Clinical Features,Retinal Nerve Fiber Layer Thickness And Lamina Cribrosa Morphology Study Of G11778A Leber Hereditary Optic Neuropathy

Object:1.To investigate the clinical features of G11778 A Leber hereditary optic neuropathy(LHON).2.To observe and compare the changes of retinal nerve fiber layer(RNFL)thickness of patients with Leber hereditary optic neuropathy of type G11778 A,type T14484 C and type G3460 A.3.To characterize the peripapillary retinal nerve fiber layer(RNFL)thickness changes in G11778 A LHON patients.4.To analyse the factors associated with visual recovery in LHON patients with disease duration longer than or equal to 6 months.5.To evaluate the differential diagnosis of G11778 A LHON and primary open-angle glaucoma(POAG)by comparing lamina cribrosa thickness(LCT),anterior lamina cribrosa surface depth(ALCSD),and peripapillary retinal nerve fiber layer thickness(RNFL).Methods:1.Clinical data of patients diagnosed with Leber hereditary optic neuropathy(LHON)(type G11778 A,type T14484 C and type G3460A)and primary open-angle glaucoma from July2017 to December 2020 in our hospital were collected.The patients’ medical history and the results of ophthalmologic examinations were analyzed.LHON patients were grouped according to disease durations: subacute phase group(<6 months),dynamic phase group(6-12 months)and chronic phase group(>12 months).G11778 A LHON patients were further grouped according to disease durations(≤3 months,3-6 months,6-9 months,9-12 months,12-24 months,24-60 months,>60 months).2.Patients diagnosed with G11778 A LHON(m.11778G>A/MT-ND4)from July 2017 to December 2020 in our hospital were included in this follow-up study.Patients were grouped according to disease duration when they were included : subacute phase group(<6 months),dynamic phase group(6-12 months)and chronic phase group(>12 months).There were two follow-up exams with an interval of 3±2 months.All relative data were collected.A bivariate logistic regression model was constructed to analyse potential factors associated with visual recovery in LHON patients(disease duration≥6 months),including age,age of onset,temporal retinal nerve fiber-layer thickness and baseline values of best corrected visual acuity(BCVA).Results:1.The clinical features of G11778 A LHON:149 cases(225 eyes)who were diagnosed as G11778 A LHON were collected.The ratio of men to women was 133:16.The mean age of recruited patients was 19.38 ±6.97 years and the mean age of onset was 16.36±5.81 years.9 patients complained of a family history and 140 patients had no clear family history.All patients presented with rapid and painless visual acuity loss in both eyes at the same time or successively without obvious inducement.Fundus examination revealed that optic disc hyperemia and edema or normal appearance was more common in subacute patients(disease duration<6 months)and temporal optic disc paleness or normal appearance was more common in patients with disease duration of 6-12 months.The patients in chronic phase(disease duration>12 months)showed much higher proportion of optic disc atrophy.Visual field examination demonstrated diffuse visual field defects(49.8%),quadrantanopia or hemianopia(17.2%)and central scotoma(10.3%)in G11778 A LHON patients.2.Analysis of retinal nerve fiber layer thickness changes in LHON patients of type G11778 A,type T14484 C and type G3460 A.I.A total of 221 eyes from patients with G11778 A LHON(n=145),22 eyes from patients with T14484 C LHON(n=11),41 eyes from patients with G3460 A LHON(n=22)and 52 eyes from normal controls(n=26)were enrolled.II.In subacute phase,the G3460 A group showed significantly thinner RNFL thickness of nasal quadrant compared with that of T14484 C group(P=0.03).In dynamic phase,the G11778 A group showed significantly thinner RNFL thicknesses of nasal(P<0.01),superior(P<0.01),inferior(P<0.01)quadrant and the 360°average(P<0.01)compared with those of T14484 C group.The G3460 A group showed significantly thinner RNFL thicknesses of nasal(P<0.01)and inferior(P<0.01)quadrant compared with those of T14484 C group.In chronic phase,there was no significant difference in RNFL thicknesses among G11778 A,T14484C,and G3460 A group.III.Within 3 months of onset,the RNFL thickness of the temporal quadrant was significantly thinner than that of the normal control group;whereas those of the remaining quadrants and the average were thicker than those of the normal control group but with no significant difference,except for the nasal quadrant(P = 0.02).For the disease duration of 3-6 months,the RNFL thicknesses of all quadrants and the average were thinner than those of the normal control group,while those of the temporal quadrant(P < 0.01)and the average thickness(P =0.02)showed a significant difference.For the disease duration of 6-9 months,the RNFL thicknesses of the superior,inferior and temporal quadrants,and the average were thinner than those of the normal control group,reaching a significant difference.For the disease durations of 9-12 months,12-24 months,24-60 months and >60 months,the RNFL thicknesses of all quadrants and the average were thinner than those of the normal control group,reaching a significant difference.Compared with 12-24 months group,the RNFL thicknesses of the disease durations of 24-60 months group and > 60 months group were thinner in all quadrants.Besides,the RNFL thickness of the superior quadrant of 24-60 months group was significantly thinner than that of the 12-24 months group(P<0.01).3.The follow-up observations of retinal nerve fiber layer thickness changes in G11778 A LHON:I.By the end of follow-up,56 cases(112 eyes)who were diagnosed as G11778 A LHON and25 healthy controls(50 eyes)were collected and the mean follow-up was 5.25±1.42 months(range,3-8 months).II.When first coming into the hospital,the subacute phase group showed significantly decreasing RNFL thickness of the