SPASTICITY CAUSES A FUNDAMENTAL REARRANGEMENT OF MUSCLE JOINT INTERACTION

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1 ABSTRACT: Sarcomere length was measured in flexor carpi ulnaris (FCU) muscles from patients with severely spastic wrist flexion contractures (n = 6), as well as from patients with radial nerve injury and a normally innervated FCU (n = 12). Spastic FCU muscles had extremely long sarcomere lengths with the wrist fully flexed (3.48 ± 0.44 µm) compared to the FCU muscles of patients with radial nerve injury (2.41 ± 0.31 µm). In three of the patients with spastic wrist flexion contractures, the slope of the FCU sarcomere length joint angle relationship was measured and found to be, essentially, normal (0.017 ± µm/, n = 3) suggesting that serial sarcomere number (and therefore muscle fiber length) was unchanged in spite of the dramatic absolute sarcomere length change. These results indicate that spasticity results in a major alteration of normal muscle joint anatomical relationships that has not previously been recognized to our knowledge. We hypothesize that the results are explained either by the inability of muscle fibers to add serial sarcomeres in response to growth, or the selective loss of FCU muscle length secondary to the central nervous system lesion John Wiley & Sons, Inc. Muscle Nerve 25: , 2002 DOI /mus SPASTICITY CAUSES A FUNDAMENTAL REARRANGEMENT OF MUSCLE JOINT INTERACTION RICHARD L. LIEBER, PhD 1 and JAN FRIDÉN, MD, PhD 2 1 Departments of Orthopaedics and Bioengineering, University of California and Veterans Administration Medical Centers, 3350 La Jolla Village Drive, San Diego, California 92161, USA 2 Department of Hand Surgery, Sahlgrenska University Hospital, Göteborg, Sweden Accepted 17 September 2001 Spasticity after brain injury may cause severe joint deformity and dramatically affect quality of life. Although muscle spasticity is neural in origin, 8,9 there is good evidence that spastic muscles are themselves abnormal. For example, muscle fiber size and fiber type distribution are abnormal in spastic muscles obtained from patients with cerebral palsy, 19 suggesting altered myosin heavy chain expression. Additionally, experiments have demonstrated that reflex stiffness of ankle extensors in patients with spastic hemiparesis may be normal, indicating a normal stretch reflex, but that intrinsic muscle stiffness is significantly Abbreviations:, type 1 error rate;, type 2 error rate; d, sarcomere length (in µm); ECRB, extensor carpi radialis brevis; EDC, extensor digitorum communis; FCU, flexor carpi ulnaris; FDS, flexor digitorum superficialis;, wavelength of laser (0.632 µm); n, diffraction order (±1, ±2, etc);, wrist joint angle (negative for flexion, positive for extension); 1/e 2, measure of laser beam width (in mm); r 2, coefficient of determination; r F, FCU moment arm (in mm);, diffraction angle measured (degrees) Key words: biomechanics; sarcomere length; spasticity; surgery; tendon transfer Correspondence to: R.L. Lieber; rlieber@ucsd.edu 2002 John Wiley & Sons, Inc. higher compared to control muscle. 20 These studies suggest that the properties of spastic muscle are not normal and yet, in spite of the prevalence of this entity, the muscle changes due to spasticity are poorly understood. As a result, it is difficult to develop rational treatment procedures to assist these patients. We developed an intraoperative method to measure sarcomere length in human muscles during reconstructive surgery. 5,15 This method was used to evaluate surgical reconstructive procedures that restore function in patients who have lost function after peripheral nerve injury 12,16 or spinal cord injury. 6 We demonstrated the importance of careful measurement of sarcomere length prior to and after tendon transfer to optimize muscle function. In the current study, we have measured sarcomere lengths in spastic flexor carpi ulnaris (FCU) muscles and compared them to theoretical predictions of sarcomere length as well as to sarcomere lengths measured in the normally innervated FCU muscles of patients with radial nerve injury. Based on our understanding Sarcomere Length in Spastic Muscles MUSCLE & NERVE February

