or microRNA microarray. Patients will undergo dynamic susceptibility contrast-enhanced MRI using a 3.0-T scanner to evaluate CBF, CBV, MTT, lesion number, and volume. Statistical Analysis ANOVA and unpaired t-tests will be used. The level of significance was set at p ≤ 0.05. Discussion Identifying a link between activation of coagulation/complement system and cerebral hypoperfusion could improve the identification of novel molecular and/or imaging biomarkers and targets, leading to the development of new effective therapeutic strategies in MS. Clinical Trial Registration Clinicaltrials.gov, identifier NCT04380220.
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Affiliation(s)
- Tatiana Koudriavtseva
- Department of Clinical Experimental Oncology, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Annunziata Stefanile
- Department of Clinical Experimental Oncology, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Marco Fiorelli
- Department of Human Neurosciences, Sapienza University of Rome, Rome, Italy
| | - Caterina Lapucci
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy
| | - Svetlana Lorenzano
- Department of Human Neurosciences, Sapienza University of Rome, Rome, Italy
| | - Silvana Zannino
- Department of Clinical Experimental Oncology, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Laura Conti
- Department of Clinical Experimental Oncology, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Giovanna D'Agosto
- Clinical Pathology and Microbiology Unit, IRCC San Gallicano Institute, Rome, Italy
| | - Fulvia Pimpinelli
- Clinical Pathology and Microbiology Unit, IRCC San Gallicano Institute, Rome, Italy
| | | | - Chiara Mandoj
- Department of Clinical Experimental Oncology, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Diana Giannarelli
- Biostatistics, Scientific Direction, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Sara Donzelli
- Oncogenomic and Epigenetic Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Giovanni Blandino
- Oncogenomic and Epigenetic Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Marco Salvetti
- Department of Neuroscience Mental Health and Sensory Organs (NEMOS), Sapienza University, Sant'Andrea Hospital, Rome, Italy
| | - Matilde Inglese
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy.,Department of Neurology, Radiology and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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9
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Rodríguez de Antonio LA, García Castañón I, Aguilar-Amat Prior MJ, Puertas I, González Suárez I, Oreja Guevara C. Non-inflammatory causes of emergency consultation in patients with multiple sclerosis. NEUROLOGÍA (ENGLISH EDITION) 2020; 36:403-411. [PMID: 34238522 DOI: 10.1016/j.nrleng.2018.02.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Accepted: 02/26/2018] [Indexed: 11/16/2022] Open
Abstract
OBJECTIVES To describe non-relapse-related emergency consultations of patients with multiple sclerosis (MS): causes, difficulties in the diagnosis, clinical characteristics, and treatments administered. METHODS We performed a retrospective study of patients who attended a multiple sclerosis day hospital due to suspected relapse and received an alternative diagnosis, over a 2-year period. Demographic data, clinical characteristics, final diagnosis, and treatments administered were evaluated. Patients who were initially diagnosed with pseudo-relapse and ultimately diagnosed with true relapse were evaluated specifically. As an exploratory analysis, patients who consulted with non-inflammatory causes were compared with a randomly selected cohort of patients with true relapses who attended the centre in the same period. RESULTS The study included 50 patients (33 were women; mean age 41.4 ± 11.7 years). Four patients (8%) were initially diagnosed with pseudo-relapse and later diagnosed as having a true relapse. Fever and vertigo were the main confounding factors. The non-inflammatory causes of emergency consultation were: neurological, 43.5% (20 patients); infectious, 15.2% (7); psychiatric, 10.9% (5); vertigo, 8.6% (4); trauma, 10.9% (5); and miscellaneous, 10.9% (5). CONCLUSIONS MS-related symptoms constituted the most frequent cause of non-inflammatory emergency consultations. Close follow-up of relapse and pseudo-relapse is necessary to detect incorrect initial diagnoses, avoid unnecessary treatments, and relieve patients' symptoms.
