- Email: [email protected]
Imaging the microcirculatory proton fraction of muscle with diffusion-weighted echo-planar imaging
Imaging the Microcirculatory Proton Fraction of Muscle with Diffusionweighted Echo-planar Imaging' Lawrence Yao, MD, Usha Sinha, PhD
Compartment :~yndrome:~s:bfiallen~ing. 'In this: feasibility i : i study, imaging :waS performed :inhuman: sUbjectg to determine::::; : whether alterations in :the Circulating blood volume:d~:i: i): muscle Secondary to exercise or changes in c0mpartmeni:: :i :i: pressure Cou!d be ~isualiZed, : : ::?:!:::= i ::; :
Materials :and Meth6dS: T~e: c a]~::rr,u ici e s: of six::s ubjec~;:::, were studied before and after exercise and also during t h e application :of external pressure to the calf: Gate& single-: shot, diffusion:weighted echo-planar imaging (115 T)was .... implemented with signal aVeraging. Parametri6 images the "perfusion" fracti0n(f) were:generated; and regiong of interest from anatomic compartments were analyzed. The: precision of f was estimated by using p~0pagation of error analysis.: ....... : :.: i :::::i: ::: : :~ i:: Results. P~a~etri~:~mages ~ep~ted:visibie 'ifi~reases:~n: ::: the microcirculatory proton fracti0n(C)of:calf muscle :after exercise (mean Changei +0.016)and Visible decreases~ :: infon the application o f 4 0 m m Hg tothe Calf after:e~erL i : cise (mean change;:-01023). Mean changes in f were: only:: significantly different from zero for the group;:howe~et;: :. under conditions of applied:presSure t5 the Calf after exer~i::: eise. Changes:inf were not: significantly different aefrss :i::: muscle compartments, The error variance i n f was ap'2;:::,: proximately 0.0i£ :, :i: :: :::~ :i:i : i:::: Conclusion: Para~e~iC::images : stun-weighted echo=pian~ imaging may depict alteratiofig:: in the circulating blood: Volume of muscle induced: by ex~: ereise and changes iS':compartment/)f6Ssure, The ~nhergni imprecision of this technique; however, appears to limit its clinical utility. Key Words. Magnetic resonance (MR), diffusion study; Muscles, abnormalities; Muscles, MR; Compartment syndrome, chronic.
The causes of calf pain in athletes are varied and include stress fracture, stress reaction, and shin splints or medial tibial stress syndrome (1,2), as well as other myotendinous conditions. The term "shin splints" is confusing and, as commonly applied, may encompass stress reactions of bone occurring before frank stress fractures, a painful stressrelated periostosis related to muscle origins, or a less common chronic or exertional compartment syndrome (1,2). Chronic compartment syndrome usually affects the anterior or deep posterior compartments of the calf, but it can occur in any compartment. Affected patients experience calf tightness, aching, or sharp pain during exercise, a condition that restricts performance and usually subsides with rest. This diagnosis may easily be confused with other entities and is currently best confirmed by taking slit catheter pressure measurements during provocative exercise. Gradient modulated signal attenuations, attributable to the molecular diffusion of tissue water and the motion of water in the microcirculation, form the basis for diffusionweighted magnetic resonance (MR) imaging. Signal losses from protons in the microcirculation are caused by the pseudorandom organization of the capillary network, which represents an incoherent motion analogous to diffusion on the dimensional scale of the imaging voxel. The apparent diffusion coefficient for protons in the microcirculation differs enough from the apparent diffusion coefficient of tissue water protons that the two contributions to gradient-induced signal loss can be distinguished. Hence,
Acad Radiol 2000; 7:27-32
1From the Department of Radiology, MRI, 2nd Floor, CCC BId9, Georgetown University Medical Center, 3800 Reservoir Road NW, Washington, DC 20007 (L.Y.); and the Department of Radiological Sciences, UCLA Center for the Health Sciences, Los Angeles, Calif (U.S.). Received March 3, 1999; revision requested May 4; revision received July 15; accepted July 27. Address reprint requests to L.Y.
©AUR, 2000
27
a.
b.
Figure 1. (a) Single-shot, echo-planar source image obtained at b = 0 through the midcalf (effective echo time, 62 msec; field of view, 20 cm; section thickness, 15 mm; matrix, 128 x 128). (b) Dark lines demarcate anatomic compartments of the calf. A = anterior, L = lateral, DP = deep posterior, SP = superficial posterior. Circles illustrate the regions of interest (ROIs) used in the data analysis of compartmental f values.
diffusion-weighted MR imaging can be used to estimate the relative size of the microcirculatory proton fraction. This fraction, characterized by a higher apparent diffusion coefficient, is loosely referred to as a "perfusion fraction" (3). This parameter is conceptually related to the circulating blood volume--neglecting differential proton relaxation effects between intra- and extravascular compartments. Non-phase-encoded, diffusion-weighted, stimulatedecho techniques have detected increases in f i n muscle after exercise (4-6). We sought to reproduce these results by using an imaging technique and to examine the effects of applied pressure. A noninvasive method of imaging the microcirculatory proton fraction, even at modest resolution, might contribute to the evaluation of chronic compartment syndrome, if this condition alters the circulating blood volume in affected muscle compartments.