2 of normal FCU structure and function, 11,18 we believe that spasticity has caused a major reorganization of the normal muscle joint relationships. METHODS Patient Characteristics and Surgical Procedures. Twelve subjects with radial nerve palsy were used to represent sarcomere length of normally innervated muscle, even though the patients themselves required surgical treatment. Although the extensor muscles were denervated, the FCUs had normal central and peripheral innervation. A portion of the sarcomere length data set from these patients has been previously published. 12,16 Patients specific to the current study ranged in age from 13 to 34 years, were receiving tendon transfers secondary to cerebral palsy (n = 5) or head injury (n = 1), and included men (n = 3) and women (n = 3). In each patient, the FCU was measured either during a single procedure or in combination with other surgical treatments. In three patients, the FCU was transferred into the extensor digitorum communis (EDC), whereas in the other three patients, it was transferred into the extensor carpi radialis brevis (ECRB). The tendon transfers were performed as previously described. 12,16 Laser Diffraction Method for Measurement of Sarcomere Length. Sarcomere length was measured by laser diffraction as previously described. 5,15 Briefly, a helium-neon laser beam (Melles-Griot, Model LHR- 007, Irvine, California) was aligned with a specially designed prism-mount such that the beam projected normally to one prism face and was reflected 90, exiting the other prism face and transilluminating an isolated muscle fiber bundle. For determination of accuracy, the device was calibrated using diffraction gratings of 2.50 µm and 3.33 µm grating spacings placed at the location of the muscle fiber bundle, which was directly upon the prism. Diffraction order spacings from the ±1st order and the ±2nd order were measured to the nearest 0.1 mm using dial calipers, which corresponded to a spatial resolution of about 0.02 µm. The FCU sheath was incised 5 cm proximal to the wrist crease, and a small fiber bundle directly beneath the incision was isolated using delicate blunt dissection along a natural fascicular plane within the muscle. The laser device was inserted beneath the fiber bundle and approximated into the normal plane of the muscle with the elbow joint maintained in 20 of flexion. This positioning was important so that sarcomere lengths were measured in the in vivo position of the fibers without artificial elongation due to elevation of the fiber bundle. Sarcomere length was measured in the midregion of the fiber bundle. Based on the dimensions of the laser beam (1/e 2 = 0.7 mm) and fiber bundles ( 1.5-mm thick), we estimate that the diffraction pattern represented the spatial average of millions of sarcomeres. In conjunction with each sarcomere length measurement, wrist joint angle was measured with an electrogoniometer (Penny & Giles Model Z110, Blackwood, Gwent, United Kingdom). The convention used was to express wrist flexion angles as negative, and extension angles as positive. Sarcomere length was measured in spastic FCU muscles in six different patients with the wrist joint fully flexed (90 of flexion). For comparative purposes, FCU sarcomere length was also measured with the wrist flexed in 12 patients undergoing transfers of the FCU secondary to radial nerve injury. Finally, in three of the six patients with spastic FCU muscles, sarcomere length was measured while the joint was rotated from the fully flexed position to the position of maximum extension. Sarcomere length (d) was calculated using the grating equation, n = dsin, where is the laser wavelength (0.632 µm), is diffraction angle, and n is the diffraction order. Mathematical Modeling. To provide an additional prediction of FCU sarcomere length as a function of wrist joint angle for normal subjects, the biomechanical model previously described 18 was implemented. This model was based on experimental measurement of prime wrist mover muscle architecture 11 and the mechanical properties of each wrist tendon. 17 Muscle properties were predicted based on architectural values obtained from cadaveric forearms. 11 Sarcomere lengths predicted by this model agree well with those directly measured intraoperatively 12,18 which suggests that normal muscle joint relationships remain intact in these cadaveric specimens in spite of the muscle atrophy present and the slight shrinkage that is known to occur with fixation. 3,4 Moment arm (in mm) of the FCU (r F ) was given by the expression r F = where represents wrist joint angle, and a negative value of r F represents a flexion moment arm. For the range of negative wrist joint angles reported in this study, this equation predicts that FCU moment arm would be 22 mm at 90 of flexion and 19 mm at 45 of flexion. Data Analysis. Average sarcomere length between spastic FCUs and FCUs from radial nerve-injured pa- 266 Sarcomere Length in Spastic Muscles MUSCLE & NERVE February 2002

