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Objective: To determine if chronic cerebral venous insufficiency exists in patients with multiple sclerosis (MS) using ultrasonography and 4-dimensional color Doppler ultrasonography examination and unverified criteria proposed by Zamboni et al. Design: Patients with MS and clinically isolated syndrome were matched by age and sex with subjects with migraine or no neurological disease. All subjects underwent gray-scale, color, and spectral Doppler ultrasonography examination of the internal jugular veins (IJVs), vertebral veins, and deep cerebral veins for stenosis, absence of signal, and reflux. Setting: Academic MS center. Patients: All patients with MS fulfilled revised McDonald criteria for the diagnosis of MS. Patients with clinically isolated syndrome exhibited a typical transient focal neurological deficit and had magnetic resonance imaging lesions typical of MS. Control subjects were recruited from the VA migraine clinic or staff. Main Outcome Measures: Five parameters of venous outflow used by Zamboni et al were examined: (1) IJV or vertebral vein reflux, (2) deep cerebral vein reflux, (3) IJV stenosis, (4) absence of flow in IJVs or vertebral veins, and (5) change in cross-sectional area of the IJV with postural change. Results: There was no significant difference in the number and type of venous outflow abnormalities in patients with MS compared with controls. Conclusion: This study does not support the theory that chronic cerebral venous insufficiency exists in MS. [ABSTRACT FROM AUTHOR]

Natalizumab (Tysabri) was the first monoclonal antibody approved for the treatment of relapsing forms of multiple sclerosis (MS). After its initial approval, 3 patients undergoing natalizumab therapy in combination with other immunoregulatory and immunosuppressive agents were diagnosed with progressive multifocal leukoencephalopathy (PML). The agent was later reapproved and its use restricted to monotherapy in patients with relapsing forms of MS. Since reapproval in 2006, additional cases of PML were reported in patients with MS receiving natalizumab monotherapy. Thus, there is currently no convincing evidence that natalizumab-associated PML is restricted to combination therapy with other disease modifying or immunosuppressive agents. In addition, recent data indicate that risk of PML might increase beyond 24 months of treatment. [ABSTRACT FROM AUTHOR]

Background: Inner (area adjacent to the fovea) and outer regions of the macula differ with respect to relative thicknesses of the ganglion cell layer (neurons) vs retinal nerve fiber layer (RNFL; axons). Objective: To determine how inner vs outer macular volumes relate to peripapillary RNFL thickness and visual function in multiple sclerosis (MS) and to examine how these patterns differ among eyes with vs without a history of acute optic neuritis (ON). Design: Study using cross-sectional optical coherence tomography. Setting: Three academic tertiary care MS centers. Participants: Patients with MS, diagnosed by standard criteria, and disease-free control participants. Main Outcome Measures: Optical coherence tomography was used to measure macular volumes and RNFL thickness. Visual function was assessed using lowcontrast letter acuity and high-contrast visual acuity (Early Treatment Diabetic Retinopathy Study charts). Results: Among eyes of patients with MS (n=1058 eyes of 530 patients), reduced macular volumes were associated with peripapillary RNFL thinning; 10-μm differences in RNFL thickness (9.6% of thickness in control participants without disease) corresponded to 0.20- mm3 reductions in total macular volume (2.9% of volume in control participants without disease, P<.001). This relation was similar for eyes of MS patients with and without a history of ON. Although peripapillary RNFL thinning was more strongly associated with decrements in outer compared with inner macular volumes, correlations with inner macular volume were significant (r=0.58, P<.001) and of slightly greater magnitude for eyes of MS patients with a history of ON vs eyes of MS patients without a history of ON (r=0.61 vs r=0.50). Lower (worse) visual function scores were associated with reduced total, inner, and outer macular volumes. However, accounting for peripapillary RNFL thickness, the relation between vision and inner macular volume remained significant and unchanged in magnitude, suggesting that this region contains retinal structures separate from RNFL axons that are important to vision. Conclusions: Analogous to studies of gray matter in MS, these data provide evidence that reductions of volume in the macula (approximately 34% neuronal cells by average thickness) accompany RNFL axonal loss. Peripapillary RNFL thinning and inner macular volume loss are less strongly linked in eyes of MS patients without a history of ON than in eyes of MS patients with a history of ON, suggesting alternative mechanisms for neuronal cell loss. Longitudinal studies with segmentation of retinal layers will further explore the relation and timing of ganglion cell degeneration and RNFL thinning in MS. [ABSTRACT FROM AUTHOR]

