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1 Cattedra di Radiologia "R," DICMI, Università di Genova,
Largo Rosanna Benzi, 8, I-16132, Genova, Italy.
2 Dipartimento di Scienze Neurologiche e della Visione, Università di
Genova, I-16132, Genova, Italy.
3 Division de Radiodiagnostic, Hôpital Cantonal Huniversitaire, Rue
Micheli du Crest, Geneve, Switzerland.
Received October 1, 2001;
accepted after revision December 7, 2001.
Address correspondence to C. Martinoli.
Abstract
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SUBJECTS AND METHODS. The median nerves of 24 patients with genetically proven Charcot-Marie-Tooth disease (12 patients with Charcot-Marie-Tooth disease type 1A, seven with Charcot-Marie-Tooth disease type 2, and five with Charcot-Marie-Tooth disease type X) were prospectively examined at the right mid forearm with a 12-5-MHz transducer. Image analysis for each patient included measurement of both the cross-sectional area and fascicular diameter of the nerve. Correlations then were made with genetic and electrophysiologic features and with findings in a control group of 50 subjects.
RESULTS. Sonography was found to be a reliable means of detecting the nerve hypertrophy and the fascicular swelling occurring in patients with Charcot-Marie-Tooth disease. The 1A type of Charcot-Marie-Tooth disease could be distinguished sonographically by a larger nerve area and fascicular diameter than those observed in patients with the other types of disease (including Charcot-Marie-Tooth disease type 2 and X-linked type) and the control subjects. In patients with Charcot-Marie-Tooth disease and control subjects, linear regression analysis did not show a correlation between either the cross-sectional area or fascicular diameter of the nerve and the patient's height, body mass, sex, or electrophysiologic parameters.
CONCLUSION. High-resolution sonography can be used to detect the hypertrophy of median nerves in patients with Charcot-Marie-Tooth disease. It can be helpful in defining the Charcot-Marie-Tooth type 1A on the basis of the larger nerve sizes and fascicular diameters than those occurring in patients with other types of the disease. In an affected kindred, sonography is promising as a screening tool for identifying individuals who should undergo genetic assessments.
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Different types of Charcot-Marie-Tooth disease have been classified according to the clinical course and the neurophysiologic, neuropathologic, and genetic features. The most common forms are the autosomal dominant types 1A and 2 and the X-linked type [2, 3]. The inheritance patterns, severity of clinical features, course of illness, and nerve conduction abnormalities of the different types of Charcot-Marie-Tooth disease often overlap, so that after evaluating a given patient or even a kindred, it may be difficult to properly classify the disease [1, 3]. Classification requires accurate DNA testing, but genetic analysis is expensive and time-consuming, especially when screening an affected family to identify which individuals may later show clinical manifestations of disease or transmit the disease to their children.
High-resolution sonography has increasingly been used for the noninvasive assessment of peripheral nerve diseases [4, 5]. The examination of nerves with this technique promises to be a suitable method for the diagnostic workup of different types of nerve lesions and conditions, such as nerve entrapments, nerve tumors, and traumatic nerve injures. However, relatively little attention has still been given to its use in patients with Charcot-Marie-Tooth disease [6]. Therefore, the purpose of our study was to describe the main features of median nerves in patients with Charcot-Marie-Tooth disease observed on high-resolution sonography and to assess the value of this technique in detecting and characterizing the disease.
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Charcot-Marie-Tooth disease is a diffuse process that involves all nerves uniformly, irrespective of their location, type, or size. Therefore, we arbitrarily selected the right median nerve as a reference for the imaging studies and data analysis. In each patient, standard electrophysiologic parameters obtained from this nerve, such as distal latencies, conduction velocity, and sensory and motor action potentials amplitudes, had been previously recorded for correlation with the imaging findings. Sonography was performed with a digital scanner (HDI-5000; ATL, Bothell, WA) equipped with a broadband (frequency band, 12-5 MHz; center frequency, 8 MHz) linear array transducer. In each study, the median nerve was examined at the middle third of the right forearm, about 10 cm proximal to the palmar crease, with the patient or control subject in the supine position, keeping his or her arm adducted. At this site, the median nerve could readily be identified by its relation to the hypoechoic bellies of the flexor digitorum superficialis muscle ventrally and the flexor digitorum profundus muscle dorsally. Scanning planes were adjusted according to the transverse and longitudinal nerve axes. On transverse planes, the median nerves have a rounded appearance in cross-sectional scanning, which made the measurements we sought more reliable. Sonographic criteria for nerve identification were based on detection of the fascicular echotexture according to criteria described elsewhere [7].
