Effectiveness of the progestin-only pill for migraine treatment in women: A systematic review and meta-analysis.

Background Migraine is highly prevalent in women (18%). Peak morbidity affects their most productive years, coinciding with peak fertility. Hormonal contraception is often tailored for migraine prevention. Estrogen-containing contraceptives may be contraindicated in women experiencing migraine with aura due to the risk of vascular events. While improvements in migraine with a progestin-only pill (POP), which inhibits ovulation are documented, the strength and quality of evidence has not been formally evaluated. Objectives To determine the effectiveness of progestin-only contraceptives for migraine treatment by systematic review and meta-analysis. Data sources and selection MEDLINE, EMBASE and Cochrane Libraries were searched (1980 to September 2016) for studies on progestin-only treatments for migraine. Studies in English on >4 non-menopausal women aged 18-50 with migraine diagnosed by formal criteria were included. Data extraction and analysis Data were quality-assessed using the GRADE system. A random effects model was used for pooled analyses. Results Pooled analyses of four studies demonstrated that desogestrel 75 mcg/day, POP significantly but modestly reduced the number of migraine attacks and migraine days. Reduced intensity and duration, reduced analgesic and triptan use were observed, along with improved headache-related quality of life. GRADE analysis indicated evidence was low to very low for each outcome measure. Adverse effects resulted in treatment cessation for <10% of participants. Two studies compared desogestrel POP to a combined oral contraceptive, demonstrating similar migraine outcomes for both treatments. Conclusions The desogestrel POP shows promise in improving migraine in women. Current evidence is observational and based on small samples of women using only one oral progestin-only formulation. Further randomized trials on additional progestin-only contraceptives are required to confirm their role in migraine management.

Pain medicine content, teaching and assessment in medical school curricula in Australia and New Zealand.

BACKGROUND: The objective of pain medicine education is to provide medical students with opportunities to develop their knowledge, skills and professional attitudes that will lead to their becoming safe, capable, and compassionate medical practitioners who are able to meet the healthcare needs of persons in pain. This study was undertaken to identify and describe the delivery of pain medicine education at medical schools in Australia and New Zealand. METHOD: All 23 medical schools in Australia and New Zealand in 2016 were included in this study. A structured curriculum audit tool was used to obtain information on pain medicine curricula including content, delivery, teaching and assessment methods. RESULTS: Nineteen medical schools (83%) completed the curriculum audit. Neurophysiology, clinical assessment, analgesia use and multidimensional aspects of pain medicine were covered by most medical schools. Specific learning objectives for pain medicine were not identified by 42% of medical schools. One medical school offered a dedicated pain medicine module delivered over 1 week. Pain medicine teaching was delivered at all schools by a number of different departments throughout the curriculum. Interprofessional learning (IPL) in the context of pain medicine education was not specified by any of the medical schools. The mean time allocated for pain medicine teaching over the entire medical course was just under 20 h. The objective structured clinical examination (OSCE) was used by 32% of schools to assess knowledge and skills in pain medicine. 16% of schools were unsure of whether any assessment of pain medicine education took place. CONCLUSION: This descriptive study provides important baseline information for pain medicine education at medical schools in Australia and New Zealand. Medical schools do not have well-documented or comprehensive pain curricula that are delivered and assessed using pedagogically-sound approaches considering the complexity of the topic, the prevalence and public health burden of pain.

Magnetization Transfer Contrast - Is it Sensitive Enough to Differentiate Demyelination from Axonal Loss?