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Affiliation(s)
| | - I García Castañón
- Servicio de Neurología, Hospital Universitario de Fuenlabrada, Fuenlabrada, Madrid, Spain
| | | | - I Puertas
- Servicio de Neurología, Hospital Universitario La Paz, Madrid, Spain
| | - I González Suárez
- Servicio de Neurología, Complejo Hospitalario Universitario de Vigo, Vigo, Pontevedra, Spain
| | - C Oreja Guevara
- Servicio de Neurología, Hospital Clínico Universitario San Carlos, Madrid, Spain
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Ali A, Asif M, Rizvi A, Farhan M, Zaman S. Discovery of a novel oxadiazine derivative of glucocorticoids endowed with DNA binding activities and molecular docking studies. JOURNAL OF TAIBAH UNIVERSITY FOR SCIENCE 2019. [DOI: 10.1080/16583655.2019.1603575] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Affiliation(s)
- Abad Ali
- Steroid Research Laboratory, Department of Chemistry, Aligarh Muslim University, Aligarh, India
- Organometallic Synthesis and Catalysis Group, Chemical Engineering Division, CSIR-National Chemical Laboratory (CSIR-NCL), Pune, India
| | - Mohd Asif
- Steroid Research Laboratory, Department of Chemistry, Aligarh Muslim University, Aligarh, India
| | - Asim Rizvi
- Department of Biochemistry, Aligarh Muslim University, Aligarh, India
| | - Mohd Farhan
- Department of Biochemistry, Aligarh Muslim University, Aligarh, India
| | - Shamsuz Zaman
- Steroid Research Laboratory, Department of Chemistry, Aligarh Muslim University, Aligarh, India
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Nazareth T, Datar M, Yu TC. Treatment Effectiveness for Resolution of Multiple Sclerosis Relapse in a US Health Plan Population. Neurol Ther 2019; 8:383-395. [PMID: 31564036 PMCID: PMC6858912 DOI: 10.1007/s40120-019-00156-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Indexed: 11/15/2022] Open
Abstract
INTRODUCTION Timely and effective resolution of multiple sclerosis (MS) relapse is critical to minimizing residual deficits, which can result in neurologic disability. Oral corticosteroids (OCS) and intravenous corticosteroids [intravenous methylprednisolone (IVMP)] are earlier line treatments; alternatives include repository corticotropin injection (RCI; H.P. Acthar® Gel), plasmapheresis (PMP), and intravenous immunoglobulin (IVIG). Contemporary insight into the use of relapse treatments and their effectiveness is needed. OBJECTIVE To evaluate relapse rates, frequency of treatments used, and treatment effectiveness (i.e., relapse resolution). METHODS A retrospective analysis of patients ages 18-89 years experiencing MS relapse from 1 January 2008 to 30 June 2015 was conducted using administrative claims data. MS relapse was defined based on established claims-based methodology. The first claim for relapse treatment (i.e., prescription or administration) was used to designate the treatment group and relapse date, respectively. Relapses occurring ≤ 30 days were considered an episode. The first relapse episode was identified for every patient. Treatment was deemed effective in resolving the relapse if no additional relapses followed within the episode; otherwise, the relapse was considered unresolved. A 5-day OCS taper following IVMP administration, designated IVMP ± OCS, was allowed. Relapse frequency, treatment use, and relapse resolution were quantified. Relapse resolution was likewise evaluated in patients continuously enrolled for 12 months before and after first treatment with RCI or PMP/IVIG, with PMP/IVIG administrations within 7 days of each other being considered a single course of therapy. RESULTS During the study period, 9574 patients experienced ≥ 1 relapse; 26.0% of patients had ≥ 2 relapses/year. The mean number of relapse episodes was 2.6 over a mean follow-up of 2.7 years for an annualized relapse rate of 1.0. Corticosteroids were the first treatment used in 90.4% of relapses (OCS = 51.8%, IVMP = 38.6%), followed by IVIG (6.0%), RCI (2.2%) and PMP (1.5%). The proportion of patients achieving relapse resolution with their first treatment was 90.5% with OCS (n = 5710), 47.8% with IVMP ± OCS (n = 3425), 96.9% with RCI (n = 195), 50.7% with PMP (n = 73), and 43.9% with IVIG (n = 171). Among continuously enrolled patients (n = 373), relapse resolution was 95.7% with RCI (n = 232) and 66.0% with PMP/IVIG (n = 141); significant cohort differences were observed. CONCLUSIONS As demonstrated in other studies, OCS were generally effective. However, real-world effectiveness varied with other treatments. Relapse resolution of the first treatment with OCS was higher than with IVMP ± OCS; similarly, relapse resolution was higher with RCI as the first treatment than with PMP/IVIG. Results demonstrate RCI's effectiveness in appropriate patients. Limitations pertaining to claims-based research apply. FUNDING Mallinckrodt Pharmaceuticals (Bedminster, NJ).
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Affiliation(s)
| | - Manasi Datar
- Comprehensive Health Insights (CHI), Humana, Louisville, KY, USA
| | - Tzy-Chyi Yu
- Mallinckrodt Pharmaceuticals, Bedminster, NJ, USA.
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Carillo KD, Wu D, Lin SC, Tsai SL, Shie JJ, Tzou DLM. Magnesium and calcium reveal different chelating effects in a steroid compound: A model study of prednisolone using NMR spectroscopy. Steroids 2019; 150:108429. [PMID: 31229509 DOI: 10.1016/j.steroids.2019.108429] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 05/16/2019] [Accepted: 06/17/2019] [Indexed: 11/21/2022]
Abstract
In this work, we used high resolution NMR spectroscopy to investigate metal cation chelation by the steroidal drug 1,4-pregnadiene-11β,17α,21-triol-3,20-dione (Prednisolone; abbreviated as Prd). Prd/MgCl2 and Prd/CaCl2 mixtures were prepared at eight different molar ratios. Using two-dimensional 1H/13C heteronuclear correlation spectroscopy, we were able to resolve most of the 1H signals, except those at 1.4-1.55 ppm, where signals for H15β, H16α and Me-19 are superimposed. The chelation sites were determined by the cation concentration-dependent 13C signals. Both ring A and ring D of Prd were found to be involved in Mg2+ chelation, whereas only ring A was involved in Ca2+ chelation. The dihedral angles deduced from the 3JH-H coupling constants indicated that ring D of Prd might undergo rather small, but different, distortions in the presence of Mg2+ and Ca2+. Additionally, using the continuous variation method, we deduced that the stoichiometric ratios of the Prd/Mg2+ and Prd/Ca2+ complexes were 1:1 and 2:1, respectively. All of the evidence led us to conclude that the Prd/Mg2+ and Prd/Ca2+ complexes are mediated by different chelating mechanisms.
