Sphingosine 1-phosphate receptor modulators in multiple sclerosis treatment: A practical review.

Four sphingosine 1-phosphate (S1P) receptor modulators (fingolimod, ozanimod, ponesimod, and siponimod) are approved by the US Food and Drug Administration for the treatment of multiple sclerosis. This review summarizes efficacy and safety data on these S1P receptor modulators, with an emphasis on similarities and differences. Efficacy data from the pivotal clinical trials are generally similar for the four agents. However, because no head-to-head clinical studies were conducted, direct efficacy comparisons cannot be made. Based on the adverse event profile of S1P receptor modulators, continued and regular monitoring of patients during treatment will be instructive. Notably, the authors recommend paying attention to the cardiac monitoring guidelines for these drugs, and when indicated screening for macular edema and cutaneous malignancies before starting treatment. To obtain the best outcome, clinicians should choose the drug based on disease type, history, and concomitant medications for each patient. Real-world data should help to determine whether there are meaningful differences in efficacy or side effects between these agents.

Mapping the Relationship of White Matter Lesions to Depression in Multiple Sclerosis.

BACKGROUND: Multiple sclerosis (MS) is an immune-mediated neurological disorder, and up to 50% of patients experience depression. We investigated how white matter network disruption is related to depression in MS. METHODS: Using electronic health records, 380 participants with MS were identified. Depressed individuals (MS+Depression group; n = 232) included persons who had an ICD-10 depression diagnosis, had a prescription for antidepressant medication, or screened positive via Patient Health Questionnaire (PHQ)-2 or PHQ-9. Age- and sex-matched nondepressed individuals with MS (MS-Depression group; n = 148) included persons who had no prior depression diagnosis, had no psychiatric medication prescriptions, and were asymptomatic on PHQ-2 or PHQ-9. Research-quality 3T structural magnetic resonance imaging was obtained as part of routine care. We first evaluated whether lesions were preferentially located within the depression network compared with other brain regions. Next, we examined if MS+Depression patients had greater lesion burden and if this was driven by lesions in the depression network. Primary outcome measures were the burden of lesions (e.g., impacted fascicles) within a network and across the brain. RESULTS: MS lesions preferentially affected fascicles within versus outside the depression network (ß = 0.09, 95% CI = 0.08 to 0.10, p < .001). MS+Depression patients had more lesion burden (ß = 0.06, 95% CI = 0.01 to 0.10, p = .015); this was driven by lesions within the depression network (ß = 0.02, 95% CI = 0.003 to 0.040, p = .020). CONCLUSIONS: We demonstrated that lesion location and burden may contribute to depression comorbidity in MS. MS lesions disproportionately impacted fascicles in the depression network. MS+Depression patients had more disease than MS-Depression patients, which was driven by disease within the depression network. Future studies relating lesion location to personalized depression interventions are warranted.

Mapping the relationship of white matter lesions to depression in multiple sclerosis.

Importance: Multiple sclerosis (MS) is an immune-mediated neurological disorder that affects nearly one million people in the United States. Up to 50% of patients with MS experience depression. Objective: To investigate how white matter network disruption is related to depression in MS. Design: Retrospective case-control study of participants who received research-quality 3-tesla neuroimaging as part of MS clinical care from 2010-2018. Analyses were performed from May 1 to September 30, 2022. Setting: Single-center academic medical specialty MS clinic. Participants: Participants with MS were identified via the electronic health record (EHR). All participants were diagnosed by an MS specialist and completed research-quality MRI at 3T. After excluding participants with poor image quality, 783 were included. Inclusion in the depression group (MS+Depression) required either: 1) ICD-10 depression diagnosis (F32-F34.*); 2) prescription of antidepressant medication; or 3) screening positive via Patient Health Questionnaire-2 (PHQ-2) or -9 (PHQ-9). Age- and sex-matched nondepressed comparators (MS-Depression) included persons with no depression diagnosis, no psychiatric medications, and were asymptomatic on PHQ-2/9. Exposure: Depression diagnosis. Main Outcomes and Measures: We first evaluated if lesions were preferentially located within the depression network compared to other brain regions. Next, we examined if MS+Depression patients had greater lesion burden, and if this was driven by lesions specifically in the depression network. Outcome measures were the burden of lesions (e.g., impacted fascicles) within a network and across the brain. Secondary measures included between-diagnosis lesion burden, stratified by brain network. Linear mixed-effects models were employed. Results: Three hundred-eighty participants met inclusion criteria, (232 MS+Depression: age[SD]=49[12], %females=86; 148 MS-Depression: age[SD]=47[13], %females=79). MS lesions preferentially affected fascicles within versus outside the depression network (ß=0.09, 95% CI=0.08-0.10, P<0.001). MS+Depression had more white matter lesion burden (ß=0.06, 95% CI=0.01-0.10, P=0.015); this was driven by lesions within the depression network (ß=0.02, 95% CI 0.003-0.040, P=0.020). Conclusions and Relevance: We provide new evidence supporting a relationship between white matter lesions and depression in MS. MS lesions disproportionately impacted fascicles in the depression network. MS+Depression had more disease than MS-Depression, which was driven by disease within the depression network. Future studies relating lesion location to personalized depression interventions are warranted.

