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Keywords:

  • cross-sectional area;
  • immune-related neuropathies;
  • ultrasound measures;
  • variability, diagnosis, outcome measures, nerve volume

Abstract

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Introduction: Nerve involvement in immune-related neuropathies is non-homogeneous, and therefore characterization of ultrasound (US) abnormalities is difficult. We developed two measures to quantify US abnormalities in immune-related neuropathies. Methods: Intranerve cross-sectional area (CSA) variability for each nerve was calculated as: maximal CSA/minimal CSA. Internerve CSA variability for each patient was calculated as: maximal intranerve CSA variability/minimal intranerve CSA variability. Six patients underwent US evaluation of the median, ulnar, and fibular nerves, and the abnormalities were scored with our newly developed measures. Results: The new measures were applicable to all nerves and patients. The highest degree of intra- and internerve CSA variability was observed in multifocal motor neuropathy, consistent with the asymmetric characteristics of this neuropathy. Conclusions: The application of intra- and internerve CSA variability measures allows us to quantify the heterogeneity of nerves and nerve segments and identify different US patterns in diverse immune-related neuropathies. Muscle Nerve, 2012

Nerve structure can be explored by ultrasound (US) to provide useful information on peripheral nervous system morphology. Echogenicity and size are the two main features assessed through US. The latter is quantifiable, usually through nerve cross-sectional area (CSA), and it is the most useful for objective evaluation of nerve abnormalities. CSA enlargement has been proven to have high diagnostic sensitivity and specificity in the study of focal nerve damage as found in cases of compression, tumors, trauma, and entrapment syndromes.1–4

Most demyelinating neuropathies present with focal or diffuse nerve enlargement and significantly increased CSA, findings that are uncommon in axonal neuropathies.5, 6 The few US studies performed in demyelinating hereditary neuropathies showed homogeneous nerve abnormalities that mirror the characteristic diffuse and uniform nerve damage.7–9

By contrast, immune-related neuropathies may be non-homogeneous and characterized by patchy size variability of the nerves.10 In this setting, the quantification of nerve abnormalities is challenging. Occasionally a nerve may have a diffuse increase in CSA, but more often nerves in the same limb have very different US features (e.g., a nerve with increased CSA close to a normal nerve), or the same nerve along its course, in contiguous segments (e.g., increased CSA distal or proximal to a segment with normal CSA).

The difficulty in quantifying the heterogeneity of CSA alterations in patients with immune-related neuropathies or in other conditions with non-homogeneous nerve involvement prompted us to develop two new measures, defined as “intranerve CSA variability” and “internerve CSA variability.” These measures provide a scoring system with common descriptors that can be used to compare data from different series and to follow up individual patients.

METHODS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

This study was performed in two phases. The first phase was aimed at developing US measures based on previous experience,11, 12 and the second was verification of the applicability of the new measures on patients with different immune-related neuropathies.

US Measures

The following measures were developed: (1) Intranerve CSA variability (for each nerve) = (maximal CSA / minimal CSA). For example, Figure 1 shows that intranerve CSA variability of the middle nerve is greater than that of the upper nerve. Note that the upper and lower nerves, although presenting different absolute CSA values, will have a very similar intranerve CSA variability. (2) Internerve CSA variability (for each patient) = maximal intranerve CSA variability/minimal intranerve CSA variability. For example, for the hypothetical patient whose nerves are represented in Figure 1, internerve CSA variability will be calculated from the ratio of the middle nerve intranerve CSA variability and the lower or upper nerve intranerve CSA variability.

thumbnail image

Figure 1. Scheme of nerve involvement patterns in immune-related neuropathies. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

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Because intra- and internerve CSA variability is independent of absolute CSA, a full description of US nerve patterns in a patient must always include the absolute CSA values.

The method generally used to calculate CSA was the “ellipse method” when applicable (when the nerve in the transverse scan had an elliptical or roundish shape) or the “tracing method” when the nerve had an “irregular” shape.

Applicability of the US Measures

We studied 6 patients with different immune-related neuropathies: 2 had multifocal motor neuropathy (MMN); 2 had chronic inflammatory demyelinating polyradiculoneuropathy (CIDP); and 2 had neuropathy with antibodies to myelin-associated glycoprotein (MAG). Diagnoses were based on clinical history, neurological evaluation, neurophysiological findings, response to drugs, and follow-up. All patients fulfilled the EFNS/PNS diagnostic criteria for either MMN or CIDP.13, 14 The characteristics of the patients are summarized in Table 1.