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Affiliation(s)
- Kathleen D Carillo
- International Graduate Program, SCST, Academia Sinica, Nankang, Taipei 11529, Taiwan, ROC; The Department of Applied Chemistry, National Chiao-Tung University, Hsinchu 30013, Taiwan, ROC; Institute of Chemistry, Academia Sinica, Nankang, Taipei 11529, Taiwan, ROC
| | - Danni Wu
- Institute of Chemistry, Academia Sinica, Nankang, Taipei 11529, Taiwan, ROC
| | - Su-Ching Lin
- Institute of Chemistry, Academia Sinica, Nankang, Taipei 11529, Taiwan, ROC
| | - Shen-Long Tsai
- Chemical Engineering Department of NTUST, Taipei 10607, Taiwan, ROC
| | - Jiun-Jie Shie
- Institute of Chemistry, Academia Sinica, Nankang, Taipei 11529, Taiwan, ROC
| | - Der-Lii M Tzou
- Institute of Chemistry, Academia Sinica, Nankang, Taipei 11529, Taiwan, ROC; Department of Applied Chemistry, National Chia-Yi University, Chia-Yi 60004, Taiwan, ROC.
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13
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Historical and Current Concepts Regarding Urodynamics in Multiple Sclerosis Patients. CURRENT BLADDER DYSFUNCTION REPORTS 2019. [DOI: 10.1007/s11884-019-00525-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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14
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Kutz CF, Dix AL. Repository corticotropin injection in multiple sclerosis: an update. Neurodegener Dis Manag 2018; 8:217-225. [PMID: 29869572 DOI: 10.2217/nmt-2018-0008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Relapse management is a crucial component of multiple sclerosis care. Acute relapses are defined as new neurological symptoms or worsening of existing symptoms persisting for >24 h that are not attributable to heat, overexertion, or infection. The most commonly used treatment for multiple sclerosis relapse is a 3-5-day course of corticosteroids, primarily intravenous methylprednisolone with or without oral steroid taper. Repository corticotropin injection is also the US FDA-approved option for managing acute relapse, particularly in the patients with inadequate response, intolerability or allergy to corticosteroid treatment; poor venous access; or limited ability to receive home or clinic infusions.
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Affiliation(s)
- Christen F Kutz
- Colorado Springs Neurological Associates, 2312 N. Nevada Avenue, Colorado Springs, CO 80907, USA
| | - Amy L Dix
- Kansas City Multiple Sclerosis Center College Park Neurology, 10600 Mastin, Overland Park, KS 66208, USA
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Abstract
OBJECTIVES To describe non-relapse-related emergency consultations of patients with multiple sclerosis (MS): causes, difficulties in the diagnosis, clinical characteristics, and treatments administered. METHODS We performed a retrospective study of patients who attended a multiple sclerosis day hospital due to suspected relapse and received an alternative diagnosis, over a 2-year period. Demographic data, clinical characteristics, final diagnosis, and treatments administered were evaluated. Patients who were initially diagnosed with pseudo-relapse and ultimately diagnosed with true relapse were evaluated specifically. As an exploratory analysis, patients who consulted with non-inflammatory causes were compared with a randomly selected cohort of patients with true relapses who attended the centre in the same period. RESULTS The study included 50 patients (33 were women; mean age 41.4±11.7years). Four patients (8%) were initially diagnosed with pseudo-relapse and later diagnosed as having a true relapse. Fever and vertigo were the main confounding factors. The non-inflammatory causes of emergency consultation were: neurological, 43.5% (20 patients); infectious, 15.2% (7); psychiatric, 10.9% (5); vertigo, 8.6% (4); trauma, 10.9% (5); and miscellaneous, 10.9% (5). CONCLUSIONS MS-related symptoms constituted the most frequent cause of non-inflammatory emergency consultations. Close follow-up of relapse and pseudo-relapse is necessary to detect incorrect initial diagnoses, avoid unnecessary treatments, and relieve patients' symptoms.