Background: Rituximab is a recombinant chimeric monoclonal antibody against CD20, a molecule expressed on cells of the B-cell lineage. A phase 2 clinical trial recently provided strong evidence of the beneficial effects of rituximab in patients with relapsing-remitting multiple sclerosis. We and other investigators previously demonstrated that rituximab therapy depletes B lymphocytes from peripheral blood and cerebrospinal fluid of patients with relapsing-remitting multiple sclerosis. Objective: To determine the effect of rituximab on the presence of B cells in cerebral perivascular spaces. Design, Setting, and Patients: Case report from a tertiary academic medical center. Cerebral white matter from autopsy material of a patient with gastrointestinal mantle-cell lymphoma who developed progressive multifocal leukoencephalopathy following rituximab therapy was evaluated by immunohistochemistry. Locationmatched brain sections of patients with multiple sclerosis not treated with rituximab, patients without central nervous system disease, and patients with progressive multifocal leukoencephalopathy not associated with rituximab were used as controls. Main Outcome Measures: Assessment of the number of B lymphocytes in cerebral perivascular spaces in a patient with gastrointestinal mantle-cell lymphoma treated with rituximab, patients with multiple sclerosis, patients with progressive multifocal leukoencephalopathy not associated with rituximab, and healthy control subjects. Results:Wewere unable to detect B cells in cerebral perivascular spaces of the patient who developed progressive multifocal leukoencephalopathy following rituximab therapy 8 months after her last dose. In contrast, B cells were detectable in all control brain tissues. Conclusions: To our knowledge, this is the first report to show B-lymphocyte depletion from brain tissue following rituximab therapy. A reduction in B-cell numbers may be an important contributing factor in the pathogenesis of central nervous system infections. [ABSTRACT FROM AUTHOR]

Objective: To extend our studies on the prolonged and differential effect of natalizumab on T lymphocyte numbers in the cerebrospinal fluid, we investigated the number and phenotypes of leukocytes and the expression of major histocompatibility complex (MHC) classes I and II in cerebral perivascular spaces (CPVS). We hypothesized that natalizumab reduces the number of antigen presenting cells in CPVS. Design: A case-control study in which inflammatory cell numbers in the CPVS of cerebral tissue were assessed by immunohistochemical staining. Subjects: A patient with multiple sclerosis (MS) who developed progressive multifocal leukoencephalopathy (PML) during natalizumab therapy. Controls included location-matched cerebral autopsy material of patients without disease of the central nervous system, patients with MS not treated with natalizumab, and patients with PML not associated with natalizumab therapy. Results: The absolute number of CPVSin the patient with MS treated with natalizumab was significantly lower than in the control groups owing to extensive destruction of the tissue architecture. The expression of MHC class II molecules and the number of CD209+ dendritic cells were significantly decreased in the CPVS of the patient with MS treated with natalizumab. No CD4+ T cells were detectable. Conclusions: Our observations may explain the differential and prolonged effects of natalizumab therapy on leukocyte numbers in the cerebrospinal fluid. [ABSTRACT FROM AUTHOR]

Background: Optical coherence tomography (OCT) is a promising new method of quantifying axon thickness in the retinal nerve fiber layer (RNFL) that has been used predominantly by ophthalmologists to monitor glaucoma. Optical coherence tomography is being considered as a potential outcome measure in multiple sclerosis (MS) clinical trials, but no data exist on the reproducibility of this technique in MS centers. Objective: To determine the reproducibility of OCT measurement of mean RNFL thickness in the undilated eyes of healthy control subjects and patients with MS. Design: Prospective analysis of 4 healthy controls to determine interrater, intrarater, and longitudinal reproducibility. Cross-sectional analysis of 3 cohorts of patients with MS (n=396) and healthy controls (n=153). Setting: Multiple sclerosis clinics at 3 academic medical centers. Patients or Other Participants: Healthy controls and patients with MS. Main Outcome Measure: Thickness of RNFL. Results: We found excellent agreement with respect to interrater (intraclass correlation [ICC], 0.89), intrarater (ICC, 0.98), and intervisit (ICC, 0.91) results. Mean RNFL thickness did not vary significantly among research centers for patients with MS (93, 92, and 90 µm) or among healthy controls (103, 105, and 104 µm) by site. Conclusions: We demonstrate that mean RNFL thickness can be reproducibly measured by trained technicians in an MS center using the OCT-3 model. The RNFL measures from cohorts of age-matched controls and patients with MS from 3 different research centers were remarkably similar. [ABSTRACT FROM AUTHOR]

