High-Resolution Ultrasound in Evaluation of Peripheral Neuropathy in Patients of Hansen’s Disease

Abstract

Introduction:

Hansen’s disease (HD) is a major public health problem in developing countries. It causes peripheral neuropathy, and if left untreated, it leads to deformities. It is important to diagnose such cases early, and prompt treatment should be given to patients to preserve nerve function.

Materials and Methods:

A total of 40 patients with HD who were already on multi-drug therapy (MDT) or treatment-naive were included in this study. These were clinically diagnosed cases of HD as per the Ridley–Jopling classification, and these patients were subjected to high-resolution ultrasonography (HRUS). A total of 19 controls were also included. The patients were clinically evaluated, and HRUS of bilateral ulnar nerves (UNs) was performed in all cases and controls. The other peripheral nerves, if clinically thickened, were evaluated using HRUS.

Results:

The cross-sectional area (CSA) of the UN in cases was significantly thickened as compared to controls. There was no difference in the CSA of patients on MDT as compared to treatment naïve patients. In two patients with pure neuritic HD, the clinical examination missed the bilateral nerve enlargement, and only unilateral nerve thickening was clinically appreciated. However, bilateral thickening was detected on HRUS.

Conclusion:

HRUS is a non-invasive and sensitive diagnostic tool that gives significant information on nerve structure and morphology. HRUS adds a new dimension to diagnosing HD, particularly the pure neuritic type, with the assessment of early nerve damage, which can prevent disabilities. HRUS is an objective diagnostic tool that can complement the clinical examination.

Introduction

Hansen’s disease (HD) continues to be a major public health problem in our country. It mainly affects peripheral nerves and skin and may lead to considerable deformities. Prompt and early diagnosis with adequate treatment along with rehabilitative strategies when deformities occur is important for patient care.[1] Nerve involvement in HD can affect the sensory, motor or autonomic functions of peripheral nerves. The clinical manifestations include sensory loss and motor loss in the distribution of the affected nerves, glove and stocking neuropathy, anesthesia on the soles of the feet, development of trophic ulcers on the feet, lepra reactions, motor weakness, and deformities. The WHO Expert Committee on leprosy has defined a case of leprosy as an individual who has one of the cardinal signs of leprosy but who has not received a full course of multi-drug therapy (MDT) for the type of leprosy identified. The cardinal signs include a definite loss of sensation in a pale (hypopigmented) or reddish skin patch, a thickened or enlarged peripheral nerve with loss of sensation and/or weakness in the muscle supplied by the nerve, or the presence of acid-fast bacilli in a slit skin smear.[2]

High-resolution ultrasound (HRUS) of the nerves affected is highly sensitive in identifying the disease process. The normal appearance of peripheral nerves on high-resolution ultrasound is described as “honeycomb appearance” on transverse sections and “bundle of straws” on longitudinal sections due to the presence of hypoechoic fascicles separated by hyperechoic septae.[3] The enlargement of the peripheral nerve is the most important finding in this disease. The echogenicity of affected nerves varies from a mild degree of loss of hyporeflectivity to a complete loss of reflectivity. The internal fascicular pattern changes from being totally edematous to partially or completely losing the fascicular pattern and also showing epineural thickening.

The purpose of this study is to evaluate the diagnostic role of HRUS in the evaluation of peripheral nerves in patients with HD and to compare the HRUS parameters between patients with treatment-naïve HD and patients on MDT.

Materials and Methods

Subjects

This was a prospective observational study performed over a period of 18 months. Written informed consent was taken from all patients and controls. The study was approved by the Institutional Ethics Committee. The study participants were selected by convenience sampling at a tertiary care hospital, and all patients who gave consent during the recruitment period were included in the study. Twenty new patients with HD who were treatment naïve and 20 patients who were already on MDT were evaluated for diagnostic confirmation and treatment in our institution. A total of 19 controls were also enrolled in our study, which consisted of cases of acne vulgaris, tinea corporis, and other dermatological diseases in whom diabetes mellitus, hypothyroidism, nerve injury, and all causes of peripheral neuropathy were ruled out.

The inclusion criteria were: (a) Age of patients greater than 18 years and less than 65 years. (b) The patients who had clinical evidence of HD and who were willing to give consent. The exclusion criteria were previous recurrent elbow trauma, ulnar nerve (UN) biopsy or surgery, diabetes mellitus, systemic lupus erythematosus, alcoholism, familiar neuropathies, and any previous peripheral neuropathies.

