Effectiveness of first generation disease-modifying therapy to prevent conversion to secondary progressive multiple sclerosis.

BACKGROUND: The use of disease-modifying therapies (DMTs) in multiple sclerosis (MS) has been associated with reduced relapse rates and accumulation of disability. However, studies examining impact of DMT on risk of transition to secondary progressive MS (SPMS) leveraging population-based nationwide data are still rare. Here, we determine the population incidence of conversion to SPMS using two consecutive nation-wide cohorts, one immediately before and one after the introduction of DMT in Sweden. METHODS: We included two consecutive population cohorts of relapsing-remitting MS (RRMS) from the Swedish national MS register for the periods 1975-1994 (n = 2161), before DMT availability, and 1995-2011 (n = 3510), in which DMTs, mainly first generation DMT (injectables), became available and eventually were used by 70% of patients. We explored the risk of transition to SPMS as a calendar year function encompassing the two cohorts. In addition, we determined the incidence of transition to SPMS through age strata below and above 50 years in untreated and treated patient subgroups. RESULTS: The risk of conversion to SPMS (adjusted for current age, current time since onset, calendar year and sex) was significantly lower in the second compared with the first population cohort (hazard ratio 0.58; CI 0.48, 0.70). The risk of SPMS conversion per calendar year decreased by 2.6% annually (p < 0.001) after 1995. The risk of SPMS conversion increased with age until age 50. Thereafter, it was unchanged or decreased among those with early MS onset age (<35 years), but continued to increase with onset at higher age, with similar trends in treated and untreated subgroups. CONCLUSION: The incidence of SPMS conversion significantly decreased at the population level after introduction of first generation DMTs by 1995. DMT efficiency was confirmed by a downward turn of the annual trajectory of the risk of SPMS conversion after 1995. An onset age determined pattern of variable SPMS incidence in higher age appeared in both treated and untreated strata. While first generation DMT delayed conversion to SPMS, their long-term effect was only moderate.

Autologous haematopoietic stem cell transplantation as a first-line disease-modifying therapy in patients with 'aggressive' multiple sclerosis.

BACKGROUND: Autologous haematopoietic stem cell transplantation (AHSCT) is an effective treatment for patients with multiple sclerosis (MS) who have highly active disease, despite the use of standard disease-modifying therapies (DMTs). However, the optimal time for offering AHSCT to patients with 'aggressive' MS is yet to be established. OBJECTIVES: The objective was to explore the safety and efficacy of AHSCT as a first-line DMT in patients with 'aggressive' MS. METHODS: All patients with 'aggressive' MS who received AHSCT as a first-line DMT in five European and North American centres were retrospectively evaluated. RESULTS: Twenty patients were identified. The median interval between diagnosis and AHSCT was 5 (1-20) months. All had multiple poor prognostic markers with a median pre-transplant Expanded Disability Status Scale (EDSS) score of 5.0 (1.5-9.5). After a median follow-up of 30 (12-118) months, the median EDSS score improved to 2.0 (0-6.5, p < 0.0001). No patient had further relapses. Three had residual magnetic resonance imaging (MRI) disease activities in the first 6 months post-transplant, but no further new or enhancing lesions were observed in subsequent scans. CONCLUSION: AHSCT is safe and effective as a first-line DMT in inducing rapid and sustained remission in patients with 'aggressive' MS.

Rapidly increasing off-label use of rituximab in multiple sclerosis in Sweden - Outlier or predecessor?

OBJECTIVES: Off-label use of rituximab to treat MS patients in Sweden is high, and the need for long-term safety data may not be met. Our objectives were to assess the rate of rituximab prescription in patients with multiple sclerosis in Sweden and, in addition, to evaluate the safety of rituximab in a single centre for patients with multiple sclerosis. MATERIAL AND METHODS: Review of the Swedish MS register was performed to study the number of MS patients treated with rituximab during the last 6 years. Investigation also included a retrospective review of medical files in search for possible side effects/adverse events in all adult patients with MS treated with rituximab at Uppsala University Hospital. RESULTS: Presently, in Sweden the rate of rituximab prescriptions in relation to other annually started of disease- modifying drugs in MS is 53.5%. CONCLUSIONS: The share of MS patients in Sweden who are treated with rituximab is very high, and also rapidly increasing. Taken into account the off-label use, cases with adverse medical conditions that could possibly be related to rituximab use should be reported thoroughly.

