Neuromyelitis optica spectrum disorders and anti-myelin oligodendrocyte glycoprotein positive optic neuropathies.

The endoscopic transorbital approach (ETOA) provides minimally invasive access to the skull base, but its orbital trajectory raises concern for subclinical optic nerve or retinal injury. We assessed the structural safety of ETOA using high-resolution optical coherence tomography as an objective neuro-ophthalmic tool, focused mainly on patients without orbital involvement. From 41 consecutive ETOA cases (2017-2024), 16 patients had analyzable baseline and approximately 12-month postoperative imaging and were included: a Group A without orbital involvement (n = 10) and a Group B with orbital or optic nerve involvement but interpretable scans (n = 6). Macular ganglion cell layer (GCL) and peripapillary retinal nerve fiber layer (RNFL) thickness were measured with spectral-domain optical coherence tomography. Paired analyses were prespecified for the Group A; the Group B was summarized descriptively. The contralateral eye served as an internal control. Across all 16 patients, no structural or functional deterioration attributable to surgery was observed. In the Group A, GCL thickness in the operated eye decreased slightly from 81.0 µm to 80.5 µm (mean change -0.5 µm), as well as in the contralateral eye used as control (-0.2 µm). RNFL thickness in the operated eye increased from 96.4 µm to 97.3 µm (mean change +0.9 µm), while the contralateral eye decreased (-1.2 µm). These changes were not statistically significant and remained within physiological variability (±2 µm for GCL; ±3 µm for RNFL). Visual acuity, visual fields, color vision, and pupillary responses were preserved, with no signs of functional impairment. In the Group B, the operated eye showed RNFL thinning (≈-7.7 µm), while GCL remained stable. This was attributed to preexisting optic neuropathy or resolution of preoperative disc edema rather than surgical injury. Importantly, functional outcomes (visual acuity, visual fields, color vision, and pupillary responses) improved or remained stable. ETOA does not induce subclinical retinal or optic nerve injury at late follow-up. The approach demonstrated structural and functional safety, particularly in patients without orbital involvement (Group A), where preservation of visual integrity is imperative. These findings support the neuro-ophthalmic safety of the transorbital corridor and justify larger prospective studies.

Objective: To investigate the consequences of the thickness of ganglion cell layer (GCL) and visual field defect of non-functional pituitary adenoma with chiasm compression. Methods: A case control study. The study included 40 (80 eyes) non-functional pituitary adenoma patients in Peking Union Medical College Hospital from March 2015 to February 2017. Twenty patients (no visual field defect group, 40 eyes) of them were detected to be chiasm compressed or touched by the adenoma with no visual field defect detected, and the other 20 patients (visual field defect group, 40 eyes) were the sex-and-age matched pituitary adenoma patients with bitemporal heminopsia. This study also included 20 (control group, 40 eyes) sex-and-age matched healthy controls. The para-papillary retinal nerve fiber layer (RNFL) thickness in 6 quadrants including nasal, temporal, nasal superior, temporal superior, nasal inferior and temporal inferior as well as the macular GCL thickness and ganglion cell-inner plexiform layer (GCIPL) thickness in 4 quadrants including nasal superior, nasal inferior, temporal superior and temporal inferior were measured. The non-parametric test was used to compare the RNFL, GCL and GCIPL thickness among the three groups. Results: The mean age among the three groups was (46±10) years and the difference among the three groups was not significant (P=0.88). The sex ratio of the three groups was 9∶11 (male∶female) and the difference among the three groups was not significant. The mean axial length among the three groups was (23.22±0.90) mm and the difference among the three groups was not significant (P=0.51). The thickness of para-papillary RNFL of temporal superior, temporal, nasal superior, nasal, nasal inferior quadrants and whole circumference was significantly thinner in the visual field defect group than the control group [(129.88±28.64) μm, (63.63±26.84) μm, (88.08±32.16) μm, (50.68±19.99) μm, (92.48±25.06) μm, and (85.00±20.65) μm vs. (141.10±18.95) μm, (79.12±16.78) μm, (113.68±21.28) μm, (69.67±14.23) μm, (117.80±31.32) μm, and (102.80±9.68) μm, t=2.26, 3.06, 4.14, 4.84, 4.25, 4.88, all P<0.05]. In the nasal quadrant, the para-papillary RNFL of the no visual field defect group was significantly thinner compared with the control group [(61.45±9.83) μm vs. (69.67±14.23) μm, t=2.97, P<0.05]. The total GCL thickness was (30.48±5.42) μm in the visual field defect group, (31.35±2.77) μm in the no visual field defect group, thinner than that in the control group [(33.32±2.92) μm, t=2.92, 3.62; both P<0.05]. The total GCIPL thickness showed no significant difference among the three groups (P=0.07). In the superior and inferior temporal quadrants, the GCL and GCIPL thickness showed no significant difference among the three groups (all P>0.05). In the superior and inferior nasal quadrants, the GCL thickness was (29.41±5.97) μm, and (28.47±5.13) μm in the visual field defect group, (31.15±3.27) μm and (30.61±2.96) μm in the no visual field defect group, and (34.23±3.16) μm and (32.97±2.78) μm in the control group. The GCL thickness in the nasal quadrant was thinner in the visual field defect group (t=4.45, 4.82)and the no visual field defect group(t=4.23, 3.63) than in the control group (all P<0.01). However, no significant difference in GCL thickness was detected between the visual field defect group and the no visual field defect group (both P>0.05). In the superior and inferior nasal quadrants, the GCIPL thickness was (54.06±10.50) μm and (51.77±9.18) μm in the visual field defect group, (58.03±4.00) μm and (56.23±5.37) μm in the no visual field defect group, and (62.26±7.11) μm and (59.39±6.64) μm in the control group. The GCIPL thickness was thinner in the nasal quadrant in the visual field defect group than in the control group (t=3.95, 4.20, both P<0.01). Only in the Superior nasal quadrant, the GCIPL was significantly thinner in the no visual field defect group than the control group (t=3.25, P<0.01). Conclusion: The optic GCL may get thinner in pituitary nonfunctional adenoma with chiasm compression patients without the RNFL layer thinning and visual field defect. (Chin J Ophthalmol, 2019, 55: 186-194).

