squiffy2
11-17-2008, 04:02 AM
http://www.msrc.co.uk/images/gallery/img_preg.jpg
At any one time, there are around 20 000 women of childbearing age with multiple sclerosis (MS) in the UK who may be considering having children. Neurologists can be asked for information from both patients and obstetric colleagues on a range of topics related to pregnancy and MS that extend beyond the well-known implications for relapse risk. This article aims to provide a brief overview for the general neurologist of the most commonly encountered issues and questions including those occasionally related to pregnancy management. The take-home message is that pregnancy does not hold adverse risks for the majority of patients with MS, or vice versa.
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system with onset typically in the second to third decade and is twice as prevalent in females as males. In the past, there has been speculation that pregnancy, together with other stressful life events, adversely affects the risk of relapse1 or the course of the disease.2 In fact, pregnancy appears to be associated with a temporary beneficial immune state for patients with MS partly mediated through an effect on T lymphocyte subsets. This effect may have relevance for autoimmune diseases in general.
The pathogenesis of MS remains incompletely understood but involves a maladaptive humoral and cell-mediated immune response to an as-yet undetermined antigen(s). The popular model begins with peripheral T cell sensitisation in response to macrophage presentation of a foreign "myelin mimicking" antigen in association with MHC class II.3 This results in peripherally activated T cells expressing, and recognising, vascular adhesion molecules facilitating their entry to the central nervous system (CNS). Inside the CNS, activated T cells release pro-inflammatory cytokines resulting in upregulation of local CNS microglia to antigen-presenting cells with the capacity to present self-myelin and other myelin-associated proteins. This leads to an "epitope spreading" phenomenon and further secondary activation of T cells triggering an autoimmune inflammatory cascade. A direct and bystander inflammatory response results in CNS conduction block, demyelination and axonal damage that variably contribute to reversible and persistent neuronal dysfunction with associated neurological disability. Other models of disease pathogenesis exist such as persistence of a foreign viral antigen as the perpetuating stimulus,4 but most models place T cells centre stage.
T cells can be subdivided into cytotoxic and helper T cells. The latter are associated with the MHC class II linked immune response underlying MS and subdivide into type-1 (Th-1) and type-2 (Th-2) helper cells. Th-1 cells release pro-inflammatory cytokines including IL2, INF- and TNF-, while Th-2 cells are broadly antagonistic, secreting IL-6 and IL-10 which suppress the Th-1 response and drive B cell maturation and antibody production.5 MS is believed primarily to be a Th-1 driven immune state with Th-1 associated pro-inflammatory cytokines promoting blood-brain barrier breakdown, further immune cell recruitment, myelin and axonal injury. The balance between Th-1 and Th-2 associated immune states therefore influences disease activity and itself appears hormonally sensitive with pregnancy favouring a Th-2 type response.
Pregnancy, by necessity, involves a relative state of immunosuppression as the fetus carries paternally derived antigens, and it is likely that high levels of oestrogen associated with pregnancy contribute to this. Oestrogen is known to be associated with a Th-2 type immune response and downregulation of microglial activity, and has been shown to suppress extrinsic allergic encephalomyeltis (EAE), an animal model of MS.6 There has been particular interest in the immunosuppressive role of oestriol, an oestrogen produced by the fetal-placental unit and detected only during pregnancy. Oestriol levels appear to mirror most closely the reduction in relapse frequency seen during the third trimester of pregnancy, and there has already been a pilot study of estriol as a therapeutic agent in non-pregnant patients with MS that reported an 80% reduction in MRI disease activity over 6 months.7 A follow-on phase II/III clinical trial is currently under way of oestriol as add-on therapy to Copaxone in female MS patients.
Unfortunately, the immunosuppressive oestrogen profile found in pregnancy does not appear to translate into a similar protective benefit in women with lower oestrogen levels seen outside pregnancy. Oestrogen levels in non-pregnant females appear associated with microglial upregulation and a less favourable Th-1 type immune response.8
There are a large number of other factors potentially linked with an immunosuppressive Th-2 associated immune response during pregnancy,9 10 an effect likely to be as beneficial to patients with other autoimmune diseases11 as it is to patients with MS.12 Of these factors, it is perhaps worth singling out the hormonal form of vitamin D, calcitriol. Calcitriol levels peak in the first trimester and fall rapidly postpartum, inversely reflecting MS disease activity. Outside pregnancy, low levels of vitamin D associated with reduced sun exposure with increasing latitude have been linked with MS susceptibility.13 The perceived immunosuppressive benefit of vitamin D has led to small pilot studies of vitamin D supplementation in patients with MS,14 though no firm conclusions regarding efficacy can yet be made.
In summary, hormonal and cytokine changes during pregnancy appear linked with a Th-2 type immune state likely to be beneficial for patients with autoimmune inflammatory conditions such as MS. Further knowledge of the nature of this effect may provide insight into additional treatment strategies for patients with MS.................................