Risk of epilepsy after a single seizure in multiple sclerosis.

BACKGROUND AND PURPOSE: The 2014 International League Against Epilepsy clinical definition of epilepsy allows diagnosis after a single unprovoked seizure if the 10-year recurrence risk exceeds 60%. Multiple sclerosis (MS) carries an increased risk of epilepsy, but the risk after a first seizure is unknown. We aimed to investigate the risk of epilepsy in patients with MS who had suffered a first seizure. METHODS: We cross-referenced data from the Swedish MS register with the national patient register for 15 810 patients with MS and 43 635 controls and included 289 patients with MS and 222 controls with a first diagnosis of seizure or status epilepticus (SE) without prior epilepsy or presumed symptomatic aetiology. Kaplan-Meier curves were used to estimate the risk of epilepsy. RESULTS: The 10-year risk of epilepsy was 51.4% [95% confidence interval (CI), 44.0-58.9] for patients with MS and 41.3% (95% CI, 33.5-49.1) for controls. The risk was 46.1% (95% CI, 35.3-56.9) for patients with relapsing-remitting MS and 60.7% (95% CI, 46.6-74.8) for patients with secondary progressive MS. For patients with MS with SE, the 10-year risk of epilepsy was 85.9% (95% CI, 67.9-100). CONCLUSIONS: Our data indicate that patients with relapsing-remitting MS have a similar risk as controls of developing epilepsy after a single seizure. Patients with secondary progressive MS could run a greater risk of subsequent epilepsy, but our data do not indicate a risk that, with certainty, exceeds the threshold specified by the International League Against Epilepsy. Patients with SE have a high risk of epilepsy, possibly motivating diagnosis and treatment.

Autologous hematopoietic stem cell transplantation for pediatric multiple sclerosis: a registry-based study of the Autoimmune Diseases Working Party (ADWP) and Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT).

Autologous hematopoietic stem cell transplantation (aHSCT) is a promising therapy for multiple sclerosis (MS), which has mainly been used in adults. The purpose of this study was to investigate efficacy and adverse events of aHSCT in the treatment of children with MS using data from the European Society for Blood and Marrow Transplantation registry. Twenty-one patients with a median follow-up time of 2.8 years could be identified. PFS at 3 years was 100%, 16 patients improved in expanded disability status scale score and only 2 patients experienced a clinical relapse. The procedure was generally well tolerated and only two instances of severe transplant-related toxicity were recorded. There was no treatment-related mortality, although one patient needed intensive care. aHSCT may be a therapeutic option for children with disease that does not respond to standard care.

Guidelines for the use of magnetic resonance imaging in diagnosing and monitoring the treatment of multiple sclerosis: recommendations of the Swedish Multiple Sclerosis Association and the Swedish Neuroradiological Society.

Multiple sclerosis (MS) is associated with inflammatory lesions in the brain and spinal cord. The detection of such inflammatory lesions using magnetic resonance imaging (MRI) is important in the consideration of the diagnosis and differential diagnoses of MS, as well as in the monitoring of disease activity and predicting treatment efficacy. Although there is strong evidence supporting the use of MRI for both the diagnosis and monitoring of disease activity, there is a lack of evidence regarding which MRI protocols to use, the frequency of examinations, and in what clinical situations to consider MRI examination. A national workshop to discuss these issues was held in Stockholm, Sweden, in August 2015, which resulted in a Swedish consensus statement regarding the use of MRI in the care of individuals with MS. The aim of this consensus statement is to provide practical advice for the use of MRI in this setting. The recommendations are based on a review of relevant literature and the clinical experience of workshop attendees. It is our hope that these recommendations will benefit individuals with MS and guide healthcare professionals responsible for their care.

