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Background: To identify the vascular risk factors associated with the occurrence of intracerebral hemorrhage (ICH) in Multiple Sclerosis (MS) patients. Methods This is an observational, retrospective cohort study using the nationwide electronic medical records (EMR) database. Patients with the diagnosis of MS were extracted from inpatient and outpatient EMR using the international classification of diseases, ninth/tenth revisions, clinical modification codes. We excluded patients younger than 18 years, and those where gender was not specified. Patients were further stratified based on their demographics, risk factors, medications, and comorbidities. Tobacco, diabetes, hypertension, and alcohol were the predicting variables; antiplatelet medication, and anticoagulant agents were the primary exposures for the development of ICH. A validated diagnosis code algorithm defined the diagnosis of ICH. Multivariable logistic regression models were utilized to assess the risk of ICH in MS patients. Results Of the total 57,099 MS patients (women: 75%, n = 41,517), 107 (.19%) sustained an ICH. Age (OR = 2.74, CI = 1.13-6.62), use of anticoagulants (OR = 2.15, 95% CI = 1.30-3.56, P = .0028), and history of tobacco exposure (OR = 2.44, CI = 1.37-4.36, P = .0025) were associated with increased risk of ICH. Use of antiplatelet and disease-modifying drugs (DMDs) showed a protective trend against ICH. Conclusions Tobacco exposure and anticoagulant use were strongly associated with increased risk of ICH in patients with MS. There might be a protective effect that antiplatelet and DMDs have in the pathophysiology of this disease. Further prospective investigations are warranted to establish these associations.

ObjectiveTo investigate the current status of postgraduate training in neuroimmunology and multiple sclerosis (NI/MS) in the United States.MethodsWe developed a questionnaire to collect information on fellowship training focus, duration of training, number of fellows, funding application process, rotations, visa sponsorship, and an open-ended question about challenges facing training in NI/MS. We identified target programs and sent the questionnaires electronically to fellowship program directors.ResultsWe identified and sent the questionnaire to 69 NI/MS fellowship programs. We successfully obtained data from 64 programs. Most programs were small, matriculating 1–2 fellows per year, and incorporated both NI and MS training into the curriculum. Most programs were flexible in their duration, typically lasting 1–2 years, and offered opportunities for research during training. Only 56% reported the ability to sponsor nonimmigrant visas. Most institutions reported having some internal funding, although the availability of these funds varied from year to year. Several program directors identified funding availability and the current absence of national subspecialty certification as major challenges facing NI/MS training.ConclusionOur study is the first to describe the current status of NI/MS training in the United States. We found many similarities across programs. We anticipate that these data will serve as a first step towards developing a standard NI/MS curriculum and help identify areas where shared resources could enhance trainee education despite differences in training environments. We identified funding availability, certification status, and nonimmigrant visa sponsorship as potential barriers to future growth in the field.

Background:Anecdotal reports suggest shortages among neurologists who provide multiple sclerosis (MS) patient care. However, little information is available regarding the current and future supply of and demand for this neurologist workforce.Methods:We used information from neurologist and neurology resident surveys, professional organizations, and previously reported studies to develop a model assessing the projected supply and demand (ie, expected physician visits) of neurologists providing MS patient care. Model projections extended through 2035.Results:The capacity for MS patient visits among the overall neurologist workforce is projected to increase by approximately 1% by 2025 and by 12% by 2035. However, the number of individuals with MS may increase at a greater rate, potentially resulting in decreased access to timely and high-quality care for this patient population. Shortages in the MS neurologist workforce may be particularly acute in small cities and rural areas. Based on model sensitivity analyses, potential strategies to substantially increase the capacity for MS physicians include increasing the number of patients with MS seen per neurologist, offering incentives to decrease neurologist retirement rates, and increasing the number of MS fellowship program positions.Conclusions:The neurologist workforce may be adequate for providing MS care currently, but shortages are projected over the next 2 decades. To help ensure access to needed care and support optimal outcomes among individuals with MS, policies and strategies to enhance the MS neurologist workforce must be explored now.

Background: There is an unmet need to develop therapeutic interventions directed at the neurodegeneration that underlies progression in multiple sclerosis. High-dose, pharmaceutical-grade biotin (MD1003) might enhance neuronal and oligodendrocyte energetics, resulting in improved cell function, repair, or survival. The MS-SPI randomised, double-blind, placebo-controlled study found that MD1003 improved disability outcomes over 12 months in patients with progressive multiple sclerosis. The SPI2 study was designed to assess the safety and efficacy of MD1003 in progressive forms of multiple sclerosis in a larger, more representative patient cohort. Methods: SPI2 was a randomised, double-blind, parallel-group, placebo-controlled trial done at 90 academic and community multiple sclerosis clinics across 13 countries. Patients were aged 18-65 years, had a diagnosis of primary or secondary progressive multiple sclerosis fulfilling the revised International Panel criteria and Lublin criteria, a Kurtzke pyramidal functional subscore of at least 2 (defined as minimal disability), an expanded disability status scale (EDSS) score of 3·5-6·5, a timed 25-foot walk (TW25) of less than 40 s, evidence of clinical disability progression, and no relapses in the 2 years before enrolment. Concomitant disease-modifying therapies were allowed. Patients were randomly assigned (1:1) by an independent statistician using an interactive web response system, with stratification by study site and disease history, to receive MD1003 (oral biotin 100 mg three times daily) or placebo. Participants, investigators, and assessors were masked to treatment assignment. The primary endpoint was a composite of the proportion of participants with confirmed improvement in EDSS or TW25 at month 12, confirmed at month 15, versus baseline. The primary endpoint was assessed in the intention-to-treat analysis set, after all participants completed the month 15 visit. Safety analyses included all participants who received at least one dose of MD1003. This trial is registered with ClinicalTrials.gov (NCT02936037) and the EudraCT database (2016-000700-29). Findings: From Feb 22, 2017, to June 8, 2018, 642 participants were randomly assigned MD1003 (n=326) or placebo (n=316). The double-blind, placebo-controlled phase of the study ended when the primary endpoint for the last-entered participant was assessed on Nov 15, 2019. The mean time in the placebo-controlled phase was 20·1 months (SD 5·3; range 15-27). For the primary outcome, 39 (12%) of 326 patients in the MD1003 group compared with 29 (9%) of 316 in the placebo group improved at month 12, with confirmation at month 15 (odds ratio 1·35 [95% CI 0·81-2·26]). Treatment-emergent adverse events occurred in 277 (84%) of 331 participants in the MD1003 group and in 264 (85%) of 311 in the placebo group. 87 (26%) of 331 participants in the MD1003 group and 82 (26%) of 311 participants in the placebo group had at least one serious treatment-emergent adverse event. One (

