Characterizing multiple sclerosis disease progression using a combined structural and functional connectivity metric.

PURPOSE: A combined resting state functional connectivity MRI (fcMRI) and diffusion tensor imaging (DTI) metric called structural and functional connectivity index (SFCI) was recently proposed for tracking disease status and progression in multiple sclerosis (MS). The metric combines fcMRI and transverse diffusivity (TD) along different functional pathways involved in principle symptomatic domains of MS. In a longitudinal study of patients with MS receiving the same MS therapy, initial worsening of transcallosal (TC) motor and frontoparietal (FP) cognitive networks, as measured by fcMRI and DTI over the first year was followed by stabilization in the second year of follow-up. In this study we have (i) probed relationships between individual and composite neurological measures of MS with SFCI and its individual components along TC motor and FP cognitive pathways and (ii) compared sensitivity of SFCI to treatment-induced longitudinal changes with each individual imaging measure. METHODS: Twenty five patients with MS (15 female, age 42 ± 8 y) participated in this study and were scanned at 3 T whole body MRI scanner with diffusion tensor imaging (DTI) and resting-state functional connectivity MRI (fcMRI) scan protocol at baseline and 6, 12, 18 and 24 months after starting fingolimod. fcMRI and TD along TC and FP pathways were combined to form structural and functional connectivity index (SFCI) at each time point. Correlations between individual/combined neurological measures and individual imaging components/SFCI at baseline and were evaluated and compared. In addition, efficacies of individual and combined imaging metrics in tracking network integrity were compared. RESULTS: Individual TD along the TC pathway was significantly inversely correlated with all individual/composite neurological scores. There were moderate correlations of TC and FP components of SFCI with most of the neurological scores, and the pathway-combined SFCI was significantly correlated with all neurological scores. Trend-level increases of both TC and FP fcMRI were observed during the second year of follow-up, both TC and FP TD increased significantly in the first year and then stabilized during the second year. A trend toward a decrease in combined imaging metrics along TC and FP were observed during the first year, followed by a trend toward an increase in these metrics during the second year, while a significant decrease in SFCI during the first year followed by a significant increase during the second year was observed. CONCLUSIONS: SFCI was more effective in tracking network integrity/disease progression than individual pathway-specific components, which supports its use as an imaging marker for MS disease status and progression.

An evaluation of the Chesapeake Bay management strategy to improve water quality in small agricultural watersheds.

Chesapeake Bay water quality has been a concern since 1970. In rural areas, agriculture is the dominant N and P source, and the voluntary application of best management practices (BMPs) is the primary management tool. Here we test the hypothesis that the current management approach of primarily voluntary, untargeted BMP implementation is insufficient to create detectable, widespread reductions in N, P, and total suspended solid (TSS) concentrations in agricultural watersheds of the Choptank basin, a tributary of Chesapeake Bay. To test this hypothesis, we assessed BMP implementation and sampled water quality on participating farms, at intermediate streams within each watershed, and at watershed outlets of four watersheds from 2013 to 2014. We also present water quality data from 2003 to 2014 at the outlets of 12 additional agricultural and one forested watershed and survey-directed interviews of farmers. By the end of 2014, large numbers of BMPs, both structural and cultural, had been implemented. Of the 16 agricultural watersheds, 50% showed significant decreases in baseflow N, 37.5% showed no changes, and 12.5% showed increasing TN. Baseflow P significantly decreased at just one watershed, increased at one, and remained stable at 14. Stormflow N was similar to baseflow, but stormflow P was 5 times higher than baseflow. These data partially support our hypothesis. Surveys suggested farmers considered themselves responsible for the quality of water leaving their farms, but out-of-pocket cost was the major impediment to further BMP adoption. We suggest that greater outreach and more financial support for farmers to implement BMPs is required to increase the types and densities of BMPs needed to achieve regional water quality goals.

Changes in structural and functional connectivity during two years of fingolimod therapy for multiple sclerosis.

