mycophenolic-acid and Multiple-Sclerosis

Patients with POAG have lower corneal endothelial cell density than healthy controls of the same age. This may be attributed to mechanical damage from elevated IOP and toxicity of glaucoma medications.. Mycophenolic acid was detected in all cats. The dose 10 mg/kg given q12h for 1 week was tolerated (n = 3). The efficacy of MMF as an immunosuppressant and long-term safety in cats of this dosage regimen is unknown.. T

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Immunosuppressives have been used in multiple sclerosis (MS) since 1966. Today, we have many treatments for the relapsing forms of the disease, including 8 US Food and Drug Administration-approved therapies, with more soon to be introduced. Given the current treatment landscape what place do immunosuppressants have in combating MS? Trial work and our experience suggest that immunosuppressives still have an important role in treating MS. Cyclophosphamide finds use in treating patients with severe, inflammatory relapsing remitting MS or those suffering from a fulminant attack. We tend to employ mycophenolate mofetil as an add-on to injectable therapy for patients experiencing breakthrough activity. Some progressive (primary progressive multiple sclerosis or secondary progressive multiple sclerosis) patients may stabilize after treatment with either cyclophosphamide or mycophenolate. We rarely employ mitoxantrone because of potential cardiac or carcinogenic effects. We prefer to use cyclophosphamide or mycophenolate mofetil in preference to methotrexate because evidence of efficacy is limited for this drug. We have less experience with azathioprine, but it may be an alternative for patients with limited options who are unable to tolerate conventional therapies.

Topics: Adult; Azathioprine; Cyclophosphamide; Female; Humans; Immunosuppressive Agents; Male; Methotrexate; Mitoxantrone; Multiple Sclerosis; Mycophenolic Acid

In 1993, interferon beta-1b, the first clinically proven disease-modifying agent for multiple sclerosis, was approved, with several comparable agents following close behind. These agents have been beneficial in reducing relapse events and MRI lesions, but all require parenteral administration, leading some otherwise eligible patients to decline such therapies. Oral agents have been studied for decades with mixed results, but a small number of medications currently being tested in phase II/III clinical trials have shown promise in efficacy and tolerability. This review assesses the results of the more thoroughly studied of these agents, some of which may soon be approved for use in multiple sclerosis.

Topics: Administration, Oral; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Cladribine; Clinical Trials as Topic; Dimethyl Fumarate; Fingolimod Hydrochloride; Fumarates; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunosuppressive Agents; Interferon beta-1b; Interferon-beta; Isoxazoles; Leflunomide; Minocycline; Multiple Sclerosis; Mycophenolic Acid; Propylene Glycols; Pyridones; Quinolones; Sphingosine

This month's Spotlight on... focuses on the clinical development of the immunomodulatory agent mycophenolate mofetil as an adjunctive therapy for multiple sclerosis. Mycophenolate mofetil (MMF) is postulated to target several mechanisms underlying the progression of this autoimmune disease, and clinical studies to date have provided evidence for treatment-associated clinical improvements or a halt in disease progression. Ongoing phase II/III clinical trials are investigating the efficacy and safety of MMF as both a monotherapy or in combination with interferon beta-1a.

Topics: Adjuvants, Immunologic; Drug Therapy, Combination; Enzyme Inhibitors; Humans; Immunologic Factors; IMP Dehydrogenase; Interferon beta-1a; Interferon-beta; Multiple Sclerosis; Mycophenolic Acid; Treatment Outcome

We describe experience with the use of mycophenolate mofetil (MMF) in neurological diseases. Although only small series of patients or case reports were described, MMF is promising in immune-mediated neuromuscular disorders. MMF has been used for the treatment of polymyositis, chronic inflammatory demyelinating polyradiculoneuropathy, and multifocal motor neuropathy. These studies showed that MMF is well tolerated and may be useful in some patients. MMF can be effective alone but mainly as an adjuvant therapy by reducing steroid requirements or the frequency of infusions of IVIg. MMF has also been tested alone as a single drug treatment or in combination with immunomodulatory drugs in multiple sclerosis in open surveillance trials or in phase II studies. None of these studies have been designed to demonstrate a clinical efficacy but preliminary results are very promising.

