Axonal water fraction as marker of white matter injury in primary-progressive multiple sclerosis: a longitudinal study.

BACKGROUND AND PURPOSE: Diffuse white matter (WM) injury is prominent in primary-progressive multiple sclerosis (PP-MS) pathology and is a potential biomarker of disease progression. Diffusion kurtosis imaging allows the quantification of non-Gaussian water diffusion, providing metrics with high WM pathological specificity. The aim of this study was to characterize the pathological changes occurring in the normal-appearing WM of patients with PP-MS at baseline and at 1-year follow-up and to assess their impact on disability and short-term disease progression. METHODS: A total of 26 patients with PP-MS and 20 healthy controls were prospectively enrolled. Diffusion kurtosis imaging single-shot echo-planar imaging (EPI) was acquired on a 3-T scanner (Philips Achieva, Best, The Netherlands) (voxel size, 2 × 2 × 2 mm3 , 30 directions for each b-value = 1000, 2000 s/mm2 and one b = 0 s/mm2 ). A two-compartment biophysical model of WM tract integrity was used to derive spatial maps of axonal water fraction (AWF), intra-axonal diffusivity, extra-axonal axial and radial diffusivities (De,axial , De,radial ) and tortuosity from the following WM tracts: corpus callosum (CC), corticospinal tract (CST) and posterior thalamic radiation (PTR). RESULTS: At baseline, patients with PP-MS showed a widespread decrease of AWF, tortuosity and De,axial and an increase of De,radial in CC, CST and PTR (P ranging from 0.001 to 0.036). At 1-year follow-up, a significant AWF decrease was detected in the body of CC (P = 0.048), PTR (P = 0.008) and CST (P = 0.044). Baseline AWF values in CST significantly discriminated progressed from non-progressed patients (P = 0.021; area under the curve, 0.854). CONCLUSION: Based on its change over time and its relationship with disease progression, among the analyzed metrics, AWF seems the most sensitive metric of WM tissue damage in PP-MS and therefore it could be considered as a marker for monitoring disease progression.

Evaluation of the symbol digit modalities test (SDMT) and MS neuropsychological screening questionnaire (MSNQ) in natalizumab-treated MS patients over 48 weeks.

BACKGROUND AND OBJECTIVES: Brief cognitive tests to monitor cognitive impairment in patients with multiple sclerosis (MS) are needed. METHODS: Performance on monthly administrations of the Symbol Digit Modalities Test (SDMT) and the MS Neuropsychological Questionnaire (MSNQ) was assessed in 660 patients with MS in 21 countries (109 sites) for 48 weeks in an open-label, safety-extension study of natalizumab. RESULTS: At baseline, the cohort's mean age was 40.1 years, 67.6% were female and the median Expanded Disability Status Scale score was 2.5. Test-retest correlations were high for both SDMT (range 0.89 for weeks 0-4 to 0.96 for weeks 44-48) and MSNQ (0.82 for weeks 0-4 to 0.93 for weeks 44-48). There were no statistically significant effects of geographic region. While SDMT scores improved by 15 points over 48 weeks (p < 0.0001), incremental monthly changes were small (effect size d < 0.3). Similar results were obtained on the MSNQ except that scores moved downward, suggesting fewer cognitive complaints over 48 weeks (p < 0.0001), but again the incremental monthly changes were small (d <-0.2). CONCLUSIONS: These results replicate earlier work in a smaller cohort treated with conventional disease-modifying therapy, and support the reliability of the SDMT and MSNQ as potential screening for monitoring tools for cognition over time.

Syringoencephalomyelia (syringocephalus).

This is the fourth recorded patient with extension of syringomyelia into the brain rostral to the mesencephalon verified at autopsy. A syrinx was demonstrated from the low thoracic segments of the spinal cord to the cervico-medullary junction, where a fibrovascular malformation and dural-arachnoid adhesions deformed the pyramids. Cavities in the spinal cord were continuous, with rostral glial-lined cavities in both corticospinal tracts through a system of sponge-like tubes. The rostral extent of these cavities on the right was the centrum semi-ovale above the neostriatum; on the left, the cavities extended to the diencephalon. A classical lateral-dorsal syringobulbia in the right medulla accompanied the syringoencephalomyelia (syringocephalus).

Distribution of the blood-brain barrier in heterotopic brain transplants and its relationship to the lesions of EAE.

