Application and Research Progress of High Frequency Ultrasound in the Diagnosis of Chronic Inflammatory Neuropathies

In recent years, clinicians have gradually improved their understanding of multiple neuropathy and have done some studies about chronic inflammatory neuropathies, for example, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, and Lewis-Sumne syndrome. The early diagnosis is very important for the next step treatment and long-term prognosis. At present, the disease mainly depends on clinical and neural electrophysiological examination, but imaging studies are few. In recent years, with the rapid development of high frequency ultrasound, it could clearly show the morphology of the nerve, and it has been an emerging diagnosis tool of polyneuropathies. This article mainly reviews the application and the latest research progress of high frequency ultrasound in these diseases.


INTRODUCTION
The diagnosis of chronic inflammatory neuropathies could be challenging (1,2). The current diagnostic criteria are mainly based on both clinical and electrophysiological parameters. Particularly in chronic inflammatory neuropathies cases with atypical clinical presentation or at early stages of the diseases, the early diagnosis rate is low, and it lacks quantitative criteria for assessing disease activity and treatment response, leading to severely affecting long-term prognostic effects of such diseases. Recent studies have shown that nerve ultrasound has a high sensitivity and acceptable specificity in a cohort of consecutive patients with a clinical suspicion of chronic inflammatory demyelinating polyneuropathy, Lewis-Sumner syndrome, and multifocal motor neuropathy, thereby improving identification of patients who may respond to treatment (3)(4)(5). Exploring the imaging characteristics of high-frequency ultrasound could help to establish combined diagnostic criteria for chronic inflammatory neuropathies, improve the accuracy of early diagnosis, and facilitate the follow-up of diseases.

THE ULTRASOUND RESEARCH PROCESS OF CHRONIC INFLAMMATORY NEUROPATHIES Chronic Inflammatory Demyelinating Polyneuropathy
The Ultrasound Imaging Features of Chronic Inflammatory Demyelinating Polyneuropathy The chronic inflammatory demyelinating polyneuropathy is an immune-mediated chronic sensorimotor polyneuropathy characterized by proximal limb weakness, weakened tendon reflex, and sensory abnormalities in distal limb, but it also includes rare clinical variants such as simple sensory abnormalities, simple motor abnormalities, and limb asymmetry (6, 7). High-frequency ultrasound can probe the morphological changes in the peripheral nerves to indirectly reflect the neuropathological changes of chronic inflammatory demyelinating polyneuropathy, so it could contribute to diagnosis and treatment (8)(9)(10). Several studies confirmed that nerve enlargement occurred in over 90% of patients with chronic inflammatory demyelinating polyneuropathy whether treated or not, but it had a different degree and morphologies. Specific results showed that the cross-sectional area of new chronic inflammatory demyelinating polyneuropathy and long-termtreated chronic inflammatory demyelinating polyneuropathy increased. The ultrasound pattern sum score system: chronic inflammatory demyelinating polyneuropathy scores were higher than new chronic inflammatory demyelinating polyneuropathy. It had also shown that newly developed chronic inflammatory demyelinating polyneuropathy nerve enlargement was mostly localized, however, chronic inflammatory demyelinating polyneuropathy was generalized. The uniformity score results showed that chronic inflammatory demyelinating polyneuropathy had higher points than new chronic inflammatory demyelinating polyneuropathy (11,12). Nerve enlargement mainly occurred in the upper limb proximal nerve segments and the arm plexus (13,14), and ultrasound had a high diagnostic rate of evaluation of nerves in these areas (13). In addition to nerve enlargement, there were increased blood flow signals, enhanced echo or disappearance of normal nerve structures (8,14). Most studies had found a relationship between nerve enlargement and slow motor conduction velocity (9). Padua and colleagues found that nerve enlargement was more pronounced in patients with longer disease duration and that echo at the disappearance of normal nerve tract structure was decreased (14).
In addition, some studies found that chronic inflammatory neuropathies had higher echoes compared to axonal neuropathy in the ulnar nerve of the forearm, the median nerve in the forearm and upper arms, and the arm plexus, which was statistically significant, and it could contribute to the identification of disease. Since most studies are monocentric, further multicentre studies of the ultrasound aspects of chronic inflammatory demyelinating polyneuropathy are required.