Six healthy subjects (four male, two female; average age, 28 years; range, 24-34 years) were imaged before and immediately after they performed a standardized exercise protocol. Exercise consisted of ascending and descending a single 5-inch (13-cm) step at a cadence of 40 steps per minute for 15 minutes. The right calf was imaged in a transmit-receive extremity coil with an MR-compatible sphygmomanometer in place around the calf. Imaging was
28
performed with and without the application of 40 mm Hg of pressure. Single-shot diffusion-weighted spin-echo-prepared echo-planar imaging was performed at 1.5 T with peripheral gating. Axial images were acquired at a single level in the midcalf, at the following settings: 20-cm field of view; 1.5-cm section thickness; effective echo time, 62 msec; image matrix, 128 x 128; repetition time, four times the R-R interval; trigger delay, 150 msec. Nine or 10 images (Fig la) were acquired at each of two large b values. Diffusion-sensitizing gradients were applied simultaneously in three orthogonal directions in each case, yielding net scalar b values of 17,972 and 54,364 sec/cmL This strategy was followed to improve the precision for the estimate o f f (see Appendix A). The total imaging time for each condition was approximately 3Vz-5 minutes, during which time 27-30 images were acquired. For b values greater than 10,000 sec/cm2, the attenuation of signal due to diffusion can be assumed to be monoexponential, with complete loss of signal from protons in the microcirculatory volume (5). The intercept in a linear fit of in(A) to large b values then equals ln(1 - f ) , wherefis the microcirculatory proton fraction, assuming equal relaxation characteristics in the two proton pools. The first image acquired at each b value was not used for analysis, to minimize nonequilibrium T1 relaxation effects. A separate analysis o f f for the anterior, deep posterior, and superficial
Changes in f by Muscle Compartment: ROI Measurements Compartment Experimental Condition Rest, pressure* After exercise After exercise, pressure*
Anterior -0,000 + 0.021 +0.008 _+ 0.046 -0.024 _+ 0.037
Superficial Posterior -0.004 + 0.018 +0.009 + 0.024 0.010 _+ 0.014
Deep Posterior
Total
-0.007 + 0.032 +0.030 + 0.030 -0.039 + 0.044
-0.004 + 0.021 +0.016 + 0.033 -0.023 + 0.033 t
Note.--Mean values _+ SDs for ROis in six subjects. *Applied pressure of 40 mm Hg. tSignificantly different from zero.
posterior compartments of the calf was based on ROIs of 70-180 mm 2 (29-74 pixels) (Fig lb). ROIs were manually selected and then fixed for each subject. Pixel-by-pixel calculations were also performed to generate parametric images o f f (Interactive Data Language, Research Systems, Boulder, Colo). For these calculations, pixel values that deviated by more than 10% from the corresponding mean intensity for that pixel (for acquisitions at the same b value) were discarded, in an attempt to reduce artifacts caused by arterial pulsation. Pixels with mean signal values less than 2.5 times background noise were set to zero. Variances f o r f w e r e estimated by using a propagation • of error approach based on the analytic expression for the variance in the estimate of the intercept in linear regression (see Appendix A) and the delta technique (7) (see Appendix B). Measurement errors for ROIs were derived from the standard deviation (SD) in signal values for the eight to nine measurements at each of the b values. Changes in muscle area were measured on the MR source images by means of commercially available software and manual segmentation of bone and subcutaneous fat from muscle (Advantage Windows, General Electric, Milwaukee, Wis). Changes in f calculated for compartmental ROIs were analyzed with a repeated-measures, multivariate analysis of variance, with anatomic compartments and experimental conditions treated as separate within-subjects factors (SPSS Inc, Chicago, Ill).
Calculated f
At rest, the mean of f for the group across the three described anatomic ROls was -0.002 + 0.027 (SD). After exercise, the same overall m e a n f f o r the group was 0.018 ~+0.040. Small consistent increases i n f w e r e seen after exercise, with a mean change for the group of 0.016 _+
0.033. At rest, the application of external pressure (40 m m Hg) induced mean decreases in f t h a t were less than 0.01 in all compartments. After exercise, the application of 40 m m Hg caused the largest decrease i n f (mean, -0.023 + 0.033). The changes i n f t h a t were calculated for anatomic ROIs under the three different experimental conditions are summarized in the Table. There were no significant differences in f a c r o s s muscle compartments (P = .86), but there was a significant difference in f across experimental conditions (P ; .03). Examination of the changes i n f i n d u c e d by experimental conditions shows that only the reduction i n f i n d u c e d by 40 m m Hg after exercise is significantly different from zero (univariate F = 12.58, P = .02). While the observed changes i n f i n d u c e d by exercise and applied pressure were greatest in the deep posterior compartment, the interaction between experimental conditions and anatomic compartments was not significant (P = .67). Increases in f across compartments were heterogeneous but discernible on parametric images o f f obtained after exercise. Decreases i n f w e r e similarly conspicuous after the application of external pressure in the postexercise state (Fig 2). Error Analysis The SD for eight to nine signal values from the same ROI at the same b value was used to estimate the error variance i n f The SDs of raw signal values averaged across anatomic compartments were 1.0%, 1.7%, and 2.2% (coefficients of variance) for images obtained at b = 0, 17,972, and 54,364 sec/cm 2, respectively, under rest conditions. After exercise, the coefficients of variance were 1.2%, 1.3%, and 2.2% for images obtained at the same respective b values. Propagation of this variance in raw signal values yields an estimated SD f o r f o f 0.011 at rest and 0.010 after exercise.