Clinical nerve examination

At the visit, demographic data like age, gender, address, family history, drug history, history of any chronic disease, and diabetes mellitus were collected. The diagnosis was established in all patients on the basis of clinical and bacteriologic criteria. In this study, a history of neuropathy was taken, which included clinical symptoms or signs (anesthesia or paresthesia in the distribution, painful nerve palpation, motor abnormalities, and corresponding deformities) in patients. The superficial cutaneous nerves like the supratrochlear nerve (STN), supraorbital (SO) nerve, and greater auricular (GA) nerve were evaluated in all patients, and if thickening was present, it was documented. In normal individuals, these nerves are not palpable, but in HD, if they are thickened, they can be palpated, and sometimes thickening can be appreciated on inspection as well. In all patients, the bilateral UN, median nerve (MN), superficial radial nerve (SRN), common peroneal nerve (CPN), and posterior tibial nerve (PTN) were palpated. A slit skin smear examination was done from two sites in all patients with HD. The total number of skin lesions and type of skin lesions were also recorded. If the patient had a lepra reaction, then it was documented.

All patients were classified as having multibacillary (MBHD) or paucibacillary (PBHD) HD, as well as having a polar tuberculoid, borderline tuberculoid (BTHD), polar lepromatous (LLHD), borderline lepromatous (BLHD), or midborderline form (BBHD), as described by Ridley and Jopling.[4]

The original definition of pure neuritic leprosy in the five-type classification of leprosy of 1982 is as follows: In this type of leprosy, there are no skin lesions. Larger nerve trunks or their branches are usually enlarged. There is a sensory loss in the areas of distribution of the nerves, and single or multiple nerves may be involved. Slit skin smears are negative.[5]

After the general and systemic examination, the patient was evaluated thoroughly by a trainee dermatologist (AM), and the findings were confirmed by another dermatologist with 8 years of experience (TR). Areas of sensory loss, nerves involved, motor involvement, motor weakness, and lepra reactions were recorded. The bacteriological index on a slit skin smear examination was recorded. A skin biopsy was done in a few cases when needed. The patient was then taken to the radiologist, who evaluated bilateral UNs in all cases. The clinically affected nerves and the opposite unaffected nerves were evaluated by the radiologist.

Radiological examination

In all cases, ultrasound (US) of the UN was performed using a high-frequency linear probe (5–17 MHz) on a Philips iU22 ultrasound system (Philips Healthcare, Best, the Netherlands). All the scans were performed by a single investigator with 8 years of experience (IK) who was blinded to the results of the clinical examination and the diagnosis. The examination was performed in a supine position with partially flexed elbows. UN was traced from the wrist to the axilla. CPNs were evaluated from the distal third of the thigh to the fibular head. Cross-sectional area (CSA) and circumference were measured at the level of perceived maximum thickening by freehand delineation of the inner border of the hyperechoic rim of the nerve sheath [Figure 1]. Loss or reduction of the fascicular morphology of the nerves was also recorded as abnormal morphology.

Figure 1.

Cross-sectional ultrasound image showing the ulnar nerve in a 35-year-old patient with Hansen’s disease superficial to the common flexor tendon overlying the medial epicondyle of the humerus. Cross-sectional area (A) and circumference (C) were measured at the level of perceived maximum thickening by freehand delineation of the inner border of the hyperechoic rim of the nerve sheath

The UN on the right and left sides was evaluated by the radiologist in all patients. Both UNs were measured in all the cases and controls, and CPN was measured in all cases with clinically thickened CPN. The other nerves were evaluated only if they were clinically affected. The unaffected opposite nerve was also evaluated. In patients with pure neuritic HD, the same procedure was followed.

Statistical analysis

Data analysis was performed using SPSS software (IBM Corp 2013, Version 22.0, Armonk, NY, USA). The results are presented as mean standard deviation (SD) for continuous variables and numbers and percentages for categorical variables. Quantitative variables were compared using the Student’s t-test. Qualitative variables were compared using the Chi-square test. Receiver-operated characteristic (ROC) curves were plotted for quantitative US parameters in the prediction of the presence of HD, and cut-off values of US parameters were derived.

Results

A total of 40 patients with HD were enrolled in this study. This included treatment-naive patients (n = 20) as well as patients who were already on MDT (n = 20). The mean age of the patients was 32.76 (range 18–64) years. The male-to-female ratio in the patients was 32:8. A total of 19 controls were taken in the study. The mean age in the control group was 31.9 ± 9.9 years. The male-to-female ratio was 14:5.

