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.     

Urinary myelin basic protein—like material as a correlate of the progression of multiple sclerosis

In the multicenter, randomized, placebo-controlled trial of alternate-day injections of recombinant interferon beta-1b in relapsing-remitting multiple sclerosis (MS), urine specimens were collected periodically from all patients (n = 64) in two of the clinical test sites over the 2 years of the study. Urine specimens were also collected over two consecutive 24-hour periods from 43 patients from a third center. Urine samples were assayed for their content of myelin basic protein-like material (MBPLM), the level of which was correlated with clinical changes, cranial magnetic resonance imaging results, and the development of progressive disease. Concordant changes in creatinine values affected some of the relationships of MBPLM. The level of urinary MBPLM correlated with a chronic progressive course and with the number of lesions and the total lesion area on cranial magnetic resonance images. A rise in the level of urinary MBPLM appeared to antedate the clinical transition from a relapsing-remitting to a chronic progressive course. By chance, the randomized entry of patients led to significant differences in urinary MBPLM levels among the three treatment groups, thus precluding correlation studies of treatment effects. However, the patient group from which 24-hour specimens were collected showed that the patients with relapsing-remitting MS changing to a chronic progressive course, and more specifically, those patients with chronic progressive MS receiving placebo, had the highest values of urinary MBPLM. These findings indicate that urinary MBPLM may offer an objective test and possibly serve as a surrogate Marchker for detecting or predicting the failure of remission or the transition to a progressive phase of MS.     

Urinary myelin basic protein-like material in patients with multiple sclerosis during interferon beta-1b treatment.

OBJECTIVES: To determine levels of urinary myelin basic protein-like material (MBPLM) in patients with multiple sclerosis (MS) openly treated with interferon beta-1b and to correlate these with clinical changes. BACKGROUND: Levels of urinary MBPLM correlate with the presence of the progressive phase of MS and with the disease burden detected on T2-weighted, cranial magnetic resonance imaging. Measurement of urinary MBPLM level may be a feasible test for monitoring or predicting response to therapeutic measures. DESIGN AND METHODS: In a prospective study at one site, 166 patients with MS (131 with relapsing-remitting [RR] and 35 with secondary progressive [SP] disease) were treated for a minimum of 1 year and up to 3 years with interferon beta-1b and underwent assessment for neurologic disability (Expanded Disability Status Scale and Scripps Neurological Rating Scale) and change in disease subtype. Urine samples were obtained at 1219 of 1378 clinic visits, and urinary MBPLM level was determined and related to creatinine level to adjust for renal function. RESULTS: Statistical analysis using the general linear models procedure confirmed previous findings that the level of urinary MBPLM related to urinary creatinine level (MBPLM/creatinine) was higher (P<.001) in patients with SP than RR MS. Of the 131 patients with RR MS, SP disease developed in 13 during the observation period. Compared with those in the RR group, the RR to SP group had a higher level (P<.001) of urinary MBPLM and did not differ from the SP group. CONCLUSIONS: The level of urinary MBPLM is higher in SP MS than RR MS but not in RR MS that converts to SP MS. Level of urinary MBPLM may permit the examination of treatment tested to prevent RR disease from becoming progressive.     

Clinical and laboratory features of primary progressive and secondary progressive MS.

OBJECTIVE: To compare the clinical and laboratory features of primary progressive (PP) and secondary progressive (SP) MS, to evaluate the role of CSF and urine myelin basic protein-like material (MBPLM) in differentiating PP from SP MS, and to assess the utility of urine MBPLM as a surrogate marker of disease activity in progressive MS. BACKGROUND: The current categorization of subtypes of MS is based solely on clinical and temporal characteristics of the disease. Laboratory markers are needed that can differentiate reliably the subtypes of MS and serve as surrogate markers of disease progression. METHODS: Clinical and paraclinical data of 51 PPMS and 140 SPMS patients were reviewed retrospectively. CSF and urine MBPLM were measured using a double-antibody radioimmunoassay. RESULTS: PPMS was more likely to present with progressive myelopathy (p < or = 0.001) after the age of 40 years (p = < or = 0.001), and it affected men relatively more often than SPMS (male-to-female ratio, 1:1.7 versus 1:3.2 respectively). Ambulatory assistance was required by PP patients more often and earlier than in those with SPMS. The incidence of abnormal CSF, evoked potential, and cranial MRI studies was similar in the two groups. Spinal cord MRI abnormalities were noted significantly more often in SP disease. There was an insignificant trend of higher CSF MBPLM in SPMS compared with PPMS. Urine MBPLM and MBPLM/creatinine were significantly higher in SPMS than in PPMS. However, the values of urine MBPLM and MBPLM/creatinine at the initial visits of patients with PPMS and SPMS were not significantly different. Urine MBPLM/creatinine was significantly higher in both PPMS and SPMS compared with normal control subjects. No correlation was found between urine MBPLM and disease duration or between urine MBPLM and clinical disability. There was no correlation between urine MBPLM/creatinine and either disease duration or clinical disability. CONCLUSIONS: These findings provide additional evidence of the differences in PPMS and SPMS, notably in the associated changes in MBPLM in urine, and also suggest a possible role for urine MBPLM in identifying patient cohorts. The high urine MBPLM levels in progressive MS patients indicate a potential role of this marker for assessing responsiveness to therapeutic interventions.     

