Nerve Ultrasound Protocol to Detect Dysimmune Neuropathies

Anna Lena Fisse; Kalliopi Pitarokoili; Ralf Gold

doi:10.3791/62900

Medicine

Nerve Ultrasound Protocol to Detect Dysimmune Neuropathies

Published: October 7, 2021 doi: 10.3791/62900

Anna Lena Fisse^1,2, Kalliopi Pitarokoili^1,2, Ralf Gold^1,2

¹Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, ²Immunmediated Neuropathies Biobank (INHIBIT), Ruhr-University Bochum

Summary

This article presents a protocol for nerve ultrasound in polyneuropathies to aid the diagnosis of inflammatory neuropathies.

Abstract

Nerve ultrasound is increasingly used in the differential diagnosis of polyneuropathy as a complementary tool to nerve conduction studies. Morphological alterations of the peripheral nerves, such as increasing the cross-sectional area (CSA), have been described in various immune-mediated polyneuropathies. The most prominent morphological changes in nerve ultrasound have been described for the chronic inflammatory demyelinating polyneuropathy (CIDP)-spectrum disease. CIDP may be distinguished from hereditary and other polyneuropathies by measuring the extent and pattern of nerve swellings (CSA increase). Typical findings in demyelinating inflammatory neuropathies are multifocal nerve swellings with inhomogeneous fascicular structure, while CSA increase in demyelinating hereditary neuropathies occurs in a more generalized and homogenous manner. In other non-inflammatory axonal neuropathies, nerves can appear with normal or slight CSA increases, especially in typical entrapment sites. This article presents technical requirements for nerve ultrasound, an examination procedure using a standardized examination protocol, current reference values for the CSA, and typical sonographic pathological findings in patients with inflammatory neuropathies.

Introduction

Next to clinical examination, evaluating any large-fiber polyneuropathy includes an electrophysiological examination to characterize the motor or sensory system's involvement and differentiate axonal from demyelinating damage¹. In axonal polyneuropathy, toxic and diabetic neuropathy are the leading causes, while in demyelinating polyneuropathies, hereditary or inflammatory neuropathies such as CIDP should be considered²^,³^,⁴. Commonly used diagnostic criteria for CIDP are the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) criteria established in 2005 and revised in 2010 and 2021⁵. These define clinical and electrophysiological criteria to diagnose CIDP and describe additional criteria such as nerve biopsy to detect demyelination or inflammation. However, in some cases, despite a thorough diagnostic workup, the cause of neuropathy remains ambiguous. In these cases, nerve ultrasound offers a complementary method to examine the nerves not functionally but morphologically⁶. Several studies proved the use of nerve ultrasound as an additional tool in diagnosing CIDP, so that the 2021 revised EFNS/PNS criteria implemented nerve ultrasound in the guideline⁵. The advantage of nerve ultrasound compared to other imaging methods such as magnet resonance neurography (MRN) is that it can be used directly by the treating neurologists as a bedside tool; it is relatively cost-efficient. It can be used repeatedly, as it is noninvasive and not painful.

Typical characteristics of CIDP observed in nerve ultrasound are cross-sectional-area (CSA) increase⁷^,⁸, also found in hereditary polyneuropathies. In CIDP, this affects individual nerve segments heterogeneously⁷^,⁹.

A variety of examination protocols have been published¹⁰^,¹¹^,¹²^,¹³^,¹⁴^,¹⁵ trying to clarify normal CSA values and determine the adequate anatomical positions of ultrasound examination. Some of these positions are similar in most examination protocols. However, a widely accepted protocol to standardize the examination process and simplify the interpretation of the measurements does not exist.

This article demonstrates the nerve ultrasound examination using a standardized protocol for polyneuropathies, presents various reference values for the CSA, and shows typical pathological findings in patients with inflammatory neuropathies.

