A Comparative Study of High-Resolution Ultrasonography with Clinical Examination in the Assessment of Peripheral Nerve Involvement in Leprosy

Abstract

Background

Peripheral nerve involvement is a well-established feature of leprosy. However, it may go unnoticed by clinicians due to a decline in clinical examination skills. High-resolution ultrasonography (HRUS) offers the advantage of identifying subclinical nerve involvement at an earlier stage.

Aims and Objectives

This article aims to evaluate and compare the effectiveness of HRUS and clinical examination in detecting peripheral nerve involvement in leprosy, the correlation of sonological findings with clinical findings, and the calculation of sensitivity, specificity, and predictive values of HRUS taking clinical examination as the reference method.

Materials and Methods

This cross-sectional observational study was conducted over 1.5 years involving 60 newly diagnosed leprosy patients. Clinical assessment and sonographic evaluation of five nerve pairs (ulnar, median, greater auricular, common peroneal, and posterior tibial) were done. Findings were recorded, analyzed, and compared.

Results

HRUS detected abnormalities in 111 of 600 (18.5%) of all nerves, surpassing the 90 of 600 (15%) nerves detected clinically. HRUS parameters demonstrated substantial agreement with clinical findings, with Cohen's kappa values of 0.740 for cross-sectional area, 0.246 for hypervascularity, and 0.166 for hypoechogenicity. The overall diagnostic performance of HRUS reported a sensitivity of 86.7%, specificity of 93.5%, and positive predictive value of 70.3% with a negative predictive value of 97.6%.

Conclusion

This study highlights the critical role of HRUS in detecting and monitoring leprosy neuropathy, emphasizing its superiority over clinical examination in identifying both early and advanced nerve involvement.

 

Scroll to top

Keywords

high-resolution ultrasonography - leprosy - ultrasonography

Introduction

Leprosy is a long-standing granulomatous condition caused by the immune system's reaction to Mycobacterium leprae infection, predominantly affecting the skin and peripheral nerves. The bacterium inhabits macrophages and Schwann cells and is distinct in its capacity to interfere with myelin, resulting in peripheral nerve damage. Early nerve involvement is characterized by axonal shrinkage and localized inflammation. This inflammation facilitates the formation of a vascular route through which M. leprae migrates from the perineurium into the endoneurium,[1] which then gets engulfed by Schwann cells within the fascicle.[2] The Ridley-Jopling classification divides leprosy into five distinct types,[3] ranging from the localized, paucibacillary tuberculoid form (TT), which presents with hypopigmented, anesthetic skin lesions, to the more widespread, multibacillary lepromatous form. Between these two ends of the spectrum are the borderline forms: borderline tuberculoid, borderline borderline, and borderline lepromatous, which are immunologically unstable. These intermediate forms are particularly prone to episodic inflammatory reactions, which can affect around 15 to 50% of patients during the disease course and even after completion of multidrug therapy.[4] Leprosy reactions include Type 1 (reversal reaction), marked by localized inflammation of skin lesions and nerve tenderness caused by edema-induced compression, and Type 2 (erythema nodosum leprosum), which manifests with systemic features like fever, painful red nodules, and joint aches. While nerve involvement is a common feature across all forms of leprosy, these reactions can precipitate acute neuritis, potentially impairing nerve function. If not promptly managed, they may lead to permanent nerve damage. Although clinical examination remains the primary method for detecting and assessing nerve involvement, it is limited by considerable interobserver variability.[5] Clinical examination can be difficult due to the deep anatomical location of the peripheral nerves.[6] In this study, clinical examination was used as the reference standard in accordance with the World Health Organization (WHO) guidelines, which continue to recommend clinical examination as the primary method for diagnosing leprosy, especially in peripheral and resource-limited settings. The WHO emphasizes early clinical diagnosis based on the cardinal signs of leprosy, including nerve involvement detectable through palpation and sensory-motor assessment. While high-resolution ultrasonography (HRUS) has demonstrated higher sensitivity and can detect subclinical changes, it is not widely available in endemic regions. Thus, the use of clinical examination as the comparator reflects both practical field relevance and WHO-endorsed diagnostic practices. HRUS offers a precise and detailed visualization of the internal structure of peripheral nerves, allowing for the identification of alterations in nerve thickness, echotexture, and blood flow. Incorporating color Doppler further enhances diagnostic accuracy by highlighting vascular changes that may indicate inflammation or other pathological processes, particularly during Type 1 lepra reactions. Its diagnostic value has been well-documented in multiple studies and scholarly publications.[7] [8] [9] It measures the maximum cross-sectional area (CSA) of nerves as an objective indicator of enlargement and captures detailed morphological features, such as the internal structure of fascicles, echogenicity,[10] and the condition of the perineurium and epineurium.[11] Distal nerves are normally hyperechoic, with a stippled (“honeycomb”) structure (with hypo-anechoic fascicles on the hyperechoic background of connective tissue surrounding them).[12] This study utilizes the capabilities of HRUS to diagnose peripheral nerve involvement in leprosy by identifying early structural changes that may not be detectable through clinical examination alone.