29
a. b. c. Figure 2. Parametric images of f (gray scale extends from -0.25 to +0.35). (a) Parametric image of f at rest shows that muscle values are close to zero. The lower values in the lateral compartment may be partly attributable to eddy current effects at the edge of the calf. (b) After exercise, a diffuse but heterogeneous increase in facross compartments is easily discerned. (c) After exercise, during the application of 40 mm Hg of external pressure. Parametric image of fdepicts a widespread but heterogeneous decrease in f. Image heterogeneity is due at least in part to error variance.
Muscle V o l u m e The mean change for the group in the total muscle volume after application of 40 m m Hg pressure at rest was - 0 . 8 % + 2%. After exercise, the mean change was - 2 . 0 % + 1.5%.
Acute compartment syndrome results when bleeding or edema secondary to physical trauma expands muscle volumes within restricted anatomic compartments. Exertional or chronic compartment syndrome is less common and more difficult to diagnose (1). This condition usually affects athletically active individuals and likely results from the expansion of exercising muscle against relatively inelastic fascial boundaries. Diagnostic criteria vary, but a compartmental pressure above 30 mm Hg measured with a slit catheter during or shortly after exercise is widely accepted as abnormal (8,9). Catheter measurements are painful and unwieldy, and accurate placement of catheters into specific muscle compartments, particularly the deep posterior compartment, can be difficult. Muscle or neural ischemia is thought to cause the symptoms of compartment syndrome. The exact pathophysiology, however, may be more complex. Symptoms in exertional compartment syndrome occasionally persist after ischemia would be expected to resolve, and MR spectroscopic studies have not consistently identified
30
markers of muscle ischemia in compartment syndrome (10). Nuclear scintigraphy studies using methoxyisobutylisonitrile, or MIBI, a radiopharmaceutical that is taken up by muscle in proportion to blood flow, have yielded mixed results (11,12). Results of a recent study using near-infrared spectroscopy, on the other hand, have confirmed the presence of deoxygenation in symptomatic muscle compartments of the leg during exercise (13). A study using laser Doppler flowmetry has shown abnormally elevated blood flow in the recovery period after exercise in patients with chronic compartment syndrome (14). At present, absent a better understanding of the physiology, relief of exertionrelated symptoms after surgical fasciotomy is the most compelling diagnostic confirmation of chronic compartment syndrome. In our subjects, the diffusion-weighted echo-planar imaging technique revealed a 1%-3% increase in the measured microcirculatory proton fraction of calf muscle after exercise. The application of external pressure appeared to diminishfto a similar degree, but only after exercise. The changes infthat we measured are similar in magnitude to the changes we observed in muscle volume. These changes, however, are less than those reported for a theoretically more precise, one-dimensional stimulated echo technique (4,5). The reasons for this difference are unclear. Previous researchers have suggested that the inherent imprecision in MR imaging measurements o f f limit the clinical utility of this parameter (15-17), particularly in
tissues wherefis small. Our imaging approach sought to maximize the precision in estimatedfwhile maintaining reasonable temporal resolution. Unfortunately, the error variance i n f w a s still similar in magnitude to the apparent physiologic changes inf. The heterogeneity infshown by parametric images likely reflects this imprecision and could mask the anatomic variations that potentially characterize compartment syndrome. Diagnosis might conceivably be improved if chronic compartment syndrome were manifested by both a diminished increase i n f w i t h exercise and a blunted reduction in f with the application of external pressure. The negative values we occasionally obtained f o r f likely reflect inherent imprecision in the measurement technique. Our neglect of diffusion anisotropy should have resulted in overestimation, not underestimation, off. Our simplified, scalar approach assumes that anatomic variations rather than absolute changes i n f w o u l d be more important for diagnosis. Furthermore, the diffusion anisotropy of muscle, while considerable, does not appear to vary systematically across anatomic compartments in the calf (unpublished data, 1997, 1998). A noninvasive tool for diagnosing chronic compartment syndrome would improve our understanding of shin splints and elucidate the pathophysiology of exertional compartment syndrome. Functional MR imaging techniques may eventually provide a valuable diagnostic