BACKGROUND: Fingolimod, an oral drug, has been reported to reduce relapse rate in multiple sclerosis (MS). However disease progression may still occur in spite of control of inflammation. Functional imbalances within and between cerebral networks associated with disruption of structural and functional network integrity, have been reported in MS. An effective therapy is expected to stabilize such functional network integrity. OBJECTIVE: The purpose of this study was to investigate changes in structural and resting-state functional connectivity of motor and cognitive networks, and associated changes in neurologic scores in MS, during 2 years of fingolimod therapy. METHODS: Twenty five subjects with MS were recruited for this study. Subjects were scanned with diffusion tensor imaging (DTI) and resting-state functional connectivity MRI (fcMRI) scan protocol at 3 T with 6-month interval over a period of 2 years. Neurologic performance scores of motor and cognitive performances were also obtained. RESULTS: DTI measures worsened during the 1st year and then stabilized; any trend of stabilization of fcMRI was delayed until the 2nd year. While motor performance did not change, cognitive performance showed improvement. Several baseline DTI measures correlated with relevant neurologic scores. CONCLUSION: Initial worsening of motor and cognitive network was reported after 1 year of treatment, but seems DTI and fcMRI measures seem to stabilize after around one year fingolimod therapy.

Effect of delayed-release dimethyl fumarate on no evidence of disease activity in relapsing-remitting multiple sclerosis: integrated analysis of the phase III DEFINE and CONFIRM studies.

BACKGROUND AND PURPOSE: Significant effects on clinical/neuroradiological disease activity have been reported in patients with relapsing-remitting multiple sclerosis treated with delayed-release dimethyl fumarate (DMF) in phase III DEFINE/CONFIRM trials. We conducted a post hoc analysis of integrated data from DEFINE/CONFIRM to evaluate the effect of DMF on achieving no evidence of disease activity (NEDA) in patients with relapsing-remitting multiple sclerosis. METHODS: The analysis included patients randomized to DMF 240 mg twice daily, placebo or glatiramer acetate (CONFIRM only) for ≤2 years. A time-to-event method was used to estimate the percentage of patients achieving NEDA. Clinical NEDA (no relapses/no 12-week confirmed disability progression) was analysed in the intention-to-treat (ITT) population. Neuroradiological (no new/newly enlarging T2 hyperintense lesions/no gadolinium-enhancing lesions) and overall NEDA (clinical and neuroradiological NEDA) were analysed in the magnetic resonance imaging (MRI) cohort. RESULTS: The ITT and MRI populations comprised 1540 and 692 patients, respectively. The percentage of patients with clinical NEDA (ITT population) and neuroradiological NEDA (MRI cohort) was higher with DMF versus placebo over 2 years [clinical NEDA: 38.9% relative reduction; hazard ratio (HR), 0.61; 95% confidence interval (CI), 0.52-0.72; P < 0.0001; neuroradiological NEDA: 40.0% relative reduction; HR, 0.60; 95% CI, 0.49-0.73; P < 0.0001]. The percentage of patients achieving overall NEDA (MRI cohort) was also higher with DMF (26%) versus placebo (12%) over 2 years, with a relative risk reduction of 42.7% (HR, 0.57; 95% CI, 0.48-0.69; P < 0.0001). CONCLUSIONS: A significantly higher percentage of patients treated with DMF achieved NEDA status over 2 years compared with placebo.

Measuring Brain Tissue Integrity during 4 Years Using Diffusion Tensor Imaging.