Background: The advent of mechanical thrombectomy in acute stroke care has reignited interest in the arena of neuro-inflammation and neuro-plasticity to optimize stroke management and further improve outcome. Even though there is an early evidence suggesting increased risk of ischemic stroke (IS) in pro-inflammatory states like lupus, rheumatoid and even multiple sclerosis, cardiovascular risk factor association has yet to be comprehensively studied in Multiple Sclerosis (MS). This is the first ever North American Study focusing on prevalence of ischemic stroke in the largest MS cohort. Method: This retrospective study included all patients diagnosed with MS from 2000 to 2016, identified using ICD-9/10 codes. The data were extracted from the Cerner's Health Facts database. From the pool of MS patients, IS was identified and their comorbidities are identified. Multiple logistic regression was used to evaluate the odds of having IS in patients with MS. Statistical analysis performed by the SAS v ersion 9.4, Cary, NC, USA. Result: A total of 83,222 patients with a diagnosis of MS were identified. IS was officially diagnosed in 2,159 (2.59%) and intracerebral hemorrhage (ICH) in 191 (0.22%) patients with MS. Patients with MS had 1.6 times more likelihood of having an IS as compared to non-MS patients (p Conclusion: This is one of the largest MS cohort studies confirming prior reports of higher incidence of IS in MS population, especially in the 41-64 age group, after adjusting for cardiovascular risk factors. Future prospective epidemiological and molecular studies can open new diagnostic and treatment avenues.

BACKGROUND AND PURPOSE Conventional MRI techniques do not necessarily provide information about multiple sclerosis (MS) disease pathology or progression. Nonconventional MRI techniques, including proton magnetic resonance spectroscopy (1H-MRS), are increasingly used to improve the qualitative and quantitative specificity of MR images. This study explores potential correlations between MRI measures of disease and disability progression as measured by the Expanded Disability Status Scale (EDSS), Functional Systems (FS), and ambulation index scores in a unique cohort of MS patients treated with glatiramer acetate that has been closely monitored for over 20 years. METHODS This was a multicenter, open-label, cross-sectional MRI substudy among participants in the GA-9004 open-label extension of the 36-month, double-blind GA-9001 study, timed to coincide with the prospectively planned 20-year clinical exam. RESULTS Of 64 patients who participated in the MRI substudy, results are presented for the 39 patients (61%) who had a 1H-MRS assessment at 20 years of treatment. Both total N-acetylaspartate relative to total creatinine (tNAA/tCr) concentration ratio and T1 lesion volume were found to be robustly associated with disability levels with different statistical approaches. Gray matter (GM) volume was found to be a more consistent parameter than white matter (WM) volume for disability allocation. The elastic net algorithm showed a trade-off between WM and GM volumes for disability estimation when different disability definitions were used. CONCLUSIONS Among patients with MS receiving long-term glatiramer acetate therapy, consistent effects on disability levels indicated by EDSS and pyramidal FS score thresholds were found for tNAA/tCr concentration ratio and T1 lesion volume.

Importance Doses of fingolimod lower than 0.5 mg per day were not investigated during the fingolimod clinical development program. Whether lower doses of fingolimod might retain efficacy with fewer safety risks remains unknown. Objective To evaluate the efficacy and safety of fingolimod, 0.5 mg, and fingolimod, 0.25 mg, compared with glatiramer acetate and to assess whether these doses of fingolimod show superior efficacy to glatiramer acetate in adult patients with relapsing-remitting multiple sclerosis. Interventions Fingolimod, 0.5 mg, or fingolimod, 0.25 mg, orally once per day or glatiramer acetate, 20 mg, subcutaneously once per day. Design, Setting, and Participants The Multiple Sclerosis Study Evaluating Safety and Efficacy of Two Doses of Fingolimod Versus Copaxone (ASSESS) was a phase 3b multicenter randomized rater-blinded and dose-blinded 12-month clinical trial conducted between August 9, 2012, and April 30, 2018 (including the time required to recruit participants). A total of 1461 patients aged 18 to 65 years with relapsing-remitting multiple sclerosis were screened, and 1064 participants were randomized. These participants had at least 1 documented relapse during the previous year or 2 documented relapses during the previous 2 years and an Expanded Disability Status Scale score of 0 to 6 at screening. Data were analyzed between September and November 2018. Main Outcomes and Measures The superiority of the fingolimod doses was tested hierarchically, with fingolimod, 0.5 mg, vs glatiramer acetate, 20 mg, tested first, followed by fingolimod, 0.25 mg, vs glatiramer acetate, 20 mg. The primary end point was the reduction in annualized relapse rate (ARR). Magnetic resonance imaging parameters, safety, and tolerability were also assessed. Results Of 1461 adult patients screened, 1064 participants (72.8%) were randomized (mean [SD] age, 39.6 [11.0] years; 792 women [74.4%]) to 3 treatment groups: 352 participants received fingolimod, 0.5 mg, 370 participants received fingolimod, 0.25 mg, and 342 participants received glatiramer acetate, 20 mg. In total, 859 participants (80.7%) completed the study. Treatment with fingolimod, 0.5 mg, was superior to treatment with glatiramer acetate, 20 mg, in reducing ARR (40.7% relative reduction); the relative reduction with fingolimod, 0.25 mg, was 14.6%, which was not statistically significant (for fingolimod, 0.5 mg, ARR, 0.15; 95% CI, 0.11-0.21; for fingolimod, 0.25 mg, ARR, 0.22; 95% CI, 0.17-0.29; for glatiramer acetate, 20 mg, ARR, 0.26; 95% CI, 0.20-0.34). Treatment with both fingolimod doses (0.5 mg and 0.25 mg) significantly reduced new or newly enlarging T2 and gadolinium-enhancing T1 lesions compared with treatment with glatiramer acetate. Adverse events were reported in similar proportions across treatment groups (312 participants [90.4%] in the fingolimod, 0.5 mg, group, 323 participants [88.3%] in the fingolimod, 0.25 mg, group, and 283 participants [87.3%] in the glatiramer acetate group). Conclusions and Relevance Fingolimod, 0.5 mg, demonstrated superior clinical efficacy compared with glatiramer acetate, 20 mg, and had a superior benefit-risk profile compared with fingolimod, 0.25 mg, in adult participants with relapsing-remitting multiple sclerosis. Trial Registration ClinicalTrials.gov Identifier:NCT01633112

Glatiramer acetate (GA) is approved for relapsing-remitting multiple sclerosis in 57 countries worldwide, with more than 2 million patient-years of exposure and over 20 years of continuous clinical use without new safety concerns. GA has an overall favorable risk-benefit profile: 30% reduced annual relapse rate and decreased brain lesion activity. In clinically definite MS or clinically isolated syndrome, GA slows brain atrophy, which may be related to its unique anti-inflammatory and neuroprotective mechanisms of action. Early treatment with GA delays the onset of clinically definite MS more effectively than late treatment in clinically isolated syndrome. GA is not associated with immunosuppression, autoimmune disease, infections or development of neutralizing antibodies. A new three-times-weekly formulation of GA is available to potentially reduce the incidence of injection-related side effects. Other safety advantages of GA include its pregnancy rating (Category B) and limited uncontrolled data suggesting that tolerability is similar in children with MS.

