We found significantly higher FF values for the sciatic nerve at level 3, the most distal of the measured levels, in the patient group compared with the control group. Comparisons among FFs measured at different levels within the CMT1A patient group showed that levels 2 and 3 had significantly higher values than level 1. Our results could imply that CMT1A patients have higher than normal intraepineurial fat within the sciatic nerve. Because interfascicular fat constitutes the major portion of fat tissue within the epineurium, the increased FF on MRI is probably attributable to an increase in the interfascicular fat component. It would be beneficial in future studies to conduct a histologic evaluation of interfascicular fat and nerve myelination in CMT1A to elucidate the potential link between them. Furthermore, Dixon-based fat quantification MRI could be used to evaluate the interfascicular fat component when studying the effects of a lipid-enriched diet, as has been tried in animal models of CMT1A,11 which could expand understanding of the disease.
Our result showing a distal tendency for increased FF in CMT1A patients could suggest a distal predominance of increased interfascicular fat. Vaggemose et al.17 suggested that interfascicular fat tissue in distal peripheral nerves could be more pronounced in CMT1A patients than in healthy controls based on a quantitative MRI data comparison between the sciatic and tibial nerves. However, their suggestion was derived from proton spin density measured from the nerve, which is not the direct fat quantification we used in our study. Our results from Dixon-based proton density fat quantification, which is a more direct method for measuring FF within a designated area, demonstrate that the distal level of the sciatic nerve had significantly higher FF than the more proximal level in CMT1A patients. On the other hand, no such difference in FF of the sciatic nerve at different levels was identified among the healthy control subjects. It would be interesting to examine the FF of more distal nerve segments, including the nerve structure in the lower leg, in a future study. Given the absence of histologic correlation in our study, the following could be a premature speculation, but our result could suggest a correlation between increased interfascicular fat and length-dependent distal axonal degeneration in CMT1A patients. Clearly, further study is warranted to verify our findings.
Although FF did not correlate meaningfully with clinical parameters, CSA at level 3, as measured by both reviewers, correlated significantly and positively with CMTNSv2. The 10 m walk test time, which represent patient locomotor ability, also correlated positively with CSA at level 3 as measured by one reviewer, and that measured by the other reviewer had a near significant result with a marginal p-value. Previous studies reported a positive correlation between the CSA in several superficial peripheral nerves and CMTNSv2 and suggested the potential value of CSA as an imaging biomarker in CMT1A patients.4,7,9 The relationship between nerve CSA and disease severity might be explained by the link between the extent of pathologic change, such as onion bulb formation resulting from repeated demyelination–remyelination cycles, and clinical manifestations.7 The sciatic nerve, although closely related to the clinical manifestation of distal lower limb muscle wasting in CMT1A, has not been deeply investigated in terms of a potential link between nerve CSA and clinical severity or the most relevant level for measurement. Some studies have reported a meaningful correlation between ambulatory function test results and MRI parameters from the thigh muscle,29,30 but to our knowledge, little has been reported about the potential correlation between sciatic nerve CSA and ambulatory function test results. Our results suggest that sciatic nerve CSA could have potential value as a quantitative imaging biomarker in CMT1A patients and that measurements made at level 3, the gluteus maximus tendon insertion level, could be the most useful. It would be beneficial to confirm the true significance of these imaging parameters in a large cohort of CMT1A patients in the future.
CMAP amplitude, a marker of motor axonal loss, has been reported to correlate with clinical impairment and disability in CMT1A patients.2,31 Our results indicate that the CSA of the sciatic nerve correlates negatively with tibial and peroneal CMAP amplitude. In addition, peroneal NCV correlated negatively with CSA at level 3 as measured by one reviewer, and that measured by the other reviewer showed a similar trend with a marginal p-value. Previous studies using ultrasound to evaluate the median nerves in CMT1A patients found significant negative correlations between NCV and CSA, whereas negative correlations between CMAP or SNAP amplitude and CSA were inconsistently demonstrated.7,32 We assume that our result is in agreement with a previous study finding that increased peripheral nerve CSA in CMT1A patients reflects axonal loss and the progress of demyelination.