Monitoring Disease Treatment Response With HFUS
A scoring tool of standardized method or Ultrasound Pattern Sum Score can better monitor the treatment response, specifically, the changes before and after treatment can be quantified by measuring the cross-sectional area of nerves. Some studies reported that the extent of nerve enlargement attenuated or disappeared after a period of treatment (17). On the other hand, it had been observed that patients with hypoecho nerve enlargement had better treatment effect compared to those with no nerve enlargement or increased echo (13,14).

Multifocal Motor Neuropathy
The Ultrasound Imaging Features of Multifocal Motor Neuropathy Multifocal motor neuropathy is an immune-mediated, simple motor neuropathy characterized by slow disease progression, a typical limb asymmetry muscle weakness that can be accompanied by muscular atrophy (18)(19)(20)(21). The characteristic electrophysiological examination criterion for multifocal motor neuropathy is the conduction block at common neurojammed sites (22). Nerve ultrasound imaging features contribute to diagnosis and differential diagnosis of multifocal motor neuropathy. Nerve enlargement of multifocal motor neuropathy, which often represents mild multifocal and asymmetry compared to chronic inflammatory demyelinating polyneuropathy, was mainly found in the arm plexus and large peripheral nerve in the extremities (23, 24). The study showed that multifocal nerve enlargement could distinguish multifocal motor neuropathy from healthy control subjects with a sensitivity of 87-100% and a specificity of 94-100% (25)(26)(27). The ratio of CSA differences of intra-and internerve and one side and other side [two ultrasound scoring systems (28,29)] was also increased in multifocal motor neuropathy patients (24,30). Individual nerve bundles within the nerve may also have varying degrees of enlargement, while adjacent bundles are intact (31). Thus, asymmetric multifocal nerve enlargement may indicate multifocal motor neuropathy, but further studies remain to determine the specificity of this finding, compared to other polynerves, such as asymmetry variants of chronic inflammatory demyelinating polyneuropathy. Some studies showed that the multifocal motor neuropathy group was more pronounced in the median forearm nerve, the ulnar nerve, and the tibia nerve, compared with normal controls. Neuroelectrophysiological examination indicated that it had lower nerve conduction velocity and compound muscle action potential at the upper arm nerve. The multifocal motor neuropathy group had important relationship between CSA of the median nerve in the upper arm and the compound muscle action potential (correlation r = 0.851). The multifocal motor neuropathy group had a higher "difference ratio of CSA between one side and the other" in the median, ulnar, and fibula nerve levels, with no significant change in the tibial and brachial plexus levels. Compared with chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy patients predominantly showed reduced echo of nerve enlargement areas (31). It rarely found increased echo compared to Lewis-Sumner syndrome and chronic inflammatory demyelinating polyneuropathy, which may contribute to the differential diagnosis of multifocal motor neuropathy and other major motor neuropathies.

Monitoring Disease Treatment Response With HFUS
Recently, it is rarely known about the treatment response and ultrasound application development of multifocal motor neuropathy. A recent study, following up 17 treated multifocal motor neuropathy patients for several months, firstly, demonstrated the degree of nerve enlargement was not proportional to clinical presentation, and secondly, the Ultrasound Pattern Sum Score score demonstrated a significant correlation between changes in motor nerve dysfunction and changes in ultrasound imaging regardless of the disease development (32).

