The high resolution sonography

On the one hand, high-resolution sonography enables a better differential diagnosis of the causes of polyneuropathy. On the other hand, this method provides valuable information in the context of follow-up measurements, especially in combination with electrophysiology and other imaging techniques. In contrast to the latter, high-resolution sonography is still a young research subject.

The quality of sonography for the examination of the peripheral nervous system has improved significantly over the past 20 years. High detail resolution, interactivity and reproducible results have made a wide range of pathologies visible. In addition to compression syndromes, traumatic lesions and tumors, inflammatory diseases of the peripheral nerves can also be visualized with a high degree of diagnostic certainty.

Polyneuropathies (PNP) represent a group of diseases that involve motor, sensory, and autonomic nerve fibers in multiple nerves to varying degrees. The most common causes in our latitudes are diabetes mellitus and alcohol abuse. In addition, drugs, especially chemotherapeutic agents, as well as other toxic substances can trigger PNP. Genetically determined PNP are rarer in comparison. An important, because therapeutically relevant group of PNP are the immunologically caused neuropathies. For their differential diagnosis, high-resolution ultrasound has become a valuable tool.

The advancement of transducers and image processing and artifact correction software in the sonography devices enables the highest quality imaging of peripheral nerves. Vascularization is assessed in addition to cross-sectional area, individual fascicles in the nerve, and echogenicity [1]. The size of the fascicles plays an important role in distinguishing neuropathies. In hereditary Charcot Marie Tooth disease (especially type Ia), the fascicles are homogeneously enlarged. In CIDP and even more so in MMN, they are heterogeneous and thickened especially in the proximal sections of the brachial nerves, whereas other fascicles in the same nerve section present normally [2]. The quality of the images is in no way inferior even in direct comparison with the surgical site and histology [3,4].

Immune Neuropathies

Immune neuropathies are divided into acute and chronic inflammatory neuropathies. The typical representative of acute inflammatory neuropathies is Guillain-Barré syndrome (GBS). Representatives of the chronic inflammatory form are Multifocal Motor Neuropathy (MMN) and Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) with their various manifestations. Both diseases are based on an autoimmune inflammatory reaction against specific components of the peripheral myelin sheath [7].

Immunopathologically, GBS and CIDP are characterized by infiltration of peripheral nerves by lymphocytes and macrophages, with macrophages in particular being found early in the disease. Infiltration of immune cells leads to demyelination of axons and secondary axonal damage. A primary immunological attack on the axons is also possible. Inflammatory edema, axonal sprouting, de- and remyelination with the formation of “onion bulbs” and later epineural fibrosis are held responsible for the swelling of the nerves [7,8].

High resolution sonography of the MMN

MMN is an acquired disease with slow progression, first described in 1986. It shows a marked increase in cross-sectional area on the nerves of the arm (especially median nerve throughout its course, less ulnar nerve) and on the tibial nerve at the level of the ankle. The proximal nerve segments of the arm are more affected than the distal ones. The brachial plexus rarely shows abnormalities, and the proximal portion of the tibial nerve and the sensory nerves (e.g., sural nerve) are also unremarkable. The differential involvement of both sides and the alternating distension of each fascicle along the course of the nerve is typical, resulting in intranerve cross-sectional variability [9,10].

Sonographic findings do not correlate with clinical severity of disease. The correlation to electrophysiological findings is weak. The nerve segments with abnormal electrophysiological findings (conduction block) were usually also affected on sonography. However, in more than 70%, pathologic findings on sonography were detected even in electrophysiologically unaffected nerve segments. This is taken as an indication that morphological changes are likely to occur before functional disturbances [9,10].

Follow-up studies in treated patients (intravenous immunoglobulin administration 0.5-2 g/kg body weight every 1-3 months) show no significant reduction in nerve thickness, despite clinical improvement. However, the nerve pathology expands and becomes more homogeneous compared to the initial variability [9].

Differential diagnosis between MMN, CIDP and amyotrophic lateral sclerosis (ALS)

Inflammatory neuropathies are characterized by an increase in the cross-sectional area of the nerves (thickening of the nerve), which is also visible in electrophysiologically unaffected nerve sections. Whereas in MMN the median nerve at the level of the upper arm is particularly affected asymmetrically, in CIDP this is the brachial plexus. CIDP is more homogeneous compared to MMN, affecting both sides and fascicles more uniformly in cross-section [11–13]. In chronic axonal neuropathies and in ALS, the cross-sectional areas of the nerves are normal, and in advanced cases, slightly atrophic [14,15].

MRI is used by means of MR neurography in the differential diagnosis of neuropathies. Gadolinium uptake was not seen in either MMN or CIDP. The MRI findings correlate very well with the sonographic findings. Both methods complement each other, because the nerves at the thigh or lumbar plexus cannot be qualitatively depicted sufficiently in sonography, on the other hand long stretches of nerves can only be examined in MRI in a time-consuming way and a dynamic examination in MRI is not possible at all. The combination of MRI and ultrasound can confirm the clinical and electrophysiological diagnosis in 80-90% of patients (Fig. 2) [16], whereas each method alone correctly diagnoses only 70-80% of patients [12,15].

Sonography and electrophysiology in CIDP.