The blood-brain barrier (BBB) is recognized as a barrier to the trafficking of molecules and cellular elements into the central nervous system (CNS). Horseradish peroxidase (HRP) exclusion is used as a measure of BBB integrity. The BBB is altered and becomes permeable during the course of experimental allergic encephalomyelitis (EAE). Heterotopic brain transplantation into the anterior eye chamber is a technique for studying genetic influences and the role of individual cell types on the development of EAE. Prior to EAE induction, HRP is excluded from the central portion of the transplant, demonstrating an intact BBB. In contrast, HRP localization is found at the periphery of the transplant, suggesting an incomplete barrier. However, EAE lesions typically occur within the more central regions of the transplant, where the BBB is intact, and not at peripherally located "leaky" areas. This suggests that endothelial cells at intact BBB sites may direct trafficking of lymphocytes (gating) into the CNS during the development of EAE, rather than the passive entry of lymphocytes into the CNS through a leaky BBB.

Lower extremity motor evoked potentials in multiple sclerosis.

Transcranial magnetic stimulation was performed on 25 patients with definite multiple sclerosis. Motor evoked potentials were recorded from the anterior tibial muscle. Central motor conduction time was calculated using the equation (F + M-1)/2 by stimulation of the common peroneal nerve. Motor evoked potentials were capable of detecting subclinical pyramidal tract lesions in multiple sclerosis. In patients with multiple sclerosis, the incidence of abnormality of motor and somatosensory evoked potentials was similar. Central motor conduction time was correlated with overall and pyramidal tract subscores on the Kurtzke Disability Status Scale and the Scripps Neurological Rating Scale. Central motor conduction time abnormalities correlated best with the presence of a Babinski's sign but also correlated significantly with weakness and hyperreflexia.

Relationship of urinary myelin basic protein-like material with cranial magnetic resonance imaging in advanced multiple sclerosis.

BACKGROUND: A significant correlation exists between disability and the volume of black holes (BHL VOL), defined as hypointense lesions on T1-weighted cranial magnetic resonance imaging. A consistent correlation has also been reported between urinary myelin basic protein-like material (MBPLM) and the transition toward secondary progression (SP) from relapsing-remitting (RR) multiple sclerosis (MS). OBJECTIVE: To improve the management of MS through a noninvasive and cost-effective test for monitoring disease activity or disease status. DESIGN AND METHODS: From 662 patients with MS (86 with RR MS, 259 with SP MS without continued attacks, and 317 with SP MS with continued attacks), 24-hour urine samples were obtained at enrollment in the phase 3 Linomide (roquinimex) drug study. The urine specimens were analyzed for MBPLM and correlated with clinical features and findings on cranial magnetic resonance imaging. RESULTS: Significant but weak correlations existed between urinary MBPLM and BHL VOL in all patients with MS (r = 0.114, P =.003; n = 662), patients with SP MS without attacks (r = 0.185, P =.003; n = 259), and all patients with SP MS (r = 0.122, P =.003; n = 576). No significant correlations were detected in the RR MS group or any of the disease groups or subgroups whose Expanded Disability Status Scale score was 5.0 or lower. In subgroup analysis, the most significant correlation was detected between urinary MBPLM after adjustment for creatinine and BHL VOL in patients with SP MS with an Expanded Disability Status Scale score of 5.5 or higher but without continued relapses (r = 0.417, P<.001; n = 138). CONCLUSIONS: In patients with advanced SP MS, urinary MBPLM may possibly serve as an indicator of failed remission and axonal damage. Urinary MBPLM correlates with disease status in MS, especially the transition of RR MS to SP MS with advancing disability.

Immunomodulation of relapsing experimental allergic encephalomyelitis.

Mice immunized to produce relapsing experimental allergic encephalomyelitis (R-EAE) were treated with immunomodulating agents known to affect acute monophasic experimental allergic encephalomyelitis. Pretreatment with either mouse spinal cord or myelin basic protein in incomplete Freund's adjuvant decreased the incidence of R-EAE from 77% to 28 and 31%, respectively. Single doses of cyclophosphamide (CY) at the time of immunization did not affect development of R-EAE. CY given repetitively in low doses decreased the incidence of R-EAE to 10%. Therefore, R-EAE can be altered by immunomodulation, but the patterns differ from those seen in acute EAE.

Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis.

Standardization of terminology used to describe the pattern and course of MS is essential for mutual understanding between clinicians and investigators. It is particularly important in design of, and recruitment for, clinical trials statistically powered for expected outcomes for given patient populations with narrowly defined entry criteria. For agents that prove safe and effective for MS, knowledge of the patient populations in definitive clinical trials assists clinicians in determining who may ultimately benefit from use of the medication. An international survey of clinicians involved with MS revealed areas of consensus about some terms classically used to describe types of the disease and other areas for which there was lack of consensus. In this report, we provide a summary of the survey results and propose standardized definitions for the most common clinical courses of patients with MS.