Topics: Humans; Immunosuppressive Agents; Multiple Sclerosis; Mycophenolic Acid; Neuromuscular Diseases

Global immunosuppression instead of focused selective or specific immunomodulating strategies may still be relevant in diseases with chronic and broad immune dysregulation such as multiple sclerosis (MS). Among classical or new immunosuppressive drugs, two of them, both inhibiting purine synthesis, show an attractive profile for MS treatment. Azathioprine (AZA) is the most anciently and widely used global immunosuppressive drug in MS. Despite founded initial fears, it can be stated today that AZA is usually well tolerated and compatible with normal daily activities, that it requires minimal monitoring and does not significantly increase the risk of cancer induction after 5 years of continuous usage at the conventional 2.5 mg/kg daily dose. The only two presently available well conducted trials of AZA in ambulatory patients with relapsing-remitting MS show marginally significant beneficial results of AZA treatment on relapse frequency and disability. Some preliminary data on brain MRI are also promising. Mycophenolate mofetil (MMF) affects mainly the desired cell types, with a good safety profile, a rapidly reversible activity, and an absence of mutagenic effect and chromosome breakage. However, it remains to be shown that promising experimental results can be converted into significant clinical results in MS. It is presently demonstrated for AZA and it is presumable for MMF that neither drug is able to cure MS. However, it can be anticipated that either drug in combination with other strategies such as recombinant beta interferon could represent a significant adjunct for the therapeutic control of MS, at least in early ambulatory relapsing-remitting MS. Presently, the choice between the old, no longer 'sexy', but well-known drug as AZA and a young, appealing, but still to be better evaluated drug (notably for the long run) as MMF is a matter of personal, community, industrial and scientific inclination.

Topics: Azathioprine; Dose-Response Relationship, Drug; Humans; Immunosuppressive Agents; Magnetic Resonance Imaging; Multiple Sclerosis; Mycophenolic Acid

Topics: Adult; Drug Resistance; Enzyme Inhibitors; Female; Humans; IMP Dehydrogenase; Male; Middle Aged; Multiple Sclerosis; Mycophenolic Acid

Disease-modifying therapies (DMTs) for multiple sclerosis (MS) target immunity and have the potential to increase the risk of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and alter its clinical course. We assessed these risks in patients with MS (PwMS).. The objective of this study was to describe the overall risk of coronavirus disease 2019 (COVID-19) infection, severe disease course, and potential population-level predictors of COVID-19 infection in PwMS, and to provide a context using a cohort of patients with systemic lupus erythematosus (SLE). In addition, the association of different MS DMTs with the incidence and clinical course of COVID-19 was evaluated. Safety data from the Biogen Global Safety Database are also presented on reported cases of COVID-19 in patients treated with Biogen MS therapies.. 30,478 PwMS with an open DMT prescription were identified within Explorys; 344 were COVID-19 positive. The most significant risk factors for acquiring COVID-19 were comorbidity score ≥ 1, body mass index ≥ 30, and Black/African ancestry. Similar risk factors were also identified for patients with SLE. Patients with MS were less likely to develop COVID-19 when treated with interferons (0.61%) and glatiramer acetate (0.51%), vs all other MS DMTs (both p < 0.001); anti-CD20 therapy was associated with the highest risk (3.45%; p < 0.0001). In the Biogen Global Safety Database, we identified 1217 patients who were COVID-19 positive treated with intramuscular interferon beta-1a, peginterferon beta-1a, natalizumab, dimethyl fumarate, diroximel fumarate, or fampridine.. Comorbidities, obesity, and Black/African ancestry, but not age, were associated with a higher risk of SARS-CoV-2 infection in PwMS. Interferons and glatiramer acetate were associated with a reduced COVID-19 risk, whereas anti-CD20 therapies were associated with an increased risk, within the treated MS cohort. COVID-19 safety reports for patients receiving Biogen MS therapies were consistent with the Explorys database and MS literature, illustrating the replicability and power of this approach.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alemtuzumab; Azathioprine; Black or African American; Cladribine; Comorbidity; COVID-19; Crotonates; Cyclophosphamide; Cyclosporine; Databases, Factual; Dimethyl Fumarate; Female; Fingolimod Hydrochloride; Hospitalization; Humans; Hydroxybutyrates; Immunologic Factors; Immunosuppressive Agents; Incidence; Interferon-beta; Logistic Models; Lupus Erythematosus, Systemic; Male; Methotrexate; Middle Aged; Mitoxantrone; Multiple Sclerosis; Mycophenolic Acid; Natalizumab; Nitriles; Obesity; Risk Factors; Rituximab; SARS-CoV-2; Toluidines; United States; White People; Young Adult