Blood–brain barrier (BBB) disruption visualized in lesions by MRI is a major biomarker of disease activity in multiple sclerosis (MS). However, in MS, destruction occurs to a variable extent in lesions as well as in gray matter (GM) and in the normal appearing white matter (NAWM). A method to quantify the BBB disruption in lesions as well as in non-lesion areas would be useful for assessment of MS progression and treatments. The objective of this study was to quantify the BBB transfer rate (Ki) in WM lesions, in the NAWM, and in the full-brain of MS patients. Thirteen MS patients with active lesions and 10 healthy controls with age and gender matching were recruited for full-brain and WM Ki studies. Dynamic contrast-enhanced MRI (DCEMRI) scans were conducted using T1 mapping with partial inversion recovery (TAPIR), a fast T1 mapping technique, following administration of a quarter-dose of the contrast agent Gadolinium-DTPA (Gd-DTPA). The Patlak modeling technique was used to derive a voxel-based map of Ki. In all patients contrast-enhanced lesions, quantified by Ki maps, were observed. Compared with controls, patients with MS exhibited an increase in mean Ki of the full-brain (P-value

It has recently been suggested that the Lublin-Reingold clinical classification of multiple sclerosis (MS) be modified to include the use of magnetic resonance imaging (MRI). An international consensus conference sponsored by the Consortium of Multiple Sclerosis Centers (CMSC) was held from March 5 to 7, 2010, to review the available evidence on the need for such modification of the Lublin-Reingold criteria and whether the addition of MRI or other biomarkers might lead to a better understanding of MS pathophysiology and disease course over time. The conference participants concluded that evidence of new MRI gadolinium-enhancing (Gd+) T1-weighted lesions and unequivocally new or enlarging T2-weighted lesions (subclinical activity, subclinical relapses) should be added to the clinical classification of MS in distinguishing relapsing inflammatory from progressive forms of the disease. The consensus was that these changes to the classification system would provide more rigorous definitions and categorization of MS course, leading to better insights as to the evolution and treatment of MS.

The ongoing US Glatiramer Acetate (GA) Trial is the longest evaluation of continuous immunomodulatory therapy in relapsing—remitting multiple sclerosis (RRMS). The objective of this study was to evaluate up to 15 years of GA as a sole disease-modifying therapy. Two hundred and thirty-two patients received at least one GA dose since study initiation in 1991 (mITT cohort), and 100 (43%, Ongoing cohort) continued as of February 2008. Patients were evaluated every 6 months using the Expanded Disability Status Scale (EDSS). Mean GA exposures were 8.6 ± 5.2, 4.81 ± 3.69, and 13.6 ± 1.3 years and mean disease durations were 17, 13, and 22 years for mITT, Withdrawn and Ongoing cohorts, respectively. For Ongoing patients, annual relapse rates (ARRs) maintained a decline from 1.12 ± 0.82 at baseline to 0.25 ± 0.34 per year; 57% had stable/improved EDSS scores (change ≤ 0.5 points); 65% had not transitioned to secondary progressive multiple sclerosis (SPMS); 38%, 18%, and 3% reached EDSS 4, 6, and 8. For all patients on GA therapy (the mITT cohort), ARRs declined from 1.18 ± 0.82 to 0.43 ± 0.58 per year; 54% had stable/improved EDSS scores; 75% had not transitioned to SPMS; 39%, 23%, and 5% reached EDSS 4, 6, and 8. In conclusion, multiple sclerosis patients with mean disease duration of 22 years administering GA for up to 15 years had reduced relapse rates, and decreased disability progression and transition to SPMS. There were no long-term safety issues.

An international group of neurologists and radiologists developed revised guidelines for standardized brain and spinal cord MR imaging for the diagnosis and follow-up of MS. A brain MR imaging with gadolinium is recommended for the diagnosis of MS. A spinal cord MR imaging is recommended if the brain MR imaging is nondiagnostic or if the presenting symptoms are at the level of the spinal cord. A follow-up brain MR imaging with gadolinium is recommended to demonstrate dissemination in time and ongoing clinically silent disease activity while on treatment, to evaluate unexpected clinical worsening, to re-assess the original diagnosis, and as a new baseline before starting or modifying therapy. A routine brain MR imaging should be considered every 6 months to 2 years for all patients with relapsing MS. The brain MR imaging protocol includes 3D T1-weighted, 3D T2-FLAIR, 3D T2-weighted, post-single-dose gadolinium-enhanced T1-weighted sequences, and a DWI sequence. The progressive multifocal leukoencephalopathy surveillance protocol includes FLAIR and DWI sequences only. The spinal cord MR imaging protocol includes sagittal T1-weighted and proton attenuation, STIR or phase-sensitive inversion recovery, axial T2- or T2*-weighted imaging through suspicious lesions, and, in some cases, postcontrast gadolinium-enhanced T1-weighted imaging. The clinical question being addressed should be provided in the requisition for the MR imaging. The radiology report should be descriptive, with results referenced to previous studies. MR imaging studies should be permanently retained and available. The current revision incorporates new clinical information and imaging techniques that have become more available.

© 2015 Elsevier Ltd. Background: Relapses of multiple sclerosis decrease during pregnancy, when the hormone estriol is increased. Estriol treatment is anti-inflammatory and neuroprotective in preclinical studies. In a small single-arm study of people with multiple sclerosis estriol reduced gadolinium-enhancing lesions and was favourably immunomodulatory. We assessed whether estriol treatment reduces multiple sclerosis relapses in women. Methods: We did a randomised, double-blind, placebo-controlled phase 2 trial at 16 academic neurology centres in the USA, between June 28, 2007, and Jan 9, 2014. Women aged 18-50 years with relapsing-remitting multiple sclerosis were randomly assigned (1:1) with a random permuted block design to either daily oral estriol (8 mg) or placebo, each in combination with injectable glatiramer acetate 20 mg daily. Patients and all study personnel, except for pharmacists and statisticians, were masked to treatment assignment. The primary endpoint was annualised relapse rate after 24 months, with a significance level of p=0·10. Relapses were confirmed by an increase in Expanded Disability Status Scale score assessed by an independent physician. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00451204. Findings: We enrolled 164 patients: 83 were allocated to the estriol group and 81 were allocated to the placebo group. The annualised confirmed relapse rate was 0·25 relapses per year (95% CI 0·17-0·37) in the estriol group versus 0·37 relapses per year (0·25-0·53) in the placebo group (adjusted rate ratio 0·63, 95% CI 0·37-1·05; p=0·077). The proportion of patients with serious adverse events did not differ substantially between the estriol group and the placebo group (eight [10%] of 82 patients vs ten [13%] of 76 patients). Irregular menses were more common in the estriol group than in the placebo group (19 [23%] vs three [4%], p=0·0005), but vaginal infections were less common (one [1%] vs eight [11%], p=0·0117). There were no differences in breast fibrocystic disease, uterine fibroids, or endometrial lining thickness as assessed by clinical examination, mammogram, uterine ultrasound, or endometrial lining biopsy. Interpretation: Estriol plus glatiramer acetate met our criteria for reducing relapse rates, and treatment was well tolerated over 24 months. These results warrant further investigation in a phase 3 trial. Funding: National Institutes of Health, National Multiple Sclerosis Society, Conrad N Hilton Foundation, Jack H Skirball Foundation, Sherak Family Foundation, and the California Community Foundation.