A total of 20 cases were diagnosed as LLHD, followed by 8 cases of pure neuritic HD of the MBHD type. A total of five patients were diagnosed with BTHD, followed by four patients of BLHD and three patients of BBHD.

A total of 640 nerves were clinically evaluated. Out of the 640 nerves clinically evaluated, 170 were clinically thickened. The STN and SO nerve were not involved in any patient. The GA nerve was thickened in only seven patients.

The mean cross-sectional area of the right and left UNs (0.14-0.15 cm²) was significantly higher in patients with HD than that of controls (0.06 cm²). Similarly, the mean circumference of the right and left UNs was significantly higher in cases than controls (P = 0.001). Comparison of the US parameters between treatment-naive patients (n = 20) and those who were already on MDT (n = 20) showed that the mean cross-sectional area and circumference were not significantly different between the two groups. Abnormal nerve echo texture with loss of fascicular structure was present in either of the UNs in 12/40 cases. Table 1 summarizes the ultrasound findings of the UNs in different study groups.

Table 1.

Summarizing the ultrasound findings of the ulnar nerves and comparison between different study groups

Comparison between cases and controls
Parameters	Case (n=40)	Control (n=19)	P
Cross-sectional area ulnar N, Right (cm2)	0.14±0.11	0.06±0.024	0.003
Cross-sectional area ulnar N, Left (cm2)	0.15±0.16	0.06±0.03	0.021
Circumference ulnar N, Right (mm)	14.3±5.03	9.97±2.69	0.001
Circumference ulnar N, Left (mm)	14.57±5.37	9.54±2.49	<0.001
Comparison between treatment-naïve patients and patients on MDT
	Treatment naive (n=20)	Patient on MDT (n=20)	P
Cross-sectional area ulnar N, Right (cm2)	0.14±0.14	0.13±0.06	0.71
Cross-sectional area ulnar N, Left (cm2)	0.14±0.14	0.15±0.17	0.87
Circumference ulnar N, Right (mm)	14.1±4.4	14.5±5.6	0.78
Circumference ulnar N, Left (mm)	13.7±3.44	15.3±6.7	0.35
Parameters	Case (n=40)	Control (n=19)	P
Nerve echotexture abnormal	12	0	0.007
Nerve echotexture normal	28	19

ROC curves drawn for US parameters [Figure 2] revealed a high area under the curve (0.77–0.824) for all the US parameters to predict the presence of HD [Table 2]. A cross-sectional area of 0.072–0.086 cm² or higher or a circumference of 11.6–12.3 mm for the left and right UNs shows high sensitivity and specificity in predicting the presence of HD.

Figure 2.

Receiver-operated characteristic curves for circumference of the right (blue) and left ulnar nerves (green) and cross-sectional area of the right (dark yellow) and left ulnar nerves (purple) to predict the presence of Hansen disease

Table 2.

Summary of the ROC curve-derived cutoff

Parameters	Area under the curve	Cut off	Sensitivity	Specificity
Cross-sectional area Ulnar N, Right	0.824	0.086 cm2	67.5	78.9
Cross-sectional area Ulnar N, Left	0.815	0.072 cm2	70	74.1
Circumference Ulnar N, Right	0.777	12.3 mm	67.5	84.3
Circumference Ulnar N, Left	0.815	11.6 mm	72.5	78.9

The US of other clinically thickened nerves such as the GA nerve, STN, SRN, MN, CPN, and PTN was done using standard technique [Table 3]. The CPN was the second most commonly thickened nerve, with a mean CSA of 0.14-0.16 cm². GA nerves were clinically thickened (n = 7) with the least cross-section area (0.05–0.06 cm²) and circumference [Table 3]. The comparison of the mean values of all these nerves between treatment-naïve patients and patients with MDT revealed no significant difference between the two groups.

Table 3.