Background and Objective: Magnetization transfer contrast imaging (MTC) exploits the principle of exchange of energy between the bound and free protons and was shown to be pathologically informative. There is, however, controversy as to whether it correlates with axonal loss (AL), demyelination (DM), or both. This study addresses the pathophysiological process that underlies the white matter injury using the metric derivative of MTC, magnetization transfer ratio (MTR), and defines the role of MTR in identifying the different stages of inflammation, that is, edema, DM, and AL, using optic nerve as the model. Materials and Methods: One hundred and forty-two patients with a single, unilateral episode of optic neuritis (ON) were included in the study. Patients were divided into three groups - those with AL, those with DM, and those who were clinically optic neurites but without any electrophysiological changes suggestive of either AL or DM. MTR and electrophysiological studies were performed in the post-acute stage of ON and the results were compared to those obtained from the unaffected optic nerve. Results: MTR was significantly reduced in the optic nerves of both DM and AL groups when compared to that in normal optic nerves (P < 0.001). The difference in MTR between the AL and DM groups did not reach statistical significance. Patient group with acute ON did not show any change in the MTR values compared to the normal controls. Conclusions: MTR is a sensitive technique to identify neuronal injury, whether it is DM or AL. It, however, cannot differentiate these two pathological processes. MTR is not sensitive to identify acute ON.

Remyelination of optic nerve lesions: spatial and temporal factors.

Optic neuritis provides an in vivo model to study demyelination. The effects of myelin loss and recovery can be measured by the latency of the multifocal visual evoked potentials. We investigated whether the extent of initial inflammatory demyelination in optic neuritis correlates with the remyelinating capacity of the optic nerve. Forty subjects with acute unilateral optic neuritis and good visual recovery underwent multifocal visual evoked potentials testing at 1, 3, 6 and 12 months. Average latency changes were analyzed. Extensive latency delay at baseline significantly improved over time with rate of recovery slowed down after 6 months. Magnitude of latency recovery was independent of initial latency delay. Latency recovery ranged from 7 to 17 ms across the whole patient cohort (average = 11.3 (3.1) ms) despite the fact that in a number of cases the baseline latency delay was more than 35-40 ms. Optic nerve lesions tend to remyelinate at a particular rate irrespective of the size of the initial demyelinated zone with smaller lesions accomplishing recovery more completely. The extent of the initial inflammatory demyelination is probably the single most important factor determining completeness of remyelination. The time period favorable to remyelination is likely to be within the first 6 months after the attack.

Axonal loss and myelin in early ON loss in postacute optic neuritis.

OBJECTIVE: To investigate the relation between retinal nerve fiber layer (RNFL) thickness and latency and amplitude of multifocal visual-evoked potentials (mfVEPs) in the postacute stage of optic neuritis in patients with early or possible multiple sclerosis. METHOD: Thirty-two patients with clinical diagnosis of unilateral optic neuritis and magnetic resonance imaging lesions typical of demyelination and 25 control subjects underwent mfVEP and optical coherence tomography imaging. RESULTS: Although there was significant reduction of RNFL thickness in the affected eyes (18.7%), a considerably larger decrease was observed for the amplitude of the mfVEPs (39.8%). Latency of the mfVEPs was also significantly delayed in optic neuritis eyes. In fellow eyes, the amplitude of mfVEPs was significantly reduced and the latency prolonged, but RNFL thickness remained unaltered. RNFL thickness correlated highly with the mfVEP amplitude (r = 0.90). There was also strong correlation between optical coherence tomography measure of axonal loss and mfVEP latency (r = -0.66). INTERPRETATION: Although our findings demonstrate strong associations between structural and functional measures of optic nerve integrity, the functional loss was more marked. This fact, together with amplitude and latency changes of the mfVEPs observed in clinically normal fellow eyes, may indicate greater sensitivity of mfVEPs in detecting optic nerve abnormality or the presence of widespread inflammation in the central nervous system, or both. The significant correlation of the mfVEP latency with RNFL thickness suggests a role for demyelination in promoting axonal loss.

Systematic Review of Pain Medicine Content, Teaching, and Assessment in Medical School Curricula Internationally.