The objective of this roundtable discussion of experts in the field of multiple sclerosis (MS) was to summarize the current understanding of MS and its therapeutic options. The experts discussed subjects ranging from the etiology of MS to the current standards for patient care. Specific topics included the subtypes of MS, with a focus on the benign subtype, brain atrophy, the role of magnetic resonance imaging or “neuroimaging studies,” disease-modifying therapies, biological markers as indicators of drug efficacy, and combination therapies. In addition, the experts speculated as to what will be available in the near future for the improved diagnosis and management of MS. This review summarizes the main points of this discussion and is intended to serve as a reference for neurologists involved in the care of patients with MS.

OBJECTIVE: Many troops deployed in Iraq and Afghanistan have sustained blast-related, closed-head injuries from being within non-lethal distance of detonated explosive devices. Little is known, however, about the mechanisms associated with blast exposure that give rise to traumatic brain injury (TBI). This study attempts to identify the precise conditions of focused stress wave energy within the brain, resulting from blast exposure, which will correlate with a threshold for persistent brain injury. METHODS: This study developed and validated a set of modelling tools to simulate blast loading to the human head. Using these tools, the blast-induced, early-time intracranial wave motions that lead to focal brain damage were simulated. RESULTS: The simulations predict the deposition of three distinct wave energy components, two of which can be related to injury-inducing mechanisms, namely cavitation and shear. Furthermore, the results suggest that the spatial distributions of these damaging energy components are independent of blast direction. CONCLUSIONS: The predictions reported herein will simplify efforts to correlate simulation predictions with clinical measures of TBI and aid in the development of protective headwear. Language: en

Gerstmann syndrome (GS) comprises four interlaced neuropsychological symptoms including finger agnosia, right-left confusion, agraphia, and acalculia. While GS is commonly associated with focal lesions to the region of the left angular gyrus, it has also been associated with numerous diffuse etiologies including atrophy, alcoholism, carbon monoxide poisoning, lead intoxication and anaphylactic shock. Thus, a vigorous debate has emerged as to whether GS represents a syndrome arising from general brain decline or a distinct and localizing lesion. We report a right-handed patient who developed neuropsychological dysfunction secondary to systemic lupus erythematosus (SLE). Neuropsychological evaluation found the patient to exhibit symptoms consistent with the GS tetrad, as well as general cognitive decline. Magnetic resonance imaging revealed a distinct focal lesion of the left parieto-occipital white matter underlying the angular gyrus as well as diffuse atrophy. (1)H-magnetic resonance spectroscopy revealed substantial metabolic derangement in a voxel placed within the visible lesion, although substantial metabolic derangement was observed in regions remote from the focal pathology. Thus, GS in this first case in SLE would appear to comprise a focal neurological tetrad of disorders within a more general pattern of cognitive decline and metabolic derangement.

In a randomized, placebo-controlled, double-blind study, glatiramer acetate (Copaxone) reduced the relapse rate and slowed accumulation of disability for patients with relapsing - remitting multiple sclerosis. Of the original 251 patients randomized to receive glatiramer acetate or placebo, 208 chose to continue in an open-label study with all patients receiving active drug. The majority of the original double-blind cohort continues to receive glatiramer acetate by daily subcutaneous injection and are evaluated at 6-month intervals and during suspected relapse. The data reported here are from approximately 6 years of organized evaluation, including the double-blind phase of up to 35 months and the open-label phase of over 36 months. Daily subcutaneous injections of 20 mg glatiramer acetate were well tolerated. The mean annual relapse rate of the patients who received glatiramer acetate since randomization and continued into the open-label study was 0.42 (95% confidence interval (CI), CI=0.34 - 0.51). The rate per year has continued to drop and for the sixth year is 0.23. Of the group who have received glatiramer acetate without interruption for 5 or more years, 69.3% were neurologically unchanged or have improved from baseline by at least one step on the Expanded Disability Status Scale (EDSS). Patients who left the open-label phase were surveyed by questionnaire. The majority responded, providing information about their current status and reasons for dropping out. This study demonstrates the sustained efficacy of glatiramer acetate in reducing the relapse rate and in slowing the accumulation of disability in patients with relapsing forms of multiple sclerosis. Multiple Sclerosis (2000) 6 255 - 266

When 251 relapsing-remitting patients with multiple sclerosis were randomized to receive daily subcutaneous injections of glatiramer acetate, previously called copolymer 1 (Copaxone; n = 125) or placebo (n = 126) for 24 months, there were no laboratory abnormalities associated with glatiramer acetate treatment and it was well tolerated with few side effects. Patients receiving glatiramer acetate had significantly fewer relapses and were more likely to be neurologically improved, whereas those receiving placebo were more likely to worsen. This study was extended for 1 to 11 months (mean of 5.2 months for the glatiramer acetate group and 5.9 months for the placebo group). The blinding and study conditions used during the core 24-month study were unchanged throughout the extension. The results of this extension study confirm the excellent tolerance and safety profile of glatiramer acetate for injection. The clinical benefit of glatiramer acetate for both the relapse rate and for neurologic disability was sustained at the end of the extension trial.

The incidence of blast-induced mild traumatic brain injury (mTBI) has been rising in US veterans due to the widespread use of improvised explosive devices. Blast-injured veterans report cognitive impairments, collectively termed post-concussive syndrome, similar to ones that follow more severe forms of TBI. These are due to diffuse axonal injury, which disrupts the neuronal cytoskeleton and commonly goes undetected by computed tomography and conventional magnetic resonance imaging (MRI). We looked for cortical function abnormalities in a group of blast mTBI subjects using independent component analysis of resting state functional MRI data, which may be more sensitive to small differences. Resting state networks of 13 mTBI veterans with moderate post-concussive syndrome and 50 control subjects were compared across 3 fMRI domains: blood oxygenation level-dependent spatial maps, time course spectra, and functional connectivity. The mTBI group exhibited hyperactivity in the temporo-parietal junctions and hypoactivity in the left inferior temporal gyrus. Abnormal frequencies in default-mode (DMN), sensorimotor, attentional, and frontal networks were detected. Functional connectivity was disrupted in 6 network pairs: DMN-basal ganglia, attention-sensorimotor, frontal-DMN, attention-sensorimotor, attention-frontal, and sensorimotor-sensorimotor. The results suggest white matter disruption across certain attentional networks and that the temporo-parietal junctions may be compensating for damage in other cortical regions.