To investigate the incidence and cause of severe visual loss following use and removal of intraocular silicone oil (SiO) after uncomplicated vitrectomy and SiO injection for primary rhegmatogenous retinal detachment (RRD). Consecutive case series of 216 patients operated with vitrectomy for primary RRD in 2004-2005. In 162 eyes, SiO (5500 centiStoke) had been used as intravitreal tamponade and in 54 eyes gas (perflouropropane, C(3) F(8) ) had been used. Following chart review, we identified 16 eyes in 16 patients (nine SiO eyes, seven gas eyes) with macula-on and documented visual acuity ≥6/12 before surgery, where SiO had been removed, cataract surgery performed and no re-detachment had occurred. Examinations included best-corrected visual acuity (BCVA) and high-definition optical coherence tomography (OCT) of the macular area. Preoperative characteristics were identical between SiO and gas eyes. Postoperative BCVA was significantly worse in SiO eyes (>6/24) compared to gas eyes (>6/7.5), p = 0.005. Three of 9 (33%) SiO eyes had final BCVA ≤6/60 and 67% had final BCVA ≤6/12. No gas eyes had final BCVA <6/9. Macular OCT revealed thinning of inner retinal layers in SiO-operated eyes (5148 pixels) compared to gas-operated eyes (6897 pixels), p < 0.002. No other visually significant structural differences were found. Severe visual loss after SiO use was observed in 1/3 of patients with otherwise good visual potential. The visual loss was associated with a significant reduction in inner retinal thickness indicating neuronal cell loss in the macular area as a possible explanation.