Development of autoimmune hepatitis (AIH) has been sporadically reported in patients with multiple sclerosis (MS) either concurrently or after treatment with immunomodulatory drugs, including interferon-beta (IFN-β) and steroids.. To report a large cohort of 14 patients with MS diagnosed with AIH during an assessment of deranged liver function tests (LFTs).. From 2005 to 2017, we prospectively identified 14 (13 women) patients with MS who suffered also from AIH after investigation in our department for the presence of deranged LFTs. Age at diagnosis of MS was 36.7 ± 9.3 years while at diagnosis of AIH 43.1 ± 12 years.. AIH diagnosis was based on elevation of aminotransferases in all patients [alanine aminotransferase: 520 IU/L (range: 115-1219)], elevation of IgG in 6, compatible autoantibody profile in all, including 5 patients with liver-specific autoantibodies and typical or compatible histological features in 11 patients. 5 patients were under treatment with IFN-β plus methylprednisolone pulses, 3 with IFN-β plus oral steroids, 1 with IFN-β, 4 with methylprednisolone pulses whereas 1 patient was free of treatment. The median time from IFN-β initiation to the development of hepatitis was 12 months (range:1-120). Treatment for AIH was initiated in 13 patients with prednisolone (0.5-1 mg/kg/day) plus mycophenolate myfetil (2 g/day) in 10 and prednisolone plus azathioprine in 3 with complete and partial response in 11 and 2 patients, respectively.. The differential diagnosis of hepatitis in MS patients should include AIH and in particular when immunomodulatory treatment has been preceded. Autoantibody testing and liver histology play fundamental role in establishing a prompt diagnosis of AIH in these patients. Treatment of AIH in patients with MS seems safe and efficient as complete or partial response was recorded in all of our patients.

Topics: Adult; Autoantibodies; Azathioprine; Female; Glucocorticoids; Hepatitis, Autoimmune; Humans; Immunologic Factors; Immunosuppressive Agents; Interferon-beta; Liver Function Tests; Male; Methylprednisolone; Multiple Sclerosis; Mycophenolic Acid; Prednisolone

To report the efficacy of mycophenolate mofetil (MMF) as adjunctive therapy for the treatment of multiple sclerosis (MS)-associated uveitis.. In this retrospective, interventional case series, patients with MS-associated uveitis who were treated by MMF as an adjunct therapy to systemic corticosteroid were studied. Patients' demographics, clinical course, response to treatment, and complications were assessed.. A total of 30 eyes of 15 patients with a mean age of 34.5 ± 8.3 years were studied. In three patients (20%), onset of uveitis preceded the diagnosis of MS. The course of MS was relapsing-remitting in 11 patients (73.3%) and secondary progressive in four patients (26.7%). At 1 year after institution of MMF, all the patients were on oral prednisolone ≤ 7.5 mg/day, all eyes were quiet without macular edema, and 53.3% of eyes gained visual improvement. Supplemental periocular and intraocular injections were needed during the first 6 months after starting MMF therapy. The systemic adverse effects were transient and minor in severity.. MMF had beneficial effects on vision and intraocular inflammation with an acceptable safety profile.

