The Value Of Corneal Confocal Microscopy In The Diagnosis Of Type 2 Diabetic Peripheral Neuropathy

Background and objective Diabetic peripheral neuropathy(DPN)is one of the most common chronic complications of diabetes,which is regarded as one of the main risk of foot ulcers,gangrene and infection factors.Early detection of DPN,active intervention can improve the quality of life of patients,significantly reduce the incidence of diabetic foot and amputation.However,patients with DPN often have no symptoms in the early stage.When the clinical symptoms are obvious,the nerve damage is quite difficult to reverse.The clinical diagnosis of DPN usually rely on typical symptoms and signs,which have poor diagnostic sensitivity and appear when DPN is obvious.On the other hand,as the symptoms of neuropathy are subjective feelings,patients cannot clearly describe them,and doctors are difficult to record and analyze,so kinds of clinical scales of DPN are used to semi-quantitativly diagnosing and assessing the of severity of DPN,as well as monitoring the effects of therapeutic drug.But many patients are difficult to accurately describe their symptoms,and physical signs got by doctors also influenced by objective factors,so it’ s difficult to assess accurately.Some scales are too cumbersome and time consuming to routinely used in the clinic.Nerve conduction velocity(NCV)is the "gold standard" which is recommended by many guidelines to diagnose DPN.It has the advantages of objective,quantitative,non-invasive and reliable,but the operation is complex and time consuming.NCV mainly detects functions of major myelinated nerve fibers and cannot detect abnormalities of small fiber neuropathy.However,diabetic neuropathy often manifests as small fiber nerve neuropathy in the early stage,so sometimes NCV results could not match the clinical manifestations,which brings confusion for clinical diagnosis,and the "gold standard" status has been questioned.New methods for DPN detection have emerged,but have certain shortages,so there are no recognized diagnostic methods replacing for NCV until now.Recent studies have indicated that corneal confocal microscopy(IVCCM)is a new method for DPN detection,which has great potential for clinical application.The purpose of this study:(1)Compare the diagnostic value of IVCCM with the existing diagnostic methods of DPN,find the optimal diagnostic cutoff of corneal nerve parameters for the diagnosis of DPN.(2)Investigate the relationship between corneal nerve morphology and diabetic microvascular complications;and analyze the influencing factors of corneal nerve parameters.Methods From September 2015 to February 2016,98 patients in hospital with type 2 diabetes mellitus were included in the T2DM group,and 30 healthy subjects were included in the normal control group(NC group).All subjects received detailed consultation about medical history and received physical examination,blood and urine routine test,ophthalmic basic examination,nerve conduction velocity,corneal confocal microscopy.Corneal nerve parameters(corneal nerve fiber density(CNFD),corneal nerve branch density(CNBD),and corneal nerve fiber length(CNFL)were recorded.Patients of T2DM group received physical examination of diabetic peripheral nerve(including ankle reflex,vibration sensation,temperature sensation and acupuncture pain,NDS score was recorded),HbAlc,fundus examination of diabetic retinopathy,8 hours urinary albumin excretion rate(UAER).T2DM group was divided into diabetic peripheral neuropathy group(DPN group)and non-diabetic peripheral neuropathy group(NDPN group);diabetic retinopathy group(DR group)and non-diabetic retinopathy group(NDR group);diabetic nephropathy group(DN group)and non-diabetic nephropathy group(NDN group).Use SPSS 21.0 software for statistical analysis.The correlation analysis was made between corneal nerve parameters with NCV and NDS score.The receiver operating characteristic curve(ROC)was made to evaluate the value of corneal nerve parameters for the diagnosis of DPN.Analyzing the differences of corneal nerve parameters among diabetic microangiopathy subgroup and the influence factors of corneal nerve parameters.Results(1)CNFD,CNBD,CNFL decreased significantly in T2DM group than in the NC group(P =0.000),decreased significantly in DPN group than in NDPN group(P=0.000,0.001,0.000).,decreased significantly in NDPN group than in NC group(P=0.027,0.003,0.001).(2)CNFD,CNBD,CNFL were positively correlated with MCV of median nerve,tibial nerve,sural nerve(r=0.348~0.453,P<0.01),and positively correlated with SCV of all sensory nerve(r=0.203~0.478,P<0.05).CNFD,CNBD,CNFL and NDS scores were significantly related(r=-0.500、-0.369、-0.442,P=0.000).According to the NDS score,the T2DM group was divided into non-DPN(NDS<3),mild DPN(NDS≥3),moderate-severe DPN(NDS≥6).CNFD,CNBD,CNFL had significant differences in the three groups(P<0.05).(3)The ROC AUCs of CNFD,CNBD,CNFL are under 0.7~0.9.Consistency test was made,and CNFL got the highest Kappa value(Kappa=0.582).When set the diagnostic cutoff point as CNFL≤20.6mm/mm2,the diagnostic sensitivity of DPN was 82.4%and the specificity was 85.7%.(4)CNFD,CNBD,CNFL are significantly decreased in the NDR and NDN groups than in the NC group(P<0.001),and get further decreased in DR and DN group(P<0.001).Corneal nerve parameters have no significant difference between NPDR(non-proliferative diabetic retinopathy)and NDR group.CNBD decreased significantly in PDR(proliferative diabetic retinopathy)group than in NPDR group(P=0.03).Corneal nerve parameters were significantly decreased in PDR group than in NDR group(P=0.000,0.001,0.01).CNFD and CNFL were significantly decreased in DN3(diabetic nephropathy stage III)group than in NDN group(P=0.015,0.024).There were no significant difference between DN4(diabetic nephropathy stage IV)and NDN groups.Corneal nerve parameters were significantly decreased in DN4 group than in NDN group(P=0.018,0.049,0.027).(5)CNFD,CNBD,CNFL were negatively related to HbAlc(r=-0.370,-0.302,-0.233,P<0.05).No significant difference between male and female(P>0.05).No significant correlation with age,course of disease,BMI,TC,TG,HDL-c,LDL-c(P>0.05).Conclusions(1)The corneal nerve parameters in the NDPN group were significantly lower than those in the NC group,which suggested that IVCCM could be used for early detection of diabetic peripheral neuropathy.(2)The parameters of corneal nerve showed a significant positive correlation with NCVs of the upper and lower extremities.These parameters also negatively correlated with NDS score.and decreased with the severity of DPN.Changes of corneal nerve were in parallel to the limb peripheral nerves.IVCCM can be used to evaluate the severity of DPN.(3)CNFD,CNFL,CNBD were of value in the diagnosis of DPN in T2DM.CNFL has better consistency with NCV in diagnosis of DPN.CNFL≤20.6mm/mm2 may be the better diagnostic cutoff with higher sensitivity and specificity.(4)Corneal neuropathy is related to the occurrence and development of diabetic retinopathy and diabetic nephropathy,and can reflect the severity of diabetic microvascular complications.In type 2 diabetic patients without diabetic retinopathy or nephropathy corneal nerve lesions have appeared.Corneal nerve parameters further decreased in proliferative diabetic retinopathy or diabetic nephropathy phase III.So IVCCM can contribute to the early diagnosis of diabetic patients at risk of microvascular complications and help taking early interventions to prevent diabetic microvascular complications.(5)Corneal nerve parameters were negatively correlated with HbAlc,which indicates that the blood glucose control has an important role in the occurrence and development of DPN.