Uncovering the association between fatigue and fatigability in multiple sclerosis using cognitive control.

BACKGROUND: Fatigue and cognitive dysfunction are two common symptoms experienced by patients with multiple sclerosis (MS). The relationship between subjective and objective fatigue (fatigability) in MS is poorly understood. Cognitive control tasks might be more conducive to fatigability and more likely to show associations between subjective and objective cognitive fatigue in MS. OBJECTIVE: To study the association between objective fatigability, as induced by a cognitive control task called the Blocked Cyclic Naming Task (BCNT), subjective fatigue and baseline cognitive functioning in patients with MS. METHODS: Twenty-one patients with MS completed baseline questions about their disease, the Montreal Cognitive Assessment (MoCA) battery and self-reported questionnaires on trait fatigue, sleep and depression. Disability was captured using the expanded disability status scale (EDSS). Participants then performed the BCNT and were asked about their level of state momentary fatigue before and after the BCNT. The BCNT consists of several blocks of either related or unrelated pictures that participants name as quickly as possible. The pictures cycled 4 times in each block and the difference in the response times (RTs) between related and unrelated blocks was captured. Data were analyzed using repeated measures analysis of variance and Pearson correlations. RESULTS: MS participants' performance declined for the related, but not unrelated blocks. The difference in RTs between related and unrelated conditions increased with repetition across cycles (p < 0.001). Participants also showed objective fatigability with less repetition priming (p = 0.02) in the 4th quarter and with greater differences between related and unrelated conditions in the later part of the task. Objective fatigability was strongly associated with participants' assessment of their level of momentary state fatigue (r = 0.612, p = 0.007). CONCLUSION: Using the appropriate tools, this study showed an association between subjective and objective cognitive fatigue in people with MS. The BCNT and cognitive control are useful tools in assessing patients with MS and should be explored in future, larger studies in this population.

Limbic pathway lesions in patients with multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a well-known demyelinating disease to cause cognitive dysfunction. The limbic system, relevant to memory, can be easily overlooked in conventional magnetic resonance imaging (MRI). PURPOSE: To investigate the distribution and frequency of demyelinating lesions affecting white matter connections of the limbic system based on localization with diffusion tensor imaging (DTI)-derived fractional anisotropy (FA) color maps compared to three-dimensional T2-weighted (T2W) and FLAIR volumes in MS patients. MATERIAL AND METHODS: One hundred and fifty patients with a known diagnosis of MS were identified for this Health Insurance Portability and Accountability (HIPAA)-compliant retrospective cross-sectional study. DTI-derived FA color maps, co-registered to T2W and FLAIR images, were analyzed for lesions affecting the three white matter tracts of the limbic system including cingulum, fornix, and mammilothalamic tracts by two investigators. The approximate location of the lesions on FLAIR was always confirmed on the co-registered DTI-derived FA color maps. RESULTS: Of the 150 patients analyzed, 14.6% had cingulum lesions, 2.6% had fornix lesions, and 2.6% had mammilothalamic tract lesions; 21.3% of patients had at least one of the three tracts affected. CONCLUSION: A relatively high frequency of lesions involving the limbic tracts may explain memory deficits and emotional dysfunction commonly experienced by patients with MS. The combined information from T2W, FLAIR, and DTI-derived FA color map allowed for more accurate localization of lesions affecting the major white matter tracts of the limbic system.