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Kumar D, Singh H, Shrivastav TG. Homologous ELISA for detection of prednisolone in human serum. FOOD AGR IMMUNOL 2017. [DOI: 10.1080/09540105.2017.1376184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
Affiliation(s)
- Dinesh Kumar
- Immuno, Isotope and Nano-technology Laboratory, Department of Reproductive Biomedicine, The National Institute of Health and Family Welfare (NIHFW), New Delhi, India
- Indian Institute of Technology Delhi (IIT-D), New Delhi, India
- All India Institute of Medical Sciences Delhi (AIIMS-D), New Delhi, India
| | - Harpal Singh
- Indian Institute of Technology Delhi (IIT-D), New Delhi, India
- All India Institute of Medical Sciences Delhi (AIIMS-D), New Delhi, India
| | - T. G. Shrivastav
- Immuno, Isotope and Nano-technology Laboratory, Department of Reproductive Biomedicine, The National Institute of Health and Family Welfare (NIHFW), New Delhi, India
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Gandomi N, Varshochian R, Atyabi F, Ghahremani MH, Sharifzadeh M, Amini M, Dinarvand R. Solid lipid nanoparticles surface modified with anti-Contactin-2 or anti-Neurofascin for brain-targeted delivery of medicines. Pharm Dev Technol 2017; 22:426-435. [DOI: 10.1080/10837450.2016.1226901] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Affiliation(s)
- Nargess Gandomi
- Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Reyhaneh Varshochian
- Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Atyabi
- Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hossein Ghahremani
- Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Sharifzadeh
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohsen Amini
- Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Rassoul Dinarvand
- Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
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Pakpoor J, Saylor D, Izbudak I, Liu L, Mowry EM, Yousem DM. Emergency Department MRI Scanning of Patients with Multiple Sclerosis: Worthwhile or Wasteful? AJNR Am J Neuroradiol 2017; 38:12-17. [PMID: 27758773 DOI: 10.3174/ajnr.a4953] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2016] [Accepted: 08/11/2016] [Indexed: 11/07/2022]
Abstract
BACKGROUND AND PURPOSE The increasing use of the emergency department MR imaging scanner at our institution raises questions about its added value to certain patient groups. We hypothesized that the use of emergency department MR imaging for identifying active demyelination in MS patients presenting with new neurologic symptoms would be of low yield. MATERIALS AND METHODS Electronic medical records were reviewed for patients with MS who had emergency department MR imaging scans for a suspected MS exacerbation between March 1, 2014, and March 1, 2016. Details surrounding patient disposition, imaging, diagnosis, and management were determined. RESULTS Of 115 patients in our study, 48 (41.7%) were ultimately diagnosed with an MS exacerbation. Nearly all patients with MS exacerbations (87.5%, 42/48) had active demyelination on their emergency department MR imaging, identified on 30.6% (33/108) of brain MRIs and 20.4% (19/93) of spinal MRIs. The presence of active demyelination at MRI was significantly associated with the ultimate diagnosis of an MS exacerbation (P < .001). MR imaging activity isolated to the spinal cord (ie, not found on concurrent brain MR imaging) was present in only 9 of 93 (9.7%) cases. Pseudoexacerbations accounted for 18 of the alternative diagnoses. CONCLUSIONS Emergency department MR imaging is a worthwhile endeavor from a diagnostic standpoint for MS exacerbations despite not being part of the diagnostic criteria. This finding has corresponding downstream impact on management decisions to admit and/or administer intravenous steroids. However, we raise the question of whether clinicians over-rely on emergency department imaging for making exacerbation diagnoses. Additionally, spinal MR imaging is of questionable value as an addition to brain MR imaging due to a low yield of isolated spinal disease.
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Affiliation(s)
- J Pakpoor
- From the Division of Neuroradiology (J.P., I.I., L.L., D.M.Y.), Russell H. Morgan Department of Radiology and Radiological Science
| | - D Saylor
- Department of Neurology (D.S., E.M.M.), Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - I Izbudak
- From the Division of Neuroradiology (J.P., I.I., L.L., D.M.Y.), Russell H. Morgan Department of Radiology and Radiological Science
| | - L Liu
- From the Division of Neuroradiology (J.P., I.I., L.L., D.M.Y.), Russell H. Morgan Department of Radiology and Radiological Science
| | - E M Mowry
- Department of Neurology (D.S., E.M.M.), Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - D M Yousem
- From the Division of Neuroradiology (J.P., I.I., L.L., D.M.Y.), Russell H. Morgan Department of Radiology and Radiological Science
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Podkowa A, Miller RJ, Motl RW, Fish R, Oelze ML. Focused Ultrasound Treatment of Cervical Lymph Nodes in Rats with EAE: A Pilot Study. ULTRASOUND IN MEDICINE & BIOLOGY 2016; 42:2957-2964. [PMID: 27639434 DOI: 10.1016/j.ultrasmedbio.2016.08.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Revised: 07/18/2016] [Accepted: 08/02/2016] [Indexed: 06/06/2023]
Abstract
In this pilot study, focused ultrasound (FUS) was used to produce hyperthermia in cervical lymph nodes of rats having experimental autoimmune encephalomyelitis (EAE) to alleviate symptoms associated with EAE. EAE was induced in dark agouti rats, and EAE scores were recorded over 21 d. At the onset of EAE symptoms, rats were treated with FUS to induce temperatures of 43-44°C for 20 min in the superficial cervical lymph nodes. An EAE remittance score was tallied for all rats, defined as the maximum EAE score observed minus the minimum EAE score observed after the maximum EAE was reached. On average, the peak remittance score for FUS-treated rats was 1.14 ± 0.48 versus 0.33 ± 0.27 for sham-treated rats. These differences were statistically significant (p = 0.037). Therefore, FUS treatment of cervical lymph nodes in rats with EAE resulted in a significant reduction in EAE score.