alternative to invasive slit catheter studies. Our diffusionweighted echo-planar imaging strategy, while statistically limited, can depict alterations in the circulating blood volume of muscle induced by exercise and mild, transient increases in compartment pressure. The inherent imprecision of this technique, however, appears to limit its clinical utility for the diagnosis of compartment syndrome. Alterations in muscle perfusion also affect T1 relaxation, but techniques that monitor T1 changes may also lack necessary precision (18). Exercise-induced changes in the T2 relaxation of muscle, while incompletely understood, may hold greater promise for the imaging diagnosis of exertional compartment syndrome (19). APPENDIX A: SAMPLING STRATEGY The variance for the estimated intercept (a) in linear regression, assuming constant measurement error, is as follows: cyi2{ 1IN + [X2/Z(X - x) 2] }. In our application, cyi2 is the measurement error for each observation of ln(A) (or var[ln(A)], derived in Appendix B), N is the number of observations, x~ are the b values, and X is the mean value
for b. For any given N and cyi, the variance for the estimated intercept is minimized by maximizing the denominator Z(X - xi)2, the sum of squares for b, which is maximized by sampling only minimal and maximal b values. The minima and maxima for b in this case were determined by the assumptions of the biexponential model and signal-to-noise considerations, respectively. On the basis of this analysis, if 20 different b values are used that are evenly spaced across the high b value interval [17,972-54,364 sec/cm2], the variance in estimatedf would be 54% higher than that obtained by repeatedly sampling at the maximal and minimal (17,972 and 54,364 sec/cm2) b values 10 times each. This analysis assumes that the b = 0 point is also sampled 10 times. With values for Sb=o, var(Sb=0), and var (Sb=~)/(Sb=~)2 that we typically observed (200, 4.0, 0.0004, respectively), this analysis predicts that 33 measurements would be required to achieve an SD(J) of less than 0.01, 117 measurements for an SD(¢) of less than 0.005, and 2,799 measurements for an SD(f) of less than 0.001. APPENDIX B: ERROR ESTIMATION In the diffusion experiment, if we assume complete attenuation of the protons with a long diffusion constant at the higher b values, then ln(A) = ln(1 - f ) - b D , where A = (Sbl Sb=0),D = the short diffusion coefficient for the noncirculating proton fraction, and f = the microcirculatory proton fraction (3). The variance of ln(A) can be estimated by using the delta technique (6), where
var [In (A)] = {8[(ln Sb,)l/8(Sb,)) 2 Var(Sb,) + {5[ ln(Sb:o)l/8(Sa:o)} 2 Var(Sb:o)
= (l[Sbl) 2 Var(Sbl) + (1]Sb=o) 2 Var(Sb=0),
assuming that the covariance of Sb=o and Sbi is zero. We can estimate wX(Sbi) and var(Sb=0), the error for measured signal values, based on the sample variance of eight to nine measurements taken at each b value. If Sb=o is itself based on n measurements, then the mean value for Sb=o can be used, and [var(Sb=o)]/n can replace var(Sb=0). In the case of monoexponential attenuation, the intercept (a) = ln(1 - f ) . Thus f = 1 - e". With the delta technique again, var(f) = [ F ' ( J ) ] Z v a r ( a ) = (-e")Evar(a), where var(a) is the variance in the estimation of the intercept in a linear regression. Var(a) can be expressed as a function of the var[ln(A)] (see Appendix A).
31
kCKNOWLEDGMEN'I
We thank Cecilia Yap for her assistance in data collection and organization. ~EFERENCE~ 1. Detmer DE. Chronic shin splints: classification and management of medial tibial stress syndrome. Sports Med 1986; 3:436-446. 2. Puranen J. The medial tibial syndrome. J Bone Joint Surg [Br] 1974; 56:712-715. 3. Le Bihan D, Breton E, Lallemand D, Aubin ML, Vignaud J, LavalJeantet M. Separation of diffusion and perfusion in intravoxel incoherent motion MR imaging. Radiology 1988; 168:497-505. 4. Mowan D. In vivo measurement of diffusion and pseudo-diffusion in skeletal muscle at rest and after exercise. Magn Reson Med 1995; 13: 193-199. 5. Morvan D, Leroy-Willig A. Simultaneous measurements of diffusion and transverse relaxation in exercising skeletal muscle. Magn Reson Imaging 1995; 13:943-948. 6. Morvan D, Leroy-Wiltig A, Malgouyres A, Cuenod CA, Jehenson P, Syrota A. Simultaneous temperature and regional blood volume measurements in human muscle using an MRI fast diffusion technique. Magn Reson Meal 1993; 29:371-377. 7. Dunn G. Design and analysis of reliability studies. New York, NY: Oxford University Press, 1989; t70-176. 8. Styf JR, Korner LM. Microcapillary infusion technique for measurement of intramuscular pressure during exercise. Clin Orthop 1986; 207:253262. 9. Pedowitz RA, Hargens AR, Mubarak SJ, Gershuni DH. Modified criteria for the objective diagnosis of chronic compartment syndrome of the leg. AmJ Sports Med 1990; 18:35-40.