 

Scroll to top

Materials and Methods

This study, approved by the institutional ethics committee, is a cross-sectional analysis conducted on 60 newly diagnosed leprosy patients over an 18-month period, spanning from August 2023 to January 2025. Leprosy was diagnosed when at least one of the following cardinal signs was present (as per the 8th WHO Expert Committee on Leprosy).[13]

1. Definite loss of sensation in a pale (hypopigmented) or reddish skin patch.

2. A thickened or enlarged peripheral nerve, with loss of sensation and/or weakness of the muscles supplied by that nerve.

3. The presence of acid-fast bacilli in a slit-skin smear.

Patients with comorbid conditions such as metabolic disorders, diabetes, uremia, hypercholesterolemia, porphyria, and vasculitic diseases like polyarteritis nodosa (PAN), as well as those with hypothyroidism, allergic vasculitis, history of trauma, chronic compressive neuropathy, or hereditary neuropathies (i.e., other causes of peripheral neuropathy), were excluded from the study. Additionally, individuals who were skin smear positive and had previously received multidrug therapy, along with those who did not provide consent, were also not included. After obtaining informed consent, five pairs of nerves, namely, ulnar nerve (UN), median nerve, greater auricular nerve, posterior tibial nerve, and common peroneal nerve, were clinically assessed. The nerves were evaluated for sensory, autonomic, and motor functions through a comprehensive examination, which included palpation to assess for thickening, tenderness, and consistency (such as cord-like or fibrosed). Autonomic function was assessed by evaluating signs such as loss of sweating on the palms and soles, hair loss, and the presence or absence of sweating as indicated by dry-appearing skin, as well as the presence of cracks or fissures.

1. Ulnar nerve (UN): We checked for numbness and paresthesias of the fourth and fifth digits of the hand. Both arms were examined by testing pinprick sensation at digit 5 using monofilament. Motor functions of the palmar, dorsal interossei, and adductor pollicis were checked.[4]

2. Median nerve (MN): Pin-prick sensation in the distribution of the median nerve (in the palm over the thenar eminence and pulp of the index finger) was checked. Motor function of abductor pollicis brevis, opponens pollicis, flexor digitorum superficialis, and flexor digitorum profundus (lateral half) were assessed.

3. Greater auricular nerve (GAN): Pin-prick sensation using monofilaments in the area of skin of the auricle, skin over the parotid gland, and mastoid process were evaluated.

4. Common peroneal nerve (CPN): Pin-prick sensation using monofilaments on the lateral part of the leg and dorsum of the foot with any evidence of foot drop was noted. Dorsiflexors of the ankle, extensor hallucis longus and tibialis anterior muscles, were assessed.

5. Posterior tibial nerve (PTN): We assessed the sole of the foot to check for sensory function of the nerve with assessment of the intrinsic muscles of the feet.

Sensory loss was considered present when the patient was unable to perceive 2 g of target force on the hand and 300 g of target force on the foot by Semmes-Weinstein monofilaments. Medical Research Council (MRC) muscle strength grading was used for muscle weakness. Muscle weakness was present when the MRC score was 4 or less. UN, GAN, CPN, and PTN were clinically graded after palpation as follows[4]:

• Grade 0 is defined as a nerve not thicker than the contralateral nerve and with normal sensation.

• Grade 1 occurs when the affected nerve is thicker than the contralateral nerve.

• Grade 2 is a thickening of the affected nerve with a rope-like consistency.

• Grade 3 is a thickened nerve with a beaded or nodular feel.

Clinical grading of nerve thickening based on palpation was not performed on MN due to its deeper location. Slit skin smear for acid-fast bacilli was sent for investigation for bacteriological and morphological index. Before starting MDT, HRUS, and color Doppler, evaluation of peripheral nerves was performed in the Department of Radio Diagnosis of our hospital. A 6 to 15 linear array transducer with a frequency range of 4.5 to 15 MHz was used in assessing peripheral nerves. Due to the superficial location of peripheral nerves, the maximum available frequency was 15 HZ. Ultrasonography (USG) of five pairs of peripheral nerves (UN, MN, GAN, CPN, and PTN) with color Doppler of peripheral nerves was done; the sonographic findings were analyzed simultaneously by two radiologists who were blinded from the clinical findings. The enlarged nerve was visualized at the cubital tunnel for the UN, carpal tunnel for the MN, the area of the fibular head and neck for the CPN, and the tarsal tunnel for the PTN.[8] For GAN, the scan was started at the posterior border of the sternocleidomastoid muscle. The probe was moved cranially and caudally in the transverse view until a structure was identified beneath the sternocleidomastoid muscle.[14] The following parameters were noted by examining nerves both transversely and longitudinally by changing the direction of the linear array transducer.

1. CSA—In mm², the selected normal values for cross-sectional area of ulnar nerve, median nerve, common peroneal nerve, posterior tibial nerve, and greater auricular nerve are 8.5, 6.2, 5.9, 6.3, and 0.84 mm², respectively.[20]

2. Echogenicity of the nerve—Normal/hypoechoic/hyperechoic.

3. Blood flow in color Doppler and change in fibrillary echotexture were estimated at multiple sites in the transverse plane, and whether a peripheral echogenic rim was maintained or lost.