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

atalizumab (Tysabri) is an effective therapy for multiple sclerosis. Recently, 3 patients who were treated with natalizumab developed progressive multifocal leukoencephalopathy (PML), an opportunistic infection of the brain with the polyomavirus JC. The pathogenesis of natalizumab-associated PML may be different from that of PML not associated with the drug. We reviewed biologically feasible interventions for patients diagnosed as having PML or other infections while receiving natalizumab therapy. Existing interventions include antiviral treatment, immunomodulatory therapies, hematopoietic growth factors, plasma exchange, intravenous immunoglobulins, and leukapheresis and autotransfusion of leukocytes. In addition, we examined the feasibility of experimental therapies, including small interfering RNA, the in vivo use of antiserum, and recombinant natalizumab-blocking molecules. There is only circumstantial evidence that any of the proposed treatments will benefit patients with multiple sclerosis treated with natalizumab who may develop PML. In addition, the expected incidence of PML in this patient population will likely be too low to test any of the proposed interventions in a controlled manner. Because it is currently impossible to identify patients at risk, and thus to prevent PML as a consequence of natalizumab therapy, it is important that neurologists be aware of possible therapeutic interventions. [ABSTRACT FROM AUTHOR]

Background: Treatment with natalizumab, a monoclonal antibody against the adhesion molecule very late activation antigen 4, an α4β1 integrin, was recently associated with the development of progressive multifocal leukoencephalopathy, a demyelinating disorder of the central nervous system caused by JC virus infection Objective: To test the effect of natalizumab treatment on the CD4+/CD8+ T-cell ratios in cerebrospinal fluid (CSF) and peripheral blood. Design: Prospective longitudinal study. Setting: Academic and private multiple sclerosis centers. Patients: Patients with multiple sclerosis (MS) treated with natalizumab, untreated patients with MS, patients with other neurologic diseases, and human immunodeficiency virus-infected patients. Main Outcome Measures: CD4+ and CD8+ T cells were enumerated in CSF and peripheral blood. The mean fluorescence intensity of unbound a 4 integrin on peripheral blood CD4+ and CD8+ T cells was analyzed before and after natalizumab therapy. Results: Natalizumab therapy decreased the CSF CD4+/CD8+ ratio of patients with MS to levels similar to those of human immunodeficiency virus-infected patients. CD4+/CD8+ ratios in peripheral blood in patients with MS progressively decreased with the number of natalizumab doses, but they remained within normal limits. Six months after the cessation of natalizumab therapy, CSF CD4+/CD8+ ratios normalized. The expression of unbound a 4 integrin on peripheral blood T cells decreases with natalizumab therapy and was significantly lower on CD4+ vs CD8+ T cells. Conclusions: Natalizumab treatment alters the CSF CD4+/CD8+ ratio. Lower expression of unbound α4 integrin on CD4+ T cells is one possible mechanism. These results may have implications for the observation that some natalizumab-treated patients with MS developed progressive multifocal leukoencephalopathy. [ABSTRACT FROM AUTHOR]

In the management of patients with multiple sclerosis (MS), providers are all faced with the highly formidable challenge of ascertaining whether, and to what degree, disease-modifying therapy is effective in the individual patient. While much has been learned in randomized, controlled clinical trials, we cannot simply extrapolate the outcomes of these initiatives and apply them to the care of a single patient. In the future, the application of pharmacogenetic techniques, proteomics, and microarray analysis will yield novel profiling information on individual patients that will substantially refine the specific therapeutic questions of relevance: (1) What is the best treatment for an individual patient? (2) Which patients require intensive therapeutic combination regimens to optimize control of the disease process? (3) What are the appropriate drug dosing targets for an individual patient? and (4) Which patients will be predisposed to the development of drug-related adverse events? Such data may provide a novel variable of drug responsiveness that will mandate its inclusion into the process of covariate analyses for clinical trials. [ABSTRACT FROM AUTHOR]

Background Rituximab, an anti-CD20 monoclonal antibody that depletes CD20+ B cells, has demonstrated efficacy in peripheral neurological diseases. Whether this efficacy can be translated to neurological diseases of the central nervous system with possible autoimmune B-cell involvement remains unknown. Objective To determine the effect of rituximab on cerebrospinal fluid B cells in patients with multiple sclerosis. Design Four patients with primary progressive multiple sclerosis were treated with rituximab. Cerebrospinal fluid and peripheral blood B-cell subsets were identified by flow cytometry from each patient before and after rituximab treatment. Results The B cells in cerebrospinal fluid were not as effectively depleted as their peripheral blood counterparts. Rituximab treatment temporarily suppressed the activation state of B cells in cerebrospinal fluid. The residual B cells underwent expansion after rituximab treatment. Conclusion The effect(s) of rituximab on the cerebrospinal fluid B-cell compartment is limited in comparison with the effect(s) on the B cells in the periphery, but this finding will need to be confirmed in a larger group of MS patients. [ABSTRACT FROM AUTHOR]