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Affiliation(s)
- Anthony Podkowa
- Bioacoustics Research Laboratory, Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Rita J Miller
- Bioacoustics Research Laboratory, Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Robert W Motl
- Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Raymond Fish
- Bioacoustics Research Laboratory, Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Michael L Oelze
- Bioacoustics Research Laboratory, Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
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Carillo KD, Arco S, Wang CC, Tzou DLM. Solid-state NMR investigation of effect of fluorination and methylation on prednisolone conformation. Steroids 2015; 104:263-9. [PMID: 26476185 DOI: 10.1016/j.steroids.2015.10.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2015] [Revised: 09/11/2015] [Accepted: 10/12/2015] [Indexed: 10/22/2022]
Abstract
Prednisolone (Prd) is a polymorphous synthetic corticosteroid that has three crystalline forms mediated by different solvents. In this study, we have demonstrated that solid-state {(1)H}(13)C cross-polarization/magic angle spinning (CP/MAS) NMR spectroscopy is able to resolve the effects of methylation and fluorination on the conformation of the steroidal rings in Prd. Two compounds were chosen for the study, 6-α-methylprednisolone (Prd-6M) and 6-α-fluoroprednisolone (Prd-6F). The (13)C signals of Prd-6F showed primarily doublet patterns, with splittings of 40-380 Hz, indicating multiple ring conformations, whereas the (13)C signals of Prd and Prd-6M exhibited a singlet pattern, indicating a unique conformation. Using evidence from chemical shift deviation and anisotropy analysis, we have demonstrated by solid-state NMR that Prd-6F adopts two different steroidal ring conformations that are different from that of Prd-6M, and less similar to that of unsubstituted Prd.
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Affiliation(s)
- Kathleen D Carillo
- University of the Philippines Diliman, Diliman, Quezon City 1100, Philippines; Institute of Chemistry, Academia Sinica, Nankang, Taipei 11529, Taiwan, ROC
| | - Susan Arco
- University of the Philippines Diliman, Diliman, Quezon City 1100, Philippines
| | - Cheng-Chung Wang
- Institute of Chemistry, Academia Sinica, Nankang, Taipei 11529, Taiwan, ROC
| | - Der-Lii M Tzou
- Institute of Chemistry, Academia Sinica, Nankang, Taipei 11529, Taiwan, ROC.
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Ross AP, Halper J, Harris CJ. Assessing relapses and response to relapse treatment in patients with multiple sclerosis: a nursing perspective. Int J MS Care 2014; 14:148-59. [PMID: 24453746 DOI: 10.7224/1537-2073-14.3.148] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
There are currently no assessment tools that focus on evaluating patients with multiple sclerosis (MS) who are experiencing a relapse or that evaluate patients' response to acute relapse treatment. In practice, assessments are often subjective, potentially resulting in overlooked symptoms, unaddressed patient concerns, unnoticed or underrecognized side effects of therapies (both disease modifying and symptomatic), and suboptimal therapeutic response. Systematic evaluation of specific symptoms and potential side effects can minimize the likelihood of overlooking important information. However, given the number of potential symptoms and adverse events that patients may experience, an exhaustive evaluation can be time-consuming. Clinicians are thus challenged to balance thoroughness with brevity. A need exists for a brief but comprehensive objective assessment tool that can be used in practice to 1) help clinicians assess patients when they present with symptoms of a relapse, and 2) evaluate outcomes of acute management. A working group of expert nurses convened to discuss recognition and management of relapses. In this article, we review data related to recognition and management of relapses, discuss practical challenges, and describe the development of an assessment questionnaire that evaluates relapse symptoms, the impact of symptoms on the patient, and the effectiveness and tolerability of acute treatment. The questionnaire is designed to be appropriate for use in MS specialty clinics, general neurology practices, or other practice settings and can be administered by nurses, physicians, other clinicians, or patients (self-evaluation). The relapse assessment questionnaire is currently being piloted in a number of practice settings.
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Affiliation(s)
- Amy Perrin Ross
- Department of Neurosciences, Loyola University Chicago, Chicago, IL, USA (APR); Consortium of Multiple Sclerosis Centers, Hackensack, NJ, USA (JH); and Department of Clinical Neurosciences-Multiple Sclerosis Clinic, University of Calgary, Alberta, Canada (CJH)
| | - June Halper
- Department of Neurosciences, Loyola University Chicago, Chicago, IL, USA (APR); Consortium of Multiple Sclerosis Centers, Hackensack, NJ, USA (JH); and Department of Clinical Neurosciences-Multiple Sclerosis Clinic, University of Calgary, Alberta, Canada (CJH)
| | - Colleen J Harris
- Department of Neurosciences, Loyola University Chicago, Chicago, IL, USA (APR); Consortium of Multiple Sclerosis Centers, Hackensack, NJ, USA (JH); and Department of Clinical Neurosciences-Multiple Sclerosis Clinic, University of Calgary, Alberta, Canada (CJH)
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Abstract
OBJECTIVE To determine the short-term safety of high-dose intravenous methylprednisolone in acute attacks of multiple sclerosis (MS). METHOD In a prospective study, we evaluated the patients with MS who received high-dose intravenous methylprednisolone for acute attacks. By repeated physical and laboratory examinations and history taking, patients were assessed for adverse effects that would be related to pulse therapy before, within, and 3 months after the treatment. RESULTS Sixty-four patients with definite MS with acute attack were enrolled in the study in which 46 (71.9%) were female. Fifty-eight patients (90.6%) developed minor adverse effects of which the most common were palpitation, flashing, dyspepsia, insomnia, and virulent taste. On the other hand, 12 patients (18.75%) developed major adverse effects, and the most common was sinus tachycardia. Six patients (9.3%) were without any adverse effects. There was a significant relationship between the dosage of methylprednisolone (3 or 5 g) and the occurrence of major adverse effects (P = 0.025). CONCLUSION This study approved that high-dose intravenous methylprednisolone is a safe treatment in MS attacks and the short-term adverse effects were mostly minor and transient.