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10. Balduini FC, Shenton DW, O'Connor KH, Heppenstall RB. Chronic exertional compartment syndrome: correlation of compartment pressure and muscle ischemia utilizing 3~P-NMRspectroscopy. Clin Sports Med 1993; 12:151-165. 11. Amendofa A, Rorabeck CH, Vellett D, Vezina W, Rutt B, Nott L. The use of magnetic resonance imaging in exertional compartment syndromes. Am J Sports Med ~990; 18:29-34. 12. Edwards PD, Miles KA, Owens SJ, Kemp PM, Jenner JR. A new noninvasive test for the detection of compartment syndromes. Nucl Med Commun 1999, 20:215-218. 13. Mohler LR, Styf JR, Pedowifz RA, Hargens AR, Gershuni DH. Intramuscular deoxygenation during exercise in patients who have chronic anterior compartment syndrome of the leg. J Bone Joint Surg [Am] 1997; 79:844-849. 14. Abraham P, Lefthedotis G, Saumet JL. Laser Doppler flowmetry in the diagnosis of chronic compartment syndrome. J Bone Joint Surg [Br] 1998; 80:365-369. 15. Pekar J, Moonen CTW, Van Zijl PCM. On the precision of diffusion/perfusion imaging by gradient sensitization. Magn Reson Med 1992; 23:122-129. 16. Conturo TE, McKinstry RC, Aronovitz JA, Nell JJ. Diffusion MRI: precision, accuracy and flow effects. NMR Biomed 1995; 8:307-332. 17. Chenevert TL, Pipe JG, Williams DM, Brunberg JA. Quantitative measurement of tissue perfusion and diffusion in vivo. Magn Reson Med 199I; 17:197-212. 18. Jean-Fran(2ois T, Kwong KK, M'Kparu F, Weiskoff RM, LaRaia PJ, Kantor HL. Perfusion changes in human skeletal muscle during reactive hyperemia measured by echo-planar imaging. Magn Reson Med 1996; 35:62-69. 19. Esketin MKK, Lotjonen JMP, Mantysaari MJ. Chronic exertional compartment syndrome: MR imaging at 0.1 T compared with tissue pressure measurement. Radiology 1998; 206:333-337.
Compartment :~yndrome:~s:bfiallen~ing. 'In this: feasibility i : i study, imaging :waS performed :inhuman: sUbjectg to determine::::; : whether alterations in :the Circulating blood volume:d~:i: i): muscle Secondary to exercise or changes in c0mpartmeni:: :i :i: pressure Cou!d be ~isualiZed, : : ::?:!:::= i ::; :
Materials :and Meth6dS: T~e: c a]~::rr,u ici e s: of six::s ubjec~;:::, were studied before and after exercise and also during t h e application :of external pressure to the calf: Gate& single-: shot, diffusion:weighted echo-planar imaging (115 T)was .... implemented with signal aVeraging. Parametri6 images the "perfusion" fracti0n(f) were:generated; and regiong of interest from anatomic compartments were analyzed. The: precision of f was estimated by using p~0pagation of error analysis.: ....... : :.: i :::::i: ::: : :~ i:: Results. P~a~etri~:~mages ~ep~ted:visibie 'ifi~reases:~n: ::: the microcirculatory proton fracti0n(C)of:calf muscle :after exercise (mean Changei +0.016)and Visible decreases~ :: infon the application o f 4 0 m m Hg tothe Calf after:e~erL i : cise (mean change;:-01023). Mean changes in f were: only:: significantly different from zero for the group;:howe~et;: :. under conditions of applied:presSure t5 the Calf after exer~i::: eise. Changes:inf were not: significantly different aefrss :i::: muscle compartments, The error variance i n f was ap'2;:::,: proximately 0.0i£ :, :i: :: :::~ :i:i : i:::: Conclusion: Para~e~iC::images : stun-weighted echo=pian~ imaging may depict alteratiofig:: in the circulating blood: Volume of muscle induced: by ex~: ereise and changes iS':compartment/)f6Ssure, The ~nhergni imprecision of this technique; however, appears to limit its clinical utility. Key Words. Magnetic resonance (MR), diffusion study; Muscles, abnormalities; Muscles, MR; Compartment syndrome, chronic.
The causes of calf pain in athletes are varied and include stress fracture, stress reaction, and shin splints or medial tibial stress syndrome (1,2), as well as other myotendinous conditions. The term "shin splints" is confusing and, as commonly applied, may encompass stress reactions of bone occurring before frank stress fractures, a painful stressrelated periostosis related to muscle origins, or a less common chronic or exertional compartment syndrome (1,2). Chronic compartment syndrome usually affects the anterior or deep posterior compartments of the calf, but it can occur in any compartment. Affected patients experience calf tightness, aching, or sharp pain during exercise, a condition that restricts performance and usually subsides with rest. This diagnosis may easily be confused with other entities and is currently best confirmed by taking slit catheter pressure measurements during provocative exercise. Gradient modulated signal attenuations, attributable to the molecular diffusion of tissue water and the motion of water in the microcirculation, form the basis for diffusionweighted magnetic resonance (MR) imaging. Signal losses from protons in the microcirculation are caused by the pseudorandom organization of the capillary network, which represents an incoherent motion analogous to diffusion on the dimensional scale of the imaging voxel. The apparent diffusion coefficient for protons in the microcirculation differs enough from the apparent diffusion coefficient of tissue water protons that the two contributions to gradient-induced signal loss can be distinguished. Hence,
Acad Radiol 2000; 7:27-32
1From the Department of Radiology, MRI, 2nd Floor, CCC BId9, Georgetown University Medical Center, 3800 Reservoir Road NW, Washington, DC 20007 (L.Y.); and the Department of Radiological Sciences, UCLA Center for the Health Sciences, Los Angeles, Calif (U.S.). Received March 3, 1999; revision requested May 4; revision received July 15; accepted July 27. Address reprint requests to L.Y.
