Corneal confocal microscopy in patients with distal symmetric polyneuropathy compared to controls

Pupe, Camila; Dieckmann, Gabriela; Dornas, Ricardo; Nascimento, Osvaldo

doi:10.1055/s-0042-1755231

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Original Article • Arq. Neuro-Psiquiatr. 80 (08) • Aug 2022 • https://doi.org/10.1055/s-0042-1755231 copy

Corneal confocal microscopy in patients with distal symmetric polyneuropathy compared to controls

Microscopia confocal de córnea em pacientes com polineuropatia simétrica distal comparados a controles

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Background

Diabetic neuropathy (DN) is a very common clinical condition throughout the world. The diagnostic tests currently recommended have low sensitivity, such as electromyography, or are invasive, such as skin biopsy. New techniques have been developed to identify the early involvement of the peripheral nerve. With the advent of corneal confocal microscopy (CCM), a reduction in corneal innervation in patients with DN has been observed.

Objective

To compare, through CCM, diabetic patients with symptomatic distal symmetric polyneuropathy (DSP) and controls.

Methods

In the present study, through CCM, we compared the morphological changes in the sub-basal epithelial corneal plexus of 35 diabetic patients with symptomatic DSP with 55 controls. Moreover, we sought to determine a pattern of change regarding the severity stages of DSP, comparing the clinical, laboratory, and nerve-conduction (NC) variables.

Results

Differences between the control and diabetic groups were observed for the following variables, respectively: age (44.9 ± 13.24 years versus 57.02 ± 10.4 years; p< 0.001); fiber density (29.7 ± 10.2 versus 16.6 ± 10.2; p< 0.001); number of fibers (4.76 ± 1.30 versus 3.14 ± 1.63; p< 0.001); number of Langerhans cells (4.64 ± 8.05 versus 7.49 ± 10.3; p= 0.035); tortuosity (p< 0.05); and thickness (p< 0.05). Furthermore, inverse relationships were found regarding fiber density and age (p< 0.01) and fiber density and the severity of the disease (p< 0.05). A positive relationship between the conduction velocity of the fibular nerve and fiber density (p< 0.05) was also observed.

Conclusion

Corneal confocal microscopy proved to be a fast, noninvasive and reproducible method for the diagnosis, staging, and monitoring of diabetic DSP.

Keywords
Diabetes Mellitus; Peripheral Nervous System Diseases; Confocal Microscopy

Variables		Diabetics (n= 35)	Controls (n= 55)	p-value
Male sex (%)		25.7%	45.5%
Age (mean ± SD)		57.2 ± 10.4	44.9 ± 13.24	< 0.001¹
Number of fibers (mean ± SD)		3.14 ± 1.63	4.76 ± 1.30	< 0.001²
Fiber density (mean ± SD)		16.6 ± 10.2	29.7 ± 10.2	< 0.001²
Number of Langerhans cells (mean ± SD)		7.49 ± 10.3	4.64 ± 8.05	0.035¹
Tortuosity (%)	Normal	−	3.6%	< 0.05
	Paralell	5.7%	45.5%
	Non-parallel	82.9%	45.5%
	Not in the same direction	11.4%	5.5%
Thickness (%)	Normal	−	3.6%	< 0.05
	Thin	74.3%	29.1%
	Medium	25.7%	63.3%
	Large	−	3.6%
Time since the onset of diabetes (mean ± SD)		9.89 ± 6.87	−	−
Time since the onset of symptoms (mean ± SD)		3.49 ± 2.56	−	−
Metabolic syndrome (yes: %)		65.7%	−	−
Diabetic foot (yes: %)		14.3%	−	−
Macrovascular complication (yes: %)		25.7%	−	−
Microvascular complication (yes: %)		57.1%	−	−
Retinopathy (yes: %)		45.7%	−	−
Nephropathy (yes: %)		37.1%	−	−
Pain (yes: %)		37.1%	−	−
Treatment: insulinotherapy (%)		48.6%	−	−
Glycated hemoglobin (%)		7.54 ± 2.14
Hypertension (yes: %)		85.7%	−	−
Dyslipidemia (yes: %)		45.7%	−	−
BMI Kg/m²(mean ± SD)		29.1 ± 5.49	−	−
Mild or moderate disability (%)		34.3%	−	−
Neuropathy Disability Score	Mild	31.4%	−	−
	Moderate	31.4%	−	−
	Severe	37.1%	−	−

		N	Mean	SD	95%CI		Min.	Max.
Number of fibers	Healthy controls	55	4.76*	1.305	4.41	5.12	2	7
	Diabetics	35	3.14*	1.630	2.58	3.70	0	7
	Total	90	4.13	1.637	3.79	4.48	0	7
Density	Healthy controls	55	29.7*	10.201	27.56	31.97	12.50	43.75
	Diabetics	35	16.6*	10.184	16.14	23.14	0.00	43.75
	Total	90	25.83	10.229	23.69	27.97	0.00	43.75
Langerhans cells	Healthy controls	55	4.64*	8.054	2.46	6.81	0	45
	Diabetics	35	7.49*	10.305	3.95	11.03	0	44
	Total	90	5.74	9.049	3.85	7.64	0	45