INTRODUCTION: Pain management is a major health care challenge in terms of the significant prevalence of pain and the negative consequences of poor management. Consequently, there have been international calls to improve pain medicine education for medical students. This systematic review examines the literature on pain medicine education at medical schools internationally, with a particular interest in studies that make reference to: a defined pain medicine curriculum, specific pain medicine learning objectives, dedicated pain education modules, core pain topics, medical specialties that teach pain medicine, elective study opportunities, hours allocated to teaching pain medicine during the curriculum, the status of pain medicine in the curriculum (compulsory or optional), as well as teaching, learning, and assessment methods. METHODS: A systematic review was undertaken of relevant studies on pain medicine education for medical students published between January 1987 and May 2018 using PubMed, Medline, Excerpta Medica database (EMBASE), Education Resources Information Center (ERIC), and Google Scholar, and Best Evidence Medical Education (BEME) data bases. RESULTS: Fourteen studies met the inclusion criteria. Evaluation of pain medicine curricula has been undertaken at 383 medical schools in Australia, New Zealand, the United States of America (USA), Canada, the United Kingdom (UK), and Europe. Pain medicine was mostly incorporated into medical courses such as anaesthesia or pharmacology, rather than presented as a dedicated pain medicine module. Ninety-six percent of medical schools in the UK and USA, and nearly 80% of medical schools in Europe had no compulsory dedicated teaching in pain medicine. On average, the median number of hours of pain content in the entire curriculum was 20 in Canada (2009), 20 in Australia and New Zealand (2018), 13 in the UK (2011), 12 in Europe (2012/2013), and 11 in the USA (2009). Neurophysiology and pharmacology pain topics were given priority by medical schools in all countries. Lectures, seminars, and case-based instruction were the teaching methods most commonly employed. When it was undertaken, medical schools mostly assessed student competency in pain medicine using written examinations rather than clinical assessments. CONCLUSIONS: This systematic review has revealed that pain medicine education at medical schools internationally does not adequately respond to societal needs in terms of the prevalence and public health impact of inadequately managed pain.

Electrophysiological evidence for heterogeneity of lesions in optic neuritis.

PURPOSE: To examine the natural history of multifocal visual evoked potentials (mfVEPs) within 12 months of the first episode of optic neuritis (ON) in patients with possible multiple sclerosis (MS). METHODS: Twenty-seven patients with a first episode of ON, no previous demyelinating events, and MRI lesions consistent with demyelination were examined with mfVEP. Changes in amplitude and latency of mfVEP were analyzed at 1, 3, 6, and 12 months after an acute attack. RESULTS: Five of 27 patients had persistent loss of amplitude after 12 months of follow-up. This loss was most marked centrally. Amplitude recovered in the remaining 22 patients at 1 month, but delayed latency, which was also most marked centrally, persisted. Of these, two distinct subgroups were identified: six patients with no improvement in latency and 16 patients with significant latency recovery over the 12 months of follow-up, suggesting remyelination. Conversion to MS was highest in the group with severe amplitude loss, followed by the group with no latency recovery. The conversion rate was lowest in the group of patients with latency improvement. CONCLUSIONS: Distinct patterns of disease evolution were identified using mfVEP in patients with first episode of optic neuritis and at high risk for MS, supporting the concept of heterogeneity of early lesions in MS.

Multifocal visual evoked potential latency analysis: predicting progression to multiple sclerosis.

OBJECTIVE: To monitor the difference in conversion rates to multiple sclerosis (MS) in 46 patients with optic neuritis between patients with multifocal visual evoked potential latency delay and those with normal latency. DESIGN: Prospective case series. SETTING: Metropolitan neuro-ophthalmology clinic. PARTICIPANTS: Forty-six patients with optic neuritis who did not have a diagnosis of MS on enrollment in the study. MAIN OUTCOME MEASURES: Conversion to MS according to the McDonald criteria. RESULTS: Analysis revealed that only 22 subjects had multifocal visual evoked potential latency delay. Over 1 year, 36.4% of patients with optic neuritis with latency delays progressed clinically to MS compared with 0% of those with normal latencies (P = .03, chi2). CONCLUSION: This may indicate that multifocal visual evoked potential latency delay can assist in predicting progression to future MS.

Multifocal visual evoked potential analysis of inflammatory or demyelinating optic neuritis.