BACKGROUND AND PURPOSE: DTI is an MR imaging measure of brain tissue integrity. Little is known regarding the long-term longitudinal evolution of lesional and nonlesional tissue DTI parameters in multiple sclerosis and the present study examines DTI evolution over 4 years. MATERIALS AND METHODS: Twenty-one patients with multiple sclerosis were imaged for up to 48 months after starting natalizumab therapy. Gadolinium-enhancing lesions at baseline, chronic T2 lesions, and normal-appearing white matter were followed longitudinally. T2 lesions were subclassified as black holes and non-black holes. Within each ROI, the average values of DTI metrics were derived by using Analysis of Functional Neuro Images software. The longitudinal trend in DTI metrics was estimated by using a mixed-model regression analysis. RESULTS: A significant increase was observed for axial diffusivity (P < .001) in gadolinium-enhancing lesions and chronic T2 lesions during 4 years. No significant change in radial diffusivity either in normal-appearing white matter or lesional tissue was observed. The evolution of axial diffusivity was different in gadolinium-enhancing lesions (P < .001) and chronic T2 lesions (P = .02) compared with normal-appearing white matter. CONCLUSIONS: An increase in axial diffusion in both gadolinium-enhancing lesions and T2 lesions may relate to the complex evolution of chronically demyelinated brain tissue. Pathologic changes in normal-appearing white matter are likely more subtle than in lesional tissue and may explain the stability of these measures with DTI.

Time course of clinical and neuroradiological effects of delayed-release dimethyl fumarate in multiple sclerosis.

BACKGROUND AND PURPOSE: Delayed-release dimethyl fumarate (DMF, also known as gastro-resistant DMF), demonstrated efficacy and safety in relapsing-remitting multiple sclerosis in the 2-year, randomized, placebo-controlled, phase 3 DEFINE and CONFIRM trials. A post hoc analysis of integrated data from DEFINE and CONFIRM was conducted to determine the temporal profile of the clinical and neuroradiological effects of DMF. METHODS: Eligible patients were randomized to receive placebo, DMF 240 mg twice (BID) or three times (TID) daily or glatiramer acetate (GA; reference comparator; CONFIRM only) for up to 96 weeks. Patients in the GA group were excluded from this analysis. RESULTS: A total of 2301 patients were randomized and received treatment with placebo (n = 771) or DMF BID (n = 769) or TID (n = 761). DMF significantly reduced the annualized relapse rate beginning in weeks 0-12 (BID, P = 0.0159; TID, P = 0.0314); the proportion of patients relapsed beginning at week 10 (BID, P = 0.0427) and week 12 (TID, P = 0.0451); and the proportion of patients with 12-week confirmed disability progression beginning at week 62 (BID, P = 0.0454) and week 72 (TID, P = 0.0399), compared with placebo. These effects were sustained throughout the 2-year study period. DMF significantly reduced the odds of having a higher number of gadolinium-enhancing lesions by 88% (BID) and 75% (TID) and the mean number of new or enlarging T2 lesions by 72% (BID) and 67% (TID), from the first post-baseline magnetic resonance imaging assessment at 24 weeks (all P < 0.0001 versus placebo). CONCLUSIONS: In phase 3 clinical trials, DMF demonstrated rapid and sustained clinical and neuroradiological efficacy in relapsing-remitting multiple sclerosis.

Fatal PML associated with efalizumab therapy: insights into integrin αLß2 in JC virus control.

OBJECTIVES: Progressive multifocal leukoencephalopathy (PML) has become much more common with monoclonal antibody treatment for multiple sclerosis and other immune-mediated disorders. METHODS: We report 2 patients with severe psoriasis and fatal PML treated for ≥3 years with efalizumab, a neutralizing antibody to αLß2-leukointegrin (LFA-1). In one patient, we conducted serial studies of peripheral blood and CSF including analyses of leukocyte phenotypes, migration ex vivo, and CDR3 spectratypes with controls coming from HIV-infected patients with PML. Extensive pathologic and histologic analysis was done on autopsy CNS tissue of both patients. RESULTS: Both patients developed progressive cognitive and motor deficits, and JC virus was identified in CSF. Despite treatment including plasma exchange (PE) and signs of immune reconstitution, both died of PML 2 and 6 months after disease onset. Neuropathologic examination confirmed PML. Efalizumab treatment was associated with reduced transendothelial migration by peripheral T cells in vitro. As expression levels of LFA-1 on peripheral T cells gradually rose after PE, in vitro migration increased. Peripheral and CSF T-cell spectratyping showed CD8+ T-cell clonal expansion but blunted activation, which was restored after PE. CONCLUSIONS: From these data we propose that inhibition of peripheral and intrathecal T-cell activation and suppression of CNS effector-phase migration both characterize efalizumab-associated PML. LFA-1 may be a crucial factor in homeostatic JC virus control.