We evaluated the relationship of optical coherence tomography (OCT)-measured ganglion cell layer (GCL) and retinal nerve fiber layer (RNFL) thickness to other functional measures of afferent visual pathway competence including high-contrast visual acuity (HCVA) and low-contrast visual acuity (LCVA), visual field sensitivity, and color vision perception in a pediatric population with demyelinating disorders. This was a cross-sectional evaluation of 37 children, aged 8-18 years, with pediatric demyelinating disorders (n = 74 eyes), and 18 healthy controls (n = 36 eyes), who were recruited from the University of Toronto, Hospital for Sick Children and the University of Calgary, Alberta Children's Hospital, Canada. A standardized visual battery, including spectral-domain OCT, visual fields, LCVA, and HCVA, was performed in all subjects. Mean RNFL thickness was 26 µm (25.6%) lower in patients with demyelination (76.2 μm [3.7]) compared to controls (102.4 μm [2.1]) (p < 0.0001). Mean GCL thickness was 20% lower in patients as compared to controls (p < 0.0001). Mean GCL and RNFL thickness were strongly correlated (r = 0.89; p < 0.0001), yet in contrast to RNFL thickness, no differences in GCL thickness were noted between optic neuritis (ON) eyes and non-ON eyes of patients. HCVA and LCVA and visual field mean deviation scores decreased linearly with lower RNFL thickness. GCL thickness was decreased in patients regardless of history of ON. The retina may be a site of primary neuronal injury in pediatric demyelination.

Background: Optic neuritis (ON) is an acute and often immune-mediated inflammatory condition of the optic nerve. Vitamin D acts as an anti-inflammatory agent and may confer neuroprotection. Visual evoked potential (VEP) and optical coherence tomography (OCT) are emerging tools for demyelinating diseases. Aims and Objectives: We tried to correlate between Vitamin D insufficiency and acute demyelinating ON using different parameters such as VEP, ganglion cell layer (GCL) thickness, and retinal nerve fiber layer (RNFL) thickness. Materials and Methods: This observational longitudinal analytical study included thirty non-consecutive patients with primary ON and 30 healthy controls. All patients with ON underwent detailed clinical and ophthalmological examination, and detailed blood workup, including serum 25 (OH) Vitamin D. VEP P100 latency, amplitude, OCT, RNFL thickness, and GCL thickness at presentation and after 3 months from May 2019 to November 2020. Results: Vitamin D insufficiency (below 30 ng/mL) was present in 60% of cases of ON. The baseline VEP showed significantly prolonged P100 latency in affected eyes in the Vitamin D insufficient group (mean 129.78±7.97 ms vs. 121.0±4.99 ms) whereas the P100 amplitude was not significantly altered between the two groups (5.5±3.13 μV vs. 7.08±3.01 μV). The baseline RNFL thickness (132.21±10.69 μm vs. 118.01±10.4 μm) and GCL thickness (76.82±2.04 μm vs. 73.06±3.2 μm) were greater in affected eyes of vitamin D insufficiency ON. There was greater RNFL thinning (79.93±3.42 μm vs. 74.80±3.5 μm) and GCL thinning (64.78±1.9μm vs. 69.02±2.22 μm) in affected eyes of ON with Vitamin D insufficiency at 3 months. Conclusion: Vitamin D insufficiency was found in most cases of ON. Insufficient Vitamin D positively correlated with optic nerve affection severity as evidenced by significantly increased baseline thickness of RNFL and GCL and more thinning of RNFL and GCL at the end of 3 months of follow-up.

Purpose: To assess the ability of Posterior Pole new protocol in optical coherence tomography (OCT) to detect areas with significant differences on retinal nerve fibre layer (RNFL) and ganglion cell layer (GCL) thicknesses in patients with multiple sclerosis (MS) versus healthy controls; in addition, to assess the correlation between RNFL and GCL thicknesses, disease duration and the Expanded Disability Status Scale (EDSS).Methods: We analysed 64 eyes of healthy controls and 100 eyes of remitting–relapsing multiple sclerosis (RR‐MS) patients by OCT Posterior Pole protocol. Analysis based on clinically definite time point (CDMS) dividing patients in two subgroups [CDMS‐1 (≤5 years) and CDMS‐2 (≥6 years)].Results: Significant differences in RNFL and GCL were found between RR‐MS group and healthy controls, and also for each CDMS subgroups on both layers. Moderate to strong correlations were found between RNFL and GCL thicknesses and CDSM; furthermore, we observed a strong correlation with EDSS 1 year after OCT exam.Conclusions: Posterior Pole protocol is a useful tool to assess MS; it can reveal differences even in early stages of the disease. RNFL thicknesses demonstrate strong correlation with disability status, while GCL correlates better with time of disease.