OBJECTIVE: To determine the sensitivity of multifocal visual evoked potentials (mVEP) in optic neuritis of an inflammatory or demyelinating nature. DESIGN: Cross-sectional study. PARTICIPANTS: Sixty-four patients participated who had a confirmed diagnosis of optic neuritis (ON) (past and acute). Based on the McDonald multiple sclerosis (MS) criteria, 25 patients (27 eyes with ON) were deemed to have isolated optic neuritis and thus not have MS (i.e., the not-MS group), and 19 patients (24 eyes with ON) had a diagnosis of MS (i.e., the MS group). The remaining 20 patients (25 eyes with ON) were at a high risk of MS, but diagnostic evaluation was equivocal, and thus were classified as the possible MS group. A control group of 20 normal patients was enrolled. TESTING: The mVEP test was performed using the Accumap. All ON patients had recent magnetic resonance imaging scans of the brain and spinal cord. MAIN OUTCOME MEASURES: Multifocal visual evoked potentials amplitude and latency values were analyzed within each group and were compared with the normal controls. RESULTS: No abnormality was recorded on mVEP in the control group. Of all the ON eyes, 74 (97.3%) were abnormal on mVEP testing. Amplitude values were abnormal in 92.6% of not-MS eyes, 92.0% of possible MS eyes, and 100% of those with MS, and latency was abnormal in 33.3%, 76.0%, and 100%, respectively. There was a significant difference in the mVEP latency z-scores among all ON groups (P<0.01; Kruskal-Wallis test). Although distribution graphs of latency z-scores in the not-MS and MS groups had single peaks and were clearly separate from each other, the latency z-score distribution within the possible MS group in postacute patients was bimodal, with each peak corresponding to the distribution of the not-MS and MS group, respectively. The mVEP latency z-scores had a sensitivity and specificity of 100% in detecting patients with ON due to MS when compared with normal patients. CONCLUSIONS: The mVEP test is a sensitive and specific tool for detecting optic neuritis. There was a significant difference in latency analysis findings between patient groups as classified according to the McDonald MS criteria. Latency results suggest a role in identifying a patient's risk for future MS.

Progressive Loss of Retinal Ganglion Cells and Axons in Nonoptic Neuritis Eyes in Multiple Sclerosis: A Longitudinal Optical Coherence Tomography Study.

PURPOSE: To examine the rate of retinal ganglion cell (RGC) layer and retinal nerve fiber layer (RNFL) changes in nonoptic neuritis (NON) eyes of relapsing remitting multiple sclerosis (RRMS) patients, and to find a specific imaging parameter useful for identifying disease progression. METHODS: Forty-five consecutive RRMS patients and 20 age- and sex-matched healthy subjects were enrolled. All patients were followed up for 3 years with annual optical coherence tomography (OCT) scans, which included a peripapillary ring scan protocol for RNFL analysis and a macular radial star-like scan to obtain RGC/inner plexiform layer (IPL) thickness measures. Healthy controls were scanned twice, 3 years apart. RESULTS: Retinal ganglion cell/inner plexiform layer and temporal RNFL (tRNFL) demonstrated highly significant thinning (P < 0.01), but all nasal segments and global RNFL (gRNFL) were not significantly different from normal controls. While receiver operating characteristics (ROC) analysis showed no advantage of RGC/IPL over tRNFL in cross-sectional detection of thinning, cut-off point based of fifth percentile in healthy controls demonstrated higher rate of abnormality for RGC/IPL. There was a significant progressive loss of RGC/IPL and tRNFL during the follow-up period. The largest thickness reduction was observed in tRNFL. ROC analysis demonstrated that tRNFL provided better sensitivity/specificity for detecting change over time than RGC/IPL (area under the curve [AUC] 0.78 vs. 0.52), which was confirmed by higher detection rate when 95th percentile of progression in healthy controls was used as a cut-off. CONCLUSIONS: This study confirmed significant thinning of RGC/IPL and tRNFL in NON eyes of RRMS patients. Progressive losses were more apparent on tRNFL, while RGC/IPL showed less change over the follow-up period.

Multifocal VEP assessment of optic neuritis evolution.