Onset and outcome of pregnancy after autologous haematopoietic SCT (AHSCT) for autoimmune diseases: a retrospective study of the EBMT autoimmune diseases working party (ADWP).

Autologous haematopoietic SCT (AHSCT) is increasingly used to control severe and refractory autoimmune diseases (AD). Many patients are women of reproductive age with a potential desire for children. We present a multicentre retrospective analysis of pregnancy and childbirth in patients who underwent AHSCT for AD. The databases of the European Blood and Marrow Transplantation and University of Sao Paulo, Ribeirão Preto, Brazil were searched for female patients aged 18-50 years who had received AHSCT for AD between 1994-2011. In 324 adult female patients, 22 pregnancies were reported in 15 patients between 1997-2011. Indications for AHSCT included multiple sclerosis (n=7), systemic sclerosis (n=5), rheumatoid arthritis (n=1), juvenile idiopathic arthritis (n=1) and Takayasu disease (n=1). Of the 22 reported pregnancies, 20 followed natural conception. 15 pregnancies (68%) resulted in healthy life births, whereas 7 (32%) failed. Exacerbations of AD occurred in two patients during second pregnancies. No maternal mortality was associated with pregnancy or postpartum. There were no reports of congenital, developmental or any other disease in the children. This retrospective analysis confirms the possibility of pregnancy and childbirth following AHSCT for severe AD. The outcome of pregnancy is generally good and most led to the birth of a healthy child.

Normal outcome of pregnancy with ongoing treatment with natalizumab.

BACKGROUND: Treatment of multiple sclerosis (MS) with natalizumab during pregnancy is not recommended due to potential risks for the foetus. Despite strong advice accidental pregnancies occur. CASE: A 32-year old woman with MS since the age of 26 was treated with natalizumab since January 2008. Treatment was stopped April 2011 due to pregnancy plans, but was restarted following an MS relapse. The patient was thoroughly informed about potential foetal risks, but nevertheless she one year later disclosed that she was pregnant in gestational week 15. Treatment was continued, since the first trimester had passed. The pregnancy course was normal and a healthy daughter was born at full gestational term. CONCLUSIONS: This is the second known case where natalizumab treatment continued throughout the whole gestational period.

Assessing tissue damage in multiple sclerosis: a biomarker approach.

OBJECTIVES: Magnetic resonance imaging (MRI) of the brain and spinal cord is the gold standard for assessing disease activity in multiple sclerosis (MS). MRI is an excellent instrument for determination of accumulated damage to the brain and spinal cord, but tells us little about ongoing tissue damage. In this study, biomarkers of oligodendrocyte, axonal and astrocyte injury were related to MRI and clinical findings and used to assess tissue damage in MS. MATERIALS AND METHODS: Cerebrospinal fluid from 44 patients with relapsing-remitting MS, 20 with secondary progressive MS and 15 controls were investigated with ELISA to determine levels of myelin basic protein (MBP), neurofilament light (NFL) and glial fibrillary acidic protein (GFAp). Patients underwent MRI of the brain and spinal cord, and gadolinium enhancing lesions, T1 lesions and T2 lesions were counted. RESULTS: Patients in clinical relapse and patients with nonsymptomatic gadolinium enhancing lesions had high levels of MBP and NFL, indicating ongoing damage to oligodendrocytes and axons. The level of MBP dropped quickly within a week from the onset of a relapse, whereas NFL remained elevated for several weeks and GFAp slowly rose during the course of a relapse. Relapsing-remitting MS patients without gadolinium enhancing lesions had values of MBP, NFL and GFAp similar to controls, while patients with secondary progressive disease had moderately increased values of all biomarkers. CONCLUSIONS: Analysis of MBP, NFL and GFAp provides direct means to measure tissue damage and is a useful addition to our methods for evaluation of MS.