Cerebrospinal fluid myelin basic protein-like material in acute monosymptomatic optic neuritis

Introduction
Cerebrospinal fluid (CSF) may provide markers of severity and outcome of optic neuritis.
Material and methods We examined the CSF from 29 patients with acute monosymptomatic optic neuritis (AMON) for content of myelin basic protein-like material (MBPLM) and correlated the levels with results of cranial magnetic resonance imaging. The length of the time from onset of AMON to the time of CSF collection did not exceed four weeks.
Results Only two patients (7%), one of whom developed an acute myelopathy one month after AMON, showed an elevated value of CSF MBPLM. No MBPLM was detected in 6 patients (21%), and other 21 (72%) had detectable levels of MBPLM but below the upper limit of normal of 0.1 ng/ml. The value of MBPLM was not significantly correlated with the interval to CSF sampling from onset of AMON or with severity of decreased visual acuity. The highest values of CSF MBPLM were observed among patients with severely decreased visual acuity and among patients with an abnormal MRI (13 of 27 i.e. 48%).
Conclusions CSF MBPLM was rarely abnormal in AMON. However, CSF MBPLM may have potential value in reflecting disease activity, as the highest values were obtained among patients with CSF sampled soon after the maximum visual dysfunction was reached, with severe visual impairment, and with an abnormal MRI.     

Cranial magnetic resonance imaging in the evaluation of myelopathy of undetermined etiology

The spinal form of MS is a clinical conundrum, the solution of which may yield many answers; to be certain that it is MS and not another disease causing the myelopathy is often difficult. We evaluated 20 patients with myelopathy of undetermined etiology (clinical findings limited to the spinal cord) using T2-weighted cranial magnetic resonance imaging (T2 MRI) and cranial computerized tomography (CT). Some patients were also studied with flash visual evoked responses (FVER) and spinal fluid analysis for myelin basic protein (MBP) and oligoclonal banding (OCB). Thirteen patients had T2 MRIs consistent with demyelinating disease (two or more areas of increased signal intensity, of appropriate size, in periventricular/subcortical white matter), while only one CT showed focal lesions. FVER were abnormal in 8 of 15 patients tested; spinal fluid OCB was present in 12 of 16 patients tested, only 1 of whom had elevated MBP. T2 MRI showed lesions typical of demyelination in the majority of study patients, was much more sensitive than CT, and was well correlated with evidence of demyelination by other tests. Although the specificity of T2 MRI in MS is unknown, it may be very high in this clinical setting.     

Clinical and laboratory characteristics of secondary progressive MS

Secondary progressive (SP) MS follows on from but is distinct in its clinical picture from relapsing remitting (RR) MS. Diagnosis is usually straightforward except during the transitional stage when the two phenotypes merge. It is clear that most patients that start with relapsing remitting MS will develop SP disease, although the underlying pathogenesis that causes this change is subject to much debate. Clinical features such as pattern and site of symptoms, and age of onset, in the relapsing remitting stage versus progressive disease, suggests a difference in the pathophysiology. Laboratory markers may give insight into the disease mechanisms. Measures of urinary and CSF myelin basic protein-like material (MBPLM) indicate demyelination and subsequent oligodendrocyte and axonal loss. Tertiary neutralising antibodies to MBP antibodies could attenuate remission and lead to continuous progression, and neuronal antibodies found in SP disease may contribute to the axonal loss. In addition, differences in nitric oxide and other inflammatory cytokine patterns might either be secondary to or causative of the pathological mechanisms.Greater understanding of progressive MS is a priority considering permanent disability results almost entirely from this stage of the disease.     

