Initial treatment strategy and clinical outcomes in Finnish MS patients: a propensity-matched study.

BACKGROUND: The optimal treatment strategy with disease-modifying therapies (DMTs) in relapsing-remitting multiple sclerosis (RRMS) remains uncertain. OBJECTIVE: To compare outcomes of initial treatment with infusion therapies and starting therapy with medium efficacy therapy in a propensity-matched cohort of Finnish RRMS patients. METHODS: A total of 154 RRMS patients initiating natalizumab, alemtuzumab, ocrelizumab or rituximab as first DMT (high efficacy DMT, heDMT group) and 1771 patients initially treated with injectable therapies, teriflunomide or dimethylfumarate and escalated based on disease activity (moderate efficacy DMT, meDMT group) were identified from the Finnish MS registry. Nearest neighbor propensity matching (1:1, caliper 0.1) was performed for age, sex, baseline Expanded Disability Status Scale (EDSS), annual relapse rate (ARR) one year prior DMT and time since MS symptom onset. Primary outcome was time to 6-month confirmed EDSS progression and the secondary outcome time to first relapse. RESULTS: In the propensity-matched group comparisons, the probability of 6-month confirmed disability progression (CDP) at 5 years after DMT start was 28.4% (95% CI 15.7-39.3) in the heDMT group (n = 66) and 47.0% (95% CI 33.1-58.1) in meDMT group (n = 66), p = 0.013. Probability of relapse at 5 years was 34.6% (95% CI 24.1-43.6) for heDMT (n = 105) and 47.2% (95% CI 36.6-56.1) for meDMT (n = 105), p = 0.019. CONCLUSIONS: Initiating MS-therapy with heDMT significantly reduced the risk of 5-year disability progression and relapse compared to using meDMT as first DMT choice in propensity-matched groups of Finnish MS-patients.

Common comorbidities and survival in MS: Risk for stroke, type 1 diabetes and infections.

BACKGROUND: Survival in MS has increased during the era of disease modifying therapies, but life expectancy in MS patients is still reduced by several years. Increased risk for common comorbidities related to brain health, such as risk for circulatory diseases have been reported in MS and could affect survival. In this paper, we studied age- and gender adjusted risks for circulatory diseases and related disorders, and their impact on overall MS survival in population of Southwest Finland. MATERIALS AND METHODS: The ICD-10 codes for hospital visits were searched from the administrative data pool from 1.1.2004 up to 31.12.2012 for the resident MS and control cases at the Hospital District of Southwest Finland. The MS population under study consisted of prevalent cases in 1.1.2004 and new cases from 1.1.2004 followed up to death or 31.12.2012. Patient documents were scrutinized to confirm the MS diagnosis (G 35) by the McDonald´s criteria and to confirm the diagnoses and causes of death for the cerebro- and cardiovascular diagnoses under study. The randomly chosen 10-fold control population was matched by birth year and gender to calculate the coincident risks (odds ratio, OR) with 95% confidence intervals (95% CI) and another separate control population from the same patient pool was used to verify the stability of the results. P-values were calculated using Pearson's χ2 test. The Kaplan- Meier analysis log rank test was applied to study survival. RESULTS: During the follow-up 1074 confirmed MS cases were treated in the hospital district, including the deceased cases after 1.1.2004 (5.9%). The probability of survival was 82.4 years among MS and 85.6 years among the control cases, log rank p < 0.001. The survival disadvantage within MS was associated with comorbidity for circulatory disease codes in ICD -10: I06-I71, log rank p < 0.001. The specific risk for ischemic and haemorrhagic stroke was significant with high OR of 1.49 (95% CI 1.03- 2.35) and 2.5 (1.24-5.06) respectively. The two-fold risk for type 1 diabetes in MS was significant, OR 2.1 (1.3-3.36). The main causes of death among the MS cases were infections and the coincident high risk for several infections was significant. There was no difference in the risk for acute myocardial infarct, transient ischemic attack, atrial fibrillation, hypertension, or obesity in comparison with the control cases. CONCLUSIONS: Given the high risk for stroke in this MS population and the observed complexity among the coincident common risk factors for circulatory diseases, the high risk for type 1 diabetes and common infections raise a need to recognize patients at risk with these conditions and with the other known risk factors such as metabolic syndrome and smoking. The survival disadvantage related to circulatory diseases observed in general population is true also in MS and should be recognized to reduce the burden of disease and premature mortality in MS.