A validation study of multicenter diffusion tensor imaging: reliability of fractional anisotropy and diffusivity values.

BACKGROUND AND PURPOSE: DTI is increasingly being used as a measure to study tissue damage in several neurologic diseases. Our aim was to investigate the comparability of DTI measures between different MR imaging magnets and platforms. MATERIALS AND METHODS: Two healthy volunteers underwent DTI on five 3T MR imaging scanners (3 Trios and 2 Signas) by using a matched 33 noncollinear diffusion-direction pulse sequence. Within each subject, a total of 16 white matter (corpus callosum, periventricular, and deep white matter) and gray matter (cortical and deep gray) ROIs were drawn on a single image set and then were coregistered to the other images. Mean FA, ADC, and longitudinal and transverse diffusivities were calculated within each ROI. Concordance correlations were derived by comparing ROI DTI values among each of the 5 magnets. RESULTS: Mean concordance for FA was 0.96; for both longitudinal and transverse diffusivities, it was 0.93; and for ADC, it was 0.88. Mean scan-rescan concordance was 0.96-0.97 for all DTI measures. Concordance correlations within platforms were, in general, better than those between platforms for all DTI measures (mean concordance of 0.96). CONCLUSIONS: We found that a 3T magnet and high-angular-resolution pulse sequence yielded comparable DTI measurements across different MR imaging magnets and platforms. Our results indicate that FA is the most comparable measure across magnets, followed by individual diffusivities. The comparability of DTI measures between different magnets supports the feasibility of multicentered clinical trials by using DTI as an outcome measure.

Measuring myelin repair and axonal loss with diffusion tensor imaging.

BACKGROUND AND PURPOSE: DTI is an MR imaging measure of brain tissue integrity and provides an attractive metric for use in neuroprotection clinical trials. The purpose of our study was to use DTI to evaluate the longitudinal changes in brain tissue integrity in a group of patients with MS. MATERIALS AND METHODS: Twenty-one patients with MS starting natalizumab were imaged serially for 12 months. Gadolinium-enhancing lesions and 20 regions of interest from normal-appearing white and gray matter brain tissue were followed longitudinally. Average values within each region of interest were derived for FA, λ(∥), λ(⊥), and MD. New T1 black holes were identified at 12 months. Analysis was performed by using mixed-model regression analysis with slope (ie, DTI change per month) as the dependent variable. RESULTS: During 1 year, FA increased in gadolinium-enhancing lesions but decreased in NABT (P < .0001 for both). Changes in FA within gadolinium-enhancing lesions were driven by decreased λ(⊥) (P < .001), and within NABT, by decreased λ(∥) (P < .0001). A higher λ(⊥) within gadolinium-enhancing lesions at baseline predicted conversion to T1 black holes at 12 months. MD was unchanged in both gadolinium-enhancing lesions and NABT. CONCLUSIONS: We observed changes in DTI measures during 1 year in both gadolinium-enhancing lesions and NABT. The DTI results may represent possible remyelination within acute lesions and chronic axonal degeneration in NAWM. These results support the use of DTI as a measure of tissue integrity for studies of neuroprotective therapies.

Results of the Avonex Combination Trial (ACT) in relapsing-remitting MS.

