Extended interval dosing of natalizumab in multiple sclerosis.

BACKGROUND: Natalizumab (NTZ), a monoclonal antibody to human α4ß1/ß7 integrin, is an effective therapy for multiple sclerosis (MS), albeit associated with progressive multifocal leukoencephalopathy (PML). Clinicians have been extending the dose of infusions with a hypothesis of reducing PML risk. The aim of the study is to evaluate the clinical consequences of reducing NTZ frequency of infusion up to 8 weeks 5 days. METHODS: A retrospective chart review in 9 MS centres was performed in order to identify patients treated with extended interval dosing (EID) regimens of NTZ. Patients were stratified into 3 groups based on EID NTZ treatment schedule in individual centres: early extended dosing (EED; n=249) every 4 weeks 3 days to 6 weeks 6 days; late extended dosing (LED; n=274) every 7 weeks to 8 weeks 5 days; variable extended dosing (n=382) alternating between EED and LED. These groups were compared with patients on standard interval dosing (SID; n=1093) every 4 weeks. RESULTS: 17% of patients on SID had new T2 lesions compared with 14% in EID (p=0.02); 7% of patients had enhancing T1 lesions in SID compared with 9% in EID (p=0.08); annualised relapse rate was 0.14 in the SID group, and 0.09 in the EID group. No evidence of clinical or radiographic disease activity was observed in 62% of SID and 61% of EID patients (p=0.83). No cases of PML were observed in EID group compared with 4 cases in SID cohort. CONCLUSIONS: Dosing intervals up to 8 weeks 5 days did not diminish effectiveness of NTZ therapy. Further monitoring is ongoing to evaluate if the risk of PML is reduced in patients on EID.

Cup to disc ratio by optical coherence tomography is abnormal in multiple sclerosis.

OBJECTIVE: To identify and characterize cup to disc ratio (CDR) and related optic nerve head abnormalities in multiple sclerosis (MS) using spectral domain optical coherence tomography (OCT). BACKGROUND: While CDR is routinely assessed by ophthalmologists in the evaluation of glaucoma, CDR and related optic nerve head metrics remain largely unexplored in MS. DESIGN/METHODS: Cirrus-HD (high density) OCT was used to evaluate average CDR, vertical CDR, optic disc area, optic cup volume, and neuro-retinal rim area in 105 MS patients and 88 age-matched healthy individuals. High-contrast (100%) visual acuity, 2.5% low-contrast letter acuity and 1.25% low-contrast letter acuity were assessed in 77 MS patients. Two-sample t-tests were used in the analysis of OCT-derived optic nerve head measures between healthy controls and MS patients. Multivariate regression (accounting for age and gender) was used to assess relationships between optic nerve head measures and visual function. RESULTS: Average CDR (p=0.007) and vertical CDR (p=0.005) were greater in MS patients compared to healthy controls, while neuro-retinal rim area was decreased in MS patients (p=0.001). CDR increased with retinal nerve fiber layer (RNFL) thinning (r=-0.29, p=0.001). 2.5% low-contrast (p=0.005) and 1.25% low-contrast letter acuity (p=0.03) were lower in MS patients with higher vertical CDR. CONCLUSIONS/RELEVANCE: CDR (as determined by spectral domain OCT) is abnormal in MS and correlates with visual function. OCT-derived CDR and related optic nerve head metrics may represent an objective measure by which to monitor disease progression, and potentially neuroprotection, in therapeutic MS trials.

Retinal architecture predicts pupillary reflex metrics in MS.

OBJECTIVE: To study the relation of retinal nerve fiber layer thinning to clinical and physiologic measures of visual function in patients with MS or neuromyelitis optica and unilateral optic neuropathy. METHODS: We studied a cohort of control subjects (n = 64) and patients (n = 24) with evidence of unilateral thinning of their average retinal nerve fiber layer as measured by optical coherence tomography in order to characterize the relationship between ganglion cell axonal degeneration and its impact upon vision and pupillary light reflex metrics using infrared pupillometry. RESULTS: When compared to the normal fellow eye, and with respect to normal subjects' eyes, we confirmed significant abnormalities in retinal nerve fiber layer thickness, total macular volume, low-contrast letter acuity, and pupillary reflex metrics in the eye with the thinner retinal nerve fiber layer. For each -5% change in pupil diameter, there was a corresponding 7.1 Amicrom reduction in the average retinal nerve fiber layer thickness. There was a significant difference between the pupillary metric of percent change in diameter and a decrease in low-contrast letter acuity (P < 0.001). Each -5% change in pupil diameter was associated with a substantial 3.4 line loss of low-contrast letter acuity (P < 0.001). Each -5% change in pupil diameter was associated with a 0.2 mm(2) decrease in total macular volume (P < 0.001). CONCLUSION: These findings further corroborate the hypothesis that the retina can be utilized as a model to advance our understanding of the mechanisms of axonal and neurodegeneration, and the corresponding impact of these processes upon the pathophysiology of MS and related disorders.