Objective This initial report, from an ongoing study, examines whether children who have symptoms of schizophrenia spectrum disorder display neuropsychological or neuroanatomic abnormalities similar to those seen in adults with schizophrenia. Method Experimental subjects were 12 children between 8 and 12 years of age who displayed symptoms of early-onset schizophrenia or schizotypal personality disorder, as assessed through the Schedule for Affective Disorders and Schizophrenia for School-Age Children. The experimental subjects were compared with 13 controls on neuropsychological test performance, magnetic resonance imaging measurements, and proton magnetic resonance spectroscopy results. Results Findings from the first phase of this project reveal significant overall group differences for several morphometric magnetic resonance imaging measurements and all neuropsychological measures. Differences between the groups were found for amygdala volume, mesial temporal volume, callosal area, and anatomic asymmetry. Magnetic resonance spectroscopy data showed a trend toward group differences. Conclusions These findings support a neurodevelopmental model of schizophrenia which postulates that environmentally or genetically programmed events in utero disrupt the establishment of fundamental aspects of brain structure and function.

We studied copolymer 1 (Copaxone) in a multicenter (11-university) phase III trial of patients with relapsing-remitting multiple sclerosis (MS). Two hundred fifty-one patients were randomized to receive copolymer 1 (n = 125) or placebo (n = 126) at a dosage of 20 mg by daily subcutaneous injection for 2 years. The primary end point was a difference in the MS relapse rate. The final 2-year relapse rate was 1.19 +/- 0.13 for patients receiving copolymer 1 and 1.68 +/- 0.13 for those receiving placebo, a 29% reduction in favor of copolymer 1 (p = 0.007) (annualized rates = 0.59 for copolymer 1 and 0.84 for placebo). Trends in the proportion of relapse-free patients and median time to first relapse favored copolymer 1. Disability was measured by the Expanded Disability Status Scale (EDSS), using a two-neurologist (examining and treating) protocol. When the proportion of patients who improved, were unchanged, or worsened by > or = 1 EDSS step from baseline to conclusion (2 years) was evaluated, significantly more patients receiving copolymer 1 were found to have improved and more receiving placebo worsened (p = 0.037). Patient withdrawals were 19 (15.2%) from the copolymer 1 group and 17 (13.5%) from the placebo group at approximately the same intervals. The treatment was well tolerated. The most common adverse experience was an injection-site reaction. Rarely, a transient self-limited systemic reaction followed the injection in 15.2% of those receiving copolymer 1 and 3.2% of those receiving placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

The process of drug approval in the United States is regulated by the Food and Drug Administration (FDA). The European Union (EU) includes 27 member states, and each member state has its own national regulatory agency responsible for the approval of clinical trial and marketing applications. Clinical studies to support drug development are increasingly becoming more global in nature as trial subjects are recruited from countries throughout the world. The regulatory environment is very dynamic as global health authorities grapple with innovations in science and technology in addition to changes in health policy in their respective countries. Cooperation amongst regulators in regional health authorities has also been advanced through engagement in the International Conference on Harmonization (ICH). The regulations and requirements continue to evolve as further strides are made in the understanding of diseases and the relevant tools, approaches, and therapies for the management of those diseases.

The objective of this modeling and simulation study was to establish the role of stress wave interactions in the genesis of traumatic brain injury (TBI) from exposure to explosive blast. A high resolution (1 mm3 voxels) five material model of the human head was created by segmentation of color cryosections from the Visible Human Female data set. Tissue material properties were assigned from literature values. The model was inserted into the shock physics wave code, CTH, and subjected to a simulated blast wave of 1.3 MPa (13 bars) peak pressure from anterior, posterior, and lateral directions. Three-dimensional plots of maximum pressure, volumetric tension, and deviatoric (shear) stress demonstrated significant differences related to the incident blast geometry. In particular, the calculations revealed focal brain regions of elevated pressure and deviatoric stress within the first 2 ms of blast exposure. Calculated maximum levels of 15 KPa deviatoric, 3.3 MPa pressure, and 0.8 MPa volumetric tension were observed before the onset of significant head accelerations. Over a 2 ms time course, the head model moved only 1 mm in response to the blast loading. Doubling the blast strength changed the resulting intracranial stress magnitudes but not their distribution. We conclude that stress localization, due to early-time wave interactions, may contribute to the development of multifocal axonal injury underlying TBI. We propose that a contribution to traumatic brain injury from blast exposure, and most likely blunt impact, can occur on a time scale shorter than previous model predictions and before the onset of linear or rotational accelerations traditionally associated with the development of TBI.

The objective of this modeling and simulation study was to establish the role of stress wave interactions in the genesis of traumatic brain injury (TBI) from exposure to explosive blast. A high resolution (1 mm{sup 3} voxels), 5 material model of the human head was created by segmentation of color cryosections from the Visible Human Female dataset. Tissue material properties were assigned from literature values. The model was inserted into the shock physics wave code, CTH, and subjected to a simulated blast wave of 1.3 MPa (13 bars) peak pressure from anterior, posterior and lateral directions. Three dimensional plots of maximum pressure, volumetric tension, and deviatoric (shear) stress demonstrated significant differences related to the incident blast geometry. In particular, the calculations revealed focal brain regions of elevated pressure and deviatoric (shear) stress within the first 2 milliseconds of blast exposure. Calculated maximum levels of 15 KPa deviatoric, 3.3 MPa pressure, and 0.8 MPa volumetric tension were observed before the onset of significant head accelerations. Over a 2 msec time course, the head model moved only 1 mm in response to the blast loading. Doubling the blast strength changed the resulting intracranial stress magnitudes but not their distribution. We conclude that stress localization, due to early time wave interactions, may contribute to the development of multifocal axonal injury underlying TBI. We propose that a contribution to traumatic brain injury from blast exposure, and most likely blunt impact, can occur on a time scale shorter than previous model predictions and before the onset of linear or rotational accelerations traditionally associated with the development of TBI.