We found significantly higher sciatic nerve CSA in the patient group than the control group at all three measured levels. Whereas the CSA comparison between levels in the normal subjects showed significantly smaller CSAs at the distal level, CMT1A patients showed significantly larger CSA at level 2 than at level 1. In other words, the normal anatomical tapering of CSA in the sciatic nerve is absent in CMT1A patients, and in fact, the reverse is true. Few peripheral nerve CSA measurements at multiple levels have been compared between normal subjects and CMT1A patients, nor have previous comparisons considered differences between levels among CMT1A patients. A CSA analysis of certain peripheral nerve structures at multiple levels in CMT1A patients that also analyzes the relationships among the values from different levels could be an interesting subject for future studies.
A significant negative correlation was demonstrated between onset age and sciatic nerve CSA. In our results, a one year decrease in the age of onset correlated with a 1.168mm2 increase in the sciatic nerve CSA. Little has been reported on the potential relationship between the onset age of CMT1A patients and nerve CSA. It is known that first symptoms generally appear during childhood or adolescence in CMT1A, but patients present with widely varying disease severity.1 It is unclear whether the progression rate of the disease is constant.1,33 It would be interesting in future studies to investigate longitudinal changes in sciatic nerve CSA and their potential link with clinical progression of the disease.
A preliminary study by Ratner et al.25 measured the CSA and FF of the sciatic nerve in normal subjects at the level of the ischial tuberosity and lesser trochanter, which are similar to levels 1 and 2 in our study, respectively. They reported that their measurements of both CSA and FF were reproducible in terms of interobserver agreement, which is also in agreement with our results. Our study also showed excellent inter-rater agreement for measurements at level 3, which is more distal than levels 1 and 2.
Previous studies have suggested that age and sex have a significant relationship with nerve FF and CSA.15,25 Our study used data from age- and sex-matched case-control subjects, which means that our results are free from that concern. Although not clearly demonstrated by previous study, a potential relationship between obesity and the FF and CSA of peripheral nerves has been suggested.25,34 Our statistical comparison of BMI between the patient and volunteer groups revealed no significant difference in our study.
Our study has several limitations. First, we did not perform a histologic analysis through nerve biopsies, so we could not evaluate the pathologic significance of the increased FF within the sciatic nerve. However, our study provides imaging evidence that the peripheral nerves of CMT1A patients could show increased interfascicular fat, warranting further study on its possible effect in pathogenesis. Second, we did not evaluate the sciatic nerve distal to level 3 because we found no appropriate anatomical landmark distal to that level, and we expected reliable measurement to be limited by further CSA tapering. Dedicated MRI of a unilateral thigh could provide a better image for evaluating the sciatic nerve at a more distal level. Third, measurement errors could have occurred in our analyses because peripheral nerves are smaller than other anatomic structures. Fourth, our subjects were in their 20s and 30s, and the CMTNSv2 of the patient group ranged from 4–21, which implies that our patients were in mild to moderate stages of the disease. It would be interesting to perform longitudinal analyses in patients with a wider distribution of ages and disease stages.
In conclusion, we found a significantly higher FF at level 3, the most distal of the measured levels, in the sciatic nerves of CMT1A patients compared with those of the controls. Comparisons of the FF measured at different levels within the CMT1A patient group showed significantly higher values for levels 2 and 3 than for level 1, whereas no such difference was seen in the controls. This could suggest the presence of increased intraepineurial fat in the sciatic nerves of CMT1A patients, with a possible distal tendency. The CSA measured at level 3 by both reviewers correlated significantly and positively with CMTNSv2. The 10 m walk test time also correlated significantly and positively with CSA at level 3 as measured by one reviewer, and that measured by the other reviewer was nearly significant. These results may imply that the sciatic nerve CSA at level 3 has potential value as an imaging marker for clinical severity in CMT1A patients. Further studies are required to confirm our findings.