Technical requirements for nerve ultrasound
The neuromuscular ultrasound is performed in B-mode (Brightness mode, two-dimensional image with gray levels) using the compound imaging of the corresponding sonographic device⁶^,¹⁶. Compound imaging enables electronic control of the piezoelectric elements in the sonic probe (transducer) to illuminate the target structure from different angles¹⁷. The ultrasound waves are reflected in several directions due to the histological structure of the peripheral nerves. As a result of the sound coming from different angles, a more significant part of the otherwise lost reflections gets back to the sound probe (receiver) and can generate images. For neuromuscular ultrasound, a high-resolution ultrasound probe with 18 MHz linear array transducer, for deeper nerves, an additional 12 MHz linear array probe (e.g., to display tibial and fibular nerve in the popliteal fossa) is used⁶^,¹⁶. Transducers with lower frequencies result in reduced spatial and lateral resolution so that the differentiation of the nerve boundaries from the surrounding structures is less precise. The optimal settings can be kept constant using a preset for neuromuscular imaging provided by the manufacturer. During the examination, the image depth and the focus position must be adjusted to the structure to be examined and constantly adapted to the position of the nerve. The B-image gain and the depth-dependent gain can be adjusted for image optimization with uniform brightness. Blood vessels are often close to neural structures and are often used as landmarks to make the measurements at the same position. To depict their anatomical interaction and distinguish between nerves and vessels, it is also necessary to display the flow velocity and direction using pulsed Doppler and color-coded duplex sonography¹⁶^,¹⁸. The pulse repetition frequency must be adapted to the expected low flow velocities in the blood vessels of the extremities, or the power Doppler must be selected for color-coding¹⁶.

Nerves reflect the ultrasound waves differently from different angles of incidence so that the sonographic image varies in echogenicity (anisotropy)¹⁶^,¹⁹. The best image is achieved from an orthograde angle since the ultrasonic waves are reflected most strongly by the nerves in this angle. For avoiding artificial anisotropy or nerve deformity, the probe must therefore be held in a neutral position during the examination without applying additional pressure perpendicular to the nerves (Figure 1). The cross-sectional area (CSA) is measured within the thin, hyperechoic epineurium (Figure 2) to avoid alterations of the epinerval tissue in the measurement¹⁹. More details on technical ultrasound can be found in References⁶^,¹⁶^,¹⁷^,¹⁸^,¹⁹^,²⁰^,²¹.

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Protocol

All examinations for this work were performed in compliance with institutional guidelines of the Ruhr-University Bochum, Germany.

1. Experimental preparations

Patient preparation
1. Check the patient inclusion criteria: examine adult patients diagnosed with polyneuropathy, suspicious of inflammatory origin.
2. Check the patient exclusion criteria: do not examine patients with open wounds or infections in the regions to be examined.
Instrumental checkpoints
1. Check the integrity of the ultrasound machine and all the materials used (see Table of Materials).
2. Enter patient name and details in the ultrasound machine before starting the ultrasound examination (depending on the machine).
3. Choose an appropriate ultrasound probe (preferred 14-18 MHz) (see Table of Materials) and preset for the neuromuscular ultrasound.
4. During the whole examination, adjust the depth and focus on obtaining optimal image quality.
5. Whenever possible, examine the complete course of each nerve in a cross-sectional view.
  NOTE: The nerves recommended for examination are: median, ulnar, radial nerve, cervical roots, brachial plexus, and vagal nerve, as well as tibial, fibular, and sural nerve (Figure 3). The examination of each of these nerves is shown in the next section and the video. The entire ultrasound examination according to the following protocol will take ~30-45 min.