©AUR, 2000
27
a.
b.
Figure 1. (a) Single-shot, echo-planar source image obtained at b = 0 through the midcalf (effective echo time, 62 msec; field of view, 20 cm; section thickness, 15 mm; matrix, 128 x 128). (b) Dark lines demarcate anatomic compartments of the calf. A = anterior, L = lateral, DP = deep posterior, SP = superficial posterior. Circles illustrate the regions of interest (ROIs) used in the data analysis of compartmental f values.
diffusion-weighted MR imaging can be used to estimate the relative size of the microcirculatory proton fraction. This fraction, characterized by a higher apparent diffusion coefficient, is loosely referred to as a "perfusion fraction" (3). This parameter is conceptually related to the circulating blood volume--neglecting differential proton relaxation effects between intra- and extravascular compartments. Non-phase-encoded, diffusion-weighted, stimulatedecho techniques have detected increases in f i n muscle after exercise (4-6). We sought to reproduce these results by using an imaging technique and to examine the effects of applied pressure. A noninvasive method of imaging the microcirculatory proton fraction, even at modest resolution, might contribute to the evaluation of chronic compartment syndrome, if this condition alters the circulating blood volume in affected muscle compartments.
Six healthy subjects (four male, two female; average age, 28 years; range, 24-34 years) were imaged before and immediately after they performed a standardized exercise protocol. Exercise consisted of ascending and descending a single 5-inch (13-cm) step at a cadence of 40 steps per minute for 15 minutes. The right calf was imaged in a transmit-receive extremity coil with an MR-compatible sphygmomanometer in place around the calf. Imaging was
28
performed with and without the application of 40 mm Hg of pressure. Single-shot diffusion-weighted spin-echo-prepared echo-planar imaging was performed at 1.5 T with peripheral gating. Axial images were acquired at a single level in the midcalf, at the following settings: 20-cm field of view; 1.5-cm section thickness; effective echo time, 62 msec; image matrix, 128 x 128; repetition time, four times the R-R interval; trigger delay, 150 msec. Nine or 10 images (Fig la) were acquired at each of two large b values. Diffusion-sensitizing gradients were applied simultaneously in three orthogonal directions in each case, yielding net scalar b values of 17,972 and 54,364 sec/cmL This strategy was followed to improve the precision for the estimate o f f (see Appendix A). The total imaging time for each condition was approximately 3Vz-5 minutes, during which time 27-30 images were acquired. For b values greater than 10,000 sec/cm2, the attenuation of signal due to diffusion can be assumed to be monoexponential, with complete loss of signal from protons in the microcirculatory volume (5). The intercept in a linear fit of in(A) to large b values then equals ln(1 - f ) , wherefis the microcirculatory proton fraction, assuming equal relaxation characteristics in the two proton pools. The first image acquired at each b value was not used for analysis, to minimize nonequilibrium T1 relaxation effects. A separate analysis o f f for the anterior, deep posterior, and superficial
Changes in f by Muscle Compartment: ROI Measurements Compartment Experimental Condition Rest, pressure* After exercise After exercise, pressure*
Anterior -0,000 + 0.021 +0.008 _+ 0.046 -0.024 _+ 0.037
Superficial Posterior -0.004 + 0.018 +0.009 + 0.024 0.010 _+ 0.014
Deep Posterior
Total
-0.007 + 0.032 +0.030 + 0.030 -0.039 + 0.044
-0.004 + 0.021 +0.016 + 0.033 -0.023 + 0.033 t
Note.--Mean values _+ SDs for ROis in six subjects. *Applied pressure of 40 mm Hg. tSignificantly different from zero.
posterior compartments of the calf was based on ROIs of 70-180 mm 2 (29-74 pixels) (Fig lb). ROIs were manually selected and then fixed for each subject. Pixel-by-pixel calculations were also performed to generate parametric images o f f (Interactive Data Language, Research Systems, Boulder, Colo). For these calculations, pixel values that deviated by more than 10% from the corresponding mean intensity for that pixel (for acquisitions at the same b value) were discarded, in an attempt to reduce artifacts caused by arterial pulsation. Pixels with mean signal values less than 2.5 times background noise were set to zero. Variances f o r f w e r e estimated by using a propagation • of error approach based on the analytic expression for the variance in the estimate of the intercept in linear regression (see Appendix A) and the delta technique (7) (see Appendix B). Measurement errors for ROIs were derived from the standard deviation (SD) in signal values for the eight to nine measurements at each of the b values. Changes in muscle area were measured on the MR source images by means of commercially available software and manual segmentation of bone and subcutaneous fat from muscle (Advantage Windows, General Electric, Milwaukee, Wis). Changes in f calculated for compartmental ROIs were analyzed with a repeated-measures, multivariate analysis of variance, with anatomic compartments and experimental conditions treated as separate within-subjects factors (SPSS Inc, Chicago, Ill).