Relationship between urinary symptoms and disease-related parameters in multiple sclerosis

Objective To find the prevalence of voiding dysfunction in patients with multiple sclerosis and to examine the relationship between the voiding dysfunction and various parameters of the disease (disease severity, disease duration, lesion site, age and sex). Methods Using the International prostate symptom score, lower urinary tract symptoms were quantitatively evaluated in all patients with multiple sclerosis who had visited our neurological department during three months. The lesion site in the central nervous system was determined by a combination of neurological and magnetic resonance imaging findings. Results Of the 47 patients who had completed the questionnaire, 25 (53 %) were considered to have symptomatic voiding dysfunction. Even at early stage of the disability, 6 of 19 (32 %) patients were symptomatic. Eight (17 %) patients had irritative urinary symptoms alone, whereas 9 (19 %) patients had obstructive urinary symptoms alone. The irritative and obstructive symptoms were concomitant in 10 (21 %) patients. Compared with reports from Western countries, the ratio of obstructive symptoms to irritative symptoms was high in Japan. The degree of irritative symptoms was well correlated with the disease severity, whereas the correlation of obstructive symptoms with the disease severity was less significant. Irritative symptoms also showed a weak correlation with the disease duration, but obstructive symptoms did not. Among the lesion sites in the central nervous system, only the presence of the spinal cord lesion was related to the degree of urinary symptoms. Urinary symptoms were not significantly influenced by the age or the sex. Quality of life was disturbed by urinary symptoms, and this disturbance paralleled the disease severity. Conclusion Urinary symptoms, especially irritative symptoms, reflect the condition of the disease. Thus, the quantified urinary symptoms may assist neurological diagnosis. Received: 5 September 2001 Received in revised form: 28 January 2002 Accepted: 1 February 2002     

1H-NMR spectroscopy combined with pattern recognition analysis reveals characteristic chemical patterns in urines of MS patients and non-human primates with MS-like disease

Proton nuclear magnetic resonance (1H-NMR) spectroscopy in combination with pattern recognition techniques were used to investigate the composition of organic compounds in urines from patients with multiple sclerosis (MS), patients with other neurological diseases (OND) and healthy controls (H). Using a valid animal model of MS, namely the common marmoset (Callithrix jacchus) model of experimental autoimmune encephalomyelitis (EAE), the relation of disease progression and alteration of the urine composition was investigated. Urine samples were collected during different stages of EAE, either induced with whole human myelin or with the myelin protein MOG in complete adjuvant. The urine samples were analysed with 1H-NMR spectroscopy allowing simultaneous detection of an array of compounds. Spectral differences between urines from EAE-affected and healthy monkeys were assessed with multivariate analysis. Evidence is provided that development of EAE is associated with changes in the chemical composition of the urine, in particular of compounds with NMR peaks in the region of the spectrum between 0.5 and 3.50 ppm. In addition, we found preliminary evidence for differences between urines from MS, OND and H groups.     

The effects of high-dose methylprednisolone on gadolinium-enhanced magnetic resonance imaging and cerebrospinal fluid measurements in multiple sclerosis

Blood-brain barrier (BBB) disruption is probably the first event in the lesion development in multiple sclerosis (MS). This stage can be visualized by gadolinium-enhanced magnetic resonance (MR) imaging of the brain. Serial MR imaging studies have indicated a continuous spectrum of disease activity with waxing and waning of acute lesions, even in clinically stable MS patients. High-dose intravenous methylprednisolone (MP) has a beneficial clinical effect; reduces gadolinium enhancement, indicating improvement of BBB integrity; and, in MS patients, decreases intrathecal immunoglobulin synthesis with reduction of cerebrospinal fluid (CSF) myelin basic protein (MBP). A correlative triad is noted between gadolinium enhancement, clinical improvement, and decrease of CSF MBP following MP treatment, indicating a relationship between restoration BBB integrity, clinical improvement and decrease of myelin breakdown. It is not clear whether MP interferes primarily with the process of demyelination or reacts non-specifically with its mediators.     