3 tients were compared by one-way ANOVA. For the three subjects in whom sarcomere lengths were obtained at two to four joint angles, linear regression was performed on each individual patient s data set to provide a slope for the relationship between sarcomere length and joint angle. [Note that the small sample sizes render use of the coefficient of determination meaningless as any two data points will always have a perfect (r 2 = 1.0) linear correlation.] These three slopes were averaged to provide the average slope for the spastic FCU muscles. This slope was compared to the theoretically predicted slope 18 of 15 nm/ by one-sampled t-test. Differences between measured and predicted sarcomere lengths were calculated by subtracting the actual sarcomere length at each joint angle from that predicted using the model equation at that specific joint angle. Onesampled t-test was used to test whether this difference was significantly different from zero. For all statistical tests, significance level ( ) was chosen as 0.05 and statistical power (1- ) exceeded 90% except where indicated. Data are presented in the text as mean ± standard error. RESULTS All spastic patients presented with wrist flexion contractures that severely limited wrist range of motion to 38 ± 8 compared to the radial nerve-injured patients, who had normal wrist range of motion ( 125 ). Average FCU sarcomere length measured from spastic patients with the wrist flexed was 3.48 ± 0.44 µm (n = 6), which was significantly longer than the 2.41 ± 0.31 µm (n = 12) measured in patients with radial nerve injury while the wrist was fully flexed (P < 0.001, Fig. 1). To investigate further the nature of muscle adaptation to spasticity, we measured sarcomere length in three of these spastic patients while changing wrist joint angle. Consistent with results presented above, we found that, with the wrist flexed, average sarcomere length was 3.54 ± 0.30 µm which was significantly longer than the FCU sarcomere lengths measured in the patients with radial nerve injury (P < 0.001) and significantly longer than the predicted sarcomere length of 2.3 µm (Fig. 2). As the wrist was extended from the flexed position to maximal extension (45 ± 15 of wrist flexion), sarcomere length increased linearly. The average slope of the sarcomere length wrist joint angle relationship was ± µm/ which was not significantly different from the predicted value of µm/ (P > 0.6, statistical power, 1- = 0.6). Comparison between measured and predicted sarcomere lengths at each angle measured in these latter three subjects revealed a consistently longer FIGURE 1. Flexor carpi ulnaris (FCU) sarcomere length measured with the wrist fully flexed in patients with spastic wrist flexion contractures (open bar, n = 6) or radial nerve injury (hatched bar, n = 12). Data represent mean ± SEM for each group. Sarcomere lengths between groups were significantly different as demonstrated by one-way ANOVA (P < 0.001). sarcomere length whose magnitude did not vary with angle (1.36 ± 0.20 µm, P > 0.7 from linear regression) and was significantly different from zero (P < 0.001). Anecdotally, it should be noted that the spastic muscles demonstrated organized microstructure as evidenced by three orders of diffraction lines observed even in the extremely flexed position where, usually, only a single order is visible. This indicates that the muscles were highly organized structurally and did not shown gross signs of degeneration or excessive fibrosis, which would preclude diffraction FIGURE 2. FCU sarcomere length measured during surgery in spastic muscle. Each symbol type represents data from a single patient. Note that the linear regression relationship (dotted line) from the three patients parallels the normal sarcomere length joint angle relationship for the FCU (solid line). Sarcomere Length in Spastic Muscles MUSCLE & NERVE February

4 measurements. This was also observed in the other muscles (e.g., pronator teres and biceps brachii) on which surgical procedures were performed). DISCUSSION The purpose of this study was to measure sarcomere length in spastic muscles in an attempt to provide insight into the nature of muscle adaptation to spasticity. These data represent the first measurement of spastic muscle properties in vivo. Sarcomere length measurements were made because of the functional dependence of force generation on sarcomere length. 7 For human muscle, the myosin filament length is 1.65 µm and actin filament length 2.6 µm as measured by quantitative electron microscopy. 