Motor nerve conduction velocity was significantly slowed in the thickened nerve sections. Conversely, the cross-sectional area in the electrophysiologically demyelinating affected nerve sections was also significantly larger than in the axonally damaged or normal nerve sections. Sonography thus correlates significantly with neurography findings, disease duration, and delayed onset of therapy (see below). However, there is no correlation between sonography and clinical parameters [17,18].

Echogenicity in CIDP

Histological workup reveals focal areas of sparsely marked fibers and regenerating neurons in the nerve segments affected by CIDP. Perivascular lymphocyte infiltrates are rarely visible [19,20]. Histology is correlated with three distinct classes of sonographic changes in CIDP: Hypoechogenic, thickened nerves with a partially blurred fascicular structure (class 1), hyper- and hypoechogenic sections of nerves (class 2) and hyperechogenic nerves with normal cross-sectional area and small or indistinguishable fascicles (class 3) [4,21].

These different structures in sonography can be traced on the pathological-anatomical preparation. Class 1 is characterized by inflammation and swelling, and “onion bulbs” are most commonly found in treated patients. Class 2 shows severe axonal damage without persistent inflammation. Class 3 shows a mixed picture of demyelination, edema, and additional axonal damage (Fig. 3) [21].

Change of the sonographic image in the course and by the therapy

In de novo CIDP patients, nerves thickened very early, but still 12% of nerves were assessed as normal. In chronic courses, 97% of the nerves were thickened, two-thirds of them generalized. The cross-sectional area of cervical nerve roots correlated with the duration of disease. The later the diagnosis was made and therapy started, the greater the cross-sectional area and thickness of individual fascicles. Possibly, this is explained by the advancing inflammation, de- and remyelination [17,22].

During the course of CIDP, atrophy of the muscles occurs. They change their sonographic appearance, becoming more echo-rich due to the shrinkage of the contractile elements and the increase in connective tissue. This can be additionally used to assess the disease, especially axonal degeneration [23].

CIDP patients on immunoglobulin therapy are followed up with clinical examinations (dynamometer, clinical examination scores, questionnaires) to guide dosage and interval of infusions. Even if patients appear stable in these studies, they may still develop new demyelinating lesions, which then result in a significantly worse prognosis. These patients may benefit from higher dosing or shorter infusion intervals. Regular follow-up examinations by electrophysiology offer a possibility, but the course can also be assessed in sonography: Patients with a clinically stable course usually show a reduction in cross-sectional area to normal findings. On the other hand, the cross-sectional areas in non-responders did not decrease, even became larger, new sites were affected, and the spread of pathologic sonographic findings became more homogeneous. Hypoechogenic nerves (probably signs of acute inflammation) showed better recovery than nerves with hyperechogenic picture (increase in perifascicular connective tissue as a sign of axonal damage or scarring) [4,21,24,25].

High-resolution ultrasonography in Guillain-Barré syndrome.

Guillain-Barré syndrome (GBS) is an acute polyradiculoneuritis characterized by ascending flaccid paresis, reflex loss, and autonomic dysfunction. The most common form in Western countries is acute inflammatory demyelinating polyradiculoneuropathy (AIDP), which corresponds to “classic GBS” and is thought to be responsible for approximately 60-90% of cases in our latitudes [7].

Data on Guillain-Barré syndrome are much sparser than on the other immune-mediated neuropathies. So far, there are almost only single case reports about sonography in the course. The thickening of the nerves is predominantly found in the arms, the brachial plexus is hardly affected. The increase in cross-sectional area is visible within the first five days, and may persist for many years, but may also normalize over time. There is a good correlation between vegetative symptoms and the cross-sectional area of the vagus nerve. In contrast, there is no correlation between nerve conduction velocity and sonography [26–29].

Surprisingly, the cross-sectional area is increased not only in demyelinating but also in axonal forms of progression. This could be because, unlike chronic axonal polyneuropathies, this case involves acute inflammatory axonal neuropathy with edema [27].

How to save time in neurographic examination of polyneuropathies?

High-resolution ultrasound examination of neuropathies is a very young science. It has developed in various centers, some of which published very elaborate study protocols. All protocols are designed for specific issues [30] and are not yet universally applicable (Fig. 4) [31]. Working through them is time-consuming. Prof. Grimm was concerned with the question of which nerve sections yield the highest yield for the diagnostic statement in order to make the examination useful for everyday life. Bilateral examination of the median nerve throughout the arm and visualization of the brachial plexus appear to be the most efficient. Additional examination of nerves of the legs does not provide relevant additional information [25].

Take-Home Messages

Thanks to technical advances, the quality of ultrasound examinations has improved considerably. This enables the differential diagnostic delineation of nerve damage.
The most common polyneuropathies in our latitudes result from diabetes mellitus and alcohol abuse. However, polyneuropathy can also be triggered by drugs (e.g. chemotherapeutic agents) or inflammation.
Immune neuropathies are divided into acute forms (e.g., Guillain-Barré syndrome GBS) and chronic forms (e.g., multifocal motor neuropathy MMN and chronic inflammatory demyelinating polyneuropathy CIPD).
For the differential diagnosis of GBS, MMN, CIPD, and amyotrophic lateral sclerosis (ALS), a high degree of diagnostic confidence was achieved by combining clinical imaging, electrophysiology, sonography, and MRI.
Electrophysiology and sonography also provide valuable information in the context of follow-up measurements.

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