Multiple Sclerosis Exacerbations Research Articles

Multiple sclerosis, brain radiotherapy, and risk of neurotoxicity: The Mayo Clinic experience

The aim of this study was a retrospective assessment of neurotoxicity in patients with multiple sclerosis (MS) receiving external beam radiotherapy (EBRT) to the brain. We studied 15 consecutively treated patients with MS who received brain EBRT. Neurologic toxicity was assessed with the Common Toxicity Criteria v.3.0. Median follow-up for the 5 living patients was 6.0 years (range, 3.3-27.4 years). No exacerbation of MS occurred in any patient during EBRT. Five patients had Grade 4 neurologic toxicity and 1 had possible Grade 5 toxicity. Kaplan-Meier estimated risk of neurotoxicity greater than Grade 4 at 5 years was 57% (95% confidence interval, 27%-82%). Toxicity occurred at 37.5 to 54.0 Gy at a median of 1.0 year (range, 0.2-4.3 years) after EBRT. Univariate analysis showed an association between opposed-field irradiation of the temporal lobes, central white matter, and brainstem and increased risk of neurotoxicity (p < 0.04). Three of 6 cases of toxicity occurred in patients treated before 1986. External beam radiotherapy of the brain in patients with MS may be associated with an increased risk of neurotoxicity compared with patients without demyelinating illnesses. However, this risk is associated with treatment techniques that may not be comparable to modern, conformal radiotherapy.

The Importance of Preconception Care for Women With Disabilities

The Importance of Preconception Care for Women With Disabilities

Restraint stress decreases virus-induced pro-inflammatory cytokine mRNA expression during acute Theiler's virus infection

Stressful life events have been associated with the onset and/or exacerbation of multiple sclerosis (MS). Our previous studies have indicated that restraint stress (RS) reduces inflammation and virus-induced chemokine expression in the Theiler's virus-induced demyelination (TVID) model of MS. Here we report that RS significantly reduced the virus-induced interferon-γ mRNA levels in the brain. Additionally, mRNA levels of lymphotoxin-β, tumor necrosis factor-α, and interferon-γ in the brain were negatively correlated with viral titers in the brain. These results indicated an immunosuppressive effect of stress during early TVID causing impaired viral clearance, which may be a potential exacerbating factor for later demyelination.

Cardiogenic shock in a young female with multiple sclerosis

A 24-year-old patient with no previous cardiovascular illness or symptoms, was admitted in profound cardiogenic shock related to severe left ventricular systolic dysfunction, accompanied by multiple sclerosis (MS) exacerbation. Initially the patient required mechanical ventilation, inotropic support, and intra-aortic balloon counter-pulsation along with invasive haemodynamic monitoring. Within a few days of high dose corticosteroid therapy patients left ventricular systolic dysfunction returned almost completely to normal, and this was accompanied by dramatic clinical improvement. We review the current literature on the relation between MS and left ventricular systolic dysfunction and heart failure.

High dose of intravenously given glucocorticosteroids decrease IL-8 production by monocytes in multiple sclerosis patients treated during relapse

The aim of our study was to determine whether high doses of intravenous methylprednisolone have significant impact on immune parameters during the multiple sclerosis (MS) exacerbations. Peripheral blood of 32 MS patients was evaluated, using two-color flow cytometry before glucocorticosteroids and after 7 days from starting therapy. Significant increase of B cells, decrease of NK cells and monocytes producing IL-8 were observed after treatment. IL-8 is one of the cytokines responsible for blood–brain-barrier disruption and migration of immune cells to the central nervous system; in this aspect, explaining glucocorticosteroid effects during MS exacerbations.

Effect of high-dose methylprednisolone treatment on CCR5 expression on blood cells in MS exacerbation

Therapy of acute exacerbations of multiple sclerosis (MS) with high-dose intravenous methylprednisolone (IVMP) has shortened the recovery period after relapses, but the mechanisms responsible for the beneficial effects of IVMP in attacks have not been clearly established. Our purpose was to analyze the effect of IVMP on the expression of chemokine receptor 5 (CCR5) protein in blood in acute MS exacerbation. Blood samples were collected from 10 patients with an acute MS exacerbation and the levels of CCR5 on CD4(+) and CD8(+) T cells and CD14(+) monocytes were analyzed by using flow cytometry before IVMP, 24 h, 1 and 3 weeks after commencement of treatment. During the 3-week period the percentages of CCR5-expressing CD4(+) T cells and CD8(+) T cells tended to decrease (P = 0.09 and 0.05, respectively), but the effect did not reach statistical significance. No marked changes were found in the percentage of CCR5-expressing CD14(+) cells. A tendency to a reduction of CCR5-expressing CD4(+) and CD8(+) blood cells induced by IVMP suggests inhibition of their potential to transmigrate into the central nervous system, which is consistent with the short-term beneficial effect of IVMP in acute exacerbation of MS.