Interpretation of the sonographic images was based on measurement of the
cross-sectional area of the median nerve and measurement of the maximal
diameter of its individual fascicles. The diameter of nerve fascicles was
directly measured on the screen by means of the electronic calipers provided
with the equipment software; the cross-sectional area was calculated according
to the ellipse formula: anteroposterior diameter x laterolateral
diameter x 
/4. Fascicular size can vary in the same nerve at a given
level because of a different configuration of the axonal bundles, so we
obtained the measurements from only the largest fascicle. We did not count the
number of fascicles in each nerve. During the measurement procedure, we took
particular care to keep the scanning plane perpendicular to the nerve axis,
both to adjust the focal zone as well as to select a gray-scale map and a
dynamic range setting that gave the optimal contrast and edge enhancement. To
correlate the nerve size with the patient's body type, we calculated a body
mass index for both the patients and members of the control group by dividing
the individual's weight by the square of his or her height. The index was then
matched with nerve measurements. All data were collected by only one observer
to avoid interobserver variability.
Depending on the distribution and scaling of the parameters, statistical analysis was performed using either the Mann-Whitney test or Kruskal-Wallis one-way analysis of variance by ranks, including a Dunn's multiple comparison analysis or a linear regression analysis. Probability (p) values of less than 0.05 were considered statistically significant.
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In patients with Charcot-Marie-Tooth disease, the sonographic appearance of the median nerve varied more than that in the control group. The nerve shape and echotexture were preserved, but the cross-sectional area and the diameter of the individual hypoechoic fascicles of the nerve varied to a greater extent among these patients. In many cases, the nerve appeared to be enlarged and, as a rule, the greater the nerve, the larger the fascicles (Fig. 2). The nerve enlargement was obvious sonographically and was not confined to specific nerve segments but affected the nerve diffusely. A linear regression analysis showed a correlation between the cross-sectional area of the nerve and its maximal fascicular diameter (r2 = 0.641). As shown in Table 1, a statistical analysis performed for the overall population of patients with Charcot-Marie-Tooth disease showed that median nerves were significantly larger in these patients than in the control group (Mann-Whitney test; p < 0.0001). No correlation was found between the cross-sectional area of the nerve in patients with Charcot-Marie-Tooth disease and their height (r2 = 0.021), body mass (r2 = 0.022), or sex (p = 0.333). Nor was a correlation observed between either the nerve area or fascicular diameter and the electrophysiologic parameters, including conduction velocities (r2 = 0.349 and r2 = 0.353, respectively), distal latencies (r2 = 0.169 and r2 = 0.195) and motor (r2 = 0.188 and r2 = 0.195) and sensory (r2 = 0.172 and r2 = 0.178) action potentials amplitudes.
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We used the results of the genetic tests to group the findings in the patients according to the type of Charcot-Marie-Tooth disease (1A, 2, or X). A significant difference in the mean cross-sectional area and fascicular diameter of the nerve among these three groups was found (Kruskal-Wallis test; p < 0.0001) (Table 1). Patients with Charcot-Marie-Tooth disease type 1A had significantly larger nerves and fascicles than patients with the other forms of the disease. In these patients, the nerve area and the diameter of fascicles were more than twice those seen in patients with Charcot-Marie-Tooth disease type 2 or Charcot-Marie-Tooth disease type X. In addition, a significant difference in nerve area was found between patients with either Charcot-Marie-Tooth disease type 1A or Charcot-Marie-Tooth disease type 2 and the members of the control group (Kruskal-Wallis test with Dunn's multiple comparison analysis, p < 0.001 and p < 0.01, respectively). The difference in the nerve area between patients with Charcot-Marie-Tooth disease type X and the control group did not reach statistical significance. Similarly, the fascicular diameter was significantly larger in the nerves of patients with Charcot-Marie-Tooth disease type 1A than in those of the members of the control group (Kruskal-Wallis test with Dunn's multiple comparison analysis, p < 0.001).
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We studied the median nerves in patients with Charcot-Marie-Tooth disease using high-resolution sonography to assess the possible value of imaging in this heterogeneous and clinically challenging group. On the short-axis scans obtained at 12-5 MHz, close observation of the median nerve provided an accurate and reliable delineation of the nerve fascicles as rounded hypoechoic areas loosely bound by the interfascicular epineurium [7, 10]. Although the histopathologic abnormalities in patients with Charcot-Marie-Tooth disease predominantly occur in the fascicular compartment, we found these changes did not alter the overall echotextural appearance of nerves unless such changes caused fascicular swelling and, as a consequence, larger nerves. Despite the larger fascicles, the decrease in the number of myelinated fibers expressed per nerve area varies depending on the severity of the disease [1]. To address this point, we attempted to verify whether a correlation exists between the maximal fascicular size and the severity of electrophysiologic features, but we did not find data to support this hypothesis.