Tizanidine treatment of spasticity caused by multiple sclerosis: results of a double-blind, placebo-controlled trial. US Tizanidine Study Group.

This multicenter, stratified, randomized, placebo-controlled, double-blind trial evaluated tizanidine for use in the United States for spasticity secondary to MS. The 15-week trial was divided into baseline (weeks 0 and 1), titration (2 mg to a maximum of 36 mg/d; weeks 2 to 4), and plateau (weeks 5 to 13) phases, followed by dose tapering (week 14) and a final visit (week 15). Primary efficacy parameters were scores on muscle tone (Ashworth Scale) and type and frequency of muscle spasms (patient diaries). All efficacy parameters were evaluated by the physician/assessor, and the physician/prescriber was responsible for all dosage adjustments. The patient, physician/assessor, and physician/prescriber made global evaluations of antispastic efficacy. Tizanidine produced a significantly greater reduction than placebo in spasms and clonus (patient diaries) but no significant differences in Ashworth scores. Patients and physician/prescribers, but not physician/assessors, gave significantly better scores in the overall assessment of efficacy and tolerability. No significant differences in other secondary efficacy parameters were noted. Adverse events were reported for 66 (61%) of the 109 placebo-treated patients and 101 (91%) of the 111 tizanidine-treated patients; 6 (6%) and 14 (13%) discontinued treatment, respectively. Patient and physician perception of improvement demonstrated more consistent differences between groups than did the Ashworth Scale, perhaps because of inexperience with this measure or failure to consider time between drug administration and assessment.

Ibuprofen treatment versus gradual introduction of interferon beta-1b in patients with MS.

Flu-like symptoms and injection site reactions are adverse effects of treatment with interferon beta-1b in patients with MS. We compared gradual dose escalation, ibuprofen treatment, or their combination in an open-label study. The combination reduced the incidence of flu-like symptoms to rates comparable with the placebo group in the pivotal trial but increased the frequency of injection site reactions, albeit modestly and transiently.

Linomide in relapsing and secondary progressive MS: part I: trial design and clinical results. North American Linomide Investigators.

OBJECTIVE: To determine whether linomide (roquinimex) is better than placebo in slowing the time to confirmed clinical worsening in patients with relapsing-remitting (RR) and secondary progressive (SP) MS. METHODS: In this 27-center, randomized, double-blind, placebo-controlled, multiple-dose, phase III trial, 715 patients with active RRMS (n = 90) or SPMS (n = 625) were randomized to receive either linomide (1.0, 2.5, or 7.5 mg orally daily) or placebo. Patients were evaluated at 3-month intervals clinically and with MRI. The planned primary outcome was the time to the development of "confirmed" clinical worsening (increase of >/= 1.0 Expanded Disability Status Scale [EDSS] score for an enrollment EDSS score /= 0.5 point for an enrollment EDSS score of >/= 5.5) not associated with an acute relapse. RESULTS: The trial was terminated 1 month after it became fully enrolled due to unanticipated serious cardiopulmonary toxicities (pericarditis, pleural effusion, myocardial infarction, and possible pulmonary embolism), pancreatitis, and death. Notable arthralgia, myalgia, bursitis, and facial and peripheral edema were common adverse events. The high dose of linomide (7.5 mg) was not well tolerated. The trial was too brief to determine unequivocal clinical benefits. Trends suggested an unconfirmed early effect on change in EDSS score at 6 months for the medium dose (2.5 mg daily). CONCLUSION: MS patients may be more prone to develop important linomide treatment-related adverse events than other previously studied patients. However, linomide may be a potentially more toxic drug than was suspected from observations made in smaller studies for other indications. Phase III trials may identify infrequent and important toxicities that may not be anticipated by phase I and II trials.

Linomide in relapsing and secondary progressive MS: part II: MRI results. MRI Analysis Center of the University of Texas-Houston, Health Science Center, and the North American Linomide Investigators.