In normal nerves, prominent arterial pulsations are typically absent, as the perineural and intraneural blood vessels are not usually detectable on Doppler imaging due to their minimal blood volume and slow flow velocities.[15]

The detection of blood flow signals in the perineural plexus or interfascicular vessels on color Doppler imaging was interpreted as an indication of nerve hypervascularity. A nerve was deemed sonologically abnormal if any one of the following criteria was observed in the cross-sectional view.[20]

1. Increased cross-sectional area.

2. Hypoechogenicity of the nerve (fascicles and interfascicular perineurium) with or without loss of architecture.

3. Hypervascularity.

Statistical Analysis

Categorical variables were expressed as frequency and percentage, while continuous variables were expressed as mean and standard deviation. The agreement between clinical examination and HRUS was assessed using Cohen's kappa statistic. The McNemar test was used for p-value calculation, where p < 0.05 was considered significant. Sensitivity, specificity, positive predictive values (PPVs), and negative predictive values (NPVs) for HRUS were calculated, taking clinical examination as the gold standard. All statistical analyses were done using Epi Info version 7.2.1.0 and Jamovi version 4.0 statistical software.

 

Scroll to top

 

Scroll to top

Results

The study included 60 participants with a mean age of 35.83 years, predominantly in the 20- to 49-year age group (76.67%), indicating that leprosy is most common in middle-aged individuals. A male predominance (75%) was observed; lower socioeconomic status was prevalent in 61.67% of cases, with only 15% of patients reporting a family history of leprosy. Using the Ridley-Jopling classification, the most common form was borderline tuberculoid (51.67%), followed by borderline lepromatous (16.67%), while multibacillary leprosy accounted for 76.67% of cases under the WHO classification. Slit skin smear positivity was seen in 36.67% of cases [Table 1].

Clinical examination of major peripheral nerves ([Table 2]) revealed that among the 600 nerves examined, 90 (15%) were clinically abnormal based on the presence of any one or more clinical signs such as thickening, sensory loss, or motor weakness. These categories are overlapping, as some nerves exhibited more than one abnormality simultaneously. Nerve thickening was seen in 12.2% (n = 73/600) of all nerves, with the UN being the most commonly thickened (26.7%), followed by the CPN (15%), PTN (10%), MN (4.2%), and GAN (4.2%). Sensory loss was more frequently observed than motor loss, affecting 11.8% of nerves, with the UN showing the highest sensory involvement (28.3%), followed by the CPN (15.8%), PTN (10.8%), and MN (4.2%). Motor loss was detected in 2.3% of nerves, primarily in the UN (10.8%) and PTN (0.8%) nerves. HRUS detected abnormalities in 18.5% (n = 111/600) of all nerves, surpassing the 15% detected clinically. Among the HRUS findings ([Table 2]), increased CSA was seen in 17% (n = 102/600) nerves, hypervascularity in 3.5% nerves (21/600), and hypoechogenicity in 2.6% nerves (17/600). The UN again had the highest frequency of USG abnormalities (30.8%, [Fig. 1]), followed by the CPN (22.5%, [Fig. 2]), PTN (21.6%, [Fig. 3]), MN (5.8%, [Fig. 4]), and GAN (4.2%, [Fig. 5]). [Table 3] illustrates HRUS findings of clinically abnormal and normal nerves. Among clinically abnormal nerves, the most significant finding was that 83.3% of clinically abnormal nerves exhibited an increased CSA, hypoechogenicity was observed in 12.2%, loss of fascicular architecture was seen in 10%, and increased blood flow on Doppler was observed in 17.7% of clinically abnormal nerves ([Figs. 6] and [7]). In clinically normal nerves, 5.3% showed increased CSA, hypoechogenicity in 1.2% nerves, and increased blood flow on Doppler was detected in only 0.98% nerves. [Table 4] illustrates the relationship between clinical findings and USG abnormalities, specifically increased CSA, increased endoneurial blood flow on Doppler, and hypoechogenicity in 600 peripheral nerves. A significant association was observed between increased CSA and all major clinical features: nerve thickening (p < 0.001), tenderness (p < 0.001), sensory loss (p < 0.001), and motor loss (p < 0.001). Among nerves with increased CSA, 60.8% had clinical thickening, 58.8% had sensory loss, and 12.7% showed motor weakness. Similarly, increased blood flow on color Doppler was significantly associated with clinical thickening (p < 0.001), tenderness (p < 0.001), sensory loss (p < 0.001), and motor loss (p < 0.001), though its prevalence was lower. Hypoechogenicity was also significantly correlated with nerve thickening (p < 0.001) and sensory loss (p < 0.001), but not with tenderness (p = 0.927) or motor loss (p = 0.072), suggesting a more selective association with inflammatory or demyelinating changes. Grade-wise nerve thickening did not show significant correlation with any HRUS parameters (p > 0.05), indicating that qualitative grading on palpation may not reflect the extent of sonological abnormality. [Table 5] illustrates the diagnostic parameters of HRUS for individual nerves. Among individual nerves, the GAN had the highest sensitivity (100%), followed by CPN (90.5%), PTN (89.5%), UN (88.6%), and MN (60%). In terms of specificity, again GAN had the highest specificity (100%) followed by MN (95.5%), UN (91.8%), CPN (89.9%), and PTN (89.1%). The highest agreement was observed for the greater auricular nerve (κ = 1.0), indicating perfect concordance, though this must be interpreted cautiously due to the small sample size (n = 5 abnormal GANs). The UN also demonstrated strong agreement (κ = 0.784), followed by the common peroneal (κ = 0.699) and posterior tibial nerves (κ = 0.659), all indicating substantial agreement. The median nerve showed moderate agreement (κ = 0.530), possibly due to its deeper anatomical position, affecting both palpation and ultrasonographic clarity. Increased CSA was the most reliable HRUS parameter, showing high sensitivity (83.3%), specificity (94.7%), and substantial agreement with clinical findings (κ = 0.740; [Table 6]). In contrast, hypoechogenicity and hypervascularity had high specificity (>98%) but low sensitivity (12.2 and 17.8%, respectively) with only slight to fair agreement (κ = 0.166 and 0.246, respectively). The combined use of all three parameters improved sensitivity to 86.7% with a κ = 0.732, supporting CSA as the dominant marker while others offer adjunctive value. The PPV was 70.3%, while the NPV was 97.6% ([Table 6]).