temporal quadrant compared with the normal control group(P<0.01).The remaining quadrants and the average RNFL thicknesses showed an initial increase but with no significant difference.At the first follow-up visit,all quadrants and the average RNFL thicknesses of subacute phase group decreased relative to baseline,among which the thinning of temporal quadrant(P<0.01),superior quadrant(P=0.03),inferior quadrant(P<0.01)and the average thicknesses(P<0.01)showed significant differences.At the second follow-up visit,all quadrants and the average RNFL thicknesses of subacute phase group decreased relative to the measured value at the first visit,among which the thinning of inferior quadrant(P=0.02),nasal quadrant(P=0.02)and the average thicknesses(P=0.01)showed significant differences.The dynamic phase group showed significantly decreasing RNFL thicknesses compared with control group(P<0.01)except for the thickness of the nasal quadrant(P=1.00)when they were included in our study.During the follow-ups,RNFL thicknesses in all quadrants of dynamic phase group decreased compare with those of the normal control group(P<0.01).The chronic phase group showed significantly decreasing RNFL thicknesses of all quadrants compared with those of the normal control group(P<0.01)when included and there was still a decreasing trend for RNFL during the follow-ups.III.LHON patients of disease duration ≥6 months were divided into two groups according to best corrected visual acuity(BCVA)improvement: BCVA improved group(BCVA improvement ≥0.3 Log MAR)(n=16 Eyes)and non-improved group(BCVA improvement<0.3 Log MAR)(n=70 Eyes).Univariate analysis showed no significant differences in baseline RNFL thicknesses between BCVA improved and non-improved groups.There were no significant differences between baseline and the RNFL thicknesses when BCVA improvement was observed in BCVA improved group.There were no significant differences between the RNFL thickness of BCVA improved group when BCVA improvement was observed and that of non-improved group measured during the second follow-up.IV.Logistic regression revealed that baseline BCVA was correlated with the visual recovery of LHON patients with disease duration≥6 months.4.Comparison of lamina cribrosa morphology and retinal nerve fiber layer thickness in patients with G11778 A LHON and POAG:I.This study included 17 G11778 A LHON patients(30 eyes),31 POAG patients(56 eyes),and 15 normal control individuals(30 eyes).II.There were no significant difference in central lamina cribrosa thickness(CLCT)(P=0.57),paracentral lamina cribrosa thickness(P-CLCT)(P=0.54),mean lamina cribrosa thickness(MLCT)(P=0.55),central anterior lamina cribrosa surface depth(CALCSD)(P=0.44),paracentral anterior lamina cribrosa surface depth(P-CALCSD)(P=0.41)and mean anterior lamina cribrosa surface depth(MALCSD)(P=0.42)between LHON group and normal control group.Compared with normal control group,POAG group showed significantly lower values of CLCT(P<0.01),P-CLCT(P<0.01)and MLCT(P<0.01),as well as significantly higher values of CALCSD(P<0.01),p-CALCSD(P<0.01)and MALCSD(P<0.01).Compared with LHON group,POAG group showed significantly lower values of CLCT(P<0.01),P-CLCT(P<0.01)and MLCT(P<0.01).CALCSD(P<0.01),p-CALCSD(P<0.01)and MALCSD(P<0.01)were significantly higher in POAG group than those of LHON group.III.Both LHON group and POAG group showed significantly thinner retinal nerve fiber layer(RNFL)thicknesses than those of normal control group(P<0.01).Compared with POAG group,LHON group showed significantly thinner RNFL thicknesses(P<0.01).The most severe RNFL thinning occurred in temporal quadrant(from 82.10 μm to 27.63 μm)of patients with LHON,whereas the more severe RNFL thinning occurred in inferior quadrant(from 138.83 μm to 99.43 μm)and superior quadrant(from 132.33 μm to 99.91 μm)of patients with POAG.Conclusions:1.G11778 A LHON mainly occurred among young males.Clinical characteristics included painless vision loss with no obvious incentive,which is consistent with previous studies,and the pattern of fundus examination and visual field changes varied considerably.2.In the disease duration of 6-12 months,G11778 A LHON patients showed significantly thinner nasal,superior,inferior quadrant and the 360° average RNFL than T14484 C LHON patients,suggesting T14484 C LHON patients may progress more slowly than G11778 A LHON patients.3.The pathological process of RNFL thinning occurred in a certain order: temporal quadrant was the first and the most,followed by the inferior and superior quadrants,and the nasal quadrant was the last.Certain patterns of RNFL involvement in patients with LHON could be helpful for differential diagnosis between LHON and other optic neuropathy.In the chronic phase of LHON,there was still a decreasing trend for RNFL,even after 24 months,suggesting that the apoptosis of retinal ganglion cell still continued.4.Baseline best corrected visual acuity(BCVA)was related to the visual recovery of LHON patients(disease duration≥6 months),suggesting that patients with better vision might be more likely to experience some degree of visual acuity recovery after subacute phase.RNFL thickness seemed to show no significant association with improvement in visual acuity.5.There were no obvious abnormal changes in lamina cribrosa morphology of LHON patients.POAG group showed the thinnest lamina cribrosa thickness and the deepest anterior lamina cribrosa surface depth among three groups.There was a thinning of RNFL thickness in both LHON group and POAG group,while LHON group showed the thinner RNFL thickness.The most severe RNFL thinning occurred in temporal quadrant of patients with LHON,whereas the more severe thinning occurred in inferior and superior quadrant of patients with POAG.The comparison of LC morphology and retinal nerve fiber layer thickness could be helpful for differential diagnosis between LHON and POAG.