Calculated f
At rest, the mean of f for the group across the three described anatomic ROls was -0.002 + 0.027 (SD). After exercise, the same overall m e a n f f o r the group was 0.018 ~+0.040. Small consistent increases i n f w e r e seen after exercise, with a mean change for the group of 0.016 _+
0.033. At rest, the application of external pressure (40 m m Hg) induced mean decreases in f t h a t were less than 0.01 in all compartments. After exercise, the application of 40 m m Hg caused the largest decrease i n f (mean, -0.023 + 0.033). The changes i n f t h a t were calculated for anatomic ROIs under the three different experimental conditions are summarized in the Table. There were no significant differences in f a c r o s s muscle compartments (P = .86), but there was a significant difference in f across experimental conditions (P ; .03). Examination of the changes i n f i n d u c e d by experimental conditions shows that only the reduction i n f i n d u c e d by 40 m m Hg after exercise is significantly different from zero (univariate F = 12.58, P = .02). While the observed changes i n f i n d u c e d by exercise and applied pressure were greatest in the deep posterior compartment, the interaction between experimental conditions and anatomic compartments was not significant (P = .67). Increases in f across compartments were heterogeneous but discernible on parametric images o f f obtained after exercise. Decreases i n f w e r e similarly conspicuous after the application of external pressure in the postexercise state (Fig 2). Error Analysis The SD for eight to nine signal values from the same ROI at the same b value was used to estimate the error variance i n f The SDs of raw signal values averaged across anatomic compartments were 1.0%, 1.7%, and 2.2% (coefficients of variance) for images obtained at b = 0, 17,972, and 54,364 sec/cm 2, respectively, under rest conditions. After exercise, the coefficients of variance were 1.2%, 1.3%, and 2.2% for images obtained at the same respective b values. Propagation of this variance in raw signal values yields an estimated SD f o r f o f 0.011 at rest and 0.010 after exercise.
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a. b. c. Figure 2. Parametric images of f (gray scale extends from -0.25 to +0.35). (a) Parametric image of f at rest shows that muscle values are close to zero. The lower values in the lateral compartment may be partly attributable to eddy current effects at the edge of the calf. (b) After exercise, a diffuse but heterogeneous increase in facross compartments is easily discerned. (c) After exercise, during the application of 40 mm Hg of external pressure. Parametric image of fdepicts a widespread but heterogeneous decrease in f. Image heterogeneity is due at least in part to error variance.
Muscle V o l u m e The mean change for the group in the total muscle volume after application of 40 m m Hg pressure at rest was - 0 . 8 % + 2%. After exercise, the mean change was - 2 . 0 % + 1.5%.
Acute compartment syndrome results when bleeding or edema secondary to physical trauma expands muscle volumes within restricted anatomic compartments. Exertional or chronic compartment syndrome is less common and more difficult to diagnose (1). This condition usually affects athletically active individuals and likely results from the expansion of exercising muscle against relatively inelastic fascial boundaries. Diagnostic criteria vary, but a compartmental pressure above 30 mm Hg measured with a slit catheter during or shortly after exercise is widely accepted as abnormal (8,9). Catheter measurements are painful and unwieldy, and accurate placement of catheters into specific muscle compartments, particularly the deep posterior compartment, can be difficult. Muscle or neural ischemia is thought to cause the symptoms of compartment syndrome. The exact pathophysiology, however, may be more complex. Symptoms in exertional compartment syndrome occasionally persist after ischemia would be expected to resolve, and MR spectroscopic studies have not consistently identified
30
markers of muscle ischemia in compartment syndrome (10). Nuclear scintigraphy studies using methoxyisobutylisonitrile, or MIBI, a radiopharmaceutical that is taken up by muscle in proportion to blood flow, have yielded mixed results (11,12). Results of a recent study using near-infrared spectroscopy, on the other hand, have confirmed the presence of deoxygenation in symptomatic muscle compartments of the leg during exercise (13). A study using laser Doppler flowmetry has shown abnormally elevated blood flow in the recovery period after exercise in patients with chronic compartment syndrome (14). At present, absent a better understanding of the physiology, relief of exertionrelated symptoms after surgical fasciotomy is the most compelling diagnostic confirmation of chronic compartment syndrome. In our subjects, the diffusion-weighted echo-planar imaging technique revealed a 1%-3% increase in the measured microcirculatory proton fraction of calf muscle after exercise. The application of external pressure appeared to diminishfto a similar degree, but only after exercise. The changes infthat we measured are similar in magnitude to the changes we observed in muscle volume. These changes, however, are less than those reported for a theoretically more precise, one-dimensional stimulated echo technique (4,5). The reasons for this difference are unclear. Previous researchers have suggested that the inherent imprecision in MR imaging measurements o f f limit the clinical utility of this parameter (15-17), particularly in