Table 1 Demographic profile of patients

Age group (years)	N	Percentage
<20 y	5	8.33
20–29 y	16	26.67
30–39 y	18	30
40–49 y	12	20
50–59 y	7	11.67
60–69 y	2	3.33
Total	60	100
Mean ± SD	35.83 ± 12.25 y
Gender	N	Percentage
Male	45	75
Female	15	25
Total	60	100
Socioeconomic status	N	Percentage
Lower	37	61.67
Lower middle	14	23.33
Upper	9	15
Total	60	100
Duration of disease (months)	N	Percentage
≤6 mo	5	8.33
6–12 mo	36	60
>12 mo	19	31.67
Total	60	100
Mean ± SD	16.17 ± 13.86 mo
Family history of leprosy	N	Percentage
Present	9	15
Absent	51	85
Total	60	100
Ridley-Jopling classification	N	Percentage
Tuberculoid	5	8.33
Lepromatous	5	8.33
Borderline borderline	5	8.33
Borderline lepromatous	10	16.67
Borderline tuberculoid	31	51.67
Indeterminate	1	1.67
Neuritic	3	5
Total	60	100
WHO classification	N	Percentage
Multibacillary	46	76.67
paucibacillary	14	23.33
Total	60	100
Slit skin smear	N	Percentage
Positive	22	36.67%
Negative	38	63.33%
Total	60	100

Table 2 Clinical and HRUS findings of major peripheral nerves in leprosy patients

Clinical findings of major peripheral nerves in leprosy patients
	Ulnar ( N  = 120)	Median ( N  = 120)	Common peroneal ( N  = 120)	Posterior tibial ( N  = 120)	Greater auricular ( N  = 120)	All nerves ( N  = 600)
Thickening	32 (26.7%)	5 (4.2%)	18 (15%)	12 (10%)	5 (4.2%)	73 (12.2%)
Grade 1	27 (22.5%)	0	17 (13.4%)	12 (10%)	4 (3.2%)	60 (10%)
Grade 2	3 (2.5%)	0	1 (0.8%)	0	1 (0.8%)	5 (0.8%)
Grade 3	2 (1.7%)	0	0	0	0	2 (0.3%)
Tenderness	2 (1.7%)	5 (4.2%)	3 (2.5%)	10 (8.3%)	0	20 (3.2%)
Sensory loss	34 (28.3%)	5 (4.2%)	19 (15.8%)	13 (10.8%)	0	71 (11.8%)
Motor loss	13 (10.8%)	0	0	1 (0.8%)	0	14 (2.3%)
HRUS findings of major peripheral nerve involvement in leprosy patients
	Ulnar ( N  = 120)	Median ( N  = 120)	Common peroneal ( N  = 120)	Posterior tibial ( N  = 120)	Greater auricular ( N  = 120)	All nerves ( N  = 600)
Increased CSA	37 (30.8%)	7 (5.8%)	27 (22.5%)	26 (21.6%)	5 (4.2%)	102 (17%)
Hypoechoic	9 (7.5%)	3 (2.5%)	3 (2.5%)	2 (1.6%)	0	17 (2.6%)
Loss of fascicular/fibrillary architecture	9 (7.5%)	1 (0.8%)	2 (1.6%)	0	0	12 (2%)
Increased blood flow on Doppler	8 (6.6%)	5 (4.2%)	2 (1.6%)	6 (5%)	0	21 (3.5%)

Fig. 1 (A, D) Transverse axis view of the right UN at the level of the medial epicondyle shows increased cross-sectional area (51 mm² encircled) with loss of normal honeycomb pattern. (B) Longitudinal axis of the right UN shows thickening of the nerve (vertical white line). (C) Increased vascularity of nerve as seen by red, blue color Doppler signals. (Landmark—UN running medial to medial epicondyle [ME].)

Fig. 2 (A) Transverse axis view of the left CPN shows increased cross-sectional area (19 mm², encircled area) associated with hypoechogenicity. (B) The longitudinal axis of the left CPN shows thickening of the nerve (white vertical dotted line). (Bony landmark—fibular head [FH]; CPN winds to the lateral head of fibula.)

