Shin C. Beh

Extended interval dosing of natalizumab in multiple sclerosis.

Background Natalizumab (NTZ), a monoclonal antibody to human α4β1/β7 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.

Multifocal visual evoked potentials are influenced by variable contrast stimulation in MS

Objective: To test the hypothesis that patients with multiple sclerosis (MS) with intereye asymmetry on low contrast letter acuity, and thickness of the retinal nerve fiber layer (RNFL), would exhibit corresponding changes in cortical timing and amplitude responses on pattern reversal multifocal visual evoked potentials (mfVEP), contingent upon variable stimulus contrast. Methods: In a cross-sectional study, we investigated a cohort of 11 normal subjects and 40 patients with MS, 21 of whom had a history of acute optic neuritis (MS-AON) with an intereye asymmetry with respect to RNFL thickness, and on low contrast letter acuity performance. Pattern reversal mfVEP was performed at high (100%), low (33.3%), and very low (14.2%) Michelson-contrast levels. Results: Compared to baseline measures at 100% contrast, the mean amplitude of the mfVEP was reduced in MS-AON eyes, upon pattern-reversal stimulation at the 2 lower contrast levels (p < 0.0001). With respect to changes in timing responses, the intereye asymmetry was increased in the MS-AON patients upon lower contrast pattern-reversal stimulation (p < 0.0001 for 33.3% compared to 100%, and p < 0.001 for 14.2% compared to 100%). The fellow eye in 12 (57%; p < 0.001) of the patients with an abnormal eye, and a history of AON, revealed abnormal amplitude and timing responses upon low contrast stimulation (signifying unmasking of occult damage). Conclusions: Our findings support the hypothesis that mfVEP metric abnormalities are contingent upon contrast magnitude during pattern reversal stimulation. Further, this paradigm was capable of unmasking occult abnormalities in a significant number of apparently unaffected eyes.

Hiding in plain sight: a closer look at posterior cortical atrophy

Posterior cortical atrophy (PCA) is a neurodegenerative syndrome dominated by deterioration of higher visual function (particularly visuospatial and visuoperceptual abilities). It is most commonly due to Alzheimers disease pathology, but may also be caused by dementia with Lewy bodies, corticobasal degeneration or Creutzfeldt-Jakob disease. Patients often present to optometrists, ophthalmologists and/or neurologists with non-specific visual complaints, and unless clinicians seek the specific symptoms and signs of PCA (beyond that of the ‘standard’ neurological examination), this infrequent disorder is easily missed, delaying its diagnosis and treatment. We review the clinical features of PCA, focusing on its visual manifestations, to help neurologists recognise this important syndrome.

Optic nerve head component responses of the multifocal electroretinogram in MS

Objective: To employ a novel stimulation paradigm in order to elicit multifocal electroretinography (mfERG)–induced optic nerve head component (ONHC) responses, believed to be contingent upon the transformation in electrical transmission properties of retinal ganglion cell axons from membrane to saltatory conduction mechanisms, as they traverse the lamina cribrosa and obtain oligodendrocyte myelin. We further sought to characterize abnormalities in ONHC responses in eyes from patients with multiple sclerosis (MS). Methods: In 10 normal subjects and 7 patients with MS (including eyes with and without a history of acute optic neuritis), we utilized a novel mfERG stimulation paradigm that included interleaved global flashes in order to elicit the ONHC responses from 103 retinal patches of pattern-reversal stimulation. Results: The number of abnormal or absent ONHC responses was significantly increased in MS patient eyes compared to normal subject eyes (p < 0.001, by general estimating equation modeling, and accounting for age and within-subject, intereye correlations). Conclusion: Studying the relationship between ONHC abnormalities and alterations in validated structural and functional measures of the visual system may facilitate the ability to dissect and characterize the pathobiological mechanisms that contribute to tissue damage in MS, and may have utility to detect and monitor neuroprotective or restorative effects of novel therapies.

Aquatic training in MS: neurotherapeutic impact upon quality of life

Three fundamental principals associated with aquatic therapy differentiate it with respect to exercise on land, and in air. These are buoyancy (reduction in weight of the body within the buoyant medium of water), viscosity (a “drag force” is generated when moving within water, when compared with the same movement in air), and the thermodynamic aspect of water exercise, during which the heat capacity of water is about 1000 times greater than that of an equivalent amount of air; equating to a heat transfer from the body into water at a rate 25 times faster than that of air. Aquatic conditioning, can improve neurologic functioning, with dividends favorably impacting activities of daily living, health maintenance, safety, and ultimately quality of life. Here, we review the application of aquatic exercise training in MS patients.