G-CSF enhances the adhesion of encephalitogenic T cells to extracellular matrix components: A possible mechanism for exacerbation of multiple sclerosis

Autologous stem cell transplantation is being considered as treatment of severe refractory autoimmune disorders, including MS. Stem cell mobilization is achieved with granulocyte-colony stimulating factor (G-CSF), however, G-CSF administration resulted in cases of worsened clinical MS status. We studied autoreactive T-cell properties, which can promote CNS inflammation in MS. We show that G-CSF enhances MS autoreactive T cell line adhesion to the ECM proteins collagen IV and fibronectin as effectively as the proinflammatory IFNγ and TNFα, known to exacerbate MS symptoms. We propose a link between clinical worsening of MS symptoms induced by G-CSF and the hyperstimulation of T cell adhesion to ECM elicited by G-CSF.

Stress und Krankheitsverlauf der Multiplen Sklerose

The hypothesis that stress might be connected to causation or exacerbation of multiple sclerosis has been under discussion for a long time. The current studies indicate that there is a coincidence between stress and disease progression. Besides the state of art in research different stress models will be introduced in the paper and the relations between disease, resources and coping will be discussed. Besides the influence of distressing life events on disease, the effect of illness-related characteristics on the coping behaviour will be considered in this regard. From the results of the presented studies and the described stress models it was concluded that the possibilities of stress avoiding intervention programs should be taken into account more strongly in the future.

The 57th Annual Meeting of the American Academy of Neurology, Miami, Florida, April 9-16, 2005

The 57th Annual Meeting of the American Academy of Neurology, Miami, Florida, April 9-16, 2005

Apoptosis of T cells in peripheral blood and cerebrospinal fluid is associated with disease activity of multiple sclerosis

Apoptotic elimination of pathogenic T cells is considered to be one of regulatory mechanisms in multiple sclerosis (MS). To explore the potential relationship between Fas-mediated apoptosis and the disease course of MS, we examined apoptosis, defined by annexin V (AV) binding, and Fas (CD95) expression in CD4 + and in CD8 + T cells in MS patients by using five-color flow cytometry. The percentage of AV +CD4 +CD3 + cells and CD95 +AV +CD4 +CD3 + cells in peripheral blood and cerebrospinal fluid (CSF) were significantly decreased in active MS patients compared with inactive MS patients. A significantly lower proportion of CD95 +AV +CD8 +CD3 + cells in CSF was observed in active MS patients compared with inactive MS patients, but not in peripheral blood. These results indicate that the resistance of T cells to Fas-mediated apoptosis is involved in exacerbation of MS and/or that Fas-mediated apoptosis of T cells is associated with remission of MS.

A Pilot, Open Label, Clinical Trial Using Hydroxyzine in Multiple Sclerosis

Multiple sclerosis (MS) is an autoimmune disorder of myelin destruction. Blood-brain-barrier (BBB) disruption precedes pathological or clinical findings and could involve mediators from perivascular brain mast cells, such as histamine and vascular endothelial growth factor (VEGF). Mast cells could be activated by many triggers, including acute stress that has been correlated with MS exacerbations. We considered that the histamine-1 (H1) receptor antagonist hydroxyzine, which also partially inhibits brain mast cells and has anxiolytic properties, may reduce MS symptoms. This open label, pilot, clinical trial investigated the effect on MS of an oral solution of hydroxyzine (100 mg per day), together with caffeine (200 mg per day) to reduce sedation. Twenty patients (8 males; 12 females) with relapsing-remitting or relapsing-progressive MS completed the study (12 +/- 1 months) and were evaluated using disability scales. Most patients on hydroxyzine (75%) remained stable or improved neurologically and all but one showed improved mood. Hydroxyzine could be used as an adjuvant in MS, but the small number of patients enrolled and the short duration of the study precludes any definitive conclusions. A double-blind, placebo-controlled study is warranted.