Identifying and addressing unmet therapeutic needs in MS.

Current disease-modifying treatments in multiple sclerosis (MS) are partially effective in reducing relapses and slowing disease progression, but these treatments do not restore function and are effective mainly in relapsing forms of MS. Unmet needs in MS include treatments for progressive forms of MS, agents with improved efficacy and safety profiles and that comprehensively manage MS symptoms, and medications with neuroprotective or remyelinating properties. Some adverse effects of disease-modifying agents could be reduced if medications are developed with more specific treatment targets, and research into the pathogenesis of MS may lead to agents that could restore myelin or protect nerves from inflammation.

Re-evaluating the treatment of acute optic neuritis.

Clinical case reports and prospective trials have demonstrated a reproducible benefit of hypothalamic-pituitary-adrenal (HPA) axis modulation on the rate of recovery from acute inflammatory central nervous system (CNS) demyelination. As a result, corticosteroid preparations and adrenocorticotrophic hormones are the current mainstays of therapy for the treatment of acute optic neuritis (AON) and acute demyelination in multiple sclerosis.Despite facilitating the pace of recovery, HPA axis modulation and corticosteroids have failed to demonstrate long-term benefit on functional recovery. After AON, patients frequently report visual problems, motion perception difficulties and abnormal depth perception despite 'normal' (20/20) vision. In light of this disparity, the efficacy of these and other therapies for acute demyelination require re-evaluation using modern, high-precision paraclinical tools capable of monitoring tissue injury.In no arena is this more amenable than AON, where a new array of tools in retinal imaging and electrophysiology has advanced our ability to measure the anatomic and functional consequences of optic nerve injury. As a result, AON provides a unique clinical model for evaluating the treatment response of the derivative elements of acute inflammatory CNS injury: demyelination, axonal injury and neuronal degeneration.In this article, we examine current thinking on the mechanisms of immune injury in AON, discuss novel technologies for the assessment of optic nerve structure and function, and assess current and future treatment modalities. The primary aim is to develop a framework for rigorously evaluating interventions in AON and to assess their ability to preserve tissue architecture, re-establish normal physiology and restore optimal neurological function.

Constructing an adaptive care model for the management of disease-related symptoms throughout the course of multiple sclerosis--performance improvement CME.

BACKGROUND: Symptom management remains a challenging clinical aspect of MS. OBJECTIVE: To design a performance improvement continuing medical education (PI CME) activity for better clinical management of multiple sclerosis (MS)-related depression, fatigue, mobility impairment/falls, and spasticity. METHODS: Ten volunteer MS centers participated in a three-stage PI CME model: A) baseline assessment; B) practice improvement CME intervention; C) reassessment. Expert faculty developed performance measures and activity intervention tools. Designated MS center champions reviewed patient charts and entered data into an online database. Stage C data were collected eight weeks after implementation of the intervention and compared with Stage A baseline data to measure change in performance. RESULTS: Aggregate data from the 10 participating MS centers (405 patient charts) revealed performance improvements in the assessment of all four MS-related symptoms. Statistically significant improvements were found in the documented assessment of mobility impairment/falls (p=0.003) and spasticity (p<0.001). For documentation of care plans, statistically significant improvements were reported for fatigue (p=0.007) and mobility impairment/falls (p=0.040); non-significant changes were noted for depression and spasticity. CONCLUSIONS: Our PI CME interventions demonstrated performance improvement in the management of MS-related symptoms. This PI CME model (available at www.achlpicme.org/ms/toolkit) offers a new perspective on enhancing symptom management in patients with MS.

Direct visualization of short transverse relaxation time component (ViSTa).

White matter of the brain has been demonstrated to have multiple relaxation components. Among them, the short transverse relaxation time component (T2<40 ms; T2⁎<25 ms at 3 T) has been suggested to originate from myelin water whereas long transverse relaxation time components have been associated with axonal and/or interstitial water. In myelin water imaging, T2 or T2⁎ signal decay is measured to estimate myelin water fraction based on T2 or T2⁎ differences among the water components. This method has been demonstrated to be sensitive to demyelination in the brain but suffers from low SNR and image artifacts originating from ill-conditioned multi-exponential fitting. In this study, a novel approach that selectively acquires short transverse relaxation time signal is proposed. The method utilizes a double inversion RF pair to suppress a range of long T1 signal. This suppression leaves short T2⁎ signal, which has been suggested to have short T1, as the primary source of the image. The experimental results confirm that after suppression of long T1 signals, the image is dominated by short T2⁎ in the range of myelin water, allowing us to directly visualize the short transverse relaxation time component in the brain. Compared to conventional myelin water imaging, this new method of direct visualization of short relaxation time component (ViSTa) provides high quality images. When applied to multiple sclerosis patients, chronic lesions show significantly reduced signal intensity in ViSTa images suggesting sensitivity to demyelination.