Topics: Adolescent; Adult; Chemotherapy, Adjuvant; Enzyme Inhibitors; Female; Fluorescein Angiography; Glucocorticoids; Humans; Male; Middle Aged; Multiple Sclerosis; Mycophenolic Acid; Prednisolone; Retrospective Studies; Tomography, Optical Coherence; Treatment Outcome; Uveitis; Visual Acuity; Young Adult

CD40 interacts with CD40L and plays an essential role in immune regulation and homeostasis. Recent research findings, however, support a pathogenic role of CD40 in a number of autoimmune diseases. We previously showed that memory B cells from relapsing-remitting multiple sclerosis (RRMS) patients exhibited enhanced proliferation with CD40 stimulation compared with healthy donors. In this study, we used a multiparameter phosflow approach to analyze the phosphorylation status of NF-κB and three major MAPKs (P38, ERK, and JNK), the essential components of signaling pathways downstream of CD40 engagement in B cells from MS patients. We found that memory and naive B cells from RRMS and secondary progressive MS patients exhibited a significantly elevated level of phosphorylated NF-κB (p-P65) following CD40 stimulation compared with healthy donor controls. Combination therapy with IFN-β-1a (Avonex) and mycophenolate mofetil (Cellcept) modulated the hyperphosphorylation of P65 in B cells of RRMS patients at levels similar to healthy donor controls. Lower disease activity after the combination therapy correlated with the reduced phosphorylation of P65 following CD40 stimulation in treated patients. Additionally, glatiramer acetate treatment also significantly reduced CD40-mediated P65 phosphorylation in RRMS patients, suggesting that reducing CD40-mediated p-P65 induction may be a general mechanism by which some current therapies modulate MS disease.

Topics: Aged; B-Lymphocytes; CD40 Antigens; Drug Therapy, Combination; Extracellular Signal-Regulated MAP Kinases; Female; Glatiramer Acetate; Humans; Immunologic Memory; Interferon beta-1a; Lymphocyte Activation; Male; MAP Kinase Signaling System; Middle Aged; Multiple Sclerosis; Mycophenolic Acid; Phosphorylation; Transcription Factor RelA

Mycophenolate mofetil (MMF) is an immunosuppressive agent, sometimes used as a disease-modifying therapy for multiple sclerosis (MS). Several studies have reported the relative safety of this treatment but, to date, its efficacy has rarely been described. We performed a retrospective study to assess the safety and efficacy of MMF in patients with MS.. Three French MS centres included all of their patients treated by MMF. The main outcome criterion was annualised relapse rate (ARR) in the 1 year period after onset of MMF compared with the 1 year control period. Treatment with another immunosuppressive drug, such as mitoxantrone or cyclophosphamide, in the 2 years preceding initiation of MMF was included in a subgroup analysis. MMF safety and progression of the Expanded Disability Status Scale (EDSS) score were also assessed.. 344 patients were included; 149 patients were previously treated with another immunosuppressant (IS group). Mean MMF treatment duration was 25.3±1.1 months. During the 1 year control period, ARR was 1.11±0.08, and for the 1 year treatment period, ARR was reduced significantly to 0.35±0.05 (p<0.0001, Wilcoxon paired test). Adverse events (occurring in 11% of patients) were mainly digestive disorders, benign infections, asthenia and transitory lymphopenia. Concerning the progression of disability, in the subgroup of patients without previous immunosuppressant treatment, EDSS remained stable between initiation and 1 year after the beginning of MMF.. Our results suggest that MMF can improve or stabilise MS patients and can be used as an alternative therapy.