Table 1. Patients' clinical features
Patient numberNeuropathyAge (y)GenderDisease duration (y)Strength deficitSensory deficit
1CIDP89Male7Mild, lower limbsLower limbs
2CIDP16Male1Severe, four limbsFour limbs
3MMN28Female14Severe, four limbsAbsent
4MMN57Male8Severe, four limbsAbsent
5Anti-MAG72Male3AbsentLower limbs
6Anti-MAG65Female10AbsentFour limbs

All patients underwent the following standardized US and clinical assessment:

  • Neurological evaluation: muscle strength was evaluated in a standardized fashion and scored on the Medical Research Council (MRC) scale.

  • Nerve US: nerves were scanned along the entire visualizable tract, and nerve CSA and echogenicity were recorded. Maximal and minimal CSAs along whole segments of the evaluated segments were also recorded; moreover, CSA was recorded at standardized sites (in parentheses). The following nerves were studied bilaterally: median nerve (wrist, forearm, elbow, arm, axilla); ulnar nerve (wrist, forearm, elbow, arm, axilla); and fibular nerve (fibular head, popliteal fossa).

We also examined the tibial and sural nerves, but due to their short visualizable course they were imaged at one site only. Because they do not contribute to the newly developed measures (intranerve ratio could not be calculated) their results are not included in this report.

All patients were clinically and sonographically assessed in the same session. Clinical and US evaluation were performed by the same neurologist/neurophysiologist.

Esaote Lab 25 Gold and Esaote 75 (Esoate, Genova, Italy) US equipment, with a broadband (frequency band 10–18 MHZ) linear transducer, were used for the evaluations.

RESULTS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Normal values (calculated as mean ± 2 SD) of CSAs at the standardized sites and of intra- and internerve variability were measured in healthy subjects. For the median nerve, 63 subjects were studied: the upper cut-off value of the intranerve ratio was 2.3 (mean 1.55, SD 0.39). For the ulnar nerve, 88 subjects were studied: the upper cut-off level of the intranerve ratio was 2.1 (mean 1.38, SD 0.35). For the fibular nerve, 43 subjects were studied: the upper cut-off value of the intranerve ratio was 2.3 (mean 1.6, SD 2.3). Internerve variability was calculated for 43 patients (all with US evaluation of fibular, median, and ulnar nerves), and the upper cut-off value was 1.9 (mean 1.3, SD 0.3).

CSA reference values were acquired after each nerve was scanned throughout its visualizable course, checked to ensure that there was minimal variability in each segment, and measured at predefined sites. Based on data from the aforementioned samples, the upper cut-off values were as follows (based on our expectations that nerve CSA would be increased and not decreased): median nerve: wrist <12 mm2, forearm <9 mm2, arm <11 mm2, axilla <12 mm2; ulnar nerve: wrist <9 mm2, forearm <8 mm2, elbow <10 mm2, arm <8 mm2, axilla <9 mm2; and fibular nerve: fibular head <13 mm2, popliteal fossa <8 mm2.

The US results in patients with the different immune-related neuropathies are summarized in Tables 2 (median nerve), 3 (ulnar nerve), and 4 (fibular nerve). Table 5 shows the results of the newly developed US measures.

Table 2. Ultrasound findings in the median nerve at standard sites
Patient numberNeuropathyCSA, wristCSA, forearmCSA, armCSA, axilla
RightLeftRightLeftRightLeftRightLeft
  1. CSA measured in mm2. Abnormal values shown in bold (normal reference values are reported in the text).

1CIDP161210616131614
2CIDP1514222142293219
3MMN1115101719282322
4MMN785551088
5Anti-MAG976912131510
6Anti-MAG131089710810
Table 3. Ultrasound findings in the ulnar nerve at standard sites
Patient numberNeuropathyCSA, wristCSA, forearmCSA, elbowCSA, armCSA, axilla
RightLeftRightLeftRightLeftRightLeftRightLeft
  1. CSA measured in mm2. Abnormal values are shown in bold (normal reference values are reported in the text).

1CIDP657716811121512
2CIDP14101821131717242118
3MMN746171419154126
4MMN464514560863
5Anti-MAG45691079888
6Anti-MAG44710757869
Table 4. Ultrasound findings in the fibular nerve at standard sites
Patient numberNeuropathyCSA, fibular headCSA, popliteal fossa
RightLeftRightLeft
  1. CSA measured in mm2. Abnormal values are shown in bold (normal reference values

  2. are reported in the text).