BackgroundEvaluation of retinal nerve fibre layer (RNFL), ganglion cell layer (GCL) and choroidal thickness (CT) with optical coherence tomography (OCT) in chronic migraine patients, to compare with healthy controls.Material and MethodNinety‐four eyes of 47 chronic migraine patients (Group 1) and 68 eyes of 34 healthy individuals (Group 2) were included in this prospective case‐control study. The right and left eyes were separately evaluated. Mean peripapillary RNFL thicknesses, mean GCL measured from superior and inferior quadrants, and mean CT were measured at three different regions (central, 500 μm nasal and temporal region of the fovea).ResultsThere was no statistically significant differences in RNFL between the two groups (p > 0.05), while CT values were significantly higher and GCL values were significantly lower in chronic migraine groups (p < 0.05). There were no statistically significant differences between migraine duration, frequency and length of attacks, presence of aura, relation to menstrual cycle, white matter lesions in cranial magnetic resonance imaging and RNFL, GCL and CT (p > 0.05).DiscussionIn this study, we observed chronic migraine disease does not have any effect on peripapillary RNFL thickness; however, increases in CT and decreases in GCL thickness were observed in migraine patients.

Purpose of the study: To assess the ability of the new Spectralis Optical Coherence Tomography (OCT) Posterior Pole protocol to detect degeneration of the inner retinal layers in patients with bipolar disorder (BD) and to assess the correlation between the neuroretinal thickness and disease duration. Materials and Methods Twenty-five eyes of 25 patients with bipolar disorder and 74 eyes of 74 healthy controls underwent retinal measurements of retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL) thickness. Measurements were obtained using the Spectralis-OCT device with the new Posterior Pole protocol which assesses the macular area by analyzing retinal thickness in a grid of 64 (8*8) cells. Results Significant differences (p < 0.05) in RNFL and GCL thickness were found between BD patients and healthy controls, in parafoveal and perifoveal cells respectively. Significant inverse correlations were found between RNFL and GCL thinning at their thickest location and the duration of bipolar disorder. Several predictive variables were observed with a binary logistic regression for the presence/absence of BD: cell 1.3 RNFL (p = 0.028) and GCL in cells 7.8 (p = 0.012), 2.7 (p = 0.043) and 1.3 (p = 0.047). Conclusion Posterior Pole OCT protocol is a useful tool to assess changes in the inner retinal layers in bipolar disorder. These observed changes, especially those affecting the GCL, may be associated with disease evolution and may be predictive of the presence of the disease. OCT data could potentially be a useful tool for clinicians to diagnose and monitor BD patients.

BackgroundMigraine is a prevalent, chronic, and multifactorial neurovascular disease.ObjectivesOur work aimed to investigate if the retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL) thickness are affected in patients with chronic migraine to improve the understanding of the etiology and pathophysiology of migraine.Subjects and methodsA case-control study conducted on 30 patients with chronic migraine and 30 aged and sex-matched healthy controls. Subjects underwent full neurological and ophthalmological history, ophthalmological examination, and measuring RNFL and GCL thickness using the spectral domain-optical coherence tomography (SD-OCT).ResultsRNFL thinning (average, superior, inferior, nasal, and temporal) was significantly more in patients with chronic migraine than healthy control (P = 0.001, 0.022, 0.045, 0.034, and 0.001, respectively). No statistically significant difference was found between chronic migraine patients and healthy controls regarding GCL thickness (average, superior, and inferior) (P value ˃ 0.05).The average RNFL thickness was significantly thinner in migraine with aura (MwA) than migraine without aura (MwoA) (P = 0.006). The average GCL thickness was thinner in MwA than MwoA (P = 0.039). No statistically significant difference was found between the eyes on the side of the headache and the eyes of the contralateral side regarding RNFL and GCL thickness (P value ˃ 0.05). Age at onset, disease duration, headache frequency, and headache intensity showed an insignificant correlation with OCT parameters.ConclusionRetinal changes could be an association with chronic migraine that may be used as a biomarker.