Poster 123: Efficacy of Outpatient Rehabilitation After Exacerbations of Multiple Sclerosis

Poster 123: Efficacy of Outpatient Rehabilitation After Exacerbations of Multiple Sclerosis

Characterizing the Mechanisms of Progression in Multiple Sclerosis

Major advancements have been achieved in our ability to diagnose multiple sclerosis (MS) and to commence treatment intervention with agents that can favorably affect the disease course. Although MS exacerbations and the emergence of disability constitute the more conspicuous aspects of the disease process, evidence has confirmed that most of the disease occurs on a constitutive and occult basis. Disease-modifying therapies appear to be modest in the magnitude of their treatment effects, particularly in the progressive stage of the disease. Therapeutic strategies currently used for MS primarily target the inflammatory cascade. Several potential mechanisms appear to be involved in the progression of MS. Characterizing these mechanisms will result in a better understanding of the various forms of the disorder and how to effectively treat its clinical manifestations. It is our objective within this 2-part series on progression in MS to offer both evidence-based observations and hypothesis-driven expert perspectives on what constitutes the cause of progression in MS. We have chosen areas of inquiry that appear to have been most productive in helping us to better conceptualize the landscape of what MS looks like pathologically, immunologically, neuroscientifically, radiographically, and genetically. We have attempted to advance hypotheses focused on a deeper understanding of what contributes to the progression of this illness and to illustrate new technical capabilities that are catalyzing novel research initiatives targeted at achieving a more complete understanding of progression in MS.

Nasal nitric oxide, the guardian of paranasal sinuses, is paradoxically increased by high doses of intravenous glucocorticoids

High concentrations of nitric oxide (NO) originating from a type-2 nitric oxide synthase (NOS2) located within the paranasal sinuses are measured in nasal air in man. NO is believed to play a central role in nonspecific defense of paranasal sinuses. Glucocorticoids (GCs), a therapeutic often used for a wide range of diseases, is known to strongly downregulate NOS2. To investigate the effect of very high intravenous doses of GCs on nasal NO in man. Nasal NO was measured in 15 patients without any history of allergy or chronic airway disorder who were treated for 3 days with a daily dose of 1000 mg methylprednisolone for an exacerbation of multiple sclerosis. Nasal NO was also measured in 30 matched control subjects. In control subjects, the maximal value of nasal NO [mean (SE)] was 233 (8) part per billion (ppb), and did not differ from patients with multiple sclerosis [maximum value: 219 (13) ppb; left nostril: 214 (12) ppb; right nostril: 215 (12) ppb]. After GCs treatment, nasal NO increased in patients [maximum value: 250 (13) ppb (P < 0.0001); left nostril: 249 (12) ppb (P < 0.0001); right nostril: 244 (13) ppb (P < 0.0001)]. We conclude that GCs do not decrease but even increase nasal NO.

Migraines Linked to Interferon-β Treatment of Multiple Sclerosis

Migraine headache is now emerging as a previously under-recognized side effect of interferon-beta, the most commonly used therapy for relapsing multiple sclerosis (MS). We describe an MS patient who developed migraine headaches, which followed a specific pattern coincident with interferon-beta administration. The frequency and severity of these migraines escalated and seemed to culminate in an MS exacerbation. Since initiation of migraine prophylaxis with daily amitriptyline, our patient reported a significant decrease in the frequency and severity of her migraines on interferon. It has been postulated that migraine headaches may trigger MS relapse. If so, migraine prophylaxis in MS patients, especially those treated with interferon-beta, is of paramount importance. Migraine headaches can be a significant source of disability. Identifying and treating migraines in MS patients serves to enhance their function and reduce disability.

The activation of memory CD4 + T cells and CD8 + T cells in patients with multiple sclerosis

To reevaluate whether an association exists between the clinical course of multiple sclerosis (MS) and the activation of memory T cells, we investigated the phenotype of T cells in peripheral blood and cerebrospinal fluid (CSF) of patients with MS using five-color flow cytometry. A cross-sectional study with 39 relapsing–remitting MS patients demonstrated that the percentage of CD25 +CD45RO +CD4 +CD3 + cells was significantly increased in peripheral blood as well as in CSF of active MS patients compared with inactive MS patients. A longitudinal study with 11 relapsing–remitting MS patients also showed a higher percentage of CD25 +CD45RO +CD4 +CD3 + cells in peripheral blood at the phase of exacerbation than during remission. On the other hand, regardless of the disease activity, the percentage of CD25 +CD45RO +CD8 +CD3 + cells in peripheral blood was significantly higher in patients with MS than in healthy control subjects. A lower percentage of CD25 +CD45RO +CD8 +CD3 + cells in CSF was observed in active MS patients compared with inactive MS patients. These results suggest that the activation of memory CD4 + T cells is associated with the exacerbation of MS and activation of memory CD8 + T cells reflects systemic immunological dysregulation in MS patients. Transient as well as continuous activation of T cells by recall antigens may be involved in the disease course of MS.