Fig. 3 (A, C) Transverse axis of the left PTN shows increased CSA (16 mm², encircled nerve) with hypoechogenicity of the nerve. (B) Longitudinal axis of the left PTN shows nerve enlargement (white vertical line) with thickening of epineurium (blue arrow). (Landmark: The posterior tibial nerve, artery, and vein run close together behind the medial malleolus [MM]. The posterior tibial artery is positioned most anteriorly, followed by the posterior tibial vein [blue color in C], and then the posterior tibial nerve [encircled nerve in A, C].)

Fig. 4 (A, C) Transverse view of the left MN shows increased CSA (18 mm²) with a honeycomb fascicular pattern at the wrist. (B) Longitudinal axis of the MN with increased thickness (white vertical line) with tram track appearance. (This section was taken at the level of the wrist, where MN travels anteriorly to the surface of the radius and is superficial to the pronator quadratus [PQ]. In the carpal tunnel, it lies along with flexor tendons [white arrows], deeper to the flexor retinaculum.)

Fig. 5 (A) Transverse axis view of the right GAN shows increased cross-sectional area (3 mm², encircled) with hypoechogenicity. (B) Longitudinal axis of GAN shows thickening of nerve (vertical white line) with hyperechoic epineurium (black arrows). (Landmark: GAN emerges along the posterior aspect of the sternocleidomastoid [SCM] muscle and ascends vertically across the SCM muscle. This USG image was obtained at the upper one-third level of the SCM muscle.)

Table 3 HRUS findings of clinically abnormal and normal nerves

USG findings of clinically abnormal peripheral nerves in leprosy patients
	Ulnar ( N  = 35)	Median ( N  = 10)	Common peroneal ( N  = 21)	Posterior Tibial ( N  = 19)	Greater auricular ( N  = 5)	All nerves ( N  = 90)
Increased CSA	31 (88.6%)	4 (40%)	18 (85.7%)	17 (89.5%)	5 (100%)	75 (83.3%)
Hypoechoic	7 (20%)	1 (10%)	2 (9.5%)	1 (5.3%)	0	11 (12.2%)
Loss of fascicular/fibrillary architecture	8 (22.9%)	0	1 (4.8%)	0 (%)	0	9 (10%)
Increased blood flow on Doppler	8 (22.9%)	2 (20%)	1 (4.8%)	5 (26.3%)	0	16 (17.7%)
USG findings of clinically normal peripheral nerves in leprosy patients
	Ulnar (N = 85)	Median (N = 110)	Common peroneal (N = 99)	Posterior tibial (N = 101)	Greater auricular (N = 115)	All nerves (N = 510)
Increased CSA	6 (7.1%)	3 (2.7%)	9 (9.1%)	9 (8.9%)	0	27 (5.3%)
Hypoechoic	2 (2.4%)	2 (1.8%)	1 (1%)	1 (0.99%)	0	6 (1.2%)
Loss of fascicular/fibrillary architecture	1 (1.2%)	1 (0.9%)	1 (1%)	0	0	3 (0.6%)
Increased blood flow on Doppler	0	3 (2.7%)	1 (1%)	1 (0.99%)	0	5 (0.98%)

Abbreviations: CSA, cross-sectional area; HRUS, high-resolution ultrasonography; USG, ultrasonography.

Fig. 6 Longitudinal view of the nerves: (A) Thickening of the epineurium of the ulnar nerve (black arrows) with a tram track appearance of the nerve, with slight hypervascularity at the level of the medial epicondyle. (B) Hypervascularity of the median nerve with increased thickness at the level of the flexor retinaculum (white vertical line).

Fig. 7 Posterior tibial nerve thickening (white vertical line) with hypervascularity at the level of the medial malleolus with loss of normal tram track pattern on longitudinal axis.

Table 4 Clinical findings in relation to HRUS parameters (cross-sectional area, increased blood flow on Doppler, and hypoechogenicity; N = 600)

Clinical findings in relation to USG findings of increased cross-sectional area in all nerves ( N  = 600)
Clinical findings		Increased CSA( N  = 102)		Normal CSA( N  = 498)		p -Value
		N	%	N	%
Nerve thickening	Yes	62	60.78	10	2	<0.001 (S)
	No	40	39.22	488	98
Thickening grade	Grade 1	55	53.92	10	3.54	0.523
	Grade 2	5	4.90	0	0
	Grade 3	2	1.96	0	0
Tenderness	Yes	16	15.69	4	0.8	<0.001 (S)
	No	86	84.31	494	99.2
Sensory loss	Yes	60	58.82	11	2.2	<0.001 (S)
	No	42	41.18	487	97.8
Motor loss	Yes	13	12.75	1	0.2	<0.001 (S)
	No	89	87.25	497	99.8
Clinical findings in relation to USG findings of increased blood flow on Doppler in all nerves ( N  = 600)
Clinical findings		Increased blood flow (N = 21)		Normal blood flow (N = 579)		p-Value
		N	%	N	%
Nerve thickening	Yes	9	42.86	63	10.88	<0.001 (S)
	No	12	57.14	516	89.12
Thickening grade	Grade 1	8	38.10	57	9.84	0.193
	Grade 2	0	0	5	0.86
	Grade 3	1	4.76	1	0.17
Tenderness	Yes	8	38.10	12	2.07	<0.001 (S)
	No	13	61.90	567	97.93
Sensory loss	Yes	14	66.67	57	9.84	<0.001 (S)
	No	7	33.33	522	90.16
Motor loss	Yes	5	23.81	9	1.55	<0.001 (S)
Clinical findings in relation to USG findings of hypoechogenicity in all nerves ( N  = 600)
Clinical findings		Increased hypoechogenicity (N = 17)		Normal hypoechogenicity(N = 583)		p-Value
		N	%	N	%
Nerve thickening	Yes	9	52.94	63	10.81	<0.001 (S)
	No	8	47.06	520	89.19
Thickening grade	Grade 1	8	47.06	57	9.78	0.193
	Grade 2	0	0	5	0.86
	Grade 3	1	5.88	1	0.17
Tenderness	Yes	1	5.88	19	3.26	0.927
	No	16	94.12	564	96.74
Sensory loss	Yes	10	58.82	61	10.46	<0.001 (S)
	No	7	41.18	522	89.54
Motor loss	Yes	2	11.76	12	2.06	0.072