tissues wherefis small. Our imaging approach sought to maximize the precision in estimatedfwhile maintaining reasonable temporal resolution. Unfortunately, the error variance i n f w a s still similar in magnitude to the apparent physiologic changes inf. The heterogeneity infshown by parametric images likely reflects this imprecision and could mask the anatomic variations that potentially characterize compartment syndrome. Diagnosis might conceivably be improved if chronic compartment syndrome were manifested by both a diminished increase i n f w i t h exercise and a blunted reduction in f with the application of external pressure. The negative values we occasionally obtained f o r f likely reflect inherent imprecision in the measurement technique. Our neglect of diffusion anisotropy should have resulted in overestimation, not underestimation, off. Our simplified, scalar approach assumes that anatomic variations rather than absolute changes i n f w o u l d be more important for diagnosis. Furthermore, the diffusion anisotropy of muscle, while considerable, does not appear to vary systematically across anatomic compartments in the calf (unpublished data, 1997, 1998). A noninvasive tool for diagnosing chronic compartment syndrome would improve our understanding of shin splints and elucidate the pathophysiology of exertional compartment syndrome. Functional MR imaging techniques may eventually provide a valuable diagnostic alternative to invasive slit catheter studies. Our diffusionweighted echo-planar imaging strategy, while statistically limited, can depict alterations in the circulating blood volume of muscle induced by exercise and mild, transient increases in compartment pressure. The inherent imprecision of this technique, however, appears to limit its clinical utility for the diagnosis of compartment syndrome. Alterations in muscle perfusion also affect T1 relaxation, but techniques that monitor T1 changes may also lack necessary precision (18). Exercise-induced changes in the T2 relaxation of muscle, while incompletely understood, may hold greater promise for the imaging diagnosis of exertional compartment syndrome (19). APPENDIX A: SAMPLING STRATEGY The variance for the estimated intercept (a) in linear regression, assuming constant measurement error, is as follows: cyi2{ 1IN + [X2/Z(X - x) 2] }. In our application, cyi2 is the measurement error for each observation of ln(A) (or var[ln(A)], derived in Appendix B), N is the number of observations, x~ are the b values, and X is the mean value
for b. For any given N and cyi, the variance for the estimated intercept is minimized by maximizing the denominator Z(X - xi)2, the sum of squares for b, which is maximized by sampling only minimal and maximal b values. The minima and maxima for b in this case were determined by the assumptions of the biexponential model and signal-to-noise considerations, respectively. On the basis of this analysis, if 20 different b values are used that are evenly spaced across the high b value interval [17,972-54,364 sec/cm2], the variance in estimatedf would be 54% higher than that obtained by repeatedly sampling at the maximal and minimal (17,972 and 54,364 sec/cm2) b values 10 times each. This analysis assumes that the b = 0 point is also sampled 10 times. With values for Sb=o, var(Sb=0), and var (Sb=~)/(Sb=~)2 that we typically observed (200, 4.0, 0.0004, respectively), this analysis predicts that 33 measurements would be required to achieve an SD(J) of less than 0.01, 117 measurements for an SD(¢) of less than 0.005, and 2,799 measurements for an SD(f) of less than 0.001. APPENDIX B: ERROR ESTIMATION In the diffusion experiment, if we assume complete attenuation of the protons with a long diffusion constant at the higher b values, then ln(A) = ln(1 - f ) - b D , where A = (Sbl Sb=0),D = the short diffusion coefficient for the noncirculating proton fraction, and f = the microcirculatory proton fraction (3). The variance of ln(A) can be estimated by using the delta technique (6), where
var [In (A)] = {8[(ln Sb,)l/8(Sb,)) 2 Var(Sb,) + {5[ ln(Sb:o)l/8(Sa:o)} 2 Var(Sb:o)
= (l[Sbl) 2 Var(Sbl) + (1]Sb=o) 2 Var(Sb=0),
assuming that the covariance of Sb=o and Sbi is zero. We can estimate wX(Sbi) and var(Sb=0), the error for measured signal values, based on the sample variance of eight to nine measurements taken at each b value. If Sb=o is itself based on n measurements, then the mean value for Sb=o can be used, and [var(Sb=o)]/n can replace var(Sb=0). In the case of monoexponential attenuation, the intercept (a) = ln(1 - f ) . Thus f = 1 - e". With the delta technique again, var(f) = [ F ' ( J ) ] Z v a r ( a ) = (-e")Evar(a), where var(a) is the variance in the estimation of the intercept in a linear regression. Var(a) can be expressed as a function of the var[ln(A)] (see Appendix A).
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kCKNOWLEDGMEN'I
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