2. Ultrasound examination

Start examining the arm nerves with the patient sitting in a neutral position with the arm resting supinated on a surface, e.g., the leg.
Place some ultrasound gel over the transducer probe, the wrist, the forearm, the elbow, and the upper arm.
For examination of the median nerve, start by performing a transverse scan at the wrist level.
Move proximally to follow the anatomical course of the median nerve to the upper arm.
Measure the CSA of the median nerve at the following sites: at the entrance to the carpal tunnel (retinaculum flexorum); at the forearm (10-15 cm proximal to retinaculum flexorum; at the elbow (crook of the elbow); at the upper arm next to the brachial artery (at the middle of the distance between the medial epicondyle and axillary fossa).
For examination of the ulnar nerve, start by performing a transverse scan at the level of the wrist ulnar to the median nerve.
Move proximally to follow the anatomical course of the ulnar nerve along the sulcus to the upper arm.
NOTE: Moving toward the upper arm, let the patient raise the arm bent at the elbow to examine the sulcus and upper arm.
Measure the CSA of the ulnar nerve at the following sites: at the entrance to Guyon's canal; at the forearm (10-15 cm proximal to Guyon's canal); at the elbow (between the medial epicondyle and olecranon); at the upper arm (at the middle of the distance between the medial epicondyle and axillary fossa).
To examine the radial nerve, let the patient hold the arm in front of the stomach bent in the elbow and scan the radial nerve directly next to the humerus.
Use color duplex mode to avoid confusion with the accompanying artery and vein.
NOTE: Color duplex mode shows blood flow in arteria profunda brachii, and might show low flow in the corresponding vein, while no flow occurs in the radial nerve. Additionally, the vein can be compressed by exerting external pressure, and the nerve cannot.
Measure the CSA of the radial nerve at the following site: radial nerve in the spiral groove.
Carry on with the examination of the vagal nerve, cervical nerve roots, and the brachial plexus.
Place ultrasound gel at the middle of the neck.
To examine the vagal nerve, perform a transverse scan at the middle of the neck and find the carotid artery.
NOTE: The vagal nerve can be found directly next to the carotid artery and jugular vein.
Measure the CSA of the vagal nerve at the following site: at carotid sheath at the level of the carotid bifurcation.
For the examination of cervical nerve roots, C5, C6, C7 move the probe dorsal and a little up and down.
NOTE: The cervical nerve roots appear between the anterior and posterior tubercle of the transverse process. C7 can be recognized by the absence of the anterior tubercle from its transverse process, while both anterior and posterior tubercles are found with the other cervical nerve roots.
Measure either the CSA or the diameter of the cervical nerve roots at the most proximal location possible, where the nerve root exits over the transverse process: C5; C6; C7.
To examine the brachial plexus, follow the anatomical course of the cervical nerve roots distally and find them perform trunks and cords.
Measure the CSA of the plexus at the following sites: Intrascalene space (between anterior and medial scalene muscle); Supraclavicular space (next to A. subclavia).
Carry on with the examination of the leg nerves.
Let the patient lie down to one side with the legs slightly bent. Place some ultrasound gel over the transducer probe, the popliteal fossa, the fibula, the malleolus, and the lower leg.
For examination of the fibular nerve, feel the fibular head, place the transducer directly behind it, and then follow the course of the nerve to the popliteal fossa.
Measure the CSA of the fibular nerve at the following sites: just proximal to the ﬁbular head; in the popliteal fossa.
To examine the tibial nerve in the popliteal fossa, find the fibular nerve and the popliteal artery in the popliteal fossa.
NOTE: The tibial nerve can be found just above the popliteal artery in most cases.
Measure the CSA of the tibial nerve at the following site: in the popliteal fossa.
For examination of the tibial nerve at the ankle, place the probe directly behind the medial malleolus.
NOTE: The tibial nerve can be found just next to the posterior tibial artery in most cases.
Measure the CSA of the tibial nerve at the following site: at the level of the medial ankle.
For examination of the sural nerve, place the probe at the lateral ankle.
NOTE: The sural nerve can be found next to a superficial vein in most cases.
Follow the anatomical course of the sural nerve proximally to the lower leg.
Measure the CSA of the sural nerve at the following site: between the lateral and medial head of the gastrocnemius muscle.
Perform all measurements on both sides.
Save the results of all the measurements (depending on the ultrasound machine) and end the examination.
NOTE: Figure 3 gives an overview of all measuring sites for CSA.

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Representative Results

Each ultrasound laboratory should establish its CSA reference values by collecting data from the healthy local population, as specific ultrasound machines and examiner or population-dependent variables can lead to slightly different results in each laboratory. However, to indicate which CSA values can be considered normal, data from two leading German nerve ultrasound groups and a recent meta-analysis of all published reference values so far¹³^,¹⁴^,¹⁵^,²²^,²³ are summarized in Table 1. Reference values for patients studied under this protocol in our department are those by Kerasnoudis et al.²² (Table 1).

Typical findings in demyelinating inflammatory neuropathies are multifocal nerve swellings with inhomogeneous fascicles, while nerve swellings in demyelinating hereditary neuropathies occur more generalized and homogenous¹²^,²⁴. The histologic correlate of increased CSA is assumed to be acute inflammation and repeated de- and remyelination; however, this remains to be investigated⁷. In other non-inflammatory axonal neuropathies, nerves can appear normal or slightly increased in size, especially in typical entrapment sites²⁵^,²⁶^,²⁷^,²⁸.

To simplify the interpretation of the results, the adjusted Bochum Ultrasound Score is suggested as a scoring system, which helps to distinguish chronic inflammatory neuropathies such as CIDP from non-inflammatory neuropathies.