1CIDP15171826
2CIDP16195160
3MMN1453213
4MMN862014
5Anti-MAG772922
6Anti-MAG18112611
Table 5. Intra- and internerve CSA variability
PatientNeuropathyIntranerve CSA variability for each nerveInternerve CSA variability
Right ulnar nerveRight median nerveRight fibular nerveLeft ulnar nerveLeft median nerveLeft fibular nerve
  1. Abnormal values shown in bold. Reference values of upper intranerve variability cut-off: median nerve = 2.3; ulnar nerve = 2.1; and fibular nerve = 2.3. Reference value of upper internerve variability cut-off = 1.9.

1CIDP2.661.601.202.402.331.522.21
2CIDP1.612.801.502.402.071.102.55
3MMN2.502.502.334.751.861.203.96
4MMN15.001.601.002.662.001.5015
5Anti-MAG2.501.661.851.601.852.141.56
6Anti-MAG1.751.851.442.501.331.002.5

There was a greater frequency of abnormal intranerve ratio in MMN, followed by CIDP, and finally anti-MAG neuropathy (Table 3). The main results were driven by the findings in the ulnar nerve. The highest values of intra- and internerve CSA variability were observed in patients with MMN. Both elevated scores mirror the well-known patchy nerve involvement in this neuropathy, with non-homogeneous damage along the course of a single nerve and among the different nerves. CIDP and neuropathy associated with anti-MAG antibodies had instead more diffuse and homogeneous nerve involvement, as indicated by the relatively low intranerve (e.g., we observed increased CSA without increased intranerve variability as seen in patient 1, right median nerve) and internerve CSA variability.

DISCUSSION

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

In order to objectively describe a condition or a phenomenon, we need measures capable of quantifying and scoring our observations. This will help with interpretation and comparison of data in a reproducible manner. The CSA is such a measure, and it is a valuable tool for evaluation of US abnormalities of peripheral nerve, especially when focal damage occurs. Proper measures for US investigation of immune-related neuropathies and other diseases with possible non-homogeneous nerve involvement have not been available. Hence, the use of CSA alone cannot adequately quantify non-homogeneous US alterations.

The challenge is to quantify changes in area, and particularly in CSA, along the course of a nerve. Transferring the idea of variability of latency to variability of area during a consecutive series of recordings, the concept of “mean consecutive difference,” adopted in jitter evaluation to evaluate neuromuscular transmission, would be appropriate, but unfortunately it is still not applicable to nerve US measures. We hope this will become possible when the appropriate software is developed to automatically calculate nerve CSA and to relate it to the course of the nerve. The need to measure the CSA variations of a single nerve along its course prompted us to develop the intranerve ratio, and the need to comprehensively assess differences among nerves led us to develop the internerve ratio. Intranerve CSA variability is more reliable when long segments of nerves are visualized. For the fibular nerve, two closely adjacent sites (fibular head and popliteal fossa, mean distance approximately 5 cm) were measured and, as expected, the results showed few or no abnormal values. A limitation of these new measures is that they do not adequately assess US nerve variability in the lower limbs. This is due to the current limited imaging capabilities of US and lower extremity anatomy (the deep location of the sciatic nerve and the short length of the fibular and tibial nerves).

A shortcoming of this investigation is that it was a pilot study aimed at describing the newly developed measures and providing preliminary data. The small number of patients with heterogeneous strength deficits (3 with severe motor deficits, 1 with mild, and 2 without motor deficit) did not allow us to evaluate the relationship between strength and nerve variability. A further study on a larger sample is ongoing, and the relationship between muscle strength and US CSA and its variability will be evaluated.

The application of intra- and internerve CSA variability measures to this sample of patients with different immune-related neuropathies has allowed us to evaluate and quantify the heterogeneity of nerves and nerve segment involvement and provide quantification of different US patterns. A wide range of US abnormalities were observed. It is tempting to speculate that the observed US variability in immune-related neuropathies may be due not only to the different pathogeneses, but also to the stage and type of nerve damage and/or the duration of disease. The ulnar nerve seemed to provide the most noteworthy data, but due to the very small sample size, the findings must be confirmed in future studies.

Because this was a pilot study with only preliminary results, the diagnostic and prognostic value of our findings must be tested in prospective studies on a larger sample of patients. Nevertheless, these measures may be a useful way to monitor treatment response. If we could observe variation of the US measures after treatment, we could acquire information on the therapeutic effects and mechanism.

REFERENCES

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES