In this study we show for the first time that qMRI values in leg muscles of patients after ICU treatment differed significantly from controls even years after ICU therapy and reflect simultaneously muscle damage and chronic myostructural abnormalities. (27–29, 44) Water T2 time and FA correlated negatively with MRC sum score, indicating the clinical relevance of our findings.
An elevated FF, such as observed in our cohort, relates to chronic muscle degeneration and shows higher sensitivity compared to MRC testing and qualitative MRI in terms of capturing muscle degeneration in myopathies. (26, 45) Fatty infiltration is a sign of previous muscle damage with fatty replacement of irreversible damaged muscle fibers. (46) A high FF in muscle supports the hypothesis that long-term motor dysfunction and muscle fatigue in patients is caused by a myostructural deficit. (2, 3, 14, 47) FF values were only slightly elevated in ICU survivors compared to controls and still in a “normal” range. In standard qualitative MRI images, those differences would most likely be considered as unsuspicious, which highlights the value of qMRI sequences in the evaluation of muscle status.
Whereas FF describes fatty infiltration very accurately and is easy to capture as percent fat per muscle, changes in the other qMRI modalities DTI and water T2 need to be closely interpreted with the expected or known disease pathology.
Whereas CIM is transient and only reflects myostructural damage due to direct muscle injury in the acute phase of ICU therapy, CIP in contrast is long-lasting due to nerve injury and serves as the major cause of functional debilitation. (48) Neurogenic myofiber atrophy due to axonal loss is usually irreversible and has already been described in muscle biopsies of CIP patients. (49)
Our electrophysiologic studies showed predominantly axonal nerve damage in calf nerves of patients and known clinical data underline that CIP usually affects distal limbs. (49) Since we could confirm a polyneuropathy in our patient cohort that is consistent with CIP, our observed differences of qMRI parameters reflect neurogenic muscle damage. The observed higher FA in patients’ muscles shows a higher proportion of longitudinal compared to radial diffusion. In neurogenic myofiber atrophy, myofibers do not lose their structural integrity initially but get atrophic. This atrophy leads to myofiber diameter reduction and consequently to an increase in FA. (29, 50) MD usually reflects the degree of overall diffusion as it equally integrates the eigenvalues λ1- λ3 as a simple mean value (MD = \(\frac{\sum (\lambda 1, \lambda 2,\lambda 3)}{3}\)) and is elevated in active muscle degeneration and inflammation whereas a reduction of MD is seen in muscle atrophy without an active degeneration. In active muscle degeneration and inflammation, the diffusion of water molecules increases in all spatial dimensions. The relation of MD and FA values is usually fixed when a simple geometrical model of homogenous muscle structure is applied and it is assumed that muscle tissue is composed of equally distributed cylinders. (29) Thus a solely myofiber atrophy would lead to an increase in FA and a decrease in MD whereas an inflammatory edema would counterwise lead to a decrease in FA and an increase in MD (as well as RD, and λ2−3). (29) Interestingly, in our patients, FA and MD were both significantly higher than in controls mostly pronounced in the calf muscles. A combination of a high FA and a high MD supports a parallel chronic myofiber atrophy and active myofiber degeneration.
That active myofiber degeneration is responsible for the elevated overall diffusion is also underlined by a significantly elevated water T2. As water T2 reflects the decay of T2 signal quantitatively, it is elevated in tissue with a higher content of fluid which relates to myofiber breakdown in muscle tissue either due to inflammation or due to other acute damaging processes such as denervation with muscle injury. (51–53)
Thus, we hypothesize that our observed combination of unanimous elevated MD, water T2, FA and FF reflect parallel active muscle degeneration and myofiber atrophy in chronic damaged muscle tissue due to ICUAW. Although FF was significantly increased between the two groups, the absolute value was still comparably low, so that an influence of the FF on the DTI parameters can be ruled out. (54, 55) This hypothesis is also underlined by a separate analysis of thigh and calf muscle qMRI values and by our clinical outcomes.
In thighs, compared to calves, chronic muscle degeneration was predominantly observed as MD was only mildly elevated compared to calves and water T2 was not elevated. In contrast, MD and water T2 were highly elevated in calves and reflect active muscle degeneration. Our data support that chronic axonal nerve damage in calves due to CIP leads to an ongoing myofiber damage and breakdown. This may be the result of overloading preserved motor units due to reduced activity and deconditioning.
Correlations of FA and MD to clinical assessments have been described in myopathies before and the significant correlation of water T2 and FA to MRC values in our study additionally supports the relevance of qMRI values. (56, 57)Since up to now there are no qMRI studies in long-term ICU survivors the presented results and the discussed pathophysiology is derived from known relations between quantitative muscle MRI parameters and myofiber degeneration. Reviews on ICUAW and known long-term data on ICU-survivors highlight the impact of motor status on long term quality of life, (58) since ICUAW and especially CIP affects peripheral nerves irreversibly and leads to ongoing neuromuscular complaints and a reduced ability to participate in daily life activities.