Pearls & Oy-sters: The medial longitudinal fasciculus in ocular motor physiology.

OBJECTIVE: To review the role played by the medial longitudinal fasciculus (MLF) in ocular motor physiology and to characterize a number of syndromes that result from lesions in this eloquent brainstem tract system. BACKGROUND: The MLF is responsible for transmitting information that is crucial for the coordination and synchronization of all major classes of eye movements. A number of disease processes can produce lesions within this small yet highly strategic white matter pathway resulting in a myriad of neuro-ophthalmologic signs and symptoms. METHODS: We carefully reviewed both the literature and our collective experiences to systematically consider the neuroanatomy and physiology of the MLF and the pathophysiologic mechanisms that underlie syndromes deriving from lesions in this pathway. RESULTS: The MLF is an important structure and is composed of numerous projection systems involved in the regulation of eye movements. Pathology at this location can produce a constellation of abnormalities, many of which can be identified upon careful bedside neurologic examination. CONCLUSION: This review of the medial longitudinal fasciculus and its constituent pathways is germane to understanding a number of important principles in neuro-ophthalmology.

Modeling Uhthoff's phenomenon in MS patients with internuclear ophthalmoparesis.

OBJECTIVE: The goal of this investigation was to demonstrate that internuclear ophthalmoparesis (INO) can be utilized to model the effects of body temperature-induced changes on the fidelity of axonal conduction in multiple sclerosis (Uhthoff's phenomenon). METHODS: Ocular motor function was measured using infrared oculography at 10-minute intervals in patients with multiple sclerosis (MS) with INO (MS-INO; n = 8), patients with MS without INO (MS-CON; n = 8), and matched healthy controls (CON; n = 8) at normothermic baseline, during whole-body heating (increase in core temperature 0.8 degrees C as measured by an ingestible temperature probe and transabdominal telemetry), and after whole-body cooling. The versional disconjugacy index (velocity-VDI), the ratio of abducting/adducting eye movements for velocity, was calculated to assess changes in interocular disconjugacy. The first pass amplitude (FPA), the position of the adducting eye when the abducting eye achieves a centrifugal fixation target, was also computed. RESULTS: Velocity-VDI and FPA in MS-INO patients was elevated (p < 0.001) following whole body heating with respect to baseline measures, confirming a compromise in axonal electrical impulse transmission properties. Velocity-VDI and FPA in MS-INO patients was then restored to baseline values following whole-body cooling, confirming the reversible and stereotyped nature of this characteristic feature of demyelination. CONCLUSIONS: We have developed a neurophysiologic model for objectively understanding temperature-related reversible changes in axonal conduction in multiple sclerosis. Our observations corroborate the hypothesis that changes in core body temperature (heating and cooling) are associated with stereotypic decay and restoration in axonal conduction mechanisms.

Accuracy of clinical detection of INO in MS: corroboration with quantitative infrared oculography.

The authors compared the accuracy of clinical detection (by 279 physician observers) of internuclear ophthalmoparesis (INO) with that of quantitative infrared oculography. For the patients with mild adduction slowing, INO was not identified by 71%. Intermediate dysconjugacy was not detected by 25% of the evaluators. In the most severe cases, INO was not identified by only 6%. Oculographic techniques significantly enhance the precision of INO detection compared to the clinical exam.

Benign paroxysmal positioning vertigo in multiple sclerosis: diagnosis, pathophysiology and therapeutic techniques.

OBJECTIVE: To report on the most common causes of vertigo in patients with multiple sclerosis (MS) and emphasize appropriate diagnostic techniques and treatment interventions. BACKGROUND: True vertigo is estimated to occur in about 20% of MS patients. Lesions within the vestibular nuclei and in the root entry zone of cranial nerve VIII represent the most common locations where demyelinating activity can provoke vertigo in patients with MS. However, other causes of vertigo should be explored in MS patients in order to avoid unnecessary treatment with corticosteroids and vestibular suppressants. Recently, we reviewed our four-year experience with new onset vertigo in our university-based MS population and found that benign paroxysmal positioning vertigo (BPPV) to be the most common cause. All patients diagnosed with BPPV were treated successfully with particle repositioning maneuvers. The remaining patients were treated with conventional therapies appropriate for the specific diagnosis. CONCLUSIONS: Empiric treatments with corticosteroids and/or vestibular suppressants should not be employed until all MS patients undergo a careful bedside examination, which includes diagnostic positional and, if indicated, particle repositioning maneuvers. Here we emphasize the pathophysiology of BPPV and illustrate the proper techniques for the diagnostic and therapeutic maneuvers.