Topics: Adult; Cyclophosphamide; Humans; Immunosuppressive Agents; Mitoxantrone; Multiple Sclerosis; Mycophenolic Acid; Retrospective Studies; Secondary Prevention; Severity of Illness Index; Treatment Outcome

Topics: Humans; Immunosuppressive Agents; Multiple Sclerosis; Mycophenolic Acid

This study evaluated the clinical and pathological effects of the immunosuppressive agent mycophenolate mofetil (MMF) in rats with experimental autoimmune encephalomyelitis (EAE; a model of multiple sclerosis [MS]).. EAE rats were randomly divided into 4 groups: model alone (n = 7); low- or high-dose MMF (20 and 30 mg/kg per day, respectively, n = 6 each) orally for 14 days; methylprednisolone (20 mg/kg per day, n = 6) injected once daily for 3 days. Six normal Wistar rats served as controls. Clinical signs and histopathological findings were evaluated 14 days after treatment started.. Oral administration of high-dose MMF significantly ameliorated the course of EAE in rats: cumulative clinical scores were lower and weight loss was less than in rats receiving methylprednisolone. The ameliorated disease course was associated with alleviation of histopathological signs of EAE. Treatment increased the blood proportion of CD8(+), CD4(+)CD25(+) and CD4(+)CD45RA(+) T cells, with a concomitant reduced proportion of CD4(+) T cells and ratio of CD4(+) to CD8(+) T cells, compared with EAE model alone rats.. MMF may have pharmacological potential in MS treatment and these findings may help in understanding the pathophysiological mechanism of MS.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; CD4-CD8 Ratio; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Enzyme Inhibitors; Female; Guinea Pigs; Immunosuppressive Agents; IMP Dehydrogenase; Interleukin-2 Receptor alpha Subunit; Leukocyte Common Antigens; Lymphocyte Count; Methylprednisolone; Multiple Sclerosis; Mycophenolic Acid; Random Allocation; Rats; Rats, Wistar; T-Lymphocyte Subsets

To investigate differences in T2 intensity of deep gray matter (dGM) structures by magnetic resonance imaging (MRI) in multiple sclerosis (MS) patients undergoing various immunomodulatory therapies.. In MS, dGM T2 hypointensities by MRI are hypothesized to represent iron deposition and are known to be associated with worse disease stage as assessed by brain atrophy, cognitive and physical disability. The relation between immunotherapies and T2 intensity, however, has been not been investigated in detail.. A total of 255 MS patients were stratified into those on no treatment (NON, n= 45), and those on immunomodulatory treatments for ≥6 months (ie, interferon beta [IFNβ]n= 118, glatiramer acetate [GA]n= 41, natalizumab [NAT]n= 39, and mycophenolate mofetil [MMF]n= 12). T2 intensities of dentate nucleus (DN), substantia nigra (SN), red nucleus (RN), and globus pallidus (GP) were measured. Group differences in T2 intensities were assessed using a linear regression model with T2 intensities as outcome variable, treatment group as main independent variable, and clinical measures such as Expanded Disability Status Scale (EDSS) score, years of MS, and 25-feet walk time (T25-FW) as covariates. To compare T2 intensities before and after treatment in a subset of NAT-treated patients, we used the Wilcoxon signed-rank test.. When adjusted for EDSS, duration of disease and T25-FW, across all deep nuclei, NAT-treated patients had significantly higher T2 intensities than untreated patients (DN p= 1.65 × 10(-5) ; SN p= 2.37 × 10(-5) ; RN p= 3.90 × 10(-6) ; GP p= 1.05 × 10(-6) ), IFNβ-treated patients (DN p= 1.65 × 10(-5) ; SN p= 2.37 × 10(-5) ; RN p= 3.90 × 10(-6) ; GP p= 1.05 × 10(-6) ), and GA-treated patients (DN p= 1.65 × 10(-5) ; SN p= 2.37 × 10(-5) ; RN p= 3.90 × 10(-6) ; GP p= 1.05 × 10(-6) ). In a subset of MS patients receiving NAT, there was a significant increase in T2 intensities in all the dGM nuclei after 24 months of treatment (DN p= 0.00021; SN p= <0.0001; RN p= 0.00015; GP p= 0.00011).. Our preliminary observations suggest that long-term NAT therapy in MS patients may affect T2 intensity levels of dGM brain nuclei, hence suggesting a potential effect of NAT beyond anti-inflammatory effect. Prospective studies are warranted to provide more insights into our preliminary observations. 