Abbreviations: CSA, cross-sectional area; HRUS, high-resolution ultrasonography; USG, ultrasonography.

Table 5 Diagnostic parameters of USG for diagnosis of nerve abnormality (individual nerves)

Parameter	Sensitivity	Specificity	PPV	NPV	Diagnostic accuracy	Cohen's kappa
Ulnar	88.6%	91.8%	81.6%	95.1%	90.8%	0.784
Median	60%	95.5%	54.6%	96.3%	92.5%	0.530
Common peroneal	90.5%	89.9%	65.5%	97.8%	80%	0.699
Posterior tibial	89.5%	89.1%	60.71%	97.8%	89.2%	0.659
Greater auricular	100%	100%	100%	100%	100%	1
All nerves	86.7%	93.5%	70.3%	97.6%	92.5%	0.732

Abbreviations: NPV, negative predictive value; PPV, positive predictive value; USG, ultrasonography.

Table 6 Diagnostic parameters of USG for the diagnosis of nerve abnormality

Parameter	Sensitivity	Specificity	PPV	NPV	Diagnostic accuracy	Cohen's kappa
Increased cross-sectional area	83.3%	94.7%	73.5%	97%	93%	0.740
Hypoechogenicity	12.2%	98.8%	64.7%	86.5%	85.8%	0.166
Hypervascularity	17.8%	99%	76.2%	87.2%	86.8%	0.246
Overall (combined)	86.7%	93.5%	70.3%	97.6%	92.5%	0.732

Abbreviations: NPV, negative predictive value; PPV, positive predictive value; USG, ultrasonography.

 

Scroll to top

Discussion

The earliest documented use of USG in leprosy was in 1987 in France, where a 5-MHz linear array real-time probe, along with a stand-off pad, was employed to detect swelling in the lateral popliteal nerve.[16] Following a period of minimal use lasting over 10 years, the advent of HRUS with 11- to 15-MHz probes reignited interest in its utilization for diagnosing and assessing leprosy.[7] In the short-axis view, healthy nerves exhibit a characteristic “honeycomb” pattern, consisting of continuous hypoechoic (dark) neuronal fascicles encased by echogenic (bright) perineurium and epineurium. When viewed in the long axis, the nerve displays a “tram-track” appearance.[17] On static cross-sectional ultrasound images, nerves and tendons can appear similar, particularly when positioned close to each other, for example, the median nerve and flexor tendons in the carpal tunnel. However, nerve fascicles are typically thicker and less numerous than the finer, more abundant fibrils seen in tendons. A distinguishing characteristic is that tendons display greater anisotropy, meaning their echogenicity varies more noticeably with changes in the angle of the ultrasound probe, often causing them to appear more hypoechoic than adjacent nerves.[18] While HRUS is useful for confirmation of nerve enlargement in all clinical types of leprosy, it is most valuable in pure neural leprosy, which is a diagnostic challenge in view of the absence of visible skin lesions and negative skin smears. HRUS can aid in distinguishing leprosy from other neuropathies, such as ulnar nerve entrapment, where nerve enlargement typically occurs at the sulcus or just above the elbow. In contrast, leprosy-related nerve thickening is usually located more proximally, ∼3 to 4 cm above the elbow.[19] In regions where peripheral nerves are located close to blood vessels, color Doppler imaging proves valuable in distinguishing nerves from nearby vascular structures. This study provided key insights into the utility of HRUS combined with color Doppler in assessing leprosy-affected nerves. The increasing significance of this imaging method stems from its ability to detect early, subclinical nerve involvement and its cost-effectiveness, making it an important tool in the prevention of disability and deformities.