Risk of osteoporotic fractures in multiple sclerosis patients in southwest Finland.

OBJECTIVES: Increased risk of osteoporotic fractures in multiple sclerosis (MS) patients compared with general population has been reported. The purpose of this study was to assess the risk of osteoporotic and other low-energy fractures in an MS cohort from a large hospital district in southwest Finland. Age-adjusted total and gender-specific prevalence for definite MS per 100 000 in a population of 472 139 was calculated as a point prevalence in December 31, 2012. MATERIALS AND METHODS: Patients with MS and comorbid fractures were identified by searching for ICD-9 and ICD-10 codes during a period from 2004 to 2012 from hospital administrative data in Turku University Hospital (TYKS) in southwest Finland Case ascertainment was performed by review of medical records. Osteoporotic fracture was defined as a low-energy fracture of the pelvis, hip, femur, tibia, humerus, collar bone, ulna/radius, vertebrae, or rib. The control population was a 10-fold age- and gender-matched population. RESULTS: The point prevalence (N 1004) of MS was 212.6/105 (CI 199.5-225.8) in December 31, 2012. A total of 100 (9.9%) of 1004 confirmed MS cases experienced at least one fracture during the study period. Relative risks (RRs) for all fractures (1.33, 95% CI 1.10-1.60) and osteoporotic fractures (1.50, 95% CI 1.18-1.90) were significantly increased in patients with MS compared with controls. In particular, RRs for hip fractures (5.00, 95% CI 2.96-8.43) and fractures of humerus (2.36, 95% CI 1.32-4.42) were elevated in patients with MS vs controls. CONCLUSIONS: We observed high prevalence of MS in southwest Finland and confirmed increased age-adjusted comorbid risk for osteoporotic fractures and other low-energy fractures compared with individually matched controls.

The incidence and triggers of adult-onset Guillain-Barré syndrome in southwestern Finland 2004-2013.

BACKGROUND AND PURPOSE: A Swiss study recently reported surgery as a potential risk factor for developing Guillain-Barré syndrome (GBS). It was sought to establish this in the Finnish adult population. METHODS: Persons over 16 years of age who received a diagnosis of GBS in 2004-2013 were identified from the patient register of Turku University Hospital and their patient records were analyzed to identify possible triggers. RESULTS: A cohort of 69 adult patients with GBS (63.8% men) was identified giving an annual incidence of 1.82/100,000. Of these, four (5.8%) had experienced a surgical procedure during the preceding 6 weeks with a relative risk of 6.28 (95% confidence interval 4.15-9.47, P < 0.001) compared with the general study population or a risk of 1.25/100,000 operations. No difference between genders was found. Only two (2.9%) patients had received a vaccination [one against seasonal influenza (P = 0.888) and one against pandemic influenza (Pandemrix(®), GlaxoSmithKline Biologicals, Rixensart, Belgium, relative risk 2.85, 95% confidence interval 1.27-6.38, P = 0.011)] during the preceding 6 weeks. The most common GBS triggers identified were respiratory tract infections in 30 cases (43.5%) and gastroenteritis in 16 cases (23.2%) whilst two patients (2.9%) had had both. CONCLUSIONS: The overall incidence of GBS in the adult population of southwestern Finland was similar to previous studies worldwide and the most common triggers were respiratory tract infections and gastroenteritis. Surgery was a rare risk factor and of vaccinations only the one against pandemic influenza raised the risk of GBS.

A Randomised, Double-Blind, Placebo-Controlled Trial with Vitamin D3 in MS: Subgroup Analysis of Patients with Baseline Disease Activity Despite Interferon Treatment.

We present a subgroup analysis of the first double-blind, placebo-controlled, randomised trial with vitamin D3 in MS. In the overall study population, there were 34 patients in the vitamin D arm and 32 patients in the placebo arm. All the patients were using interferon-ß-1b (IFNB) therapy. The subgroup consisted of 15 patients in the vitamin D arm and 15 patients in the placebo arm, who had either at least one relapse during the year preceding the study or enhancing T1 lesions at the baseline MRI scan. We measured the total number of MRI T1 enhancing lesions, the number of new/enlarging T2 lesions and T2 lesion volume (BOD) (mm(3)), EDSS (Expanded Disability Status Scale), annual relapse Rate (ARR), timed 25-foot walk (T25FW), and timed 10-foot tandem walk (TT10W) at baseline and at 12 months in the vitamin D-treated and in the placebo-treated patients. There was a statistically significant reduction in the number of T1 enhancing lesions, a smaller T2 lesion volume growth and less new/enlarging T2 brain MRI lesions in the vitamin D3-treated than in the placebo-treated subgroup patients. The MRI results were slightly more pronounced in the subgroup than in the overall study population.

Expression of LIF and LIF receptor beta in Alzheimer's and Parkinson's diseases.

BACKGROUND: Signaling through the leukemia inhibitory factor (LIF) receptor (LIFR) is crucial for nervous system development. There are few studies concerning the expression of LIF and LIFR in normal and degenerating adult human brain. OBJECTIVES: To study the expression of LIF and LIFR in Alzheimer's disease (AD), Parkinson's disease (PD), and control brains. PATIENTS AND METHODS: LIF and LIFR mRNA copy numbers were determined by quantitative real-time RT-PCR from four brain regions of 34 patients with AD, 40 patients with PD, and 40 controls. Immunohistochemistry was performed in seven PD and in four AD patients and in seven normal controls. RESULTS: In general, the LIF copy numbers were 1 log higher than the LIFR copy numbers. In the AD brains, LIF expression was higher than in the controls in the hippocampus and in the temporal cortex, and in the PD brains in the hippocampus and in the anterior cingulated cortex. Expressions of LIF and LIFR in different brain regions were opposite except for the AD hippocampus and PD anterior cingulated cortex, where the expression patterns were parallel. CONCLUSIONS: Co-operative expression of LIF and LIFR in AD hippocampus and PD anterior cingulated cortex may indicate a role for LIF in neuronal damage or repair in these sites.

Serum level of CNTF is elevated in patients with amyotrophic lateral sclerosis and correlates with site of disease onset.

We measured serum levels of neurotrophic cytokines ciliary neurotrophic factor (CNTF) and leukaemia inhibiting factor (LIF) in 96 patients either with familial amyotrophic lateral sclerosis (FALS, n = 18) or sporadic ALS (SALS, n = 78) and in 27 inflammatory neurological controls (13 multiple sclerosis and 14 Guillain-Barré syndrome) and in 27 healthy controls. Serum level of CNTF was significantly higher in ALS patients than in inflammatory neurological controls or healthy controls, and significantly higher in patients with ALS onset from upper or lower extremities than in patients with a purely bulbar onset of the disease. Serum CNTF levels did not significantly differ between patients with FALS and SALS, and it did not correlate with the age of onset or duration of the disease. No detectable serum levels of LIF were observed in the patient groups or in the healthy controls.

A longitudinal study of serum 25-hydroxyvitamin D and intact parathyroid hormone levels indicate the importance of vitamin D and calcium homeostasis regulation in multiple sclerosis.

BACKGROUND: Past sun exposure and vitamin D3 supplementation have been associated with a reduced risk of multiple sclerosis (MS). There are no previous longitudinal studies of vitamin D in MS. OBJECTIVES: To compare regulation of vitamin D and calcium homeostasis between patients with MS and healthy controls. To study the correlation of parameters of vitamin D metabolism with MS activity. METHODS: We measured 25-hydroxyvitamin D (25(OH)D), parathyroid hormone (PTH), calcium, phosphate, magnesium, chloride, alkaline phosphatase, albumin and thyroid stimulating hormone in serum every 3 months and at the time of relapse over 1 year in 23 patients with MS and in 23 healthy controls. MRI burden of disease and T2 activity were assessed every 6 months. RESULTS: Vitamin D deficiency (S-25(OH)D < or = 37 nmol/l) was common, affecting half of the patients and controls at some time in the year. Seasonal variation of 25(OH)D was similar in patients and controls, but 25(OH)D serum levels were lower and intact PTH (iPTH) serum levels were higher during MS relapses than in remission. All 21 relapses during the study occurred at serum iPTH levels > 20 ng/l (2.2 pmol/l), whereas 38% of patients in remission had iPTH levels < or = 20 ng/l. Patients with MS had a relative hypocalcaemia and a blunted PTH response in the winter. There was no correlation between serum 25(OH)D and MRI parameters. CONCLUSIONS: The endocrine circuitry regulating serum calcium may be altered in MS. There is an inverse relationship between serum vitamin D level and MS clinical activity. The role of vitamin D in MS must be explored further.

High sensitivity measurement of CRP and disease progression in multiple sclerosis.

The authors measured serum C-reactive protein (CRP) serially in patients with multiple sclerosis (MS) who participated the PRISMS study using a high-sensitivity technique. CRP values were similar in patients with MS and in healthy controls but higher during MS relapses than in remission (p = 0.010). CRP levels were lower during treatment with high-dose interferon beta 1a than placebo (p = 0.035) and higher during first 12 months of study in patients who progressed by year 4 compared with stable patients (p = 0.007).

25-Hydroxyvitamin D levels in serum at the onset of multiple sclerosis.

Past sun exposure and vitamin D supplementation have been associated with a reduction in the risk of MS. We measured the serum concentration of 25-hydroxyvitamin D (25[OH]D) at the time of MS diagnosis in 40 MS patients and 40 controls. We found no difference in the serum levels of 25(OH)D between MS patients and controls when all samples or samples obtained during winter months were compared, but MS patients had significantly lower serum 25(OH)D concentrations in June to September than the controls. The vitamin D stores were adequate for bone metabolism (> 37 nmol/L) in 70% of MS patients throughout the year and within the hypovitaminosis level (< 37 nmol/L) in 30% of MS patients at some time of the year. During MS-relapses, 25(OH)D levels were lower than in remission, but mostly within the reference range observed in relation with normal bone metabolism. We conclude that the vitamin D stores in most MS patients are adequate for their normal bone metabolism. However, lower vitamin D levels during MS relapses than in remission suggest that vitamin D could be involved in the regulation of the clinical disease activity of MS. The optimal serum levels of vitamin D for the regulation of immune responses remain to be determined.

Induction of postnatal schwann cell death by the low-affinity neurotrophin receptor in vitro and after axotomy.

Schwann cells express the low-affinity neurotrophin receptor (p75), but no role for either the neurotrophins or their cognate receptors in Schwann cell development has been established. We have found that Schwann cells isolated from postnatal day 1 (P1) or P2 mice that were p75-deficient exhibited potentiated survival compared to wild-type cells after growth factor and serum withdrawal. There was, however, no disparity in the survival of p75-deficient and wild-type Schwann cells isolated at embryonic day 15, suggesting that the death-inducing effects of p75 are developmentally regulated. A comparable degree of cell death was also observed in the sciatic nerves of both wild-type and p75-deficient mice at P1. However, 24 hr after axotomy, there was a 13-fold increase in the percentage of apoptotic nuclei in the distal nerve stumps of the transected sciatic nerves of neonatal wild-type but not p75-deficient mice. The expression of both the p75 and nerve growth factor (NGF) genes was upregulated after axotomy in neonatal wild-type nerves. Collectively, these results suggest that NGF-mediated activation of p75 is likely to be an important mediator of Schwann cell apoptosis in the context of peripheral nerve injury.

Treatment of experimental autoimmune encephalomyelitis with antisense oligonucleotides against the low affinity neurotrophin receptor.

Upregulated expression of the low-affinity neurotrophin receptor (p75) in the central nervous system (CNS) during experimental autoimmune encephalomyelitis (EAE) has recently been demonstrated. To investigate whether p75 plays a role in disease pathogenesis, we adopted a gene therapy approach, utilizing antisense oligonucleotides to downregulate p75 expression during EAE. Phosphorothioate antisense oligonucleotides (AS), nonsense oligonucleotides (NS) or phosphate buffered saline (PBS) were injected daily for 18 days after immunization of SJL/J (H-2s)-mice with myelin proteolipid protein (PLP) peptide 139-151. In the AS group, there was a statistically significant reduction in both the mean maximal disease score (1.85 in the AS, 2.94 in the NS and 2.75 in the PBS-groups, respectively, P < 0.025) and in the cumulative disease incidence ( approximately 60% in the AS group and approximately 90% in the control groups). Histological and immunohistochemical analysis showed reduced inflammation and demyelination, as well as reduced p75 expression at the blood-brain barrier (BBB) in the AS-treated mice in comparison with both control groups. There was no difference, however, in p75 expression on neural cells within the CNS between the three groups of mice. We conclude that p75 could play a proactive role in the pathogenesis of EAE and may exert its effect at the level of the BBB.

Molecular mechanisms regulating motor neuron development and degeneration.