OBJECTIVE: To evaluate multifocal visual evoked potentials (mfVEP) changes in optic neuritis (ON) and fellow eyes during first year after the attack. METHODS: Eighty-seven patients and twenty-five controls were examined. Patients were classified as multiple sclerosis (MS) group, high risk (HR) or low risk (LR) groups for conversion to MS. mfVEP recordings and retinal nerve fiber layer (RNFL) thickness were analyzed. RESULTS: Recovery of amplitude and shortening of latency was fastest within the first 3months. The largest amplitude reduction and longest latency delay of the ON eye were recorded in the MS group. This was accompanied by deterioration of both parameters in fellow eyes (p<0.03). mfVEP remained stable in fellow eyes of the LR group. Inter-eye asymmetry showed similar amount of amplitude reduction and latency delay in all three groups. RNFL thickness strongly correlated with mfVEP amplitude as early as 3 months after ON (R(2)=0.6, p=0.001). CONCLUSION: mfVEP amplitude is an early predictor of post-ON axonal loss. The apparent more severe involvement of ON eyes in the MS subgroup may be due to subclinical inflammation along the visual pathway. SIGNIFICANCE: Severity of amplitude reduction and latency delay after episode of ON is not MS-related. Retro-chiasmal demyelination is a possible factor contributing to amplitude and latency differences between MS and non-MS patients.

Decoding diffusivity in multiple sclerosis: analysis of optic radiation lesional and non-lesional white matter.

OBJECTIVES: Diffusion tensor imaging (DTI) has been suggested as a new promising tool in MS that may provide greater pathological specificity than conventional MRI, helping, therefore, to elucidate disease pathogenesis and monitor therapeutic efficacy. However, the pathological substrates that underpin alterations in brain tissue diffusivity are not yet fully delineated. Tract-specific DTI analysis has previously been proposed in an attempt to alleviate this problem. Here, we extended this approach by segmenting a single tract into areas bound by seemingly similar pathological processes, which may better delineate the potential association between DTI metrics and underlying tissue damage. METHOD: Several compartments were segmented in optic radiation (OR) of 50 relapsing-remitting MS patients including T2 lesions, proximal and distal parts of fibers transected by lesion and fibers with no discernable pathology throughout the entire length of the OR. RESULTS: Asymmetry analysis between lesional and non-lesional fibers demonstrated a marked increase in Radial Diffusivity (RD), which was topographically limited to focal T2 lesions and potentially relates to the lesional myelin loss. A relative elevation of Axial Diffusivity (AD) in the distal part of the lesional fibers was observed in a distribution consistent with Wallerian degeneration, while diffusivity in the proximal portion of transected axons remained normal. A moderate, but significant elevation of RD in OR non-lesional fibers was strongly associated with the global (but not local) T2 lesion burden and is probably related to microscopic demyelination undetected by conventional MRI. CONCLUSION: This study highlights the utility of the compartmentalization approach in elucidating the pathological substrates of diffusivity and demonstrates the presence of tissue-specific patterns of altered diffusivity in MS, providing further evidence that DTI is a sensitive marker of tissue damage in both lesions and NAWM. Our results suggest that, at least within the OR, parallel and perpendicular diffusivities are affected by tissue restructuring related to distinct pathological processes.

Latency of multifocal visual evoked potentials in nonoptic neuritis eyes of multiple sclerosis patients associated with optic radiation lesions.

PURPOSE: The aim of the study was to test the hypothesis that latency delay of multifocal visual evoked potentials (mfVEP) in nonoptic neuritis (NON) eyes of multiple sclerosis (MS) patients is related to retrochiasmal demyelinating lesions. METHODS: A total of 57 MS patients with no history of optic neuritis at least in one eye, and 25 age- and sex-matched healthy controls was enrolled. Probabilistic tractography was used to reconstruct optic radiation (OR) fibers. The MS lesion volume within and outside of OR was calculated. Diffusion tensor imaging (DTI) indices were measured along OR fibers. The relationship of the mfVEP latency with OR lesions and DTI indices was examined. RESULTS: Average mfVEP latency in the MS cohort was significantly delayed compared to controls (P < 0.0001). Of the patients, 77% demonstrated OR lesions. Axial, radial, and mean diffusivity were significantly abnormal in MS patients (P < 0.001). Partial correlation demonstrated significant association between mfVEP latency delay and OR lesion load. There was also significant correlation between MfVEP latency and OR DTI. Subgroup analysis revealed significantly higher correlations in patients without a history of ON in either eye compared to the fellow eye of patients with previous ON. CONCLUSIONS: The findings of this study support our hypothesis that latency delay of the mfVEP in eyes of MS patients without previous ON is related to retrogenicular demyelinating lesions. Additionally, this study demonstrated that a previous episode of ON in the fellow eye may be a significant confounding factor, masking the relationship between the latency and OR lesions.