Retinal architecture and mfERG: Optic nerve head component response characteristics in MS

Objective: To describe a novel neurophysiologic signature of the retinal ganglion cell and to elucidate its relationship to abnormalities in validated structural and functional measures of the visual system. Methods: We used multifocal electroretinogram–generated optic nerve head component (ONHC) responses from normal subjects (n = 18), patients with multiple sclerosis (MS) (n = 18), and those with glaucoma (n = 3). We then characterized the relationship between ONHC response abnormalities and performance on low-contrast visual acuity, multifocal visual-evoked potential–induced cortical responses, and average and quadrant retinal nerve fiber layer (RNFL) thicknesses, as measured by spectral-domain optical coherence tomography. Results: Compared with the eyes of normal subjects, the eyes of patients with MS exhibited an increased number of abnormal or absent ONHC responses (p < 0.0001). For every 7-letter reduction in low-contrast letter acuity, there were corresponding 4.6 abnormal ONHC responses at 2.5% contrast (p < 0.0001) and 6.6 abnormalities at the 1.25% contrast level (p < 0.0001). Regarding average RNFL thickness, for each 10-μm thickness reduction, we correspondingly observed 6.8 abnormal ONHC responses (p = 0.0002). The most robust association was between RNFL thinning in the temporal quadrant and ONHC response abnormalities (p < 0.0001). Conclusion: Further characterization of ONHC abnormalities (those that are reversible and irreversible) may contribute to the development of novel neurotherapeutic strategies aimed at achieving neuroprotective, and perhaps even neurorestorative, effects in disorders that target the CNS in general, and MS in particular.

Neuro-ophthalmic Manifestations of Cerebellar Disease

The cerebellum is responsible for refining ocular movements, thereby guaranteeing the best possible visual acuity and clarity despite changes in body or head positions or movement of the object of interest. The cerebellum is involved in the control of all eye movements, in their real-time, immediate modulation, and in their long-term adaptive calibration. The flocculus-paraflocculus complex and the caudal vermis (nodulus and uvula) together constitute the vestibulocerebellum. Lesions affecting these different regions give rise to 3 principal clinical cerebellar syndromes. This article discusses the various neuro-ophthalmic manifestations of various cerebellar disorders, as well as some therapeutic options for oscillopsia.

Damping of monocular pendular nystagmus with vibration in a patient with multiple sclerosis

Acquired pendular nystagmus (PN) occurs commonly in multiple sclerosis (MS) and results in a highly disabling oscillopsia that impairs vision. It usually consists of pseudo-sinusoidal oscillations at a single frequency (3–5 Hz) that often briefly stop for a few hundred milliseconds after saccades and blinks. The oscillations are thought to arise from instability in the gaze-holding networks (“neural integrator”) in the brainstem and cerebellum.1,2 Here we describe a patient with monocular PN in whom vibration on the skull from a handheld muscle massager strikingly diminished or stopped her nystagmus.

Isolated mammillary body involvement on MRI in Wernicke's encephalopathy

A 48-year-old woman, with a remote history of gastric-banding as well as recent-onset post-prandial vomiting and excessive wine-drinking, was admitted with progressively-worsening gait incoordination. She showed gaze-evoked nystagmus and gait ataxia. Brain MRI revealed conspicuous, isolated, symmetrical T2/FLAIR-hyperintensities and gadolinium-enhancement of the mammillary bodies. Serum thiamine and folate were low. Following thiamine and folate replacement therapy, her ataxia resolved. Given the rising number of bariatric procedures, we discuss the importance of recognizing thiamine-deficiency in these patients. Additionally, while isolated involvement of the mammillary bodies is a rare finding in this disorder, we highlight radiologic changes that neurologists should recognize.

Retinal Architecture and Melanopsin-Mediated Pupillary Response Characteristics: A Putative Pathophysiologic Signature for the Retino-Hypothalamic Tract in Multiple Sclerosis.

Importance A neurophysiologic signature of the melanopsin-mediated persistent constriction phase of the pupillary light reflex may represent a surrogate biomarker for the integrity of the retinohypothalamic tract, with potential utility for investigating alterations in homeostatic mechanisms associated with brain disorders and implications for identifying new treatments. Objective To characterize abnormalities of retinal architecture in patients with multiple sclerosis (MS) and corresponding alterations in the melanopsin-mediated sustained pupillary constriction response. Design, Setting, and Participants The case-control study was an experimental assessment of various stimulus-induced pupillary response characteristics and was conducted at a university clinical center for MS from September 6, 2012, to February 2015. Twenty-four patients with MS (48 eyes) and 15 individuals serving as controls (30 eyes) participated. The melanopsin-mediated, sustained pupillary constriction phase response following cessation of a blue light stimulus was compared with the photoreceptor-mediated pupillary constriction phase response following cessation of a red light stimulus. Optical coherence tomography was used to characterize the association between pupillary response characteristics and alterations in retinal architecture, specifically, the thickness of the retinal ganglion cell layer and inner plexiform layer (GCL + IPL). Main Outcomes and Measures Association of pupillary response characteristics with alterations in retinal architecture. Results Of 24 patients with MS included in the analysis, 17 were women (71%); mean (SD) age was 47 (11) years. Compared with eyes from individuals with MS who had normal optical coherence tomography–derived measures of retinal GCL + IPL thickness, eyes of patients who had GCL + IPL thickness reductions to less than the first percentile exhibited a correspondingly significant attenuation of the melanopsin-mediated sustained pupillary response (mean [SD] pupillary diameter ratios at a point in time, 0.18 [0.1] vs 0.33 [0.09]; P < .001, generalized estimating equation models accounting for age and within-patient intereye correlations). Conclusions and Relevance In this case-control study, attenuation of the melanopsin-mediated sustained pupillary constriction response was significantly associated with thinning of the GCL + IPL sector of the retina in the eyes of patients with MS, particularly those with a history of acute optic neuritis. Melanopsin-containing ganglion cells in the retina represent, at least in part, the composition of the retinohypothalamic tract. As such, our findings may signify the ability to elucidate a putative surrogate neurophysiologic signature that correlates with a constellation of homeostatic mechanisms in both health and illness.