Multicenter proton magnetic resonance spectroscopic imaging (MRSI) studies were performed on 58 primary progressive multiple sclerosis (PPMS) patients from four centers for investigating the efficacy of glatiramer acetate (GA) treatment. These patients were drawn from 943 subjects who participated in the PROMiSe trial. In these MRSI studies, patients were followed over a period of 3 years. MRSI data were acquired by all the centers using the same pulse sequence, and spectral analysis was performed at a single site using a customized analysis software package. Quantitative metabolite ratios, N-acetyl aspartate (NAA)/creatine (Cr) and choline (Cho)/Cr, were compared between GA-treated and placebo-treated PPMS patients. There was no significant difference in metabolite ratios between GA-treated and placebo-treated patients. The difference in metabolite ratios between the normal-appearing tissues (NAT) and lesion-containing regions (LCR) in GA treated patients was not significantly different from placebo treated patients. Strong lipid resonances, even in the absence of lesions, were observed on MRSI data in both gray matter and white matter in placebo- and GA-treated PPMS patients. No significant difference in number of patients with lipids between the two groups over a period of 3 years was found. Multiple Sclerosis 2008; 14: 73—80. http://msj.sagepub.com

A decade of continuous glatiramer acetate (GA) use by relapsing remitting multiple sclerosis (RRMS) patients was evaluated in this ongoing, prospective study, and the neurological status of 'Withdrawn' patients was assessed at a 10-year long-term follow-up (LTFU) visit. Modified intention-to-treat (mITT, n=232) patients received > or =1 GA dose since 1991; 'Ongoing' patients (n = 108) continued in November 2003. Of 124 patients, 50 Withdrawn patients returned for LTFU. Patients were evaluated every six months (EDSS). Mean GA exposure was 6.99, 10.1 and 4.26 years for mITT, Ongoing, and Withdrawn/LTFU patients, respectively. While on GA, mITT relapse rates declined from 1.18/year prestudy to approximately 1 relapse/5 years; median time to > or = 1 EDSS point increase was 8.8 years; mean EDSS change was 0.73 +/- 1.66 points; 58% had stable/improved EDSS scores; and 24, 11 and 3% reached EDSS 4, 6 and 8, respectively. For Ongoing patients, EDSS increased 0.50 +/- 1.65; 62% were stable/improved; and 24,8 and 1% reached EDSS 4, 6 and 8, respectively. For Withdrawn patients at 10-year LTFU, EDSS increased 2.24 +/- 1.86; 28% were stable/improved; and 68, 50 and 10% reached EDSS 4, 6 and 8, respectively. While on GA nearly all patients (mean disease duration 15 years) remained ambulatory. At LTFU, Withdrawn patients had greater disability than Ongoing patients.

The past decade has witnessed a revolution in the treatment of multiple sclerosis (MS), the most common demyelinating disorder of the human CNS. After being considered as an untreatable disease for more than a century, six disease-modifying treatments have been approved between 1993 and 2006. Glatiramer acetate (GA) is a worldwide drug approved for the treatment of relapsing-remitting MS in 1996. The drug is a synthetic copolymer of four amino acids based on the composition of myelin basic protein, one of several putative autoantigens implicated in the pathogenesis of MS. Three separate double-blind, placebo-controlled trials have established its efficacy in relapsing-remitting MS. Observations from an ongoing study, the longest prospective study in MS therapeutics so far, suggest that the effect of GA in reducing the relapse rate and neurological disability is maintained over a 10-year period. Independent investigators have identified several putative immunological mechanisms of action of GA, with the unique observation of the generation of GA-reactive T-helper 2 (anti-inflammatory) polarised lymphocytes within days to weeks of initiating therapy and sustaining an anti-inflammatory milieu for years in the peripheral immune system and, presumably, in the CNS. Emerging data from immunological and imaging studies quantifying axonal injury in the brain point towards neuroprotective abilities of GA. Combined with its remarkable safety and tolerability, long-term efficacy and neuroprotective effect, GA presents it self as a first-line choice in relapsing-remitting MS, and holds immense promise in developing its potential as a combination therapy in MS, as well as extending its indications to other neurodegenerative diseases.

Objective – To assess the long-term effectiveness of continuous glatiramer acetate (GA) therapy in relapsing-remitting multiple sclerosis (RRMS). Methods – This open-label extension followed a randomized, placebo-controlled, double-blind study of GA of approximately 30 months duration. Patients originally randomized to GA continued on it (group A) and those randomized to placebo switched to GA (group B). Results – Of 251 original patients, 142 (56.6%) remained in the study after 8 years. Annual relapse rate for both groups declined to approximately 0.2 (approximately one relapse every 5 years). However, a significantly larger proportion of patients in group A had stable or improved Expanded Disability Status Scale scores compared with group B (65.3% vs 50.4%, respectively; P = 0.0263), possibly attributable to the delay of GA treatment for approximately 30 months in group B. GA was well tolerated and no drug-related laboratory changes were observed. Conclusions – These data support early initiation of GA therapy as an efficacious and well-tolerated long-term treatment for RRMS patients.

Sarcomatous metastasis to the central nervous is generally considered uncommon and rarely shows evidence of hemorrhage. Consequently, patients with fibrosarcoma are rarely screened for metastatic disease in the central nervous system. We present a case of fibrosarcoma with metastasis to brain accompanied by overt hemorrhage into the tumor. It is suggested that patients with fibrosarcoma be routinely screened for metastasis to the central nervous system and that sarcomatous metastasis be considered in the differential diagnosis of hemorrhagic CNS tumors.

The aim of this study was to assess the long-term safety and efficacy of glatiramer acetate (GA) for patients with multiple sclerosis (MS) who received active treatment versus those on placebo for approximately 30 months (24-35 months) before receiving GA during a six-year organized, prospective open label study. Entry required two relapses in the previous two years and an Expanded Disability Status Scale (EDSS) score of 0-5. Patients (251) were equally randomized to daily subcutaneous G A, 20 mg, or to placebo. A fter approximately 30 months, 208 patients continued in an open label study: 101 continued on G A and 107 switched from placebo to active drug. Groups were well matched at randomization and entry to the open label study. Patients always on G A showed a steady decline in relapses: a mean of 1.5 per year at entry, a mean of 0.42 over the entire six years (95% C I=0.34-0.51), a 72% reductio n (P =0.0001). They averaged a relapse every four+ years (yearly rate 0.23 in year six) and 26/101 remain relapse free. Patients did less well if on placebo for 30 months, but relapses then declined, and by year six the rates were similar. O f patients always on GA, 69% showed neurological improvement of > 1 EDSS steps or remained stable compared with 57% if G A treatment was delayed. O f relapse-free patients always on G A over six years, only three of 26 (11%) were worse by]-1 EDSS steps, whereas nine of 21 (43%) in the placebo/active group were worse (P B-0.03). Disability, measured every six months, showed that the group of patients always on G A was relatively stable over the six years, while the group who received placebo for the first two-and-a-half years did significantly less well. Daily injections of GA were well tolerated. This longest ever organized MS treatment trial shows that delaying therapy with GA increases the risk of neurologic disability, reinforcing the rationale for using G A as a first-line treatment early in the course of relapsing-remitting MS.