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Marcus JF, Waubant EL. Updates on clinically isolated syndrome and diagnostic criteria for multiple sclerosis. Neurohospitalist 2013; 3:65-80. [PMID: 23983889 DOI: 10.1177/1941874412457183] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Clinically isolated syndrome (CIS) is a central nervous system demyelinating event isolated in time that is compatible with the possible future development of multiple sclerosis (MS). Early risk stratification for conversion to MS helps with treatment decisions. Magnetic resonance imaging (MRI) is currently the most useful tool to evaluate risk. Cerebrospinal fluid studies and evoked potentials may also be used to assess the likelihood of MS. Four clinical trials evaluating the benefits of either interferon β (IFN-β) or glatiramer acetate (GA) within the first 3 months after a high-risk CIS demonstrate decreased rates of conversion to clinically definite MS (CDMS) and a lesser degree of MRI progression with early treatment. In the 3-, 5-, and 10-year extension studies of 2 formulations of IFN-β, the decreased conversion rate to CDMS remained meaningful when comparing early treatment of CIS to treatment delayed by a median of 2 to 3 years. Diagnostic criteria have been developed based on the clinical and MRI follow-up of large cohorts with CIS and provide guidance on how to utilize clinical activity in combination with radiographic information to diagnose MS. The most recent 2010 McDonald criteria simplify requirements for dissemination in time and space and allow for diagnosis of MS from a baseline brain MRI if there are both silent gadolinium-enhancing lesions and nonenhancing lesions on the same imaging study. The diagnostic criteria for MS require special consideration in children at risk for acute disseminated encephalomyelitis (ADEM), in older adults who may have small vessel ischemic disease, and in ethnic groups that more commonly develop neuromyelitis optica (NMO).
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Abstract
In this era of the Patient Centered Medical Home model of care, chronic diseases such as multiple sclerosis (MS) are managed in partnership with specialty care practices. For the patient and family living with MS, assuring that patients get proper care when and where they need it requires that nurse practitioners understand their role in assessing and managing complex chronic diseases.
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Ross AP, Ben-Zacharia A, Harris C, Smrtka J. Multiple sclerosis, relapses, and the mechanism of action of adrenocorticotropic hormone. Front Neurol 2013; 4:21. [PMID: 23482896 PMCID: PMC3591751 DOI: 10.3389/fneur.2013.00021] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2012] [Accepted: 02/13/2013] [Indexed: 12/27/2022] Open
Abstract
Relapses in multiple sclerosis (MS) are disruptive and frequently disabling for patients, and their treatment is often a challenge to clinicians. Despite progress in the understanding of the pathophysiology of MS and development of new treatments for long-term management of MS, options for treating relapses have not changed substantially over the past few decades. Corticosteroids, a component of the hypothalamic-pituitary-adrenal axis that modulate immune responses and reduce inflammation, are currently the mainstay of relapse treatment. Adrenocorticotropic hormone (ACTH) gel is another treatment option. Although it has long been assumed that the efficacy of ACTH in treating relapses depends on the peptide’s ability to increase endogenous corticosteroid production, evidence from research on the melanocortin system suggests that steroidogenesis may only partly account for ACTH influences. Indeed, the melanocortin peptides [ACTH and α-, β-, γ-melanocyte-stimulating hormones (MSH)] and their receptors (Melanocortin receptors, MCRs) exert multiple actions, including modulation of inflammatory and immune mediator production. MCRs are widely distributed within the central nervous system and in peripheral tissues including immune cells (e.g., macrophages). This suggests that the mechanism of action of ACTH includes not only steroid-mediated indirect effects, but also direct anti-inflammatory and immune-modulating actions via the melanocortin system. An increased understanding of the role of the melanocortin system, particularly ACTH, in the immune and inflammatory processes underlying relapses may help to improve relapse management.
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Affiliation(s)
- Amy Perrin Ross
- Department of Neurosciences, Loyola University Chicago Chicago, IL, USA
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Borisow N, Döring A, Pfueller CF, Paul F, Dörr J, Hellwig K. Expert recommendations to personalization of medical approaches in treatment of multiple sclerosis: an overview of family planning and pregnancy. EPMA J 2012; 3:9. [PMID: 22738272 PMCID: PMC3464716 DOI: 10.1186/1878-5085-3-9] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2012] [Accepted: 06/22/2012] [Indexed: 12/18/2022]
Abstract
Multiple sclerosis is the most common chronic autoimmune disease of the central nervous system which preferentially affects females at childbearing age. For this reason, patients and treating physicians were frequently confronted with questions concerning family planning, pregnancy and birth. Preventive and personalized treatment approaches are considered, because topics as heredity, risk of congenital malformations, influence of pregnancy on MS and aspects of drug therapy during the period of conception, pregnancy, puerperium and lactation have to be discussed. Here, we provide an overview about the current state of knowledge regarding these issues.