Background Intramedullary neurosarcoidosis may be the first and only manifestation of the disease and may mimic an idiopathic inflammatory demyelinating syndrome both clinically and on neuroimaging results. Methods and Results Two patients who were seen initially with a relapsing-remitting neurologic course and a cervical intramedullary lesion on magnetic resonance imaging findings are reported. Both proved to have neurosarcoidosis. A computed axial tomographic scan of the chest showed hilar adenopathy, which provided a clue to the diagnosis. Conclusions Symptoms due to an intramedullary cervical lesion can be the first manifestation of neurosarcoidosis. The clinical course can mimic a demyelinating illness. A high index of suspicion and a search for sarcoidosis at extraneural sites are required for an early diagnosis. Steroid treatment is associated with a favorable outcome. [ABSTRACT FROM AUTHOR]

Background: Sexual dysfunction in patients with multiple sclerosis is typically characterized by diminished libido, erectile and ejaculatory dysfunction in men, and poor lubrication and anorgasmy in women. In contrast, hypersexual behavior and paraphilias are distinctly uncommon in this population of patients, but have been associated with various focal brain lesions. Patient and Methods: We describe a man with clinically definite multiple sclerosis who developed profound and abrupt disinhibition and paraphilic behavior during an exacerbation. Results: Neuroimaging revealed a marked increase in the number of enhancing lesions in the right sides of the hypothalamus and mesencephalon and extending into the right sides of the red nucleus, substantia nigra, and internal capsule. The altered sexual behavior was characterized by an obsessive and insatiable desire to touch women's breasts. Conclusions: Acquired sexual paraphilic behavior is uncommon in patients with multiple sclerosis but may occur when inflammatory demyelination involves the hypothalamic and septal regions of the basal prosencephalon. Our experience with this man illustrates the great difficulty involved in treating such patients when the paraphilic behavior becomes persistent. [ABSTRACT FROM AUTHOR]

Background: Sympathomimetic-induced metabolic derangements within the central nervous system can result in conspicuous changes in neurological functioning and corresponding radiographic abnormalities that can be reversible. Objective: To describe a patient with a "kaleidoscopic" visual illusion who was found by magnetic resonance imaging to have a transient lesion in the splenium of the corpus callosum. Design: Case report. Setting: The University of Texas Southwestern Medical Center, Dallas. Patient: A 17-year-old adolescent girl who developed an episode of kaleidoscopic vision while using sympathomimetic-containing diet pills that was associated with a reversible lesion of the splenium of the corpus callosum. Her brother has a history of migraine and experienced a similar episode while using illicit stimulant agents. Intervention: Withdrawal of the medication resulted in the cessation of the episodes and normalization of the magnetic resonance image. Main Outcome Measures: Clinical and radiographic improvement. Results: Sympathomimetic-induced metabolic derangements can be associated with reversible lesions within the brain. Conclusions: We hypothesize that the visual fragmentation was a manifestation of a migraine triggered by sympathomimetic-containing diet pills, and that the transient lesion in the corpus callosum was a manifestation of a reversible metabolic derangement. Both the visual fragmentation and the lesion in the corpus callosum resolved once the patient stopped receiving diet pills. [ABSTRACT FROM AUTHOR]

Background: Relative afferent pupillary defects are typically related to ipsilateral lesions within the anterior visual pathways. Objective: To describe a patient who had a workup for headache and was found to have an isolated left relative afferent pupillary defect without any other neurological findings. Dosign: We review the neuroanatomy of the pupillary light reflex pathway and emphasize the nasotemporal bias of decussating fiber projections, which accounts for the relative afferent pupillary defect contralateral to the described lesion. Result: Magnetic resonance imaging of the brain revealed a pineal tumor compressing the right rostral midbrain. Conclusion: While rare, a relative afferent pupillary defect can occasionally occur secondary to lesions in the postchiasmal pathways. In these circumstances, the pupillary defect will be observed to be contralateral to the side of the lesion. [ABSTRACT FROM AUTHOR]

Editorial. Discusses the therapeutic dilemma of idiopathic monosymptomatic demyelinating syndromes. Factor that led to the assessment of anti-inflammatory and immunosuppresant therapeutic strategies; Implication of magnetic resonance imaging (MRI) activity in early relapsing remitting multiple sclerosis; Use of MRI in patients with monosymptomatic syndromes.