Motor neurons are a well-defined, although heterogeneous group of cells responsible for transmitting information from the central nervous system to the locomotor system. Spinal motor neurons are specified by soluble factors produced by structures adjacent to the primordial spinal cord, signaling through homeodomain proteins. Axonal pathfinding is regulated by cell-surface receptors that interact with extracellular ligands and once synaptic connections have formed, the survival of the somatic motor neuron is dependent on the provision of target-derived growth factors, although nontarget-derived factors, produced by either astrocytes or Schwann cells, are also potentially implicated. Somatic motor neuron degeneration leads to profound disability, and multiple pathogenetic mechanisms including aberrant growth factor signaling, abnormal neurofilament accumulation, excitotoxicity, and autoimmunity have been postulated to be responsible. Even when specific deficits have been identified, for example, mutations of the superoxide dismutase-1 gene in familial amyotrophic sclerosis and polyglutamine expansion of the androgen receptor in spinal and bulbar muscular atrophy, the mechanisms by which somatic motor neuronal degeneration occurs remain unclear. In order to treat motor system degeneration effectively, we will need to understand these mechanisms more thoroughly.

Nerve growth factor signaling through p75 induces apoptosis in Schwann cells via a Bcl-2-independent pathway.

Apoptosis is involved in the regulation of Schwann cell numbers during normal development and after axonal damage, but the molecular regulation of Schwann cell death remains unknown. We have used stably transfected rat Schwann cell lines to study the potential roles of nerve growth factor (NGF), the antiapoptotic protein Bcl-2 and the cytokine response modifier A (CrmA) in modulating Schwann cell death in vitro. Bcl-2 inhibited Schwann cell apoptosis induced by survival factor withdrawal, whereas CrmA did not. In contrast, Bcl-2-transfected Schwann cells were susceptible to apoptosis in response to exogenous NGF, whereas CrmA-expressing cell lines were resistant. Demonstration of high levels of the low-affinity neurotrophin receptor p75 but not the high-affinity TrkA receptor on the Bcl-2-transfected cell lines suggested that the NGF-induced killing was mediated by p75. This was confirmed by resistance of Schwann cells isolated from p75 knockout mice to the NGF-induced cell death. Nerve growth factor also promoted the death of wild-type mouse and rat Schwann cells in the absence of survival factor withdrawal. Endogenous Bcl-2 mRNA was expressed by wild-type Schwann cells in all conditions that promoted survival but was downregulated to undetectable levels after survival factor withdrawal. In conclusion, our results demonstrate the existence of two separate pathways that expedite apoptosis in Schwann cells: a Bcl-2-blockable pathway initiated on loss of trophic support, and a Bcl-2-independent, CrmA-blockable pathway mediated via the p75 receptor.

Therapy with antibody against leukocyte integrin VLA-4 (CD49d) is effective and safe in virus-facilitated experimental allergic encephalomyelitis.

Experimental allergic encephalomyelitis (EAE) is facilitated in resistant BALB/c mice by intraperitoneal infection with an avirulent Semliki Forest virus (SFV-A7). Viral infection increases the incidence of EAE from 15-30% to 60-90% and speeds up appearance of paralysis from 24 to 14 days. In this paper, we describe treatment of virus-facilitated EAE with monoclonal antibodies (mAbs) against leukocyte and/or endothelial cell adhesion molecules. Therapy with mAb against ICAM-1 (intercellular adhesion molecule-1) had a modest effect, but caused hemorrhagic brain and spinal cord lesions. Therapy with mAb against Mac-1 (alpha M beta 2-integrin) was well tolerated but had no effect. Therapy with mAb against VLA-4 (alpha 4 beta 1-integrin) was safe, diminished both clinical and histopathological signs of EAE, decreased induction of VCAM-1 (vascular cell adhesion molecule-1) on brain vessels and diminished infiltration of VLA-4+ cells into the brain. The amount of viral antigen in the brain was not altered. We conclude that facilitation of leukocyte entry into the brain is a major mechanism for viral facilitation of EAE in the BALB/c mouse, and that facilitation can be inhibited by anti-adhesion therapy. This may have implications for treatment of relapses triggered by viral infections in multiple sclerosis.

Semliki Forest virus infection leads to increased expression of adhesion molecules on splenic T-cells and on brain vascular endothelium.

Semliki Forest virus A7 (SFV-A7) is a neurotropic alphavirus that leads to an asymptomatic encephalitis in adult immunocompetent mice. We studied the expression of leukocyte and endothelial cell adhesion molecules in the spleen and in the central nervous system (CNS) during SFV-A7 infection. Kinetics of the expression of LFA-1 alpha/CD11a, LFA-1 beta/CD18, Mac-1/CD11b, VLA-4/CD49d, ICAM-1/CD54 and L-selectin/CD62L was determined on splenic CD4+ and CD8+ T-cells and macrophages by flow cytometry. Time course of the expression of these antigens and VCAM-1/CD106 as well as viral antigens in the CNS was studied by immunoperoxidase staining. In the spleen, a sustained increase in LFA-1-expression and a temporary increase at day 7 in the expression of VLA-4, Mac-1 and ICAM-1 were detected on CD8+ T-cells. L-selection was down-regulated on CD4+ cells. Adhesion molecules on macrophages remained unchanged. In the CNS, expression of Mac-1+, VLA-4+ and LFA-1+ cells increased in parallel with the kinetics of the expression of their ligands ICAM-1 and VCAM-1 on brain vessels. Upregulation of adhesion of molecules peaked between days 5-8 and was most prominent in the cerebellar and brain stem white matter where viral antigens were most abundant. We conclude that the adhesion molecules profile of splenic T cells is altered during SFV-A7 infection which may influence their homing into the CNS. Macrophages are probably recruited non-specifically as a consequence of activation of the brain vascular endothelium in the inflamed areas of the brain.

Measles virus hemagglutinin mediates monocyte aggregation and increased adherence to measles-infected endothelial cells.

The effect of measles virus (MV) infection on monocyte adhesion was studied using human peripheral blood monocytes and monocytic and endothelial cell lines. The infection of monocytic U-937 cells led to the formation of large cellular aggregates. Aggregation was independent of intercellular adhesion molecule-1 (ICAM-1)/lymphocyte function-associated antigen-1 (LFA-1), but could be inhibited by monoclonal antibodies (mAb) against the MV hemagglutinin glycoprotein (MV-H). mAb against the MV receptor, CD46, also blocked aggregation. No significant changes in the cell surface expression of adhesion molecules CD11a, CD11b, CD11c, CD18, CD54, CD44, CD49d (alpha 4-integrin) and CD62L (L-selectin) were observed on MV-infected monocytes. Infection of a human endothelial cell line, EAhy 926 (HEC), with MV led to a two-fold increase in 1CAM-1 expression and a two-fold increase in monocyte adherence to the HEC (from 22 +/- 1.6% to 42 +/- 4.8%). However, ICAM-1 mAb reduced monocyte adhesion to the control and MV-infected HEC to a similar degree, whereas anti-MV-H antibodies abolished the difference between binding to infected and control HEC. We conclude that MV hemagglutinin mediated both the homo typic aggregation in infected monocyte cultures and increased monocyte adherence to the infected endothelial cells.

Blood-brain barrier breakdown and increased intercellular adhesion molecule (ICAM-1/CD54) expression after Semliki Forest (A7) virus infection facilitates the development of experimental allergic encephalomyelitis.

This report describes two mechanisms by which virus infection can facilitate demyelinating autoimmune inflammation in the murine CNS. In the BALB/c mouse model of experimental allergic encephalomyelitis (EAE), peripheral infection with an avirulent strain (A7) of Semliki Forest virus (SFV) increased the morbidity to EAE by infecting endothelial cells and damaging the blood-brain barrier (BBB). An influx of hematogenous CD18+ (LFA-1+ and MAC-1+) cells into the CNS compartment was followed by a local increase in intercellular adhesion molecule 1 (ICAM-1) expression on the vascular endothelium. Although SFV A7 infection without EAE induction caused multifocal cerebral vascular endothelial cell infection and BBB damage followed by cellular infiltration and transient increase of ICAM-1, inflammation and demyelination of CNS white matter with classical clinical signs of EAE was observed only in EAE-induced BALB/c mice, whereas the control mice remained neurologically healthy. The upregulation of ICAM-1 after virus infection was detected after the CD18+ (LFA-1+ and MAC-1+) cells had infiltrated the CNS both after EAE induction and also in nonsensitized control mice. The observed increase in ICAM-1 expression was transient in nonsensitized SFV A7 infected mice just as in the cellular infiltrates in the CNS, but EAE induction resulted in prolongation in both the cellular infiltrates and upregulation of ICAM-1. Thus, SFV A7 infection causes BBB damage and prolongs increased ICAM-1 expression on brain endothelium. This results in increased and more rapid morbidity to EAE in mice which have been sensitized with neuroantigen. However, SFV A7-infected mice without neuroantigen sensitization remain neurologically healthy.