Multiple sclerosis update.

Multiple sclerosis (MS) is a chronic but incurable disease of the central nervous system (CNS) that is often diagnosed in the second or third decade of life. It is more common among women than men, significantly impairs patient quality of life, and is associated with substantial costs to patients, healthcare systems, and society. Of the approximately 2.3 million individuals worldwide that have MS, more than 400,000 reside in the United States. Although the etiology of MS is not completely understood, a great deal of evidence suggests a complex relationship between environmental and genetic factors. The pathophysiology of MS involves an aberrant attack by the host immune system on oligodendrocytes, which synthesize and maintain myelin sheaths in the CNS. There are 4 identified disease courses in MS, and approximately 85% of people with MS present with relapsing-remitting MS, which is characterized by discrete acute attacks followed by periods of remission. Signs and symptoms of MS are dependent on the demyelinated area(s) of the CNS and often involve sensory disturbances, limb weakness, fatigue, and increased body temperature. The criteria for a diagnosis of MS include evidence of damage in at least 2 separate areas of the CNS, evidence that the damage occurred at different time points, and the ruling out of other possible diagnoses. Diseasemodifying drugs (DMDs) that reduce the frequency of relapses, development of brain lesions, and progression of disability are the standard of care for relapsing forms of MS, and the use of DMDs should be initiated as early as possible.

Exposure to CYP3A4-inducing and CYP3A4-non-inducing antiepileptic agents and the risk of fractures.

PURPOSE: To evaluate whether exposure to Cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4)-inducing antiepileptics increases fracture risk compared to CYP3A4-non-inducing antiepileptics. METHODS: We performed a retrospective cohort study of initiators of antiepileptic agents using a UK medical record database (The Health Improvement Network) from 1995 to 2007. We considered an antiepileptic user an initiator if he or she had not received a prescription for an antiepileptic agent within the first year after entry in the database. Proportional hazards regression was used to calculate hazard ratios for fracture during long-term (≥ 6 months) exposure to CYP3A4 inducing versus CYP3A4 non-inducing antiepileptics. RESULTS: We identified 4077 initiators of CYP3A4-inducing antiepileptics and 6433 initiators of CYP3A4-non-inducing antiepileptics with at least 6 months of antiepileptic exposure. During 6006 person-years exposed to CYP3A4-inducing antiepileptics, 118 fractures were identified for an incidence rate of 1.96 (95% confidence interval (CI): 1.63-2.35) fractures per 100 person-years. During 7184 person-years exposed to CYP3A4-non-inducing antiepileptics, 127 fractures were identified, for an incidence rate of 1.77 (95% CI: 1.47-2.10) fractures per 100 person-years. The adjusted hazard ratio for CYP3A4-inducing antiepileptic versus CYP3A4-non-inducing antiepileptic was 1.21 (95% CI: 0.93-1.56). No duration-response relationship was evident. CONCLUSIONS: Our results do not support the hypothesis that CYP3A4 induction by antiepileptic agents increases the fracture risk. Further research will be needed to evaluate whether mechanisms other than CYP3A4 induction might explain some of the elevated risk of fractures associated with long-term use of antiepileptic agents.

Fingolimod for the treatment of relapsing multiple sclerosis.

Fingolimod is the first oral agent approved in the USA for the treatment of relapsing forms of multiple sclerosis. Fingolimod is a sphingosine 1-phosphate receptor modulator that binds to sphingosine 1-phosphate receptors on lymphocytes, resulting in a downregulation of the receptor and a reversible sequestration of lymphocytes in lymphoid tissue. Effector memory T cells are not sequestered so that immune surveillance may be minimally affected. Two large-scale Phase III clinical trials have demonstrated the efficacy of fingolimod compared with placebo and intramuscular interferon ß-1a in relapsing-remitting multiple sclerosis. Due to its mechanism of action, fingolimod administration may be associated with first-dose bradycardia and macular edema. Therefore, patients should be observed for 6 h at the time of their first dose and undergo ophthalmologic evaluation prior to treatment initiation and at 3-4 months after initiation.