Quantitative oculographic characterisation of internuclear ophthalmoparesis in multiple sclerosis: the versional dysconjugacy index Z score.

BACKGROUND: There is a poor correlation between multiple sclerosis disease activity, as measured by magnetic resonance imaging, and clinical disability. OBJECTIVE: To establish oculographic criteria for the diagnosis and severity of internuclear ophthalmoparesis (INO), so that future studies can link the severity of ocular dysconjugacy with neuroradiological abnormalities within the dorsomedial brain stem tegmentum. METHODS: The study involved 58 patients with multiple sclerosis and chronic INO and 40 normal subjects. Two dimensional infrared oculography was used to derive the versional dysconjugacy index (VDI)-the ratio of abducting to adducting eye movements for peak velocity and acceleration. Diagnostic criteria for the diagnosis and severity of INO were derived using a Z score and histogram analysis, which allowed comparisons of the VDI from multiple sclerosis patients and from a control population. RESULTS: For a given saccade, the VDI was typically higher for acceleration v velocity, whereas the Z scores for velocity measures were always higher than values derived from comparable acceleration VDI measures; this was related to the greater variability of acceleration measures. Thus velocity was a more reliable measure from which to determine Z scores and thereby the criteria for INO and its level of severity. The mean (SD) value of the VDI velocity derived from 40 control subjects was 0.922 (0.072). The highest VDI for velocity from a normal control subject was 1.09, which was 2.33 SD above the normal control mean VDI. We therefore chose 2 SD beyond this value (that is, a Z score of 4.33) as the minimum criterion for the oculographic confirmation of INO. Of patients thought to have unilateral INO on clinical grounds, 70% (16/23) were found to have bilateral INO on oculographic assessment. CONCLUSIONS: INO can be confirmed and characterised by level of severity using Z score analysis of quantitative oculography. Such assessments may be useful for linking the level of severity of a specific clinical disability with neuroradiological measures of brain tissue pathology in multiple sclerosis.

MRI characteristics of the MLF in MS patients with chronic internuclear ophthalmoparesis.

OBJECTIVE: The authors imaged the medial longitudinal fasciculus (MLF) in 58 patients with MS and chronic internuclear ophthalmoparesis (INO) to determine which MRI technique best shows the characteristic lesion associated with this ocular motor syndrome. METHODS: Using quantitative infrared oculography, the authors determined the ratios of abduction to adduction for velocity and acceleration, to confirm the presence of INO and to determine the severity of MLF dysfunction in 58 patients with MS and INO. Conventional MRI techniques, including proton density imaging (PDI), T2-weighted imaging, and fluid-attenuated inversion recovery (FLAIR) imaging, were used to ascertain which technique best shows MLF lesions within the brainstem tegmentum. T1-weighted imaging was performed to determine the frequency of brainstem tegmentum hypointensities. RESULTS: All patients studied had evidence of an MLF lesion hyperintensity on PDI, whereas T2-weighted imaging and FLAIR imaging showed these lesions in 88% and 48% of patients, respectively. With PDI, dorsomedial tegmentum lesions were seen in the pons in 93% of patients and in the midbrain of 66% of patients. Lesions were observed at both locations in 59% of patients. One patient had an MLF lesion with a corresponding T1 hypointensity. CONCLUSIONS: PDI best shows the MLF lesion in patients with MS and INO.

Ocular contrapulsion in multiple sclerosis: clinical features and pathophysiological mechanisms.

The objective was to describe in multiple sclerosis, a cerebellar eye movement syndrome that resulted from an acute episode of inflammatory demyelination. Contrapulsion is an ocular motor disturbance characterised by a triad of (1) hypermetric saccadic eye movements in a direction opposite from a precisely localised lesion within a specific white matter pathway, the uncinate fasciculus, at the level of the superior cerebellar peduncle (SCP); (2) hypometric saccades towards the side of the lesion; (3) oblique saccades directed away from the side of the lesion on attempted vertical saccades. Infrared oculography was used to demonstrate the characteristic features of contrapulsion in two patients with multiple sclerosis. Brain MRI showed lesions within the region of the uncinate fasciculus and superior cerebellar peduncle in both patients. Eye movement recordings showed saccadic hypermetria away from the side of the lesion and saccadic hypometria towards the side of the lesion. The hypometria decomposed into a series of stepwise movements as the eye approached the target. Oblique saccades directed away from the side of the lesion were seen on attempted vertical saccades. In conclusion, ocular contrapulsion can be seen in patients with multiple sclerosis and results from a lesion in the region of the SCP, involving the uncinate fasciculus.

Vertigo in MS: utility of positional and particle repositioning maneuvers.