OBJECTIVE: To assess the safety, tolerability, and efficacy of interferon beta-1a (IFNbeta-1a) combined with methotrexate (MTX), i.v. methylprednisolone (IVMP), or both in patients with relapsing-remitting multiple sclerosis (RRMS) with continued disease activity on IFNbeta-1a monotherapy. METHODS: Eligibility criteria included RRMS, Expanded Disability Status Scale score 0-5.5, and > or = 1 relapse or gadolinium-enhancing MRI lesion in the prior year on IFNbeta-1a monotherapy. Participants continued weekly IFNbeta-1a 30 microg i.m. and were randomized in a 2 x 2 factorial design to adjunctive weekly placebo or MTX 20 mg p.o., with or without bimonthly IVMP 1,000 mg/day for 3 days. The primary endpoint was new or enlarged T2 lesion number at month 12 vs baseline. The study was industry-supported, collaboratively designed, and governed by an investigator Steering Committee with independent Advisory and Data Safety Monitoring committees. Study operations, MRI analyses, and aggregated data were managed by an academic coordinating center. RESULTS: The 313 participants had clinical and MRI characteristics typical of RRMS. Combinations of IFNbeta-1a with MTX or IVMP were generally safe and well tolerated. Although trends suggesting modest benefit were seen for some outcomes for IVMP, the results did not demonstrate significant benefit for either adjunctive therapy. The data suggested IVMP reduced anti-IFNbeta neutralizing antibody titers. CONCLUSIONS: This trial did not demonstrate benefit of adding low-dose oral methotrexate or every other month IV methylprednisolone to interferon beta-1a in relapsing-remitting multiple sclerosis.

Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function.

BACKGROUND: Accelerating the clearance of therapeutic monoclonal antibodies (mAbs) from the body may be useful to address uncommon but serious complications from treatment, such as progressive multifocal leukoencephalopathy (PML). Treatment of PML requires immune reconstitution. Plasma exchange (PLEX) may accelerate mAb clearance, restoring the function of inhibited proteins and increasing the number or function of leukocytes entering the CNS. We evaluated the efficacy of PLEX in accelerating natalizumab (a therapy for multiple sclerosis [MS] and Crohn disease) clearance and alpha4-integrin desaturation. Restoration of leukocyte transmigratory capacity was evaluated using an in vitro blood-brain barrier (ivBBB). METHODS: Twelve patients with MS receiving natalizumab underwent three 1.5-volume PLEX sessions over 5 or 8 days. Natalizumab concentrations and alpha4-integrin saturation were assessed daily throughout PLEX and three times over the subsequent 2 weeks, comparing results with the same patients the previous month. Peripheral blood mononuclear cell (PBMC) migration (induced by the chemokine CCL2) across an ivBBB was assessed in a subset of six patients with and without PLEX. RESULTS: Serum natalizumab concentrations were reduced by a mean of 92% from baseline to 1 week after three PLEX sessions (p < 0.001). Although average alpha4-integrin saturation was not reduced after PLEX, it was reduced to less than 50% when natalizumab concentrations were below 1 mug/mL. PBMC transmigratory capacity increased 2.2-fold after PLEX (p < 0.006). CONCLUSIONS: Plasma exchange (PLEX) accelerated clearance of natalizumab, and at natalizumab concentrations below 1 mug/mL, desaturation of alpha4-integrin was observed. Also, CCL2-induced leukocyte transmigration across an in vitro blood-brain barrier was increased after PLEX. Therefore, PLEX may be effective in restoring immune effector function in natalizumab-treated patients.

Multiple sclerosis: chemokine receptor expression on circulating lymphocytes in correlation with radiographic measures of tissue injury.