The Ultrasound Imaging Features of Lewis-Sumner Syndrome
Lewis-Sumner syndrome belongs to a variant of chronic inflammatory demyelinating polyneuropathy, an autoimmune disease, mainly showing limb asymmetric sensory, motor peripheral neuropathy. The most commonly involved nerves are the median nerve and the ulnar nerve. The electrophysiological examination has the motor nerve block, and the pathological characteristics are mainly mild demyelinating lesions.
No studies analyzed lewis-sumner syndrome as a single entity, but many studies described its ultrasound performance second only to chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy (33). Overall, researchers agreed that most Lewis-Sumner syndrome patients had nerve enlargement. In many cases, neuromorphological changes were similar to chronic inflammatory demyelinating polyneuropathy, with nerve enlargement ranging from mild to widespread.  However, recent studies showed that Lewis-Sumner syndrome nerve enlargement was mainly regional and limited to a single major nerve tract, rarely affecting asymmetric distributed nerve in the arm and roots (34). Interestingly, the echo intensity of enlarged nerves usually decreased, but sometimes also increased, with as described by chronic inflammatory demyelinating polyneuropathy, and the cranial nerves were more susceptible in Lewis-Sumner syndrome than in chronic inflammatory demyelinating polyneuropathy, such as vagus enlargement (35,36). In summary, the Lewis-Sumner syndrome ultrasound morphology behaved similar to an overlapping chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy. This may explain the intermediate treatment response and Lewis-Sumner syndrome clinical presentation, sometimes like typical chronic inflammatory demyelinating polyneuropathy, sometimes like multifocal motor neuropathy. However, Lewis-Sumner syndrome generally reflected nerve enlargement of the sensory nerve, which can be distinguished from multifocal motor neuropathy (25).
Specific cases were shown in Figure 3 (32).

Monitoring Disease Treatment Response With HFUS
With regard to ultrasound changes during treatment, most investigators found recoverance of enlarged nerves in response to treatment (17,37). It had also been reported that nerve enlargement continued with despite improved clinical symptoms (36). However, prospective studies of disease and ultrasound monitoring remain unknown.

THE CLINICAL ULTRASOUND SCORING SYSTEM Bochum Scoring
Measuring: the ulnar nerve in the Guyon canal; the ulnar nerve in the upper arm; the radial nerve in the spiral groove; the sural nerve in the calf Recording: every site scored one point, then added together Results: identification of chronic inflammatory demyelinating polyneuropathy from multifocal motor neuropathy and Lewis-Sumner syndrome (CSA cutoff value≥ 2). Sensitivity was 80%, and specificity was 87.5% (38). Specific cases were shown Table 1 (13).
Results: In chronic inflammatory demyelinating polyneuropathy the enlargement was regional, homogeneous, or inhomogeneous with equal contribution. In multifocal motor neuropathy rebional enlargement next to normal segments predominated (25).

Intra-and Internerve CSA Variabiity and Difference Ratio Between One Side and the Other Side
Measuring: any of the two nerves Recording: Intranerve variability: the ratio of the maximum and the minimum CSA. Internerve variability: the ratio of the maximum and minimum of intranerve variability. The difference ratio between one side and other side: the ratio of maximum and minimum nerve variability.
Results: The ratio of intra-and internerve of multifocal motor neuropathy were higher than chronic inflammatory demyelinating polyneuropathy. Compared with multifocal motor neuropathy, chronic inflammatory demyelinating polyneuropathy had a higher ratio of intra-and internerve, but its ratio of one side and other side were lower.

SUMMARY
As clinicians' awareness of chronic inflammatory neuropathy gradually increases, and the continuous development of high-frequency ultrasound, there are increasing studies about the clinical application of nerve ultrasound. The researchers explored the ultrasound characteristics of the disease, and it had a high specificity and sensitivity. The chronic inflammatory neuropathies mainly show nerve enlargement, increased blood flow signals, enhanced echo, or disappearance of normal nerve structures, morever, there are some few differences of them. However, the current study was small-sample studies, there were still limitations, and large-sample multicenter studies are needed in the future. Moreover, researchers should combine with the new ultrasound technology, such as elastography, ultrasound imaging, microvascular imaging, to continue to explore the ultrasound manifestations of such diseases, optimize the neural ultrasound scoring system, quantifying the diagnostic criteria for nerve ultrasound as well as the post-treatment evaluation system to better serve the clinical practice and meet the requirements of precision medicine.

AUTHOR CONTRIBUTIONS
All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.

FUNDING
This work was supported by grants from Qingdao Medical Research Guidance Plan of 2020 (No. WJZD018).