Stratus OCT Quality Control in Two Multi-Centre Multiple Sclerosis Clinical Trials.

The University of California (UC) Davis Reading Center evaluated 19,961 scans from 981 subjects in two multiple sclerosis therapeutic trials with the aim of determining the influence of optical coherence tomography quality control procedures on error rates. There was no optical coherence tomography technician certification in Trial 1, and technicians had very limited monitoring and feedback during the trial in view of the fact that data were received retrospectively. However, technicians were certified in Trial 2 and submitted data in accordance with the protocol. Trial 2 scans had higher signal strengths, fewer errors, and more useable data than the scans in Trial 1. Thus, certified technicians and prompt transmission of data for ongoing quality control monitoring provided higher quality data in multiple sclerosis trials.

The current landscape and unmet needs in multiple sclerosis.

When introduced in the early and middle 1990s, current first-line pharmacologic therapies for multiple sclerosis (MS)--interferon beta-1a, interferon beta-1b, and glatiramer acetate--constituted a major advancement in MS treatment. Nevertheless, disease progression, although typically delayed with these agents, remains inevitable in most patients and constitutes a significant limitation of the currently available treatments. Moreover, the first-line therapies all require frequent subcutaneous or intramuscular injections, delivery modalities that are associated with subpar treatment adherence. The demand for more effective agents has produced a new generation of MS therapies with impressive efficacy profiles--although their long-term safety and tolerability remain largely unknown. Some of the new agents have been formulated for oral administration, which will likely have a positive impact on treatment adherence. These new agents are appearing during a time of major change in MS research. As the old expectation of inevitable disease progression is being reconsidered, the notion of sustained disease inactivity has become a credible, still somewhat elusive, goal. Neuroprotection may also be possible with new and existing treatments. At the same time, new imaging techniques, such as measuring disease progression via T1-hypointense lesions ("black holes"), and a better understanding of pathophysiologic factors in MS--such as the role of neurotrophic growth factors and oxidative stress--are changing the ways that efficacy is measured and how new agents are developed.

Longitudinal study of vision and retinal nerve fiber layer thickness in multiple sclerosis.

OBJECTIVE: Cross-sectional studies of optical coherence tomography (OCT) show that retinal nerve fiber layer (RNFL) thickness is reduced in multiple sclerosis (MS) and correlates with visual function. We determined how longitudinal changes in RNFL thickness relate to visual loss. We also examined patterns of RNFL thinning over time in MS eyes with and without a prior history of acute optic neuritis (ON). METHODS: Patients underwent OCT measurement of RNFL thickness at baseline and at 6-month intervals during a mean follow-up of 18 months at 3 centers. Low-contrast letter acuity (2.5%, 1.25% contrast) and visual acuity (VA) were assessed. RESULTS: Among 299 patients (593 eyes) with >or=6 months follow-up, eyes with visual loss showed greater RNFL thinning compared to eyes with stable vision (low-contrast acuity, 2.5%: p < 0.001; VA: p = 0.005). RNFL thinning increased over time, with average losses of 2.9microm at 2 to 3 years and 6.1microm at 3 to 4.5 years (p < 0.001 vs 0.5-1-year follow-up interval). These patterns were observed for eyes with or without prior history of ON. Proportions of eyes with RNFL loss greater than test-retest variability (>or=6.6microm) increased from 11% at 0 to 1 year to 44% at 3 to 4.5 years (p < 0.001). INTERPRETATION: Progressive RNFL thinning occurs as a function of time in some patients with MS, even in the absence of ON, and is associated with clinically significant visual loss. These findings are consistent with subclinical axonal loss in the anterior visual pathway in MS, and support the use of OCT and low-contrast acuity as methods to evaluate the effectiveness of putative neuroprotection protocols.

An approach to comparing accuracies of two FLAIR MR sequences in the detection of multiple sclerosis lesions in the brain in the absence of gold standard.