The adjusted Bochum Ultrasound Score is calculated from the number of sites with significantly enlarged CSA of six of the above-described measurement sites: median nerve at the forearm, the median nerve at the upper arm, ulnar nerve at the forearm, ulnar nerve at the upper arm, the radial nerve at the upper arm and sural nerve at the calf. Examination of only these six sites will take ~15 min. Each of these six sites is scored with 1 point if the nerve shows pathological CSA enlargement on one or both sides of the body. Thus, the minimum score is 0 points, and the maximum score is 6 points. With this scoring system, if ≥2 points are assigned, the diagnosis of CIDP is possible with a sensitivity of ~53% and a specificity of ~83%, even if additional axonal damage in nerve conduction studies results in difficult detection by electrophysiological criteria.

Different groups have proposed other scoring systems to differentiate between neuropathies¹⁰^,¹¹^,¹⁸^,²⁹^,³⁰. None of these scores is widely used. The adjusted Bochum Ultrasound Score is based on earlier publications which describe the Bochum Ultrasound Score¹⁰ derived from four measurement sites to distinguish CIDP from Guillain-Barré Syndrome and the Nerve ultrasound protocol³⁰ derived from nine measurement sites to differentiate CIDP from MMN, MADSAM and vasculitic or paraproteinemic neuropathy. These different scores should be used according to the exact question. The adjusted Bochum Ultrasound Score was developed to diagnose CIDP if nerve conduction studies show possible CIDP defined by electrophysiological EFNS/PNS criteria⁵.

However, even if the adjusted Bochum Ultrasound Score only uses six nerve sites for calculation, still all other described nerve sites and the whole course of each nerve should be examined to detect focal lesions³¹ or exclude homogenous enlargement. In the case of homogenous nerve enlargement, hereditary neuropathy should be considered²⁴. Scoring systems for homogeneity and alterations of the fascicular structure were described before and may aid in evaluating homogeneity⁸^,²⁴^,³².

For ultrasound images of a healthy person, see Figure 4; for example, images from a CIDP patient, see Figure 5.

Figure 1: Examination of the median nerve at the wrist. To avoid artificial anisotropy or nerve deformity, the probe must be held in a neutral position during the examination without applying additional pressure perpendicular to the nerves. Please click here to view a larger version of this figure.

Figure 2: Measurement of the cross-sectional area (CSA). The cross-sectional area is measured within the thin, hyperechoic epineurium. Please click here to view a larger version of this figure.

Figure 3: Overview of measuring sites for CSA. Blue stars - median nerve, green stars - ulnar nerve, red star - radial nerve, pink star - vagal nerve, yellow stars - cervical roots and brachial plexus, white stars - fibular nerve, purple stars - tibial nerve, brown star - sural nerve. Please click here to view a larger version of this figure.

Figure 4: Example images of a healthy person of the six nerve sites used in adjusted Bochum ultrasound score. A - median nerve at the forearm, B - median nerve at the upper arm, C - radial nerve at the upper arm, D - ulnar nerve at the forearm, E - ulnar nerve at the upper arm, F - sural nerve at the calf. Please click here to view a larger version of this figure.

Figure 5: Example images of a patient with CIDP of the six nerve sites used in adjusted Bochum ultrasound score. A - median nerve at the forearm, B - median nerve at the upper arm, C - radial nerve at the upper arm, D - ulnar nerve at the forearm, E - ulnar nerve at the upper arm, F - sural nerve at the calf. Please click here to view a larger version of this figure.

		Kerasnoudis et al.²²		Grimm et al.²³	Meta-Analysis by
		Kerasnoudis et al.²²		Grimm et al.²³	Fisse et al.^13-15
Nerve	Site	mean CSA	standard deviation	mean CSA	mean CSA	95% CI
Nerve	Site	(mm²)	standard deviation	(mm²)	(mm²)	(mm²)
Median nerve	Wrist	8.43	2.07	10.6	8.3	7.9 - 8.7
	Forearm	6.6	1.6	7.2	6.4	5.9 - 6.9
	Elbow	-	-	9.2	-	-
	Upper arm	8.4	2.87	9.1	8.3	7.5 - 9.0
Ulnar nerve	Guyon loge	5.16	1.03	-	4.1	3.6 - 4.6
	Forearm	5.46	1.26	5.9	5.2	4.8 - 5.7
	Elbow	5.33	1.4	8.7	5.9	5.4 - 6.5
	Upper arm	6.53	1.82	7	6.6	5.1 - 6.1
Radial nerve	Upper arm	3.26	1.52	-	5.1	4.0 - 6.2
Vagal nerve	Carotid sheath	-	-	2.2	2.2	1.5 – 2.9
C5		-	-	2.4*	5.6	4.6 – 6.7
C6		-	-	3.4*	8.8	7.4 – 10.3
C7		-	-	-	9.5	8.0 – 10.9
Brachial plexus	Intrascalene space	30.93	10.82	-	-	-
	Supraclavicular space	46.13	18.27	-	-	-
Fibular nerve	Fibula Head	7.1	2.3	-	8.4	6.8 – 9.9
	Popliteal fossa	8.60	1.77	8.4	7.9	6.6 – 9.2
Tibial nerve	Popliteal fossa	8.43	2.68	23.2	25.9	17.5 – 34.4
	Malleolus	6.36	1.45	10.2	10	7.7 – 12.4
Sural nerve	Heads of gastrocnemius muscle	1.82	0.64	2.2**	2.4	1.7 – 3.1
* Grimm et al.²³ measured diameter, not the CSA for C5 and C6 root.
** Grimm et al.²³ measured sural nerve at the lateral ankle.