Upregulated survivin expression in activated T lymphocytes correlates with disease activity in multiple sclerosis

Programmed cell death (apoptosis) is critical for the normal development and homeostasis of the immune system. There is emerging evidence that failure of apoptosis to eliminate potentially pathogenic, autoreactive T lymphocytes may be involved in the pathogenesis of multiple sclerosis (MS). This failure is related to multiple abnormalities of apoptosis-regulatory molecules that involve survivin, a recently described cell cycle-regulated anti-apoptosis protein. In this study, we investigated the relationship between survivin expression in peripheral T lymphocytes and clinical features of MS. We detected a significant over-expression of survivin in mitogen stimulated T lymphocytes from patients with active MS when compared with corresponding expression in patients with stable MS or those with inflammatory and non-inflammatory neurologic disorders. This over-expression of survivin in patients with active MS correlated with cellular resistance to apoptosis and with features of disease activity, such as disease duration and the number of enhanced lesions on cranial magnetic resonance imaging. There was no correlation between cellular survivin levels and the expression of other apoptosis-inhibitory proteins, such as Bcl-2 and Fas-associated death domain-like interleukin-1beta-converting enzyme inhibitory protein (FLIP). Our findings indicate that cellular over-expression of the novel anti-apoptosis protein survivin is a feature of clinically active MS.     

Cellular hypersensitivity to gangliosides and myelin basic protein in multiple sclerosis

Peripheral blood lymphocytes from patients with multiple sclerosis (MS), other neurological diseases and healthy controls were investigated for the presence of cell-mediated hypersensitivity to brain gangliosides and myelin basic protein using an active E-rosette assay. Sensitivity to myelin basic protein and gangliosides was found in MS patients in acute relapse and with progressive disease, whereas no sensitivity was found in MS patients in remission. Patients with other neurological diseases showed no response to gangliosides, but sensitization to myelin basic protein was found in a patient with leucoencephalopathy and in 4 of 6 stroke patients. Healthy controls did not respond to either antigen. In MS patients a positive correlation was seen between lymphocyte responses to myelin basic protein and to gangliosides. The data suggest that in comparison to gangliosides, myelin basic protein is a weaker stimulator of active rosette-forming cells. Moreover, cellular hypersensitivity to myelin basic protein is not MS-specific and may be present as a consequence of brain damage. However, cellular hypersensitivity to gangliosides appears to be more specific to MS and may be important in the pathogenesis of the disease.     

Neuromyelitis optica

Neuromyelitis optica (NMO), otherwise known as Devic's disease, is an idiopathic, severe, inflammatory disorder that preferentially affects the optic nerves and spinal cord. Clinical, laboratory and immunopathological evidence suggests that NMO is a humorally mediated disease distinct from MS. A spinal cord lesion extending contiguously over three or more vertebral segments is characteristic of NMO and, in combination with a cranial magnetic resonance imaging scan that does not meet radiological criteria for MS, is over 94% sensitive and 96% specific for NMO diagnosis. The serum autoantibody marker, neuromyelitis optica-immunoglobulin G (NMO-IgG), appears specific for NMO and suggests that the disease spectrum includes cases of recurrent longitudinally extensive transverse myelitis and Japanese opticospinal MS. Its target antigen is the water channel aquaporin-4, suggesting that NMO may represent a novel autoimmune channelopathy. Relapsing NMO has a poor prognosis; therapy, typically with immunosuppression, is necessary as early as possible in the disease course to prevent attack-related disability.     

Short-term dynamics of circulating T cell receptor V beta repertoire in relapsing-remitting MS

To understand the short-term dynamics of the circulating T cell receptor V beta (TCRBV) repertoire in relapsing-remitting multiple sclerosis (MS), we monitored the TCRBV profiles of untreated MS patients and healthy controls. Expansions of TCRBV genes in MS patients were significantly more frequent than in controls (P<0.001), were predominantly oligoclonal (80%) and were significantly correlated with immune responses to myelin basic protein (MBP) (P<0.02) and with inflammatory disease activity detected by magnetic resonance imaging (MRI) (P<0.05). Autoreactive T cell responses against myelin antigens may be implicated in perturbations of TCR repertoire in untreated MS patients, detectable even in the absence of clinically evident manifestations.     

Evidence of demyelination in mild cognitive impairment and dementia using a direct and specific magnetic resonance imaging measure of myelin content

Introduction

We investigated brain demyelination in aging, mild cognitive impairment (MCI), and dementia using a direct magnetic resonance imaging marker of myelin.