Background Optic neuritis is one of the common clinical neuro-ophthalmic diseases.Spectral-domain OCT (SD-OCT) is a valuable tool in assessing the thickness changes of retina, while enhanced depth imaging (EDI) OCT can further quantitatively and morphologically evaluate the changes of retina and choroid.The pathological mechanism of optic neuritis is unclear now. Objective This study was to quantitatively measure the retinal and choroidal thickness in early optic neuritis eyes by SD-OCT and EDI OCT. Methods A prospective cohort study was carried out in Tianjin Eye Hospital from July 2015 to May 2016.Twenty eyes of 20 patients with acute optic neuritis were enrolled as optic neuritis group and 22 eyes of 20 healthy subjects with matched age and gender were included in the normal control group.The mean thickness of retinal nerve fiber layer (RNFL) and choriod in superior, inferior, nasal and temporal quadrants at 3.4 mm around optic disc was measured, and the mean thickness of RNFL, ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL) and photoreceptor layer also was measured by EDI OCT.Pattern visual evoked potential (P-VEP) and visual field were examined in all the individuals, the correlations of mean defect (MD) with the thickness of RNFL, choroid and the thickness of RNFL, GCL, IPL, INL, OPL, ONL, photoreceptor layer at macular area were evaluated. Results The RNFL thickness values were (424.00±160.30), (428.40±169.83) and (108.15±50.66)μm in superior, inferior, nasal quadrants at 3.4 mm arear around optic disc in the optic neuritis group, which were significantly higher than (265.68±26.25), (283.27±52.81) and (72.68±12.01)μm in the normal control group (t=4.571, 3.814, 3.190, all at P 0.05). The thickness of RNFL, GCL and IPL at 1 mm area around macula and the thickness of GCL, IPL, INL at 3 mm area around macula were evidently thining in the optic neuritis group compared with the normal control group (all at P 0.05), and the thickness of RNFL, GCL, IPL, INL, OPL, ONL, photoreceptor layer at macular area was significantly linear correlated with MD. Conclusions EDI OCT can reflect the RNFL edema around optic disc and thining of various layers of retina at macular area in acuter optic neuritis eyes, however, the choroidal thickess is unchanged.EDI OCT is a useful tool in quantitative evaluation of retinal and choroidal thickness of early optic neuritis. Key words: Optic neuritis; Tomography, optical coherence; Retina; Chorioid; Macula; Optical disc

Impact of Glaucoma Severity on Rates of Neuroretinal Rim, Retinal Nerve Fiber Layer, and Macular Ganglion Cell Layer Thickness Change

To compare retinal layer thickness in HIV-infected subjects with (CI-HIV) and without (NCI-HIV) cognitive impairment, with a control population and to correlate this with the cognitive status of the patient and other clinical parameters. Single-center cross-sectional study. Participants with controlled HIV infection aged between 40 and 70 years and sex-matched and age-matched controls were enrolled. Retinal nerve fiber layer (RNFL), ganglion cell layer (GCL) and inner plexiform layer (IPL) thickness were assessed using optical coherence tomography. These measurements in HIV patients were compared with those in controls. Age-related and sex-related changes were compared in both groups. Other variables studied in HIV patients included: duration of HIV infection, CD4 cell count nadir, antiretroviral therapy regimen and cognitive status using the Montreal Cognitive Assessment (MoCA) test. Sixty-nine individuals, 34 with and 35 without cognitive impairment, and 70 controls were enrolled. GCL was significantly thinner in CI-HIV patients compared with NCI-HIV patients and controls (P = 0.01 and P = 0.02, respectively). GCL and IPL thickness significantly decreased with age in patients with HIV (P = 0.0003, P = 0.02, respectively, for the entire cohort). This change was not seen in controls. MoCA test score significantly decreased with age in HIV patients and controls. GCL thickness positively correlated with cognitive function across the entire HIV cohort (P = 0.02). GCL was thinner in HIV patients with cognitive impairment. GCL thickness correlated positively with cognitive function and negatively with age in HIV patients. GCL thickness may reflect accelerated cognitive aging in HIV.

To evaluate peripapillary vascular flow using optical coherence tomography angiography (angio-OCT) in patients with optic nerve head drusen (ONHD). Angio-OCT allows non-invasive visualization and quantification peripapillary vascular flow. Cross-sectional study. Seventy-six eyes of 40 patients. Between January 2018 and May 2019, consecutive patients with ONHD and healthy controls underwent a complete ocular assessment, including visual acuity testing, biomicroscopy, tonometry, funduscopy, automated perimetry, retinography and autofluorescence, spectral-domain OCT and peripapillary angio-OCT. Peripapillary vascular flow, vascular density, retinal nerve fibre layer (RNFL) and ganglion cell layer (GCL) thicknesses. We included 23 patients with ONHD (42 eyes, 32 with visible drusen; mean age 50.96 years, 12 men) and 17 control patients (34 eyes; mean age 47.12 years, 7 men), without significant differences in age or sex. Vascular flow and density were significantly lower in patients with ONHD (0.409% and 40.18%, respectively) than in normal eyes (0.438% and 43.30%, respectively) (P = .006 and P < .001). RNFL and GCL thicknesses were significantly lower in patients with ONHD (81.81 and 77.43 μm, respectively) than in controls (91.38 and 81.97 μm, respectively) (P = .001 and P = .032). We obtained high correlation indexes between RNFL and GCL and vascular flow and density (RNFL = 0.702 and 0.744, respectively, and GCL = 0.808 and 0.857, respectively). Angio-OCT demonstrated significant reductions in peripapillary vascular flow and vascular density in patients with ONHD, with strong correlations with RNFL and GCL thicknesses.

The aim of this study was to investigate retinal nerve fiber layer (RNFL), ganglion cell layer (GCL) thickness, macular changes (central subfield thickness (CST), cube average thickness (CAT), cube volume (CV) in patients with migraine using spectral-domain optical coherence tomography (OCT) and to assess if there was any correlation with white matter lesions (WML). In this prospective case-control study, RNFL, GCL thickness and macular changes of 19 migraine patients with aura (MA), 41 migraine without aura (MO) and 60 age- and gender-matched healthy subjects were measured using OCT device. OCT measurements were taken at the same time of the day to minimize the effects of diurnal variation. The average, inferior and superior quadrant RNFL thickness were significantly thinner in patients with migraine (p=0.017, p=0.010, p=0.048). There was also a significant difference between patients with and without aura in the mean and superior quadrant RNFL thickness (p=0.02, p=0.043).While there was a significant thinning in CST and CAT in patients with migraine (p=0.020), there were no significant difference in GCL measurements (p=0.184). When the groups were compared to the control group, there were significant differences between MA and the control group regarding average, superior and inferior quadrant RNLF thickness (p<0.001, p=0.025, p<0.001). On the other hand, there were significant differences between MO and the control group regarding average and inferior faces (p=0.037, p=0.04). When OCT measurements were evaluated according to the frequency of attacks, CST and GCL thickness were significantly thinner in patients who had more than four attacks a month (p=0.024, p=0.014). In patients with WML, only CV measurements were significantly thinner than migraine patients without WML (p=0.014). The decreased RNFL, CST, CAT and CV of the migraine patients might be related to the vascular pathology of the disease. Because WML was not correlated with the same measurements except CV, we think that further studies are needed to evaluate the etiopathologic relationship between OCT measurements and WML in migraine patients.

Purpose: To analyse macular ganglion cell layer (GCL) and visual parameters in patients with Fibromyalgia (FM) over 5 years, compared with controls.Methods: Eighty patients with FM and 38 sex‐matched healthy subjects underwent a complete ophthalmic evaluation, including assessment of visual acuity (VA) with ETDRS chart, contrast sensitivity vision (CSV) with Pelli Robson, colour vision with Farnsworth and Lanthony D15 tests and retinal evaluation using Spectral domain Optical coherence tomography (SD‐OCT). Only one eye per subject was randomly selected and included. Patients were classified into three different groups (1, atypical; 2, depressive; 3, biologic) to analyse progression depending on the disease phenotype. All subjects were re‐evaluated after 5 years to quantify changes in visual function parameters, ganglion cell layer (GCL) and retinal nerve fibre layer (RNFL) thickness. Association between progressive ophthalmologic changes and disease severity was analysed.Results: After a period of 5 years of follow up, patients with FM showed progressive changes in visual function parameters and GCL thickness. They presented low contrast VA (p = 0.024) and decreased GCL thickness and the RFNL. Changes in GCL thickness were associated with disease severity. In atypical and biological phenotypes, correlations between disease severity scores and structural changes were observed.Conclusions: In patients with FM has been detected progressive visual dysfunction and neuroretinal degeneration. The evaluation of visual parameters and GCL/RNFL thickness using SD‐OCT could be a non‐invasive and useful tool for monitoring FM progression.