For the full report please go to MSRC: MS Research News : Pregnancy And MS Research (http://www.msrc.co.uk/index.cfm?fuseaction=show&pageid=1936)
At any one time, there are around 20 000 women of childbearing age with multiple sclerosis (MS) in the UK who may be considering having children. Neurologists can be asked for information from both patients and obstetric colleagues on a range of topics related to pregnancy and MS that extend beyond the well-known implications for relapse risk. This article aims to provide a brief overview for the general neurologist of the most commonly encountered issues and questions including those occasionally related to pregnancy management. The take-home message is that pregnancy does not hold adverse risks for the majority of patients with MS, or vice versa.
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system with onset typically in the second to third decade and is twice as prevalent in females as males. In the past, there has been speculation that pregnancy, together with other stressful life events, adversely affects the risk of relapse1 or the course of the disease.2 In fact, pregnancy appears to be associated with a temporary beneficial immune state for patients with MS partly mediated through an effect on T lymphocyte subsets. This effect may have relevance for autoimmune diseases in general.
The pathogenesis of MS remains incompletely understood but involves a maladaptive humoral and cell-mediated immune response to an as-yet undetermined antigen(s). The popular model begins with peripheral T cell sensitisation in response to macrophage presentation of a foreign "myelin mimicking" antigen in association with MHC class II.3 This results in peripherally activated T cells expressing, and recognising, vascular adhesion molecules facilitating their entry to the central nervous system (CNS). Inside the CNS, activated T cells release pro-inflammatory cytokines resulting in upregulation of local CNS microglia to antigen-presenting cells with the capacity to present self-myelin and other myelin-associated proteins. This leads to an "epitope spreading" phenomenon and further secondary activation of T cells triggering an autoimmune inflammatory cascade. A direct and bystander inflammatory response results in CNS conduction block, demyelination and axonal damage that variably contribute to reversible and persistent neuronal dysfunction with associated neurological disability. Other models of disease pathogenesis exist such as persistence of a foreign viral antigen as the perpetuating stimulus,4 but most models place T cells centre stage.
T cells can be subdivided into cytotoxic and helper T cells. The latter are associated with the MHC class II linked immune response underlying MS and subdivide into type-1 (Th-1) and type-2 (Th-2) helper cells. Th-1 cells release pro-inflammatory cytokines including IL2, INF- and TNF-, while Th-2 cells are broadly antagonistic, secreting IL-6 and IL-10 which suppress the Th-1 response and drive B cell maturation and antibody production.5 MS is believed primarily to be a Th-1 driven immune state with Th-1 associated pro-inflammatory cytokines promoting blood-brain barrier breakdown, further immune cell recruitment, myelin and axonal injury. The balance between Th-1 and Th-2 associated immune states therefore influences disease activity and itself appears hormonally sensitive with pregnancy favouring a Th-2 type response.
Pregnancy, by necessity, involves a relative state of immunosuppression as the fetus carries paternally derived antigens, and it is likely that high levels of oestrogen associated with pregnancy contribute to this. Oestrogen is known to be associated with a Th-2 type immune response and downregulation of microglial activity, and has been shown to suppress extrinsic allergic encephalomyeltis (EAE), an animal model of MS.6 There has been particular interest in the immunosuppressive role of oestriol, an oestrogen produced by the fetal-placental unit and detected only during pregnancy. Oestriol levels appear to mirror most closely the reduction in relapse frequency seen during the third trimester of pregnancy, and there has already been a pilot study of estriol as a therapeutic agent in non-pregnant patients with MS that reported an 80% reduction in MRI disease activity over 6 months.7 A follow-on phase II/III clinical trial is currently under way of oestriol as add-on therapy to Copaxone in female MS patients.
Unfortunately, the immunosuppressive oestrogen profile found in pregnancy does not appear to translate into a similar protective benefit in women with lower oestrogen levels seen outside pregnancy. Oestrogen levels in non-pregnant females appear associated with microglial upregulation and a less favourable Th-1 type immune response.8
There are a large number of other factors potentially linked with an immunosuppressive Th-2 associated immune response during pregnancy,9 10 an effect likely to be as beneficial to patients with other autoimmune diseases11 as it is to patients with MS.12 Of these factors, it is perhaps worth singling out the hormonal form of vitamin D, calcitriol. Calcitriol levels peak in the first trimester and fall rapidly postpartum, inversely reflecting MS disease activity. Outside pregnancy, low levels of vitamin D associated with reduced sun exposure with increasing latitude have been linked with MS susceptibility.13 The perceived immunosuppressive benefit of vitamin D has led to small pilot studies of vitamin D supplementation in patients with MS,14 though no firm conclusions regarding efficacy can yet be made.
In summary, hormonal and cytokine changes during pregnancy appear linked with a Th-2 type immune state likely to be beneficial for patients with autoimmune inflammatory conditions such as MS. Further knowledge of the nature of this effect may provide insight into additional treatment strategies for patients with MS.................................
For the full report please go to MSRC: MS Research News : Pregnancy And MS Research (http://www.msrc.co.uk/index.cfm?fuseaction=show&pageid=1936)