Trigeminal involvement in multiple sclerosis: magnetic resonance imaging findings with clinical correlation in a series of patients

Trigeminal involvement detected by magnetic resonance imaging (MRI) in multiple sclerosis (MS) patients is usually associated with trigeminal neuralgia (TN) or painless paraesthesia in the trigeminal distribution. Our aim is to review the incidence of trigeminal involvement on MRI in a series of patients with MS at our institution, with further clinical correlation. We reviewed MRI scans of 275 MS patients for the presence of gadolinium enhancement on postcontrast T1-weighted images, anatomical and signal abnormalities on different sequences at the pontine trigeminal root entry zone (REZ) and in the cisternal portion of the nerves. We observed enhancement in the cisternal portion of the nerves and signal abnormalities (with or without enhancement) at the pontine trigeminal REZ in 8 (2.9%) patients, and enhancement was bilateral in 6 (75%) of those. Despite the inflammatory activity, none of them had TN and 3 (37.5%) had only painless paraesthesias in the correspondent V3 distribution. We also found a marked trigeminal hypertrophy in 2 (25%) patients, both with a longer period of disease. Our results confirm a high and clinically silent incidence of trigeminal involvement in MS patients, and suggest a simultaneous role of the central and peripheral type of myelin in trigeminal demyelination.     

Gd-DTP A-enhanced lesions in the brain of patients with acute optic neuritis

The cerebral hemispheres of 19 patients with acute monosymptomatic optic neuritis (AMON) were investigated using magnetic resonance imaging (MRI) and Gadolinium-DTPA (Gd-DTPA). Using T1-weighted and T2-weighted imaging sequences it was disclosed that 14 of 19 patients had lesions and that enhancement was seen in seven patients. It is known that patients with AMON and silent lesions in the CNS have a highly increased risk of developing multiple sclerosis (MS) later on. If it is accepted that a silent lesion in patients with AMON does represent a multiple sclerosis (MS) plaque, and that an enhancing silent lesion represents an acute MS lesion, we may hypothesize that the disease process ultimately leading to MS starts long before the first symptom or sign ever appears. It would seem that at least half of the silent lesions in the cerebral hemispheres of patients with AMON had existed before the onset of the AMON, and that the disease actually started before the onset of the AMON.     

Short-term evolution of autoreactive T cell repertoire in multiple sclerosis.

T cells reactive to self-antigens are present in the peripheral blood of patients with autoimmune diseases as well as in healthy subjects. Although T cell-response to the self-myelin antigen myelin basic protein (MBP) has been widely investigated in multiple sclerosis (MS) patients, very little is known about the evolution over time of this response and its correlation with the disease activity. In recent years magnetic resonance imaging (MRI) techniques have provided new tools for following the inflammatory activity in the central nervous system (CNS) of MS patients. In the present study the T cell response to MBP was longitudinally investigated in terms of frequency, epitope specificity, and cytokine production profile in four patients with relapsing-remitting MS enrolled in a gadolinium-enhanced MRI serial study. In spite of different profiles of inflammatory activity within the CNS, all the patients examined showed major changes in their reactivity to MBP during the follow-up period in terms of both frequency and epitope specificity. Episodic expansions of MBP-specific T cell populations were observed in each patient, and overall they did not correlate with disease activity. In these patients the expansions: 1) occurred in the context of a steady level of disease activity, 2) correlated with a burst of CNS inflammation, 3) followed the appearance of a new active lesion, and 4) were observed even in the absence of detectable signs of CNS inflammation during the entire follow-up period. These results suggest that the evolution over time of the T cell response to a self-antigen such as MBP is more complex than previously expected. The short-term repertoire dynamics of autoreactive T cells in MS underscore the importance of longitudinal studies for evaluating autoreactivity to myelin antigens and probably to any self-antigen in other autoimmune diseases.     

A new approach for evaluating antigen-specific T cell responses to myelin antigens during the course of multiple sclerosis

We used a flow cytometry assay to measure proliferation and cytokine production of self-antigen-specific T cells in individual patients during the clinical course of multiple sclerosis (MS). Myelin-associated oligodendrocytic basic protein (MOBP) was selected for proof of principles in the assay, along with myelin basic protein (MBP) to assess specific activated T cells in 10 MS patients over an 18-month period, in parallel with brain magnetic resonance imaging (MRI) scans and clinical rating scale. A positive correlation occurred between antigen-specific T cell proliferation and interferon-gamma production with clinical relapses and MRI lesion activity that was absent when the same patients were in remission.