RATIONALE AND OBJECTIVES: The purpose of this study was to present a new methodology to compare accuracies of two imaging fluid attenuated inversion recovery (FLAIR) magnetic resonance sequences in detection of multiple sclerosis (MS) lesions in the brain in the absence of ground truth, and to determine whether the two sequences, which differed only in echo time (TE), have the same accuracy. MATERIALS AND METHODS: We acquired FLAIR images at TE(1) = 90 ms and TE(2) = 155 ms from 46 patients with MS (24-69 years old, mean 45.8, 15 males) and 11 healthy volunteers (23-54 years old, mean 37.1, 6 males). Seven experienced neuroradiologists segmented lesions manually on randomly presented corresponding TE(1) and TE(2) images. For every image pair, a "surrogate ground truth" for each TE was generated by applying probability thresholds, ranging from 0.3 to 0.5, to the weighted average of experts' segmentations. Jackknife alternative free-response receiver operating characteristic analysis was used to compare experts' performance on TE(1) and TE(2) images, using successively the TE(1)- and TE(2)-based ground truths. RESULTS: Supratentorially, there were significant differences in relative accuracy between the two sequences, ranging from 8.4% to 12.1%. In addition, we found a higher ratio of false positives to true positives for the TE(2) sequence using the TE(2) ground truth, compared to the TE(1) equivalent. Infratentorially, differences in the relative accuracy did not reach statistical significance. CONCLUSION: The presented methodology may be useful in assessing the value of new clinical imaging protocols or techniques in the context of replacing existing ones, when the absolute ground truth is not available, and in determining changes in disease progression in follow-up studies. Our results suggest that the sequence with shorter TE should be preferred because it generates relatively fewer false positives. The finding is consistent with results of previous computer simulation studies.

Macular volume determined by optical coherence tomography as a measure of neuronal loss in multiple sclerosis.

BACKGROUND: Inner (area adjacent to the fovea) and outer regions of the macula differ with respect to relative thicknesses of the ganglion cell layer (neurons) vs retinal nerve fiber layer (RNFL; axons). OBJECTIVE: To determine how inner vs outer macular volumes relate to peripapillary RNFL thickness and visual function in multiple sclerosis (MS) and to examine how these patterns differ among eyes with vs without a history of acute optic neuritis (ON). DESIGN: Study using cross-sectional optical coherence tomography. SETTING: Three academic tertiary care MS centers. PARTICIPANTS: Patients with MS, diagnosed by standard criteria, and disease-free control participants. MAIN OUTCOME MEASURES: Optical coherence tomography was used to measure macular volumes and RNFL thickness. Visual function was assessed using low-contrast letter acuity and high-contrast visual acuity (Early Treatment Diabetic Retinopathy Study charts). RESULTS: Among eyes of patients with MS (n = 1058 eyes of 530 patients), reduced macular volumes were associated with peripapillary RNFL thinning; 10-microm differences in RNFL thickness (9.6% of thickness in control participants without disease) corresponded to 0.20-mm(3) reductions in total macular volume (2.9% of volume in control participants without disease, P < .001). This relation was similar for eyes of MS patients with and without a history of ON. Although peripapillary RNFL thinning was more strongly associated with decrements in outer compared with inner macular volumes, correlations with inner macular volume were significant (r = 0.58, P < .001) and of slightly greater magnitude for eyes of MS patients with a history of ON vs eyes of MS patients without a history of ON (r = 0.61 vs r = 0.50). Lower (worse) visual function scores were associated with reduced total, inner, and outer macular volumes. However, accounting for peripapillary RNFL thickness, the relation between vision and inner macular volume remained significant and unchanged in magnitude, suggesting that this region contains retinal structures separate from RNFL axons that are important to vision. CONCLUSIONS: Analogous to studies of gray matter in MS, these data provide evidence that reductions of volume in the macula (approximately 34% neuronal cells by average thickness) accompany RNFL axonal loss. Peripapillary RNFL thinning and inner macular volume loss are less strongly linked in eyes of MS patients without a history of ON than in eyes of MS patients with a history of ON, suggesting alternative mechanisms for neuronal cell loss. Longitudinal studies with segmentation of retinal layers will further explore the relation and timing of ganglion cell degeneration and RNFL thinning in MS.

The treatment of multiple sclerosis with inosine.