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Affiliation(s)
- Nadja Borisow
- NeuroCure Clinical Research Center and Clinical and Experimental Research Center for Multiple Sclerosis, Charité - Universitätsmedizin Berlin, Charitéplatz 1, Berlin, 10117, Germany.
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Biswas S, Benedict SH, Lynch SG, LeVine SM. Potential immunological consequences of pharmacological suppression of gastric acid production in patients with multiple sclerosis. BMC Med 2012; 10:57. [PMID: 22676575 PMCID: PMC3386885 DOI: 10.1186/1741-7015-10-57] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2012] [Accepted: 06/07/2012] [Indexed: 12/15/2022] Open
Abstract
Corticosteroids are standard treatment for patients with multiple sclerosis experiencing acute relapse. Because dyspeptic pain is a common side effect of this intervention, patients can be given a histamine receptor-2 antagonist, proton pump inhibitor or antacid to prevent or ameliorate this disturbance. Additionally, patients with multiple sclerosis may be taking these medications independent of corticosteroid treatment. Interventions for gastric disturbances can influence the activation state of the immune system, a principal mediator of pathology in multiple sclerosis. Although histamine release promotes inflammation, activation of the histamine receptor-2 can suppress a proinflammatory immune response, and blocking histamine receptor-2 with an antagonist could shift the balance more towards immune stimulation. Studies utilizing an animal model of multiple sclerosis indicate that histamine receptor-2 antagonists potentially augment disease activity in patients with multiple sclerosis. In contrast, proton pump inhibitors appear to favor immune suppression, but have not been studied in models of multiple sclerosis. Antacids, histamine receptor-2 antagonists and proton pump inhibitors also could alter the intestinal microflora, which may indirectly lead to immune stimulation. Additionally, elevated gastric pH can promote the vitamin B12 deficiency that patients with multiple sclerosis are at risk of developing. Here, we review possible roles of gastric acid inhibitors on immunopathogenic mechanisms associated with multiple sclerosis.
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Affiliation(s)
- Sangita Biswas
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA
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Oleen-Burkey M, Castelli-Haley J, Lage MJ, Johnson KP. Burden of a Multiple Sclerosis Relapse. PATIENT-PATIENT CENTERED OUTCOMES RESEARCH 2012; 5:57-69. [DOI: 10.2165/11592160-000000000-00000] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
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Saldova R, Huffman JE, Adamczyk B, Mužinić A, Kattla JJ, Pučić M, Novokmet M, Abrahams JL, Hayward C, Rudan I, Wild SH, Wright AF, Polašek O, Lauc G, Campbell H, Wilson JF, Rudd PM. Association of medication with the human plasma N-glycome. J Proteome Res 2012; 11:1821-31. [PMID: 22256781 DOI: 10.1021/pr2010605] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Glycosylation is highly variable depending on many environmental factors. Using our fully quantitative high-throughput normal phase hydrophilic interaction liquid chromatography platform we have identified glycosylation changes associated with medication in the plasma N-glycome from three different population cohorts: ORCADES from the Orkney Islands in Scotland and CROATIA-Vis and CROATIA-Korcula from the Croatian islands of Vis and Korcula. Associations between glycosylation and the use of hormones (oral contraceptives, hormone replacement therapy), nonsteroidal anti-inflammatory drugs (aspirin and other NSAIDs), oral steroids (prednisolone) and steroid inhalers (beclomethasone) were investigated. Significant differences associated with usage of oral contraceptives were found with increased core-fucosylated biantennary glycans. Decreases in core-fucosylated biantennary glycans, core-fucosylated triantennary glycans with outer-arm fucose, and high mannosylated glycans were associated with the use of anti-inflammatory drugs. All of the changes in glycosylation were independent of blood group status. In conclusion, hormones and anti-inflammatory medication were associated with changes in glycosylation, possibly as a result of the modulatory effect of these drugs on the inflammatory response. In general, cancer is associated with inflammation, and many glycoproteins in the plasma are acute phase related to the host response. These preliminary data indicate the importance of correcting the levels of glycans used as biomarkers for the effects of medication.