Sonographically, the patients with Charcot-Marie-Tooth disease had significantly larger nerves and fascicles than did the control group. However, it was not possible to extrapolate a reliable threshold for normal or abnormal nerve measurements that could be used to differentiate between normal and diseased nerves because of some overlap of values between the two groups. To study this heterogeneous group of patients further, we analyzed the major types of Charcot-Marie-Tooth in our patients and found a subset with similar genetic characteristics who had nerves and fascicles much larger than the rest of the population; these patients had the form of the disease referred to as type 1A. This information agrees with prior morphometric studies of nerves obtained at biopsy and at autopsy that found a striking enlargement of nerves in patients with Charcot-Marie-Tooth 1A caused by an increase in the transverse fascicular area. In our series, a nerve area of 10 mm2 and a fascicular diameter of 0.6 mm appeared to distinguish Charcot-Marie-Tooth 1A from the other types of the disease and the normal nerves; all measurements in patients with Charcot-Marie-Tooth 1A nerves showed higher values.
We discovered some overlap between the findings in patients with Charcot-Marie-Tooth type 2 and those with Charcot-Marie-Tooth type X; the measurements for patients with Charcot-Marie-Tooth type 2 occupied an intermediate position between those of the more abnormal type 1A group and relatively normal type X group. This finding potentially limits the ability to distinguish between these latter types using sonography. However, both type 2 and type X are less common than type 1A, which accounts for about three quarters of the cases, and, at least in the X-linked type, the modalities of disease transmission are more predictable [11]. Another relative limitation of our study is that no patients with minor types of the disease, such as Charcot-Marie-Tooth disease type 1B or type 1C, were included, but it has been reported that the incidence of these forms is extremely low [11].
Previous researchers have examined the nerves of patients with Charcot-Marie-Tooth disease using sonography [6]. They found enlarged nerves in only 22% of the cases, but no effort was made in their study to match the patients' nerve sizes with their genetic phenotype. Hence, the researchers did not identify any sonographic characteristic that could reliably be used to predict the types of the disease. In addition, 12% of the nerves examined in the previous study were smaller than those in a group of healthy subjects. This latter finding was not explained by the findings of the histopathologic studies, and we never encountered it in our series. On the basis of our data, we propose both the fascicular diameter and the nerve area as sonographic parameters for nerve evaluation in patients with Charcot-Marie-Tooth disease. Each of the two measurements could alternatively be used to indicate the increased nerve size and distinguish the 1A form of Charcot-Marie-Tooth disease from the other forms. We believe that the decision as to which is the better of the two parameters to use should be made by the examiner and the quality of the equipment available [10].
Nerve swelling may be observed in some congenital and acquired diseases, such as nerve compressive syndromes, fibrolipomatous hamartoma, and leprosy [12,13,14]. However, these conditions do not affect all nerves uniformly, as Charcot-Marie-Tooth disease does, but only short segments of one or few nerves at a typical location. In addition, these conditions alter the nerve echotexture on sonography with configurations that are clearly different from those observed in Charcot-Marie-Tooth disease and can be excluded from the differential diagnosis on the basis of the patient's history and clinical symptoms. Uniformly hypertrophied nerves with preserved fascicular echotexture seem to be a specific feature of Charcot-Marie-Tooth disease and could help to diagnose the disease in patients who are unaware that they have it. Despite the increased size of nerves in patients with Charcot-Marie-Tooth disease, we did not find substantial clinical or sonographic signs of median nerve entrapment at the carpal tunnel level. However, carpal tunnel syndrome has to be considered as a possible clinical presentation in these patients. In such cases, the sonologist's responsibility is not only to confirm the focal problem but also to recognize the generalized nerve abnormalities typical of Charcot-Marie-Tooth disease.
As a possible alternative to sonography, MR imaging has been shown to depict the internal structure of nerves and to provide, in many respects, the same information as sonography—including nerve size and the shape and delineation of the sheaths and axonal structures [15]. In the clinical setting, however, selection of the appropriate imaging technique depends on accessibility and time-and cost-effectiveness. Although performing sonography of nerves requires a relatively long learning curve (as well as the use of high-frequency transducers to avoid interpretation errors), this technique has proven to be convenient and accurate for this purpose. At our institution, the examination time for median nerve assessment in patients with Charcot-Marie-Tooth disease did not exceed 5 min. We are currently using this technique as a screening tool for possible genetic evaluation of individuals within an affected kindred. It should be noted that family history may be noncontributory in these patients because the disease may have no abnormal manifestations. A door-to-door survey to identify affected individuals and the pattern of inheritance among kinships might be more successful with a noninvasive and well-tolerated means such as sonography than with large-scale conventional tests that require patients to wait a long time for a response, such as a serologic evaluation.
In conclusion, high-resolution sonography is able to depict the hypertrophy of median nerves in patients with Charcot-Marie-Tooth disease and can play a role in helping the neurologist to identify unrecognized disease in patients with nonspecific symptoms. Sonography can help in the differentiation of Charcot-Marie-Tooth type 1A and provide a useful initial screening tool for individuals in an affected kindred who may need genetic assessments. We do not recommend sonography as the only tool for identification and characterization of Charcot-Marie-Tooth disease, but we believe that it may serve as an important adjunct to electrodiagnosis in patients with this condition by noninvasively revealing some important diagnostic information. Further work with a much larger series of patients is necessary to fully analyze the impact and reliability of this technique.
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