BACKGROUND: Leukocytes expressing inflammatory chemokine receptors (CKRs), most consistently CCR2, CCR5, and CXCR3, have been identified in multiple sclerosis (MS) tissue lesions and provide attractive therapeutic targets. Our previous studies found large inter-individual differences in expression of these CKRs but stable levels over time within subjects. This observation suggests a CKR "set-point" within individuals, which might relate to inflammatory injury in MS. We evaluated the correlation between CKR levels and magnetic resonance imaging (MRI) measures of disease activity. METHODS: Fifty-five relapsing remitting MS (RRMS) and secondary progressive MS (SPMS) patients were prospectively followed with annual CKR and MRI studies. Multiparameter flow cytometry was used to determine CCR2, CCR5, and CXCR3 expression on CD4 and CD8 cells. Simultaneous cranial MRIs were performed, and quantitative measures of T2, T1, and gadolinium lesions, brain parenchymal fraction (BPF), and whole brain and fractionated magnetization transfer ratio (MTR) were performed using automated software. Spearman's rank correlations evaluated the relationship between CKR levels and MRI measures. RESULTS: Significant correlations were observed between CXCR3 expression on CD8 cells and measures of new (T1) and total (T1, T2) lesion volumes, lesion MTR, and BPF; higher levels of CXCR3 expression were correlated with greater injury on MRI (|r| = 0.27-0.42). In contrast, CD4 cell CKR expression was only minimally correlated with MRI measures. CONCLUSIONS: Over 2 years, we observed significant correlations between the percent of CD8 cells expressing CXCR3 and MRI measures of MS inflammatory activity and tissue destruction. These observations are consistent with a pathogenic role for cytotoxic T cells in MS brain and have significant implications regarding T-cell targeted therapeutic strategies.

Avonex Combination Trial in relapsing--remitting MS: rationale, design and baseline data.

OBJECTIVE: To review the rationale, design and baseline data of the Avonex Combination Trial (ACT), an investigator-run study of intramuscular interferon beta-1a (IM IFNbeta-1a) combined with methotrexate (MTX) and/or IV methylprednisolone (IVMP) in relapsing-remitting multiple sclerosis (RRMS) patients with continued disease activity on IM IFNbeta-1a monotherapy. METHODS: Eligibility criteria included RRMS, Expanded Disability Status Scale score 0-5.5, and >or=1 relapse or gadolinium-enhancing MRI lesion in the prior year while on IM IFNbeta-1a monotherapy. Subjects continued IFNbeta-1a 30 mcg IM weekly and were randomized in a 2 x 2 factorial design to adjunctive weekly placebo or MTX 20 mg PO, with or without IVMP 1,000 mg/day for three days every other month. ACT was industry-supported, and collaboratively designed and governed by an Investigator Steering Committee with independent Advisory and Data Safety Monitoring Committees. Study operations, MRI analysis and aggregated data were managed by the Cleveland Clinic MS Academic Coordinating Center. RESULTS: In total 313 subjects were enrolled with clinical and MRI characteristics typical of RRMS. Most subjects (86.9%) qualified with a clinical relapse, with or without an enhancing MRI lesion, in the preceding year. At baseline, 21.4% had enhancing lesions, and 5.1% had anti-IFNbeta neutralizing antibodies. ACT's management and operational structures functioned well. CONCLUSION: This study provides an innovative model for academic-industry collaborative MS research and will enhance understanding of the utility of combination therapy for RRMS patients with continued disease activity on an established first-line treatment.

Optimal reference population for the multiple sclerosis functional composite.

A reference population is used when integrating the individual components of the Multiple Sclerosis Functional Composite (MSFC) into a single composite score. The choice of reference populations may have a significant impact on the resulting MSFC score, yet the impact of different reference populations has not been evaluated. We evaluated the impact of different reference populations when deriving the Multiple Sclerosis Functional Composite (MSFC) in a group of MS patients followed longitudinally for two years. Reference populations included the study population at baseline (n = 60), a group of healthy controls (n = 18) and the National MS Society Task Force reference population (n = variable). We found that the choice of reference population had a significant impact on the resulting MSFC Z-score, sometimes compromising the statistical sensitivity to change over time. Our results suggest that longitudinal studies employing a multisystem composite Z-score should use a reference population with similar patients, which can most easily be achieved by using the baseline measures of the population under study. These results have significant implications to sample size estimates for longitudinal clinical studies and therapeutic trials.

MRI findings in Susac's syndrome.