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Affiliation(s)
- Radka Saldova
- NIBRT Dublin-Oxford Glycobiology Laboratory, National Institute for Bioprocessing Research and Training , Fosters Avenue, Mount Merrion, Blackrock, Dublin 4, Ireland
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Vasheghani-Farahani A, Sahraian MA, Darabi L, Aghsaie A, Minagar A. Incidence of various cardiac arrhythmias and conduction disturbances due to high dose intravenous methylprednisolone in patients with multiple sclerosis. J Neurol Sci 2011; 309:75-8. [DOI: 10.1016/j.jns.2011.07.018] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2011] [Revised: 07/08/2011] [Accepted: 07/14/2011] [Indexed: 01/11/2023]
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Sweeney ME, Slusser JG, Lynch SG, Benedict SH, Garcia SL, Rues L, LeVine SM. Deferiprone modulates in vitro responses by peripheral blood T cells from control and relapsing-remitting multiple sclerosis subjects. Int Immunopharmacol 2011; 11:1796-801. [PMID: 21807124 DOI: 10.1016/j.intimp.2011.07.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2011] [Revised: 07/06/2011] [Accepted: 07/14/2011] [Indexed: 10/17/2022]
Abstract
T cells are important mediators of autoimmune inflammation in relapsing-remitting multiple sclerosis (RRMS). Previous studies found that deferiprone, an iron chelator, suppressed disease activity in a mouse model of multiple sclerosis, and inhibition of T cell proliferation was implicated as a putative mechanism. The objective of the present study was to examine the effects of deferiprone on suppressing in vitro responses of T cells from control and RRMS subjects. Peripheral blood T cells were co-stimulated with anti-CD3+anti-CD28 and cultured with or without interleukin 2 (IL-2). Proliferating CD4+ T cells from control and RRMS subjects, cultured with or without IL-2, decreased in response to 75 μM deferiprone, although the extent of decreased proliferation of CD4+ T cells from RRMS subjects was less than for control subjects. Proliferating CD8+ T cells from control subjects, cultured with or without IL-2, also decreased in response to 75 μM deferiprone, and this decrease was seen in proliferating CD8+ T cells from RRMS cultured with IL-2. CD4+CD25+ and CD8+CD25+ cells from control subjects, cultured with or without IL-2, declined in 75 μM deferiprone, but the decrease was smaller than for the CD4+ and CD8+ proliferative responses. CD4+CD25+ and CD8+CD25+ cells from RRMS subjects showed more variability than for control subjects, but CD4+CD25+ cultured with IL-2 and CD8+CD25+ cells cultured without IL-2 significantly declined in 75 μM deferiprone. CD4+FoxP3+ and CD4+CD25+FoxP3+ cells tended to remain constant or increase. In summary, deferiprone induced declines in proliferative responses at a dosage that is within peak serum pharmacological concentrations.
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Affiliation(s)
- Matthew E Sweeney
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA
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Intravenous immunoglobulins are a therapeutic option in the treatment of multiple sclerosis relapse. Clin Neuropharmacol 2011; 34:84-9. [PMID: 21301327 DOI: 10.1097/wnf.0b013e31820a17f3] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE The objective of the study is to evaluate the efficacy and tolerability of intravenous immunoglobulin (IVIG) monotherapy in the treatment of multiple sclerosis (MS) relapse. BACKGROUND High-dose intravenous methylprednisolone (IVMP) and plasmapheresis have been shown to shorten the recovery period of an MS relapse. Options for those who have contraindications for or are unresponsive to these treatments are very limited. Intravenous immunoglobulin has been used experimentally in these situations, even though there are no previous studies on its efficacy as monotherapy in MS relapse. SUBJECTS AND METHODS Twelve consecutive MS patients with acute MS relapse were treated with IVIG 0.4 g/kg per day for 5 days, and the next 5 patients received IVMP 1000 mg/d for 3 days. Volumetric brain magnetic resonance imaging (MRI) and clinical evaluation using expanded disability status scale (EDSS) were performed at baseline and at 3 weeks after treatment. EDSS score after 1 year of the treatment was collected from the patient records. MRI evaluation was performed blindly but not the clinical examination and EDSS scoring. RESULTS A significant reduction in the volumes of T2-, fluid-attenuated inversion recovery-, and gadolinium-enhanced lesions was detected in the IVIG-treated group, but not in the IVMP-treated patients. The difference between the groups did not reach statistical significance. The EDSS score improved equally in both groups. CONCLUSIONS Intravenous immunoglobulin did not show inferiority compared with IVMP in the treatment of an acute MS relapse evaluated clinically and radiologically. Therefore, we suggest that IVIG may be tried as a therapy in acute MS relapse, especially in case of contraindications to IVMP and plasmapheresis.
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Chastek BJ, Oleen-Burkey M, Lopez-Bresnahan MV. Medical chart validation of an algorithm for identifying multiple sclerosis relapse in healthcare claims. J Med Econ 2010; 13:618-25. [PMID: 20883151 DOI: 10.3111/13696998.2010.523670] [Citation(s) in RCA: 92] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
OBJECTIVE Relapse is a common measure of disease activity in relapsing-remitting multiple sclerosis (MS). The objective of this study was to test the content validity of an operational algorithm for detecting relapse in claims data. METHODS A claims-based relapse detection algorithm was tested by comparing its detection rate over a 1-year period with relapses identified based on medical chart review. According to the algorithm, MS patients in a US healthcare claims database who had either (1) a primary claim for MS during hospitalization or (2) a corticosteroid claim following a MS-related outpatient visit were designated as having a relapse. Patient charts were examined for explicit indication of relapse or care suggestive of relapse. Positive and negative predictive values were calculated. RESULTS Medical charts were reviewed for 300 MS patients, half of whom had a relapse according to the algorithm. The claims-based criteria correctly classified 67.3% of patients with relapses (positive predictive value) and 70.0% of patients without relapses (negative predictive value; kappa 0.373: p < 0.001). Alternative algorithms did not improve on the predictive value of the operational algorithm. Limitations of the algorithm include lack of differentiation between relapsing-remitting MS and other types, and that it does not incorporate measures of function and disability. CONCLUSIONS The claims-based algorithm appeared to successfully detect moderate-to-severe MS relapse. This validated definition can be applied to future claims-based MS studies.
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