Our study compared the findings of clinical examination with ultrasound findings. Cross-sectional area, echogenicity of nerve, and blood flow on color Doppler were the parameters noted on HRUS. In our study, out of 600 nerves, 90 (15%) were clinically involved and 111 (18.5%) were sonologically abnormal. Increased cross-sectional area was the most frequently associated sonological parameter. In a study conducted by Venugopal et al,[20] out of the 320 nerves 71 (22.18%) were clinically abnormal, while 63 nerves (19.7%) were sonologically abnormal. In the study conducted by Ashwini et al,[21] 86 out of 210 nerves (41%) showed thickening on clinical examination, while sonographic evaluation identified thickening in 138 nerves (65.7%). In our study, 33/600 (5.5%) nerves were clinically normal but sonologically abnormal. In a study by Kumaran et al,[22] 41 out of 240 nerves (17.1%) that were clinically normal were found to be enlarged on sonography, which was comparatively higher as compared with our study and indicated that HRUS was able to diagnose subclinical nerve involvement. In our study, a significant correlation was observed between clinical features such as nerve thickening, sensory impairment, motor loss, and sonological findings like increased CSA, endoneurial blood flow, and hypoechogenicity. However, the clinical grade of nerve thickening did not show any association with HRUS parameters. Jain et al observed a strong correlation between clinical indicators such as the degree of nerve thickening, sensory deficits, and muscle weakness and sonographic abnormalities, including altered nerve echotexture, endoneurial blood flow, and increased CSA.[4]

In our study, sensitivity and specificity were highest for the greater auricular nerve (100%) and sensitivity was lowest for the median nerve (60%), while specificity remained above 89% for all nerves, ensuring minimal false positives. PPV was highest for the greater auricular nerve (100%) but lower for the median nerve (54.6%), suggesting that ultrasound was more effective in correctly identifying ulnar and common peroneal nerve abnormalities than median nerve abnormalities. NPV was consistently high (>95%). Cohen's kappa showed strong agreement between clinical and USG findings, particularly for the greater auricular (1.0) and ulnar nerves (0.784) and lowest for the median nerve (0.530).

In comparison to our findings, Venugopal et al[20] reported that HRUS demonstrated the highest sensitivity for the right median nerve (100%), while the lowest sensitivity was observed for both the right and left posterior tibial nerves (40% each). The highest specificity was noted for the right and left common peroneal nerves (100% each), whereas the right UN showed the lowest specificity at 73.1%. Dugad et al[23] conducted a detailed evaluation of each ultrasonographic parameter for individual nerves and reported high diagnostic performance. For the UN, echogenicity showed a sensitivity of 94.74%, a PPV of 100%, and an accuracy of 94.74%. Similarly, for other nerves, the sensitivity, PPV, and accuracy were all above 80%: for MN (88.88%, 100%, and 88.88%), lateral popliteal nerve (80.00%, 100%, and 80.00%), and posterior tibial nerve (85.71%, 100%, and 85.71%), respectively. Since the study focused solely on positive findings, specificity and NPV were not calculated by them.

The overall sensitivity of HRUS when combining all three parameters was 86.7%, specificity was 93.5%, the PPV was 70.3%, and the NPV was 97.6%. The diagnostic accuracy of HRUS was 92.5%, confirming that it is a highly reliable tool for detecting nerve involvement in leprosy, which is quite in alignment with the findings of Venugopal et al,[20] where he reported overall sensitivity of HRUS as compared with clinical examination as 63% and specificity as 92.7%, PPV of 71.4%, and NPV of 89.9%.

In this study, a nerve was considered abnormal on HRUS if it exhibited any one of three parameters: increased CSA, hypoechogenicity, or hypervascularity, following the diagnostic approach used by Venugopal et al.[20] While CSA alone accounted for the majority of HRUS positive findings and demonstrated the highest sensitivity (83.3%) and agreement (κ = 0.740), we included hypoechogenicity and hypervascularity to ensure a more comprehensive evaluation. Although their individual sensitivities were low (12.2%, κ = 0.166) and (17.8%, κ = 0.246, respectively), these features may capture specific pathological changes, particularly inflammatory activity or early nerve damage, which is not always associated with nerve enlargement. Thus, the combined definition, while CSA-dominant, may provide additive diagnostic value. However, we acknowledge this approach could be refined in future studies, potentially through a weighted scoring system. The overall Cohen's kappa value (κ = 0.732) indicates a substantial agreement between HRUS and clinical examination, suggesting that both methods largely correlate in detecting nerve abnormalities.

 

Scroll to top

Limitations

While some studies incorporated control groups to determine baseline ultrasound parameters, our study did not include a control group due to a limited sample size. The GAN showed 100% sensitivity, specificity, and diagnostic accuracy; however, this result is based on only five clinically abnormal GANs. Such a small sample size limits the statistical reliability and may lead to overestimation. These perfect values should therefore be interpreted with caution. We acknowledge this as a methodological limitation, and larger studies are needed to validate these findings. Another key limitation was the absence of formal interobserver agreement analysis between the two radiologists. While findings were reviewed jointly to resolve discrepancies in real time, future studies should include statistical evaluation of interobserver reliability using kappa or intraclass correlation coefficients to enhance methodological rigor. Additionally, there are no universally established cutoff or reference values for normal nerve CSAs; hence, cutoff values in our study were adopted from previously published research. Follow-up HRUS after initiating treatment for leprosy was not done.

 

Scroll to top

Conclusion

HRUS was able to identify abnormalities in several nerves that appeared normal on clinical examination. Conversely, some nerves that were clinically abnormal showed no sonological changes. This indicates that HRUS alone cannot replace clinical evaluation in assessing peripheral nerve involvement in leprosy. Instead, it would be beneficial to use HRUS as a complementary tool alongside clinical examination, wherever the technology is accessible. Doing so may enhance diagnostic accuracy in more patients, especially since peripheral nerve involvement is a key diagnostic criterion for leprosy. Future research could explore whether combining HRUS with clinical assessment allows for earlier and more accurate detection of nerve involvement in leprosy cases.