Neuropathy
		Mild (n= 11)	Moderate (n= 11)	Severe (n= 13)
Age (years)¹ 1 One-way anaçysis of variance (Tukey).		54.3 ± 13.6	60.7 ± 7.97	53.3 ± 15.0
BMI² 2 Kruskal-Wallis test. (Kg/m² 2 Kruskal-Wallis test. )		30.4 ± 5.9	29.2 ± 5.28	28 ± 2.0
Time since the onset of diabetes (years)¹ 1 One-way anaçysis of variance (Tukey).		4.18 ± 4.2^*§	11.7 ± 5.7^*§	17.3 ± 7.1^*§
Time since the onset of symptoms (years)¹ 1 One-way anaçysis of variance (Tukey).		1.91 ± 14.5^**§	3.30 ± 2.9	6.67 ± 2.9^**§
HbA1C¹ 1 One-way anaçysis of variance (Tukey). (%)		6.27 ± 1.35	7.40 ± 1.57	7.0 ± 1.0
CCM	Numberoffibers² 2 Kruskal-Wallis test.	3.82 ± 1.6	3.20 ± 1.8	3.00 ± 2.0
	Langerhanscells¹ 1 One-way anaçysis of variance (Tukey).	7.0 ± 9.8	10.0 ± 14.1	2.33 ± 4.0
	Density² 2 Kruskal-Wallis test.	23.8 ± 10.0	20 ± 11.3	18.75 ± 12.5
NCS	Sural amplitude uV(d¹ 1 One-way anaçysis of variance (Tukey). /e² 2 Kruskal-Wallis test. )	11.3 ± 4.1^*§/11.64 ± 3.2^§ § p< 0.05.	4.0 ± 1.3^*§/6.5 ± 4.7^§ § p< 0.05.	3.0 ± 1.7^*§/4.0 ± 3.6^§ § p< 0.05.
	Fibular conductionvelocity in m/s(d² 2 Kruskal-Wallis test. /e² 2 Kruskal-Wallis test. )	47.1 ± 4.1^§ § p< 0.05. /46.3 ± 3.1^§ § p< 0.05.	43.9 ± 4.5^§ § p< 0.05. /44.2 ± 4.8^§ § p< 0.05.	41.3 ± 4.9^§ § p< 0.05. /41.6 ± 3.5^§ § p< 0.05.
	Fibular CMAP mV(d² 2 Kruskal-Wallis test. /e¹ 1 One-way anaçysis of variance (Tukey). )	4.45 ± 1.7/4.5 ± 2.0^**§	4.7 ± 1.89/4.1 ± 1.4^**§	5.0 ± 1.7/3.6 ± 0.6^**§

		Clinical and laboratory						CCM		NCS
		Age	TD	TS	BMI	HbA1C	NDS	Dens	LC	ARS	ALS	CVRF	CVLF	RFA	LFA
Clínical and laboratory	Age² 2 Spearman correlation.	1
	TD² 2 Spearman correlation.	0.162	1
	TS² 2 Spearman correlation.	0.101	0.791^ p <0.01.	1
	BMI² 2 Spearman correlation.	-0.158	-0.340^* * p< 0.05.	-0.075	1
	HbA1C² 2 Spearman correlation.	-0.206	0.325	0.167	-0.220	1
	NDS² 2 Spearman correlation.	0.011	0.580^ p <0.01.	0.487^ p <0.01.	-0.113	0.537^ p <0.01.	1
CCM	Dens¹ 1 Pearson correlation.	-0.432^ p <0.01.	-0.085	0.043	0.047	-0.174	-0.405^* * p< 0.05.	1
CCM	LC² 2 Spearman correlation.	0.315	0.042	-0.033	0.183	0.017	-0.038	-.318	1
NCS	ARS² 2 Spearman correlation.	-0.303	-0.677^ p <0.01.	-0.437^* * p< 0.05.	0.023	-0.316	-0.863^ p <0.01.	.200	-.086	1
	ALS¹ 1 Pearson correlation.	-0.293	-0.538^ p <0.01.	-0.247	0.173	-0.145	-0.581^ p <0.01.	.074	.084	.567^ p <0.01.	1
	CVRF¹ 1 Pearson correlation.	-0.305	-0.437^* * p< 0.05.	-0.261	0.057	-0.278	-0.637^ p <0.01.	0.386^* * p< 0.05.	0.139	0.584^ p <0.01.	0.485^* * p< 0.05.	1
	CVLF¹ 1 Pearson correlation.	-0.366^* * p< 0.05.	-0.260	-0.262	-0.137	-0.309	-0.632^ p <0.01.	0.446^* * p< 0.05.	-0.153	0.556^ p <0.01.	0.424^* * p< 0.05.	0.860^ p <0.01.	1
	RFA¹ 1 Pearson correlation.	-0.173	-0.172	-0.010	0.156	-0.224	-0.274	0.304	0.149	0.066	-0.047	0.499^ p <0.01.	0.364^* * p< 0.05.	1
	LFA² 2 Spearman correlation.	0.031	-0.165	-0.201	0.192	-0.623^ p <0.01.	-0.405^* * p< 0.05.	0.185	-0.063	0.199	-0.162	0.406^* * p< 0.05.	0.349	0.362^* * p< 0.05.	1

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[1] Address for correspondence Osvaldo Nascimento (e-mail: osvaldo_nascimento@hotmail.com).