Background: Visual dysfunction is one of the most common causes of disability in multiple sclerosis (MS). The Multiple Sclerosis Functional Composite (MSFC), a new clinical trial outcome measure, does not currently include a test of visual function.Objective: To examine contrast letter acuity as a candidate visual function test for the MSFC.Methods: Binocular contrast letter acuity testing (Sloan charts) was performed in a subgroup of participants from the International Multiple Sclerosis Secondary Progressive Avonex Controlled Trial (IMPACT Substudy) and in MS patients and disease-free control subjects from a cross-sectional study of visual outcome measures (Multiple Sclerosis Vision Prospective cohort [MVP cohort]). High-contrast visual acuity was measured in both studies; MVP cohort participants underwent additional binocular testing for contrast sensitivity (Pelli–Robson chart), color vision (D-15 desaturated test), and visual field (Esterman test, Humphrey Field Analyzer II).Results: Contrast letter acuity (Sloan charts, p < 0.0001, receiver operating characteristic curve analysis) and contrast sensitivity (Pelli–Robson chart, p = 0.003) best distinguished MS patients from disease-free control subjects in the MVP cohort. Correlations of Sloan chart scores with MSFC and Expanded Disability Statue Scale (EDSS) scores in both studies were significant and moderate in magnitude, demonstrating that Sloan chart scores reflect visual and neurologic dysfunction not entirely captured by the EDSS or MSFC.Conclusions: Among clinical measures, contrast letter acuity (Sloan charts) and contrast sensitivity (Pelli–Robson chart) demonstrate the greatest capacity to identify binocular visual dysfunction in MS. Sloan chart testing also captures unique aspects of neurologic dysfunction not captured by current EDSS or MSFC components, making it a strong candidate visual function test for the MSFC.

To determine the incidence and prevalence of neuropsychiatric systemic lupus erythematosus (NPSLE) and glomerulonephritis in ethnically diverse pediatric onset SLE inpatient and outpatient populations.Seventy-five pediatric onset patients with SLE including Native American, Asian, Black, Spanish-American, and Caucasian subjects were evaluated prospectively and cross sectionally. During the 6 year study, 55 patients became inpatients. Subjects underwent medical interview, physical examination, laboratory review, neuropsychiatric inventory, and chart review. Classification of NPSLE was accomplished with the 1999 ACR NPSLE case definitions.Prospectively, NPSLE occurred in 95% of pediatric SLE patients and was more common than glomerulonephritis (55%; por = 0.0001). NPSLE prevalence (%) and incidence (event/person/yr) were as follows: headache 72%, 95; mood disorder 57%, 0.41; cognitive disorder 55%, 0.49; seizure disorder 51%, 0.94; acute confusional state 35%, 0.6; anxiety disorder 21%, 0.28; peripheral nervous system disorder 15%, 0.16; cerebrovascular disease 12%, 0.32; psychosis 12%, 0.16; chorea 7%, 0.01; demyelinating syndrome 4%, 0.01; and myelopathy 1%, 0.001. Cross sectionally, active NPSLE was present in 93% of inpatients and 69% of outpatients. When only serious forms of NPSLE were considered (stroke, seizures, major cognitive disorder, chorea, psychosis, major depression, acute confusional state), serious or life-threatening NPSLE occurred in 76% of all SLE subjects prospectively, and in 85% and 40% of inpatients and outpatients cross sectionally, which in each instance was more common than glomerulonephritis (por = 0.001).NPSLE is one of the most common serious complications of pediatric SLE, and is particularly increased in pediatric inpatients.

The frequency, preventability, severity, root causes, and projected costs of adverse drug events (ADEs) occurring after or causing admission to a four-hospital integrated academic health network were studied. The sample included all admissions during a 53-day study period. Events were identified through daily record review of a random patient sample, computerized flags, and self-reporting. A case review committee validated the occurrence, classification, and root causes of the events. Additional length of stay and costs associated with ADEs were analyzed by using a case-control, multiple linear regression model. The estimated ADE rate during hospitalization was 4.2 events per 100 admissions, with a cost of $2162 per ADE. In addition, 3.2% of admissions were caused by ADEs, with an associated cost of $6685 per event. Fifteen percent of hospital ADEs and 76% of ADEs causing admission were judged preventable. The annual cost to the organization for events occurring during hospitalization was $1.7 million, and the cost of preventable ADEs was $260,000, while the projected costs of preventable ADEs causing admission were $3.8 million. The rate of admissions to the mental health center caused by ADEs was higher than for other settings at 13.6%, with a cost of preventable ADEs of $1.3 million. Patient noncompliance was judged to be the cause of the 69% of the ADEs causing admission. Seventy-one percent of the serious medication errors occurred at the prescribing stage of the medication-use process. ADEs were frequent, costly, and often preventable and resulted in many admissions to a mental health center.

Matrix metalloproteinases (MMPs) are increased in the CSF of patients with multiple sclerosis. Devic's neuromyelitis optica (DNO) is a demyelinating syndrome that involves the optic nerve and cervical cord but differs pathologically from multiple sclerosis. Therefore, we hypothesized that the type of inflammatory reaction that causes MMPs to be elevated in multiple sclerosis would be absent in patients with DNO. CSF was collected from 23 patients with relapsing-remitting or secondary progressive multiple sclerosis, all of whom were experiencing acute symptoms, from seven patients with DNO, and from seven normal volunteers. Diagnoses were made according to current criteria on the basis of clinical manifestations, imaging results and CSF studies. IgG synthesis was increased in the CSF of multiple sclerosis patients but not in that of DNO patients. Zymography, reverse zymography and ELISA (enzyme-linked immunosorbent assay) were used to measure gelatinase A (MMP-2), gelatinase B (MMP-9) and tissue inhibitors of metalloproteinases (TIMPs). Zymograms showed that multiple sclerosis patients had elevated MMP-9 compared with DNO patients and controls (P: < 0.05). TIMP-1 and TIMP-2 levels were similar in all three groups. We conclude that multiple sclerosis patients have higher MMP-9 levels in the CSF than patients with DNO, which supports the different pathological mechanisms of these diseases.

The authors compared the frequency of paranasal sinus inflammatory changes (SIC) on brain magnetic resonance imaging (MRI) obtained from 23 patients with new onset acute optic neuritis (ON) and 48 control patients who underwent outpatient MRI of the brain for reasons other than ON. The authors found a higher frequency of paranasal SIC in patients with ON (83%) than in controls (54%) (p = 0.02). The distribution of paranasal SIC (in ON and in controls) was maxillary (83% and 52%), ethmoid (4% and 2%), frontal (9% and 14%), and sphenoid (4% and 10%). Frequency of the maxillary SIC was significantly higher (p = 0.02) in patients with ON than in controls. Further evaluation of maxillary paranasal SIC with a grading system showed the presence of thickened mucosal lining of the sinuses (grade I) in 17% (ON) and 23% (controls), mucous retention cysts within the sinuses (grade II) in 48% (ON) and 25% (controls), and severe mucosal thickening with complete or near-complete filling of the sinus or an air-fluid level within the sinus (grade III) in 17% (ON) and 4% (controls). Combined frequency of grade II and grade III SIC was significantly higher in the ON group than in controls (p = 0.005), as was the frequency of grade III SIC alone (p = 0.02). Grade I SIC did not significantly differ between the groups. There was a trend (p = 0.09) toward a higher prevalence of bilateral sinus inflammatory changes in patients with bilateral ON. These findings suggest that ON may be associated with sinus inflammatory changes.