Topics: Adult; Antibodies, Monoclonal, Humanized; Cerebellar Nuclei; Female; Glatiramer Acetate; Globus Pallidus; Humans; Immunologic Factors; Interferon-beta; Magnetic Resonance Imaging; Male; Middle Aged; Multiple Sclerosis; Mycophenolic Acid; Natalizumab; Peptides; Red Nucleus; Retrospective Studies; Substantia Nigra

Langerhans cell histiocytosis (LCH) with multiple organ involvement is a rare disorder in adults. Extrapituitary involvement of the central nervous system (CNS) is uncommon. We report the unusual case of a 55-year-old woman presenting with a left-sided hemiataxia-hemiparesis, left hemisensory loss and short-lasting episodes of an alien left hand due to lesions of the internal capsule and the right thalamus, extending into the mesencephalon associated with extensive surrounding edema, without pituitary involvement. The neuroradiological image suggested glioblastoma multiforme. Brain biopsy revealed inflammatory tissue and "pseudotumoral" multiple sclerosis was suspected. Biopsy of concomitant lung and bone lesions disclosed Langerhans cell histiocytosis. The treatment with pulsed steroids in association with mycophenolate mofetil led to a sustained, clinical neurological remission.

Topics: Age of Onset; Alien Limb Phenomenon; Biopsy; Bone and Bones; Brain; Brain Diseases; Brain Neoplasms; Cerebellar Ataxia; Dexamethasone; Diagnosis, Differential; Drug Therapy, Combination; Female; Glioblastoma; Histiocytosis, Langerhans-Cell; Humans; Lung; Magnetic Resonance Imaging; Middle Aged; Multiple Sclerosis; Mycophenolic Acid; Paresis

Topics: Acute Disease; Adjuvants, Immunologic; Aged; Anti-Inflammatory Agents; Antibodies, Antinuclear; Budesonide; Drug Synergism; Glatiramer Acetate; Hepatitis, Autoimmune; Humans; Iatrogenic Disease; Interferon beta-1b; Interferon-beta; Liver; Male; Mannitol; Multiple Sclerosis; Mycophenolic Acid; Peptides; Treatment Outcome

The effect of liver transplantation on pre-existing multiple sclerosis (MS) has never been reported. We report the three year post-transplant neurological outcome of a patient with MS.. A Caucasian woman with MS received an urgent liver transplant for fulminant liver failure at the age of 59. Her Extended Disability Scale Score (EDSS) pretransplant was 5.0 and clinically she had cerebellar and brainstem dysfunction. Post-transplant immunosuppression consisted of tacrolimus, mycophenolate mofetil and tapering corticosteroids that were discontinued after 1.5 years. Post-transplant her EDSS decreased to 2.0 and after three years she is clinically asymptomatic with only very mild dysarthria on neurologic examination. Long-term maintenance immunosuppression consists of low dose tacrolimus.. Combination immunosuppression with tacrolimus may have a beneficial effect on MS although an effect of donor allograft itself can not be excluded.

Topics: Female; Follow-Up Studies; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Failure; Liver Transplantation; Middle Aged; Multiple Sclerosis; Mycophenolic Acid; Prednisone; Remission Induction; Tacrolimus; Treatment Outcome