The consensus findings of an international author group recommend a therapeutic strategy based on proactive monitoring and shared decision-making in MS. Early diagnosis and improved treatment access are also key components.

SummaryBackground Relapses of multiple sclerosis decrease during pregnancy, when the hormone estriol is increased. Estriol treatment is anti-infl ammatory and neuroprotective in preclinical studies. In a small single-arm study of people with multiple sclerosis estriol reduced gadolinium-enhancing lesions and was favourably immunomodulatory. We assessed whether estriol treatment reduces multiple sclerosis relapses in women.

IntroductionWe present international consensus recommendations for improving diagnosis, management and treatment access in multiple sclerosis (MS). Our vision is that these will be used widely among those committed to creating a better future for people with MS and their families. MethodsStructured discussions and literature searches conducted in 2015 examined the personal and economic impact of MS, current practice in diagnosis, treatment and management, definitions of disease activity and barriers to accessing disease-modifying therapies (DMTs). Graphical abstract Keywordsmultiple sclerosis consensus statement treatment strategy disease activity disease-modifying therapy (DMT) magnetic resonance imaging (MRI)Highlights  Consensus recommendations on MS diagnosis, management and treatment are presented.  Neurological reserve, a component of brain health, can compensate for CNS damage.  We propose a therapeutic strategy that aims to maximize lifelong brain health.  Proactive monitoring, shared decision-making and improved treatment access are key.  Early referral, diagnosis and treatment initiation are also of crucial importance.

Multiple sclerosis (MS) is a chronic autoimmune disease of the CNS characterized by inflammation, demyelination, and axonal injury. These pathologic effects are manifested in clinical symptoms of relapse and disability. Various disease-modifying therapies have been developed in recent years to modulate the body's immune response. Among the most widely used are the beta interferons (IFNbeta). All produce comparable biological effects and are approved for the treatment of relapsing-remitting MS (RRMS). Although the precise mechanisms through which IFNbeta achieves its antiinflammatory and immunomodulatory effects remain uncertain, several modes of action have been proposed, including inhibition of T-cell activation and proliferation; apoptosis of autoreactive T cells; induction of regulatory T cells; inhibition of leukocyte migration across the blood-brain barrier; cytokine modulation; and potential antiviral activity. Endogenously produced IFNbeta in the injured brain is also now believed to contribute to mediation of antiinflammatory and regenerative effects. All these mechanisms are believed to underlie the therapeutic effect of IFNbeta in the treatment of RRMS.

Bone marrow, or cells selected from bone marrow, were reported recently to give rise to cells with a neural phenotype after in vitro treatment with neural-inducing factors or after delivery into the brain. However, we showed previously that untreated bone marrow cells express products of the neural myelin basic protein gene, and we demonstrate here that a subset of ex vivo bone marrow cells expresses the neurogenic transcription factor Pax-6 as well as neuronal genes encoding neurofilament H, NeuN (neuronal nuclear protein), HuC͞HuD (Hu-antigen C͞Hu-antigen D), and GAD65 (glutamic acid decarboxylase 65), as well as the oligodendroglial gene encoding CNPase (2,3 cyclic nucleotide 3-phosphohydrolase). In contrast, astroglial glial fibrillary acidic protein (GFAP) was not detected. These cells also were CD34 ؉ , a marker of hematopoietic stem cells. Cultures of these highly proliferative CD34 ؉ cells, derived from adult mouse bone marrow, uniformly displayed a phenotype comparable with that of hematopoietic progenitor cells (CD45 ؉ , CD34 ؉ , Sca-1 ؉ , AA4.1 ؉ , cKit ؉ , GATA-2 ؉ , and LMO-2 ؉ ). The neuronal and oligodendroglial genes expressed in ex vivo bone marrow also were expressed in all cultured CD34 ؉ cells, and GFAP was not observed. After CD34 ؉ cell transplantation into adult brain, neuronal or oligodendroglial markers segregated into distinct nonoverlapping cell populations, whereas astroglial GFAP appeared, in the absence of other neural markers, in a separate set of implanted cells. Thus, neuronal and oligodendroglial gene products are present in a subset of bone marrow cells, and the expression of these genes can be regulated in brain. The fact that these CD34 ؉ cells also express transcription factors (Rex-1 and Oct-4) that are found in early development elicits the hypothesis that they may be pluripotent embryonic-like stem cells.

A better understanding of immune-mediated mechanisms in the pathogenesis of multiple sclerosis and the contribution of environmental risk factors toward the development of multiple sclerosis will help further improve therapeutic approaches to prevent disease progression.

Because 4-aminopyridine (AP) improves residual deficits in some multiple sclerosis (MS) patients but has a narrow toxic-to-therapeutic margin, we compared the safety and efficacy of two target peak serum concentration ranges (low: 30 to 59 ng/ml and high: 60 to 100 ng/ml). We enrolled eight MS patients with temperature-sensitive visual and motor deficits in a randomized, placebo-controlled, double-blind, crossover trial of short-term oral AP treatment. We randomized patients to a sequence of three treatments on three separate days: placebo, low serum concentration, and high serum concentration. We determined dosing to achieve the desired steady-state peak serum concentration ranges from a test dose and population pharmacokinetic parameters using bayesian estimation. Contrast sensitivity, standard neurologic examination, ratings of videotaped neurologic examinations, and quantitative strength assessment all improved with treatment, but flicker fusion frequency, visual evoked response latencies, and Expanded Disability Status Scale scores did not. All patients experienced side effects during the high-serum-concentration arm. A grand mal seizure occurred at a serum AP level of 104 ng/ml, and an acute confusional episode occurred at 114 ng/ml. AP treatment produced improvements in residual deficits in MS patients, but the occurrence of significant toxicity suggests that AP serum levels should be monitored and peak levels above 100 ng/ml should be avoided. Concentration-control methodology may be useful in testing putative treatments for other neurologic diseases.

In a randomized, placebo-controlled, double-blind study, glatiramer acetate (Copaxone) reduced the relapse rate and slowed accumulation of disability for patients with relapsing - remitting multiple sclerosis. Of the original 251 patients randomized to receive glatiramer acetate or placebo, 208 chose to continue in an open-label study with all patients receiving active drug. The majority of the original double-blind cohort continues to receive glatiramer acetate by daily subcutaneous injection and are evaluated at 6-month intervals and during suspected relapse. The data reported here are from approximately 6 years of organized evaluation, including the double-blind phase of up to 35 months and the open-label phase of over 36 months. Daily subcutaneous injections of 20 mg glatiramer acetate were well tolerated. The mean annual relapse rate of the patients who received glatiramer acetate since randomization and continued into the open-label study was 0.42 (95% confidence interval (CI), CI=0.34 - 0.51). The rate per year has continued to drop and for the sixth year is 0.23. Of the group who have received glatiramer acetate without interruption for 5 or more years, 69.3% were neurologically unchanged or have improved from baseline by at least one step on the Expanded Disability Status Scale (EDSS). Patients who left the open-label phase were surveyed by questionnaire. The majority responded, providing information about their current status and reasons for dropping out. This study demonstrates the sustained efficacy of glatiramer acetate in reducing the relapse rate and in slowing the accumulation of disability in patients with relapsing forms of multiple sclerosis. Multiple Sclerosis (2000) 6 255 - 266