Table 1: Reference CSA values for patients. Proposed reference values are based on the publication of Kerasnoudis et al.²², Grimm et al.²³ and a recent meta-analysis by Fisse et al.¹³^,¹⁴^,¹⁵. Reference values for patients studied in our department under the protocol presented here are those by Kerasnoudis et al.²².

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Discussion

Nerve ultrasound is a helpful additional diagnostic tool in polyneuropathies. It can give information on the possible causes of polyneuropathy depending on the extent and pattern of nerve enlargement. Moreover, CSA alterations in the longitudinal disease course of patients with CIDP were described to correlate to clinical disease course and treatment response³³^,³⁴^,³⁵^,³⁶.

Critical steps within the protocol
For obtaining reproducible results, consistent methodology and standardization of the examinations are essential³⁷^,³⁸. Each examiner must consider deviations resulting from different ultrasound devices and local differences of demographics. To ensure the high quality and reproducibility of ultrasound measurements, specific training of the examiner is also necessary¹³^,¹⁴^,¹⁵^,²¹^,³⁹.

Modifications and troubleshooting of the technique
Typical findings in demyelinating inflammatory neuropathies are multifocal nerve swellings with inhomogeneous fascicles³³^,⁴⁰. Therefore, the measurement of CSA of specific nerve sites is necessary, but the whole nerve must be scanned. Also, evaluation of fascicular structure and echogenicity can help in inconclusive cases, as not only CSA increase of the entire nerve but also intrafascicular swellings as well as hypoechoic and hyperechoic nerves are found in CIDP. Hypoechoic nerves are considered to result from acute edema, while hyperechoic nerve result from fibrous remodeling⁴⁰^,⁴¹.

Limitations of the technique
There are anatomical limitations for nerve ultrasound, i.e., examination of cervical nerve roots can be difficult to impossible in patients with obesity and short neck. Also, imaging of proximal nerve roots of the lower extremity nerves of the lumbosacral plexus is not possible due to the limited penetration depth of the ultrasonic rays. An alternative method, evaluating these nerves, is possible by MRN⁴², but ultrasound is the more common method due to its spatial and temporal flexibility and cost-effective use⁴³.

Significance with respect to existing methods
Nerve ultrasound is recommended as an additional and complementary tool in diagnosing polyneuropathies to evaluate nerve morphology. Standard diagnostic workouts, including nerve conduction studies and other tools such as cerebrospinal fluid analysis, should still be performed.

Future applications of the technique
For experts in polyneuropathies, nerve ultrasound is of interest for diagnosis in clinical routine and as it can give insights into possible pathophysiologic aspects, i.e., represent inflammation. Therefore, nerve ultrasound is a promising method not only in clinical use but also in neuromuscular research. Also, with increasing progress in ultrasound technology, future ultrasound characteristics such as shear wave elastography or vascularization of peripheral nerves may add further aspects in assessing polyneuropathies.

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Disclosures

The authors declare no conflicts of interest related to this manuscript.

Acknowledgments

We acknowledge the support from Ruhr-University Bochum for our research on neuromuscular ultrasound.

Materials

Name	Company	Catalog Number	Comments
Affiniti 70	Philips GmbH	n/a	with preset for neuromuscular ultrasound
L18-5 linear array transducer	Philips GmbH	n/a
Ultrasound gel	C + V Pharma Depot GmbH	n/a

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