Bilateral and recurrent optic neuritis in multiple sclerosis.

OBJECTIVE: To assess the frequency of bilateral and recurrent optic neuritis (ON) in multiple sclerosis (MS) and to compare these results with epidemiological data of ON in neuromyelitis optica (NMO) and recurrent ON without other signs of disease. METHODS: We identified 472 patients with diagnosis of MS from the Swedish Multiple Sclerosis Register. These patients were evaluated for the presence of ON and whether the ON was the presenting symptom of MS; unilateral or bilateral; monophasic or recurrent. RESULTS: Twenty-one percent presented with ON as their first manifestation of MS. The proportion of patients developing a second attack of ON before demonstration of other manifestations of MS was 5.5% and the frequency of recurrent bilateral ON as the presenting symptom was 3.8%. Only two patients presented with simultaneously appearing bilateral ON corresponding to 0.42%. CONCLUSION: Recurrent ON, whether unilateral or bilateral, is a common presentation of MS. As MS is a much more common disease than NMO, care must be taken when evaluating the work-up of patients with recurrent ON. In some cases repeated MRI and lumbar punctures are warranted to improve diagnostic accuracy, even in the presence of the serological marker NMO-IgG.

Thrombophilia in children with cystic fibrosis.

In some children with cystic fibrosis (CF), percutaneous long lines occlude sooner than expected (due to thrombophlebitis or thrombosis), and many have a totally implantable venous access device (TIVAD), a recognized complication of which is thrombosis. This complication is more likely if the child has an underlying thrombotic tendency, which may be enhanced in the presence of inflammatory lung disease. There are no reports of an identified association of heritable thrombophilia with CF, although individual cases have been recognized. Our aim was to determine the incidence of thrombophilia in children with CF. In a tertiary pediatric CF center, blood was screened for thrombophilia at annual review, and retested if abnormal. A thrombotic abnormality was found in 41/204 (20%) patients. These included activated protein C resistance (10/204, 5%) with a prevalence similar to that expected, but the following abnormalities had an increased prevalence: antithrombin deficiency (2/204, 1%), protein S deficiency (11/204, 5%), protein C deficiency (8/204, 4%), and lupus anticoagulant (18/204, 9%). There were no differences found in those with thrombophilia for the following parameters: age, gender, genotype, lung function, presence of Pseudomonas aeruginosa, prothrombin time, serum IgE, aspergillus-specific IgE, liver function, and blood inflammatory markers. Fifteen children had TIVADs, 4 of whom had evidence of thrombophilia. In conclusion, a significant proportion of patients had a thrombophilic abnormality. We recommend that thrombophilia screening be performed prior to insertion of a TIVAD, and also in those with a history of venous thrombosis, blocked TIVADs, or recurring problems with long lines.

Automated quantitation of peripheral blood neutrophil activation in patients with myocardial ischaemia.

BACKGROUND: Coronary ischaemic syndromes are associated with neutrophil activation. The Bayer automated haematology analysers can detect increased light scatter of neutrophil populations, which correlates with neutrophil activation. We aimed to assess the role of an automated analyser in detecting systemic neutrophil activation in peripheral blood samples of patients with coronary ischaemia. METHODS: A prospective cross-sectional study was undertaken in 18 patients with chronic stable angina, 9 with unstable angina and 26 normal control subjects. Whole blood samples were taken to assess neutrophil count and light scatter, and serum samples were taken from some patients for assessment of Troponin T, C-reactive protein (CRP) and myeloperoxidase (MPO). In addition, whole blood was stimulated in vitro with interleukin (IL)-8 and N-formyl-methionyl-leucyl-phenylalanine (fMLP) to assess changes in neutrophil light scatter detected by the analyser. RESULTS: Neutrophil light scatter was increased in patients with chronic stable and unstable angina compared to normal control subjects (normal subjects 74.1 (73.3, 75.0) (mean arbitrary units (95% confidence intervals, (CI)) vs. 78.6 (76.9, 80.3) in the chronic stable angina group P<0.001 and 77.1 (75.3, 79.0) in the unstable angina group P<0.007). In vitro stimulation of whole blood produced comparable increases in neutrophil light scatter when morphological changes in neutrophils were demonstrable under electron microscopy. CONCLUSIONS: Automated measurement of neutrophil activation by light scatter is possible using the Advia 120 analyser and is superior to a neutrophil count in discriminating groups with angina. This technique may be useful in monitoring disease activity and progression in coronary artery disease and in guiding the use of anti-inflammatory therapies.

Prospective double-blind randomized study of the effects of four intravenous fluids on platelet function and hemostasis in elective hip surgery.

A prospective randomized double-blind study was performed to determine the effects of three colloids, Haemaccel, Gelofusine and albumin, and also saline on platelet activation, platelet aggregation (induced by adenosine diphosphate (ADP), epinephrine, collagen) platelet agglutination by ristocetin and other hemostatic variables in 55 patients undergoing primary unilateral total hip replacement. The fluids were administered according to normal clinical practice and assessments were made immediately before, at the end, and 2 h after the end of surgery. Surgery was accompanied by thrombin generation (increases in thrombin/antithrombin III complex, prothrombin F1 +2 fragment) platelet activation (betaTG) and compromised coagulation. Generally, the platelet activation appeared to result in platelet desensitization and brought about a persistent reduction in platelet aggregation to ADP and epinephrine, irrespective of the fluid used. Additionally, Haemaccel and Gelofusine inhibited ristocetin-induced platelet agglutination and albumin inhibited collagen-induced platelet aggregation. Gross inhibitory effects of Haemaccel that had been predicted from an earlier in vitro study did not occur. Particular fluids had selective additional effects on the hemostatic system. Albumin infusion served to maintain plasma albumin at normal concentrations postsurgery. The two gelatin preparations, Haemaccel and Gelofusine, maintained plasma viscosity. All three colloids led to a transient increase in activated partial thromboplastin time postsurgery and also a transient fall in the concentration of factor VIII, which were accompanied by a transient increase in bleeding time, but there was no measurable increase in blood loss. Inhibition of platelet aggregation by certain colloids may provide additional protection against the increased thrombotic risk in patients following major surgery.

Study of five cell salvage machines in coronary artery surgery.

We evaluated the effectiveness, ease of use and safety of five machines for blood salvage during coronary artery surgery. All were equally effective in concentrating red cells. We measured haemoglobin, packed cell volume, free haemoglobin, white cells, neutrophil elastase, platelets, thrombin-antithrombin complex (TAT), prothrombin activation peptide F1.2, fibrin degradation product (d-dimers), tissue plasminogen activator (tPA) and heparin in wound blood, in washed cell suspensions and in a unit of bank blood prepared for each patient. All machines were equally safe and easy to use and were equally effective in removing heparin and the physiological components measured. There were no adverse effects on patients. Clotting factors are severely depleted both in salvaged blood, even before washing, and in bank blood. Cell savers are a valuable adjunct to coronary artery surgery, but careful monitoring of coagulation is required when the volumes of either bank blood or salvaged blood are large.

Systemic platelet effects of contrast media: implications for cardiologic research and clinical practice.