US parameters of other clinically thickened nerves

Nerves	No. of patients	Mean CSA (cm2)±SD	Mean circumference (mm)
Right common peroneal nerve	32	0.14±0.09	16.0±6.1
Left common peroneal nerve	32	0.16±0.12	16.3±6.8
Right median nerve	4	0.09±0.02	11.7±3.3
Left median nerve	3	0.09±0.01	13.4±4.9
Right greater auricular nerve	7	0.05±0.033	8.02±2.6
Left greater auricular nerve	7	0.06±0.044	9.9±3.9
Right superficial radial nerve	9	0.11±0.09	12.5±5.8
Left superficial radial nerve	9	0.11±0.08	12.2±6.1
Right posterior tibial nerve	2	0.07±0.03	12.0±5.6
Left posterior tibial nerve	2	0.08±0.01	13.1±4.1

Out of the 40 cases, the UN was evaluated bilaterally in all patients. On clinical examination of all the UNs, a total of 67 were thickened. Assuming the radiological cut-off was 0.07, a total of nine UNs were radiologically uninvolved. A thorough clinical examination missed the bilateral UN thickening in two patients with pure neuritic HD, which was detected on HRUS.

Discussion

HD is classified into PBHD and MBHD on the basis of the number of skin lesions and the number of nerves affected. The clinical examination is not very reliable, and inter-observer differences are common. A delay in diagnosis leads to permanent nerve damage and deformities. Patients with pure neuritic HD pose a diagnostic challenge because clinical examination is very subjective, and in the initial stages of the disease, nerve thickening may not be well appreciated. But HRUS is highly sensitive, and it will detect any changes in nerve echotexture and thickening.

The use of HRUS in the evaluation of peripheral nerves has been extensively described in the literature.[6,7] In one study, HRUS and color Doppler were done on 30 patients with peripheral nerve lesions, and it was found that HRUS was highly useful in characterizing different peripheral nerve lesions.[8] This study highlights the need for training in peripheral nerve palpation and the utility of HRUS as a more objective complement to clinical assessment.

In another study, HRUS of peripheral nerves was performed in 20 leprosy patients, and they found a significant correlation between ultrasound findings (cross-sectional area, nerve echotexture, and endoneural vascular flow) and clinical parameters that included nerve thickening, sensory loss, and muscle weakness. The authors concluded that ultrasonography exhibits more nerve damage than a clinical examination.[9]

There is a growing interest in HRUS as a diagnostic tool for peripheral neuropathies. Nerve palpation is subjective and requires a lot of expertise. The reliability of the palpation of superficial peripheral nerves is unsatisfactory, and inter-observer differences exist.[10,11] Similar to previous studies, our results demonstrate that HRUS can demonstrate neural involvement in HD with higher sensitivity compared to clinical examination. Various studies have calculated the mean cross-sectional area of UN involvement in HD. The reported mean CSA of the UN ranges from 12.9, 16.1, and 17.69 sq mm.[12,13,14] Our mean CSA (14–15 sq mm) was comparable to previous studies. In addition, we could derive a cut-off value of 7.2–8.6 sq mm, showing moderate sensitivity and high specificity for the diagnosis of HD. This cut-off value was slightly lower than that calculated by Elias et al., who derived a cut-off value of 9.8 sq mm with higher sensitivity and specificity. This may be due to constitutional anatomical variation between the Indian population in our study and the Brazilian population studied by Elias et al.[13] A study by Madhusudhan et al.[12] evaluated nerve thickness on HRUS of various nerves and calculated the mean cross-sectional area of the MN (10.3 sq mm), posterior tibial nerve (13.4 sq mm), and CPN (12.3 sq mm). Our study showed comparable mean cross-sectional area for the MN (9 sq mm) and a considerably lower mean CSA for the posterior tibial nerve (7-8 sq mm). We also found that the CSA of the CPN (14–16 sq mm) was slightly higher than the previously reported value. This may be due to the fact that we measured the CSA of only those patients in whom these nerves were thickened. In addition, we also evaluated the mean CSA of clinical neural involvement for the GA nerve (5–6 sq mm) and SRN (11 sq mm).

We realize that our study has several limitations. Firstly, the number of patients in this study is relatively less. Secondly, we did not use Doppler to evaluate the nerves, which has been shown to yield a considerable diagnostic advantage in HD in the literature. Thirdly, we did not measure the CSA in nerves other than the UN in controls or in patients who did not show clinically thickened nerves.

In conclusion, our study demonstrated that HRUS is highly sensitive in the detection of nerve involvement and damage in HD. Clinical examination is very subjective and might miss out on nerve involvement in a few cases. HRUS offers accuracy and is a good non-invasive modality that can be used to get information on nerve structure and morphology, particularly in patients of pure neuritic type HD. The usefulness of early diagnosis and prompt treatment in the prevention of disabilities is already well known, so we can use HRUS as an added tool in the diagnosis of HD.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interests.