OBJECTIVE: To determine the safety and efficacy of roquinimex (linomide) in the management of relapsing-remitting and secondary progressive MS as monitored by MRI. BACKGROUND: Preclinical studies and several short term randomized trials of linomide suggested clinical and MRI-measured benefits with acceptable risk for closely followed MS patients. METHODS: The North American Linomide Trial formally screened 853 individuals for relapsing or secondary progressive, clinically definite MS; recent disease activity or progression; and an Expanded Disability Status Scale score at entry of 3.0 to 6.5 inclusive. MRI was obtained on 811 subjects at pre-enrollment, 718 cases at enrollment, and then at three monthly intervals until the trial was prematurely terminated for unacceptable toxicity. RESULTS: Enhancement was found on 40.2% of 718 entry scans. Statistically robust correlations were found between clinical demographic data and several entry MRI measures including CSF volume, a reflection of brain atrophy. Assessment of the effect of treatment on MRI-measured disease was limited by early trial termination. However, active treatment for 3 months reduced the proportion of patients with one or more enhancements. An exploratory analysis suggested that 2.5 mg was the most active of three doses tested in limiting the total volume of enhanced tissue, the proportion of MRI-defined lesions designated as "black holes," and by a novel MRI composite disease measure. CONCLUSIONS: The short term signature of the effect of linomide on MRI-measured aspects of the disease suggests that safer drugs of this class might be useful in the management of MS. The use of a composite index of the heterogeneous nature of the pathology of MS as captured by MRI may have merit as an outcome measure in clinical trials.

Management of patients receiving interferon beta-1b for multiple sclerosis: report of a consensus conference.

Results of a double-blind, placebo-controlled study in ambulatory patients with relapsing-remitting MS showed that interferon beta-1b reduced the rate of exacerbations by one-third compared with placebo and limited new disease activity in the brain as evidenced by MRI. Interferon beta-1b, administered subcutaneously at a dosage of 0.25 mg (8 million IU) every other day is indicated for the treatment of ambulatory patients with relapsing-remitting MS. Interferon beta-1b may help a wider range of patients, but it should be prescribed only for patients with a diagnosis of clinically definite or laboratory-supported definite MS. The decision to treat a patient with interferon beta-1b should be individualized; that is, based on each patient's clinical presentation and course of MS. The most common adverse effects include (1) injection-site reactions and (2) flu-like symptoms, which are generally manageable and usually abate after the first few months of treatment. Spasticity may increase. Patients with severe depression or suicidal ideation should be monitored carefully, and symptomatic treatment should be pursued. Interferon beta-1b is contraindicated in pregnant and nursing women. Interferon beta-1b is effective in reducing the progression of total disease burden as seen on MRI in patients with MS. Its use is relatively straightforward and generally does not require alteration in the symptomatic treatment of MS. Patient education and support remain the mainstays of maintaining compliance through the early phases of therapy.

A multicenter, randomized, double-blind, placebo-controlled trial of influenza immunization in multiple sclerosis.

We determined the effect of influenza vaccine in patients with relapsing/remitting MS. Considerable controversy surrounds the question of whether to administer influenza vaccines to MS patients. Prevention of a febrile viral illness is clearly desirable in MS, and previous studies suggest that immunization is safe. Despite this, many clinicians avoid vaccination because they fear precipitating an MS exacerbation. We conducted a multicenter, prospective, randomized, double-blind trial of influenza immunization in patients with relapsing/remitting MS. In the autumn of 1993, 104 patients at five MS centers received either standard influenza vaccine or placebo. Patients were followed for 6 months for evaluation of neurologic status and the occurrence of influenza. Influenza was operationally defined as fever > or = 38 degrees C in the presence of coryza, cough, or sore throat at a time when the disease was present in the community. Attacks were defined in the standard manner, requiring objective change in the examination. Patients were examined at 4 weeks and 6 months after inoculation and were contacted by telephone at 1 week and 3 months. They were also examined at times of possible attacks but not when they were sick with flu-like illness. Three vaccine patients and two placebo patients experienced attacks within 28 days of vaccine (no significant difference). Exacerbation rates in the first month for both groups were equal to or less than expected from published series. The two groups showed no difference in attack rate or disease progression over 6 months. Influenza immunization in MS patients is neither associated with an increased exacerbation rate in the postvaccination period nor a change in disease course over the subsequent 6 months.

T cell receptor V beta gene utilization in myelin basic protein specific clones from CXJ1 recombinant inbred mice.

CXJ1 mice are a recombinant inbred strain generated from experimental allergic encephalomyelitis (EAE) resistant BALB/c and EAE susceptible SJL/J progenitors. CXJ1 derive their major histocompatibility complex (MHC) class II and TCR genes from the BALB/c progenitor. However, their susceptibility to EAE is similar to SJL/J. Utilizing myelin basic protein (MBP)-specific CD4+ hybridoma clones and a MBP-specific T cell line (TCL) from CXJ1, we found the predominant T cell receptor (TCR) V beta chain expression to be V beta 8 and V beta 13. Our data support the concept of preferential, but not exclusive, TCR V beta usage in the MBP-specific response which is independent of MHC class II haplotype or immunodominant peptide.

Characteristics of the T lymphocytes involved in experimental allergic encephalomyelitis.