A 4-year experience with new-onset vertigo in a university-based MS population was retrospectively reviewed. Of 1,153 patients with MS, 25 could be clinically evaluated during the vertiginous episode. Of these, 13 (52%) were diagnosed with benign paroxysmal positioning vertigo and eight (32%) had acute MS exacerbations with corresponding lesions within the brainstem. All patients diagnosed with benign paroxysmal positioning vertigo were treated successfully with particle repositioning maneuvers.

Expression of intercellular adhesion molecule 1 (ICAM-1) in Alzheimer's disease.

In this study, 13 clinically and pathologically diagnosed cases of Alzheimer's disease were analyzed for the presence of intercellular adhesion molecule 1 (ICAM-1), ICAM-2, lymphocyte function associated antigen-1 (LFA-1), HLA-DR, LN-1, and LN-2. ICAM-1 was observed primarily on neuritic plaques and cerebrovascular endothelium. ICAM-1 was also shown to be present in brain tissue derived from 14 normal cases; however, the degree of immunoreactivity was quantitatively less compared to Alzheimer cases and was largely restricted to cerebrovascular endothelium. LFA-1 was shown to be present on microglial cells and leukocytes. Consistent with the findings of previous reports, HLA-DR was found to be expressed on microglial cells. In this study we failed to demonstrate dual immunolocalization for ICAM-1 and LFA-1, ICAM-1 and HLA-DR, or ICAM-1 and LN-2. As microglial cells express both HLA-DR and LFA-1, they may serve to mediate antigen presentation functions by interacting with lymphocyte ICAM-1. Alternately, the expression of these immune-associated glycoproteins on glial cells may be epiphenomenal occurring secondary to some aspect of the disease process. Finally, the presence of ICAM-1 within neuritic plaques raises the question as to whether adhesion may play some role in the process of neurite outgrowth and neurodegeneration.

The induction of intercellular adhesion molecule 1 (ICAM-1) expression on human fetal astrocytes by interferon-gamma, tumor necrosis factor alpha, lymphotoxin, and interleukin-1: relevance to intracerebral antigen presentation.

Antigen presentation reactions are dependent upon the expression of the class II major histocompatibility antigens (MHC), the T-cell receptor, and the presented antigen. Recent studies demonstrate that such processes also require the presence of adhesion molecules such as lymphocyte functional antigen 1 (LFA-1) and its cell surface ligand, intercellular adhesion molecule 1 (ICAM-1). It has been suggested that the brain astrocyte can function as a facultative antigen presenting cell (APC). This hypothesis is based upon the ability to induce the expression of the class II MHC antigens on astrocytes, and on their ability to present myelin basic protein to encephalitogenic T-cells in vitro. The best in vivo data showing that astrocytes serve as intracerebral APCs is the finding that astrocytes in multiple sclerosis plaques are DR+ (class II MHC in human). However, it still remains to be resolved whether the in vivo expression of the MHC antigens in disease states is instrumental to antigen presentation mechanisms or whether these cell surface glycoproteins are expressed secondary to brain immune responses. If astrocytes function as immunocompetent APCs within the brain, it would seem that they would also be able to express molecules important for intercellular adhesion. Here, we present the first data that indicates that human astrocytes are capable of expressing ICAM-1 in response to cytokines that either induce or upregulate the expression of DR. In essence, cytokines derived from different cell types seem to exert similar pleiotropic effects on the modulation of MHC and ICAM-1 expression on astrocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Vasoactive intestinal polypeptide inhibits the expression of the MHC class II antigens on astrocytes.

The brain has been traditionally viewed as an immunologically privileged site. However, recent findings suggest that the brain is in fact equipped with its own immune circuitry. Astrocytes and microglia have been considered the most likely candidates to assume the role of intracerebral antigen presenting cells (APC). Using the techniques of immunofluorescence cytochemistry and flow cytometric analysis, we observed that vasoactive intestinal polypeptide (VIP) can significantly inhibit gamma-interferon (IFN-gamma)-induced Ia expression on astrocytes derived from newborn Lewis rats. Further, we analyzed a number of neuropeptides and transmitters for their ability to exert a similar inhibitory modulation on IFN-gamma induced Ia expression or for the ability to induce or augment Ia expression on rat astrocytes. Our results showed that only norepinephrine (NE), a major brain neurotransmitter, and VIP, a ubiquitous brain peptide, have the ability to inhibit Ia expression on Lewis rat astrocyte cultures. Alternately, we report that cholecystokinin (CCK), a brain/gut peptide, has the ability to induce Ia on about 5-10% of the cells analyzed. These findings suggest that endogenous brain substances have the ability to modulate intracerebral immune responses by regulating the expression of Ia on astrocytes.