 

Scroll to top

 

Scroll to top

Conflict of Interest

None declared.

• References

• 1 Scollard DM. Endothelial cells and the pathogenesis of lepromatous neuritis: insights from the armadillo model. Microbes Infect 2000; 2 (15) 1835-1843
• 2 Mattos KA, Oliveira VG, D'Avila H. et al. TLR6-driven lipid droplets in Mycobacterium leprae-infected Schwann cells: immunoinflammatory platforms associated with bacterial persistence. J Immunol 2011; 187 (05) 2548-2558
• 3 Kundu SK. Features of Ridley-Jopling classification and its application in the clinical field. Int J Lepr Other Mycobact Dis 1979; 47 (01) 64-65
• 4 Jain S, Visser LH, Praveen TL. et al. High-resolution sonography: a new technique to detect nerve damage in leprosy. PLoS Negl Trop Dis 2009; 3 (08) e498
• 5 Chen S, Wang Q, Chu T, Zheng M. Inter-observer reliability in assessment of sensation of skin lesion and enlargement of peripheral nerves in leprosy patients. Lepr Rev 2006; 77 (04) 371-376
• 6 Scollard DM, McCormick G, Allen JL. Localization of Mycobacterium leprae to endothelial cells of epineurial and perineurial blood vessels and lymphatics. Am J Pathol 1999; 154 (05) 1611-1620
• 7 Martinoli C, Derchi LE, Bertolotto M. et al. US and MR imaging of peripheral nerves in leprosy. Skeletal Radiol 2000; 29 (03) 142-150
• 8 Elias Jr J, Nogueira-Barbosa MH, Feltrin LT. et al. Role of ulnar nerve sonography in leprosy neuropathy with electrophysiologic correlation. J Ultrasound Med 2009; 28 (09) 1201-1209
• 9 Frade MA, Nogueira-Barbosa MH, Lugão HB, Furini RB, Marques Júnior W, Foss NT. New sonographic measures of peripheral nerves: a tool for the diagnosis of peripheral nerve involvement in leprosy. Mem Inst Oswaldo Cruz 2013; 108 (03) 257-262
• 10 Boom J, Visser LH. Quantitative assessment of nerve echogenicity: comparison of methods for evaluating nerve echogenicity in ulnar neuropathy at the elbow. Clin Neurophysiol 2012; 123 (07) 1446-1453
• 11 Visser LH, Jain S, Lokesh B, Suneetha S, Subbanna J. Morphological changes of the epineurium in leprosy: a new finding detected by high-resolution sonography. Muscle Nerve 2012; 46 (01) 38-41
• 12 Ihnatsenka B, Boezaart AP. Ultrasound: basic understanding and learning the language. Int J Shoulder Surg 2010; 4 (03) 55-62
• 13 World Health Organization. WHO expert committee on leprosy. World Health Organ Tech Rep Ser 2012; (968) 1-61 , 1, 61
• 14 Lieba-Samal D, Pivec C, Platzgummer H. et al. High-resolution ultrasound for diagnostic assessment of the great auricular nerve–normal and first pathologic findings. Ultraschall Med 2015; 36 (04) 342-347
• 15 Suk JI, Walker FO, Cartwright MS. Ultrasonography of peripheral nerves. Curr Neurol Neurosci Rep 2013; 13 (02) 328
• 16 Fornage BD, Nerot C. Sonographic diagnosis of tuberculoid leprosy. J Ultrasound Med 1987; 6 (02) 105-107
• 17 Shook S. Ultrasound of peripheral nerve and muscle. In: Conference for the American Society of Neuroimaging (17–20 January). Las Vegas; 2013
• 18 Thain LM, Downey DB. Sonography of peripheral nerves: technique, anatomy, and pathology. Ultrasound Q 2002; 18 (04) 225-245
• 19 Beekman R, Visser LH, Verhagen WI. Ultrasonography in ulnar neuropathy at the elbow: a critical review. Muscle Nerve 2011; 43 (05) 627-635
• 20 Venugopal R, Binesh VG, Puthussery PV, George S, Asokan N. Comparison of high resolution ultrasonography with clinical examination in the assessment of peripheral nerve involvement in leprosy. Indian Dermatol Online J 2021; 12 (04) 536-540
• 21 Ashwini B, Nanda Kishore B, Basti RS, Martis J, Hundi GK, Jayaraman J. Ultrasound as a diagnostic modality for the involvement of peripheral nerves in leprosy. Indian J Lepr 2018; 90 (01) 1-4
• 22 Kumaran MS, Thapa M, Narang T, Prakash M, Dogra S. Ultrasonography versus clinical examination in detecting leprosy neuropathy. Lepr Rev 2019; 90 (04) 364-370
• 23 Dugad K, Pathak S, Rastogi R. Role of high-resolution ultrasonography in leprosy. Asian J Med Sci 2022; 13 (11) 246-253

Publikationsverlauf

Artikel online veröffentlicht:
16. September 2025