BACKGROUND: Susac syndrome (SS) is a self-limited syndrome, presumably autoimmune, consisting of a clinical triad of encephalopathy, branch retinal artery occlusions, and hearing loss. All three elements of the triad may not be present or recognized, and MR imaging is often necessary to establish the diagnosis. OBJECTIVE: To determine the spectrum of abnormalities on MRI in SS. METHODS: The authors reviewed the MR images of 27 previously unreported patients with the clinical SS triad, and 51 patients from published articles in which the MR images were depicted or reported. RESULTS: All 27 patients had multifocal supratentorial white matter lesions including the corpus callosum. The deep gray nuclei (basal ganglia and thalamus) were involved in 19 (70%). Nineteen (70%) also had parenchymal enhancement and 9 (33%) had leptomeningeal enhancement. Of the 51 cases from the literature, at least 32 had callosal lesions. The authors could not determine the presence of callosal lesions in 18 of these patients, and only one was reported to have a normal MRI at the onset of encephalopathy. CONCLUSIONS: The MR scans in SS show a rather distinctive pattern of supratentorial white matter lesions that always involve the corpus callosum. There is often deep gray matter, posterior fossa involvement, and frequent parenchymal with occasional leptomeningeal enhancement. The central callosal lesions differ from those in demyelinating disease, and should support the diagnosis of SS in patients with at least two of the three features of the clinical triad.

High-dose methylprednisolone for acute closed spinal cord injury--only a treatment option.

BACKGROUND: A systematic review of the evidence pertaining to methylprednisolone infusion following acute spinal cord injury was conducted in order to address the persistent confusion about the utility of this treatment. METHODS: A committee of neurosurgical and orthopedic spine specialists, emergency physicians and physiatrists engaged in active clinical practice conducted an electronic database search for articles about acute spinal cord injuries and steroids, from January 1, 1966 to April 2001, that was supplemented by a manual search of reference lists, requests for unpublished additional information, translations of foreign language references and study protocols from the author of a Cochrane systematic review and Pharmacia Inc. The evidence was graded and recommendations were developed by consensus. RESULTS: One hundred and fifty-seven citations that specifically addressed spinal cord injuries and methylprednisolone were retrieved and 64 reviewed. Recommendations were based on one Cochrane systematic review, six Level I clinical studies and seven Level II clinical studies that addressed changes in neurological function and complications following methylprednisolone therapy. CONCLUSIONS: There is insufficient evidence to support the use of high-dose methylprednisolone within eight hours following an acute closed spinal cord injury as a treatment standard or as a guideline for treatment. Methylprednisolone, prescribed as a bolus intravenous infusion of 30 mg per kilogram of body weight over fifteen minutes within eight hours of closed spinal cord injury, followed 45 minutes later by an infusion of 5.4 mg per kilogram of body weight per hour for 23 hours, is only a treatment option for which there is weak clinical evidence (Level I- to II-1). There is insufficient evidence to support extending methylprednisolone infusion beyond 23 hours if chosen as a treatment option.

Aphemia: an isolated disorder of articulation.

Aphemia is a disorder with prominent speech abnormality. Since its description by Broca, there has been debate regarding the neuropsychological disorganization underlying aphemia: is aphemia an articulatory disorder or a language disorder? We describe a patient with markedly impaired articulation, but preserved receptive and written language function and buccal-facial coordination. The location of his stroke was in the left precentral gyrus, undercutting a small area of motor and premotor cortex. This case suggests that aphemia can occur as an isolated articulation deficit without language involvement or more widespread bulbar apraxia, and may be a severe form of apraxia of speech.

Acute, chronic, and recurrent varicella zoster virus neuropathy without zoster rash.

The authors report three patients with acute, chronic, and recurrent neuropathy associated with varicella zoster virus (VZV) infection but without zoster rash. CSF of all three patients contained VZV immunoglobulin G antibody, but not herpes simplex virus. In two patients, serum/CSF ratios of VZV immunoglobulin G were reduced compared to normal ratios for immunoglobulin G and albumin, and one patient also had VZV immunoglobulin M in CSF. All three patients received antiviral therapy and improved. The diagnosis of nervous system infection by VZV may be confirmed by the presence of antibody to VZV in CSF even without detectable VZV DNA.