Thoracic myelitis as a possible cause of myocardial infarction

During the course of an inflammatory process in the thoracic part of the spinal cord, a previously healthy male suffered two myocardial infarctions in separate coronary territories. A coronary angiogram revealed only minor wall changes in one coronary artery. We hypothesize that the myocardial infarctions may have been caused by vasospastic reactions secondary to his spinal cord pathology, and present the case report and a review of the literature.

Differences in systemic and central nervous system cellular immunity relevant to relapsing–remitting multiple sclerosis

In order to elucidate the differences between systemic and central nervous system (CNS) immunity that are relevant to exacerbations of multiple sclerosis (MS), paired peripheral blood and cerebrospinal fluid (CSF) samples obtained from 36 non-treated patients with relapsing-remitting MS (RRMS) were simultaneously examined using flow cytometry to determine the percentages of functional lymphocyte subsets, as well as enzyme-linked immunosorbent assays for measuring soluble immune mediators. Active RRMS patients (n = 27) were characterized by an increase in CD4+ CXCR3+ Th1 cells in blood as compared with inactive patients (n = 9), and this parameter was inversely correlated with plasma levels of IL-10 and IL- 12p70. In contrast, an increase in the percentage of CD4+ CD25+ cells and a decrease in the percentage of CD8+ CD11a(high) cells were features of CSF samples from those with active RRMS. Further, CSF CD4+ CD25+ cells had a close association with leukocyte counts as well as albumin and CXCL10 levels in the CSF, and, thus, could be useful as a measure for inflammatory reactions in the CNS. On the other hand, CD8+ CD11a(high) cells may function as immunoregulatory cells, as their percentage in the CSF showed a positive correlation with CSF levels of the anti-inflammatory cytokine IL-4. These findings suggest that MS relapses occur in a combination with altered cell-mediated immunity that differs between the peripheral blood and CSF compartments, while measurement of lymphocyte subsets may be helpful for monitoring disease status.

Tissue preconditioning may explain concentric lesions in Baló's type of multiple sclerosis

Lesions of Baló's concentric sclerosis are characterized by alternating layers of myelinated and demyelinated tissue. The reason for concentric demyelination in this variant of multiple sclerosis is unclear. In the present study we investigated the immunopathology in autopsy tissue of 14 patients with acute multiple sclerosis or fulminant exacerbations of chronic multiple sclerosis with Baló-type lesions in the CNS, focusing on the patterns of tissue injury in actively demyelinating lesions. We found that all active concentric lesions followed a pattern of demyelination that bears resemblances to hypoxia-like tissue injury. This was associated with high expression of inducible nitric oxide synthase in macrophages and microglia. At the edge of active lesions and, less consistently, in the outermost layer of preserved myelin, proteins involved in tissue preconditioning, such as hypoxia-inducible factor 1alpha and heat-shock protein 70, were expressed mainly in oligodendrocytes and to a lesser degree also in astrocytes and macrophages. Due to their neuroprotective effects, the rim of periplaque tissue, where these proteins are expressed, may be resistant to further damage in an expanding lesion and may therefore remain as a layer of preserved myelinated tissue.

Demyelination and Neurological Sequelae in Etanercept and Infliximab Therapies: A Review of the Literature

Etanercept (Enbrel) and infliximab (Remicade) are two relatively new drugs, referred to as biologics, which target the cytokine tumor necrosis factor-α (TNF-α). Both are used in the treatment of psoriasis and psoriatic arthritis. Recently, there have been rare reports of demyelinating and neurological sequelae in patients while on these therapies. The authors sought to systematically review the reported cases of new-onset neurological symptoms and exacerbation of established multiple sclerosis (MS) found in the literature to determine the causality, if any, of demyelinating events by these therapies. Although these two medications may uncover latent multiple sclerosis in patients who are prone to the disease, no cause-and-effect relationship can currently be established.