Both heterogeneity and restricted heterogeneity of the encephalitogenic myelin basic protein (MBP) peptide-specific T cell receptors (TCRs) were demonstrated in inbred animals depending on the strain-specific genetic characteristics, the stage of the disease, the compartment of the lymphocytes obtained and the methodology used. Nevertheless, the similar features of some MBP-specific TCRs demonstrated across species suggest that conservation of these autoantigen-specific molecules undoubtedly exists, even though the degree of this conservation is controversial. However, the unequivocal heterogeneity of the immune response directed at one of the most important myelin constituents, proteolipid lipoprotein (PLP), which occurs either as a primary or a secondary event during experimental allergic encephalomyelitis (EAE), indicates the complexity of the in vivo situation. Intramolecular and intermolecular spreading of antigen specificity during the course of the disease indicates that a TCR directed therapy may not be the choice of intervention in established disease even in individual strains of laboratory animals with restricted heterogeneity of the primary MBP-specific response. Studying the sequence of events, the recruited regulatory cells and cytokines, and the stromal factors controlling persistence or death of activated, memory cells in the tissue lesion, may reveal new therapeutic modalities with more universal applicabilities.

Down-regulation of interferon-gamma-induced class II expression on human glioma cells by recombinant interferon-beta: effects of dosage treatment schedule.

We have examined the influence of human recombinant interferon-beta (IFN-beta) and interferon-gamma (IFN-gamma) on class II antigen expression on cultured glioblastoma multiforme cells by flow cytometry. Class II molecules were not constitutively expressed on these cells, nor induced by IFN-beta. IFN-gamma increased class II expression in a dose-dependent fashion. We demonstrate that IFN-beta is either antagonistic or synergistic with IFN-gamma in class II induction depending upon dose and schedule of administration. Both interferons at 100 IU/ml reduce class II expression by 18%, compared to IFN-gamma alone. Pretreatment with IFN-beta for 72 h, followed by both interferons yielded a 90% reduction. In contrast, lower concentrations (10 IU/ml) of both interferons were synergistic.

Interleukin-6 induction in vitro in mouse brain endothelial cells and astrocytes by exposure to mouse hepatitis virus (MHV-4, JHM).

Interleukin-6 (IL-6) induction, as detected by bioassay and Northern analysis, was examined in vitro in endothelial cells or astrocytes derived from BALB/c (susceptible) or SJL (resistant) mice following exposure to mouse hepatitis virus (MHV-4) or UV inactivated MHV-4 (UV-MHV-4). In BALB/c endothelial cells, up to 16-fold more IL-6 (> 640 U/ml) was induced, compared to SJL cells which showed a minimal response (40 U/ml), relative to basal levels (< 20 U/ml). In contrast, both BALB/c and SJL astrocytes showed a substantial IL-6 response to MHV-4 and UV-MHV-4 exposure, although a strain difference persisted. Despite strain and cell specific differences in released IL-6, equivalent levels of IL-6 mRNA were induced in all cell types following exposure to MHV-4 or UV-MHV-4.

Mouse hepatitis virus (MHV-4, JHM) blocks gamma-interferon-induced major histocompatibility complex class II antigen expression on murine cerebral endothelial cells.

The regulation of gamma-interferon-induced major histocompatibility complex (MHC) class II antigen expression on mouse cerebral endothelial cells by the neurotropic mouse hepatitis virus (MHV-4, JHM) was studied in vitro. The results presented demonstrate that MHV-4 can selectively block gamma-interferon-induced class II antigen expression on cerebral endothelial cells. The blocking effect of class II expression occurs in a strain-dependent manner, and is limited to virus-susceptible mouse strains. Virus replication is not required to obtain the blocking effect since UV-inactivated MHV-4 produces the same result. MHV-4 blocking of gamma-interferon-induced class II antigen expression is observed at both the cell surface (flow cytometry) and transcriptional level (Northern analysis).

Differential modulation of MHC class I antigen expression on mouse brain endothelial cells by MHV-4 infection.

Virus-induced modulation of mouse cerebral endothelial cell class I and class II antigens by the neurotropic coronavirus, MHV-4 (JHM), was examined by flow cytometry. In susceptible BALB/c, H-2Kd was downregulated, while H-2Dd was upregulated following infection by MHV-4. In contrast, H-2K and H-2D antigens were both upregulated in either MHV-4-susceptible B10.S and (BALB/c x SJL) F1, or MHV-4-resistant SJL-derived cerebral endothelial cells following infection with this virus. Class II antigen expression was unchanged following MHV-4 infection. Virus-induced MHC class I modulation is genetically regulated, and may influence virus clearance by class I-dependent CTL.