BACKGROUND: Angiographic contrast media cause platelet activation and decrease aggregability in vitro. We have previously shown in vitro a significant antiplatelet effect of contrast media at the concentrations obtained locally in the coronary artery during angioplasty. It is not known, however, whether a systemic effect is present. METHOD: Thirty patients undergoing diagnostic coronary angiography were prospectively randomized to receive the nonionic medium iohexol, ionic low-molecular-weight medium ioxaglate, or ionic high-molecular-weight medium diatrizoate. Platelet aggregability was measured before and after the investigation with whole blood electrical impedance aggregometry (WBEA) with collagen agonist and the PFA-100 (Dade, Miami, Fla) platelet function analyzer with combined shear, collagen, and adenosine diphosphate as agonists. RESULTS: With WBEA, with iohexol no difference in impedance change was seen: (medians and ranges) before, 9.8 Omega (4.8-19.2 Omega) versus after, 9.6 Omega (2-19.2 Omega) (P not significant [NS]). With ioxaglate a significant fall was seen: before, 8.6 Omega (6.4-15.2 Omega) versus after, 6.6 Omega (0-12.4 Omega) (P =.004). With diatrizoate a significant and greater fall was seen: before, 10.8 Omega (6.4-17.6 Omega) versus after, 6.6 Omega (0-10.8 Omega) (P =.002). With PFA, no difference in closure time was seen with any medium: iohexol before, 99 seconds (79-142 seconds) versus after, 142 seconds (63-128 seconds) (P NS); ioxaglate before, 120 seconds (75-258 seconds) versus after, 95 seconds (74-258 seconds) (P NS); and diatrizoate before, 114.5 seconds (65-250 seconds) versus after, 100.5 seconds (72-300 seconds) (P NS). CONCLUSIONS: Ionic but not nonionic contrast media have a systemic antiplatelet effect at diagnostic angiographic doses when measured with WBEA. Such an effect has not been shown before. This may explain the observed improved clinical outcome with ionic contrast media but also might confound platelet studies in coronary angioplasty.

High molecular weight kininogen deficiency: a patient who underwent cardiac surgery.

A 66 year old male, referred for cardiac surgery, was found to have high molecular weight kininogen deficiency (activity <1%). Apart from activated partial thromboplastin time (APTT) >300 s, tests of haemostasis were otherwise normal (factors VIII, IX, XI, XII and prekallikrein). No inhibitor of coagulation was found. The activated coagulation time (ACT) was 800 s pre-operatively and >1000 s after heparin. Heparin levels were measured directly by an anti-Xa chromogenic assay, with values of between 2.9 and 3.2 u/ml during cardiopulmonary bypass. Thrombin-antithrombin levels rose from 2.3*g/l before surgery to a peak of 83.5*g/l at the end of cardiopulmonary bypass. Cross linked fibrin d-dimers (XDP) levels rose from 100 ng/ml before operation to 600 ng/ml after protamine administration. The patient had no excess bleeding and no thrombotic complications from surgery. This patient shows that high molecular weight kininogen is not required for thrombin formation or fibrinolysis during cardiac surgery and illustrates the need to measure heparin directly in patients with such contact factor deficiencies.

Diurnal variation in platelet aggregation iwth the PFA-100 platelet function analyser.

BACKGROUND: Myocardial infarction is commoner in the morning, and previous small studies suggesting diurnal variation in platelet aggregation have been limited to optical aggregometry with platelet-rich plasma and low shear. This phenomenon was studied using whole blood at high shear rates. METHOD: Fifteen healthy volunteers were venesected at 0800 hrs supine in bed immediately before rising, at 0830 hrs 30 min after rising, at 1200 hrs and 1700 hrs. Samples underwent the high shear method of PFA-100 using additional chemical agonists of collagen with ADP or collagen with epinephrine. PFA-100 results are reported as closure time of the experimental aperture in seconds, a longer time indicating less platelet aggregation. RESULTS: With both epinephrine and ADP, a non-significant shortening of closure time was seen on rising. Subsequently, with both agonists the closure time lengthened through the day. With ADP the difference was small (medians 0830 hrs: 85 s, 1700 hrs: 87.5 s) but statistically significant (p = 0.03). With epinephrine it was much more marked (medians 0830 hrs: 114.3 s, 1700 hrs: 140.5 s) and highly significant (p = 0.002). CONCLUSIONS: These findings demonstrate a diurnal rhythm in platelet function using whole blood at high shear rates. This is likely to be more applicable to the in vivo situation than previously reported optical aggregometry studies.