Background: Schizophrenia is commonly considered a neurodevelopmental disorder. Our aim was to determine whether the proton magnetic resonance spectroscopic (1H-MRS) changes seen in adults with schizophrenia are displayed in children at risk for developing schizophrenia. Methods: Children with symptoms of schizophrenia-spectrum disorders (n = 16; mean age = 132 months) and a comparison group (n = 12; mean age 130 months) took part in a 1H-MRS study of the left frontal lobe. Areas of peaks from N-acetylaspartate (NAA), choline (Cho), and creatine (Cre) were determined and ratios of NAA/Cre and Cho/Cre calculated and compared between groups. Results: The mean ratio of NAA/Cre was significantly lower in schizophrenia-spectrum subjects than the comparison group (1.67 vs. 1.92; p < .05). Medication status did not affect results in schizophrenia-spectrum subjects. Conclusions: Our findings suggest that the metabolic changes associated with adult schizophrenia are observed in children with some or all of the symptoms of schizophrenia, supporting a neurodevelopmental theory for schizophrenia.

Contrast-enhanced MRI in patients with MS shows that increased permeability of the blood-brain barrier (BBB) commonly occurs. The changes in capillary permeability often precede T2-weighted MRI evidence of tissue damage. In animal studies, intracerebral injection of the matrix metalloproteinase (MMP) 72-kDa type IV collagenase (gelatinase A) opens the BBB by disrupting the basal lamina around capillaries. Steroids affect production of endogenous MMPs and tissue inhibitors to metalloproteinases (TIMPs). To determine the role of MMP activity in BBB damage during acute exacerbations of MS, we measured MMPs in the CSF of patients with MS. Patients (n = 7) given steroids to treat an acute episode of MS had CSF sampled before and after 3 days of methylprednisolone (1 g/day). Patients had a graded neurologic examination and gadolinium-enhanced MRI before treatment. CSF studies included total protein, cell count, and a demyelinating profile. We measured levels of MMPs, urokinase-type plasminogen activator (uPA), and TIMPs by zymography, reverse zymography, and Western blots. The MMP, 92-kDa type IV collagenase (gelatinase B), fell from 216 +/- 70 before steroids to 54 +/- 26 relative lysis zone units (p < 0.046) after treatment. Similarly, uPA dropped from 3880 +/- 800 to 2655 +/- 353 (p < 0.03). Four patients with gadolinium enhancement on MRI had the most pronounced drop in gelatinase B and uPA. Western immunoblots showed an increase in a complex of gelatinase B and TIMPs after treatment, suggesting an increase in a TIMP (p < 0.05). Reverse zymography of CSF samples showed that steroids increased a TIMP with a molecular weight similar to that of mouse TIMP-3 (p = 0.053). Our results suggest that increased gelatinase B is associated with an open BBB on MRI. Steroids may improve capillary function by reducing activity of gelatinase B and uPA and increasing levels of TIMPs.NEUROLOGY 1996;46: 1626-1632

An animal model of central nervous system demyelination was created by injecting rat internal capsules with lysophosphatidylcholine (LPC). The resulting chemically induced demyelinating lesions were readily visible in T1 -weighted spin-echo, T2 weighted spin-echo, and inversion-recovery magnetic resonance imaging (MRI) sequences. Changes in lesions were followed over 8 weeks and correlated with histopathology. Histologically, lesions were characterized initially by an acute, inflammatory phase with edema and blood-brain barrier breakdown, followed by macrophage-mediated removal of myelin debris and finally by remyelination after 3 to 4 weeks. MRI can differentiate lesion stages in the LPC model and may be useful in investigating mechanistic aspects of the demyelinating process. In addition the well-localized lesions may be amenable to study by techniques of volume-localized NMR Spectroscopy. © 1990 Academic Press, Inc.

Eight women with multiple sclerosis were followed up through pregnancy. Clinical conditions, T-cell subsets, and levels of immunoactive pregnancy-associated proteins were measured twice during the pregnancy and twice during the first postpartum year. None of the women's conditions worsened during pregnancy, although one woman reported a slight increase of symptoms. Six of the eight women experienced relapses within the first 7 weeks after delivery. The number and percent of CD8 suppressor T cells were lower, and the CD4 helper-CD8 suppressor T-cell ratio was higher in the pregnant patients with multiple sclerosis compared with pregnant control women throughout pregnancy and the first 6 months post partum. There was no evident relationship between these parameters and clinical disease activity. Levels of alpha-fetoprotein, alpha 2-pregnancy-associated glycoprotein, and pregnancy-associated plasma protein A, all immunosuppressive proteins associated with pregnancy, were not significantly different in pregnant patients with multiple sclerosis and pregnant controls without multiple sclerosis. The study suggested that the risk of clinical relapse after delivery may be higher than has been reported previously. Furthermore, although there were differences in suppressor T cells, they were not predictably linked to changes in clinical disease activity.

Proton nuclear magnetic resonance spectroscopy is a noninvasive technique allowing the localized, in vivo detection of proton-containing brain metabolites. We used this technique to study eight patients with cerebral infarction or ischemia. A stimulated echo-pulse sequence with chemical shift imaging was used to acquire spectra from multiple contiguous 4-cc volumes extending from the site of ischemia to the opposite hemisphere. Six patients had a reduction in the signal from N- acetyl groups (NAG) in the stroke area compared with controls, and those with the lowest NAG to phosphocreatinekreatine ratios had the least recovery of function. Lactate was observed within the infarcted region in two patients at 9 and 11 days after infarction and may have been present in other patients up to 15 weeks after stroke.

Publisher Summary This chapter explores a few unresolved questions pertaining to the mathematical analysis of fluorescence decay data. Several studies have focused on compartmental analysis identification problems. The chapter discusses applications of the techniques to the analysis of multiexponential fluorescence decay data. It explores the problem of determination of the amplitudes and time constants for the N exponential components present in the data. The chapter discusses the treatment of nonrandom errors such as scattered light, zero time shifts, and cutoff errors. The method of analysis used is based on moment techniques. The chapter discusses the experiments in which a sample containing fluorescent molecules is excited with a short pulse of light. Many of the excited molecules emitted photons fluorescently and a single photon was detected randomly by the instrument. The time between excitation and the detected emission was measured, and the event is recorded. This process was repeated until a histogram was developed representing the fluorescence decay profile. In the study, each fluorescent component was assumed to decay exponentially.