Relationship between optical coherence tomography and electrophysiology of the visual pathway in non-optic neuritis eyes of multiple sclerosis patients.

PURPOSE: Loss of retinal ganglion cells in in non-optic neuritis eyes of Multiple Sclerosis patients (MS-NON) has recently been demonstrated. However, the pathological basis of this loss at present is not clear. Therefore, the aim of the current study was to investigate associations of clinical (high and low contrast visual acuity) and electrophysiological (electroretinogram and multifocal Visual Evoked Potentials) measures of the visual pathway with neuronal and axonal loss of RGC in order to better understand the nature of this loss. METHODS: Sixty-two patients with relapsing remitting multiple sclerosis with no previous history of optic neuritis in at least one eye were enrolled. All patients underwent a detailed ophthalmological examination in addition to low contrast visual acuity, Optical Coherence Tomography, full field electroretinogram (ERG) and multifocal visual evoked potentials (mfVEP). RESULTS: There was significant reduction of ganglion cell layer thickness, and total and temporal retinal nerve fibre layer (RNFL) thickness (p<0.0001, 0.002 and 0.0002 respectively). Multifocal VEP also demonstrated significant amplitude reduction and latency delay (p<0.0001 for both). Ganglion cell layer thickness, total and temporal RNFL thickness inversely correlated with mfVEP latency (r = -0.48, p<0.0001 respectively; r = -0.53, p<0.0001 and r = -0.59, p<0.0001 respectively). Ganglion cell layer thickness, total and temporal RNFL thickness also inversely correlated with the photopic b-wave latency (r = -0.35, p = 0.01; r = -0.33, p = 0.025; r = -0.36, p = 0.008 respectively). Multivariate linear regression model demonstrated that while both factors were significantly associated with RGC axonal and neuronal loss, the estimated predictive power of the posterior visual pathway damage was considerably larger compare to retinal dysfunction. CONCLUSION: The results of our study demonstrated significant association of RGC axonal and neuronal loss in NON-eyes of MS patients with both retinal dysfunction and post-chiasmal damage of the visual pathway.

Axonal loss of retinal neurons in multiple sclerosis associated with optic radiation lesions.

OBJECTIVE: To investigate the potential links between thinning of retinal ganglion cell axons in eyes of patients with multiple sclerosis (MS) without past optic neuritis (ON) and MS-related inflammatory damage of the posterior visual pathway. METHODS: Temporal retinal nerve fiber layer (tRNFL) thickness was analyzed in eyes with no history of ON (NON) from 53 patients with relapsing-remitting MS. Fifty normal age- and sex-matched controls were examined with optical coherence tomography. Low-contrast visual acuity charts were used for functional assessment of vision. The optic tract (OT) and optic radiation (OR) were identified using probabilistic tractography, and volume of T2 fluid-attenuated inversion recovery lesions and diffusion tensor imaging (DTI) indices were measured within both structures. Cross-sectional diameter of the OT was also calculated. RESULTS: tRNFL thickness was significantly reduced in NON eyes and was associated with reduced low-contrast visual acuity. Lesions within the OR were detected in the majority of patients. There was a significant correlation between thinning of the tRNFL and OR lesion volume (adjusted for non-OR lesion volume, age, sex, and disease duration). tRNFL thickness also correlated with OR DTI indices. No OT lesions were identified in any of the patients and no relationship between retinal nerve fiber layer loss and potential markers of OT lesions was found. CONCLUSION: The results demonstrate a strong tract-specific association between loss of tRNFL fibers and MS-related inflammation within OR.

Vision loss and partial third nerve palsy following contralateral peribulbar anesthesia.