OBJECTIVE: The objective of this study is to evaluate the safety and tolerability of inosine in patients with relapsing-remitting multiple sclerosis (RRMS). The secondary objectives are to assess the effects of inosine administration on serum urate (UA) levels, the progression of neurologic disability, the cumulative number of new, active lesions on magnetic resonance imaging (MRI), and changes in serum levels for markers of inflammation. DESIGN: Oral administration of inosine was used to raise serum levels of the natural peroxynitrite scavenger UA in 16 patients with RRMS during a 1-year randomized, double-blind trial. OUTCOME MEASURES: The endpoints studied were relapse rate, disability assessed by the Kurtzke Expanded Disability Status Scale (EDSS), MRI, and analysis of serum levels of nitrotyrosine, and oxidative and pro-inflammatory makers. RESULTS: Increased serum UA levels correlated with a significant decrease in the number of gadolinium-enhanced lesions and improved EDSS. A number of MRI intensity-based parameters were altered by inosine treatment, in certain cases correlating with changes in serum UA levels. In a patient with low serum UA and high lesion activity, raising UA levels by inosine treatment decreased serum nitrotyrosine while increasing the ratio of Th2 to Th1 cytokines in circulating cells. The only side-effect correlated with inosine treatment was kidney stone formation in 4/16 subjects. CONCLUSIONS: These data suggest that the use of inosine to raise serum UA levels may have benefits for at least some MS patients. The effect of this treatment is likely to be a consequence of inactivation of peroxynitrite-dependent free radicals. Close monitoring of serum UA levels as well as other measures are required to avoid the potential development of kidney stones.

Retinal imaging by laser polarimetry and optical coherence tomography evidence of axonal degeneration in multiple sclerosis.

BACKGROUND: Optical coherence tomography (OCT) and scanning laser polarimetry with variable corneal compensation (GDx) are similar yet provide information on different aspects of retinal nerve fiber layer (RNFL) structure (thickness values similar to histology for OCT vs birefringence of microtubules for GDx). OBJECTIVES: To compare the ability of OCT and GDx to distinguish eyes of patients with multiple sclerosis (MS) from eyes of disease-free controls and thus identify RNFL abnormalities. We also sought to examine the capacity of these techniques to distinguish MS eyes from those without a history of optic neuritis and to correlate with visual function. DESIGN: Cross-sectional study. SETTING: Academic tertiary care MS center. PARTICIPANTS: Eighty patients with MS (155 eyes) and 43 disease-free controls (85 eyes) underwent both OCT and GDx imaging using protocols that measure RNFL thickness. MAIN OUTCOME MEASURES: Areas under the curve (AUC), adjusted for within-patient, intereye correlations, were used to compare the abilities of OCT and GDx temporal-superior-nasal-inferior-temporal average RNFL thicknesses to discriminate between MS and control eyes and to distinguish MS eyes with a history of optic neuritis. Visual function was evaluated using low-contrast letter acuity and high-contrast visual acuity. RESULTS: Average peripapillary RNFL thickness (360 degrees around the optic disc) was reduced in patients with MS compared with controls for both methods. Age-adjusted AUC did not differ between OCT (0.80; 95% confidence interval [CI], 0.72-0.88) and GDx (0.78; 95% CI, 0.68-0.86; P = .38). Optical coherence tomography-measured RNFL thickness was somewhat better at distinguishing MS eyes with a history of optic neuritis from those without (OCT: AUC, 0.73; 95% CI, 0.64-0.82; GDx: AUC, 0.66; 95% CI, 0.57-0.66; P = .17). Linear correlations of RNFL thickness for OCT vs GDx were significant yet moderate (r = 0.67, P < .001); RNFL thickness measures correlated moderately and significantly with low-contrast acuity (OCT: r = 0.54, P < .001; GDx: r = 0.55, P < .001) and correlated less with high-contrast visual acuity (OCT: r = 0.44, P < .001; GDx: r = 0.32, P < .001). CONCLUSIONS: Scanning laser polarimetry with variable corneal compensation measurements of RNFL thickness corroborates OCT evidence of visual pathway axonal loss in MS and provides new insight into structural aspects of axonal loss that relate to RNFL birefringence (microtubule integrity). These results support validity for RNFL thickness as a marker for axonal degeneration and support use of these techniques in clinical trials that examine neuroprotective and other disease-modifying therapies.