Editorial. Discusses research concerning fatigue in multiple sclerosis (MS). Factors that can contribute to fatigue experienced by patients with MS; Relationship between axonal injury and fatigue in MS patients.

Importance: Infection with JC virus (JCV) may lead to development of demyelinating progressive multifocal leukoencephalopathy in patients with multiple sclerosis (MS) who are treated with natalizumab., Objective: To determine whether mononuclear cells in circulation from MS patients treated with natalizumab harbor JCV DNA., Design, Setting, and Participants: In this prospective investigation, we enrolled 49 MS patients from the Clinical Center for Multiple Sclerosis at The University of Texas Southwestern Medical Center and 18 healthy volunteers. We drew 120-mL blood samples from 26 MS patients at baseline and at approximately 3-month intervals to 10 months during the course of natalizumab infusions. One blood sample was drawn from 23 MS patients receiving natalizumab for more than 24 months and from 18 healthy volunteers., Interventions: Natalizumab treatment of MS., Main Outcomes and Measures: The blood samples were separated using flow cytometry into CD34+, CD19+, and CD3+ cell subsets; DNA templates were prepared using quantitative polymerase chain reaction for JCV DNA identification. Plasma samples were tested for anti-JCV antibodies by enzyme-linked immunosorbent assays performed at the Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological and Communicative Diseases and Stroke., Results: Thirteen of the 26 patients (50%) with baseline and follow-up blood samples had detectable viral DNA in at least 1 cell compartment at 1 or more points. Ten of the 23 patients (44%) receiving treatment for more than 24 months and 3 of the 18 healthy volunteers (17%) also had detectable viral DNA in 1 or more cell compartment. Fifteen of the 49 MS patients (31%) were confirmed to harbor JCV in CD34+ cells and 12 of 49 (24%) in CD19+ cells. Only 1 of 18 healthy volunteers were viremic in CD34+ cells and none in CD19+ cells. Nine patients and 1 healthy volunteer were viremic but had seronegative test results for JCV antibodies., Conclusions and Relevance: JC virus DNA was detectable within cell compartments of natalizumab-treated MS patients after treatment inception and longer. JC virus DNA may harbor in CD34+ cells in bone marrow that mobilize into the peripheral circulation at high concentrations. Latently infected cells initiate differentiation to CD19+ cells that favors growth of JCV. These data link the mechanism of natalizumab treatment with progressive multifocal leukoencephalopathy.

Objective: To determine the relationships between conventional and segmentation-derived optical coherence tomography (OCT) retinal layer thickness measures with intracranial volume (a surrogate of head size) and brain substructure volumes in multiple sclerosis (MS)., Design: Cross-sectional study., Setting: Johns Hopkins University, Baltimore, Maryland., Participants: A total of 84 patients with MS and 24 healthy control subjects., Main Outcome Measures: High-definition spectral-domain OCT conventional and automated segmentation-derived discrete retinal layer thicknesses and 3-T magnetic resonance imaging brain substructure volumes., Results: Peripapillary retinal nerve fiber layer as well as composite ganglion cell layer+inner plexiform layer thicknesses in the eyes of patients with MS without a history of optic neuritis were associated with cortical gray matter (P=.01 and P=.04, respectively) and caudate (P=.04 and P=.03, respectively) volumes. Inner nuclear layer thickness, also in eyes without a history of optic neuritis, was associated with fluid-attenuated inversion recovery lesion volume (P=.007) and inversely associated with normal-appearing white matter volume (P=.005) in relapsing-remitting MS. As intracranial volume was found to be related with several of the OCT measures in patients with MS and healthy control subjects and is already known to be associated with brain substructure volumes, all OCT-brain substructure relationships were adjusted for intracranial volume. CONCLUSIONS Retinal measures reflect global central nervous system pathology in multiple sclerosis, with thicknesses of discrete retinal layers each appearing to be associated with distinct central nervous system processes. Moreover, OCT measures appear to correlate with intracranial volume in patients with MS and healthy control subjects, an important unexpected factor unaccounted for in prior studies examining the relationships between peripapillary retinal nerve fiber layer thickness and brain substructure volumes.