We report the case of a 72-year-old woman who experienced transient complete visual loss and a partial third nerve palsy in 1 eye following cataract surgery under local anesthesia in the fellow eye. Symptoms and signs were determined to result from the administration of a peribulbar block, which was presumably associated with ipsilateral transoptic nerve sheath spread. We believe this is the first report of contralateral amaurosis and oculomotor nerve palsy following peribulbar anesthesia.

Inner nuclear layer thickening is inversley proportional to retinal ganglion cell loss in optic neuritis.

AIM: To examine the relationship between retinal ganglion cell loss and changes in the inner nuclear layer (INL) in optic neuritis (ON). METHODS: 36 multiple sclerosis (MS) patients with a history of ON and 36 age and sex-matched controls underwent Optical Coherence Tomography. The paramacular retinal nerve fiber layer (RNFL), combined ganglion cell and inner plexiform layers (GCL/IPL) and inner nuclear layer (INL) thickness were measured at 36 points around the fovea. To remove inter-subject variability, the difference in thickness of each layer between the ON and fellow eye of each patient was calculated. A topographic analysis was conducted. RESULTS: The INL of the ON patients was thicker than the controls (42.9µm versus 39.6µm, p=0.002). ON patients also had a thinner RNFL (27.8µm versus 32.2µm, p<0.001) and GCL/IPL (69.3µm versus 98.1µm, p<0.001). Among the controls, there was no correlation between RNFL and GCL/IPL as well as RNFL and INL, but a positive correlation was seen between GCL/IPL and INL (r=0.65, p<0.001). In the ON group, there was a positive correlation between RNFL and GCL/IPL (r=0.80, p<0.001) but a negative correlation between RNFL and INL (r=-0.61, p<0.001) as well as GCL/IPL and INL (r=-0.44, p=0.007). The negative correlation between GCL/IPL and INL strengthened in the ON group when inter-subject variability was removed (r=-0.75, p<0.001). Microcysts within the INL were present in 5 ON patients, mainly in the superior and infero-nasal paramacular regions. While patients with microcysts lay at the far end of the correlation curve between GCL/IPL and INL (i.e. larger INL and smaller GCL/IPL compared to other patients), their exclusion did not affect the correlation (r= -0.76, p<0.001). CONCLUSIONS: INL enlargement in MS-related ON is associated with the severity of GCL loss. This is a continuous relationship and patients with INL microcysts may represent the extreme end of the scale.

Axonal loss in non-optic neuritis eyes of patients with multiple sclerosis linked to delayed visual evoked potential.

OBJECTIVE: Recent studies demonstrate significant thinning of the retinal nerve fiber layer (RNFL) in multiple sclerosis (MS) non-optic neuritis (MS-NON) eyes. However, the pathologic basis of this reduction is not clear. The aim of the current study was to investigate the relationship of the RNFL thickness in MS-NON eyes with latency delay of the multifocal visual evoked potential (mfVEP), a surrogate marker of the visual pathway demyelination. METHODS: Total and temporal RNFL thickness and latency of the mfVEP in 45 MS-NON eyes of 45 patients with relapsing-remitting MS and 25 eyes of age- and gender-matched controls were measured and analyzed. RESULTS: There was significant reduction of total and temporal RNFL thickness (p = 0.015 and p = 0.006, respectively) and significant latency delay (p < 0.0001) in MS-NON eyes. Both total and temporal RNFL thickness were associated with latency of the mfVEP (r2 = 0.43, p < 0.0001 and r2 = 0.36, p = 0.001, respectively). MS-NON eyes with normal latency (n = 26) showed no significant reduction of RNFL thickness compared with controls (p = 0.44 and p = 0.1 for total and temporal RNFL, respectively), whereas eyes with delayed latency (n = 19) demonstrated significantly thinner RNFL (p = 0.001 and p = 0.0005). MS-NON eyes with delayed latency also had significantly thinner RNFL compared with those with normal latencies (p = 0.013 and p = 0.02). In patients with no previous optic neuritis in either eye, delayed latency and reduced RNFL were bilateral whenever present. CONCLUSIONS: The study demonstrated significant association between RNFL loss and a latency delay of the mfVEP in MS-NON eyes.