15 Thus, human muscles are predicted to generate maximum force at a sarcomere length of 2.6 µm, with linearly decreasing force as the muscle lengthens to a sarcomere length of 4.25 µm. As a result of this sarcomere length-tension relationship, the highly stretched FCU muscles from spastic patients would be predicted to generate only 40% of their maximum force with the wrist flexed, and this magnitude would decrease with wrist extension. This dramatic alteration of the sarcomere length joint angle relationship severely alters the wrist joint angle at which specific sarcomere lengths are achieved (Table 1). Functionally, this means that the normal muscle generates greater force than the spastic muscle at all joint angles. In fact, the wrist joint cannot even flex enough to achieve optimal sarcomere length in these spastic patients (Table 1). The classic adaptation reported for muscles subjected to chronic length change is sarcomere number alteration that is a strong function of the relative muscle length during immobilization. For example, Williams and Goldspink demonstrated that rat soleus muscles add serial sarcomeres when chronically stretched, and subtract serial sarcomeres when Table 1. Wrist joint angles corresponding to specific sarcomere lengths* Patient population Important sarcomere lengths 2.1 µm 3.5 µm 4.5 µm Normal Spastic Not possible *Wrist joint angle in degrees calculated using experimental regression relationships (negative angles signify flexion while positive angles signify extension): Normal regresson relationship: (degrees) = (d-3.47)/0.015 Spastic regression relationship: (degrees) = (d-4.83)/0.017 where d is sarcomere length (in µm) and the slope is given in units of µm/degree. chronically shortened. 21 We thus expected, in spastic wrist flexion contractures, to find very short FCU sarcomere lengths (as the wrist was highly flexed) or normal sarcomere lengths with a decreased sarcomere number if the muscles had adapted as expected. This was clearly not the case (see Figs. 1 and 2). Our initial interpretation of the very long sarcomere lengths measured with the wrist joints fully flexed (Fig. 1) was that the sarcomere number regulating system within the muscle had been severely deranged. We first hypothesized that FCU sarcomere number severely decreased, resulting in long sarcomere lengths and very high passive muscle tension. This idea was appealing based on the well-known ability of muscle to alter sarcomere number in response to altered neuromuscular input or mechanical environment 1,2,22 and the general conception that spastic muscles are highly active. We subsequently tested this hypothesis by measuring the relationship between sarcomere length and wrist joint angle, which is a direct manifestation of the muscle fiber length:moment arm ratio for any muscle joint combination. 10,14,23 These measurements convincingly disproved our hypothesis (Fig. 2). Specifically, the slope of the sarcomere length joint angle relationship was normal, demonstrating maintenance of the same fiber length:moment arm ratio, even in severe spasticity. There are only three structural explanations for the increased resting sarcomere length and the identical slope of the fiber length:moment arm ratio (Fig. 3). First, tendon or muscle length may decrease, resulting in a long resting sarcomere lengths with maintenance of the sarcomere length joint angle slope (Fig. 3B). Second, sarcomere number may increase in proportion to an increase in average moment arm (Fig. 3C). Finally, sarcomere number may decrease in proportion to a decrease in average moment arm (Fig. 3D). Of these possibilities, we view muscle shortening as the most probable because no dramatic changes in the absolute magnitude of the moment arm were seen clinically. If anything, average moment arm may have increased due to the chronic wrist flexion, but this value was not directly measured. Of course, this argument assumes that muscle deformation due to joint rotation is the same in normal and spastic patients. If the connective tissue material properties of spastic patients is quite different from normal, the magnitude of muscle deformation with identical wrist rotation will vary between groups and this argument may not apply. However, the absolute change in sarcomere length would still be meaningful. 268 Sarcomere Length in Spastic Muscles MUSCLE & NERVE February 2002

5 A precise mechanism that would explain muscle shortening is not currently available. Usually, muscle adaptation is explained in terms of fiber length, not muscle length changes. Because fiber length remained constant but sarcomeres were consistently highly stretched, shortening had to occur at some other level. We hypothesize that spasticity caused muscle shortening without fiber shortening, which could occur in a highly pennated muscle such as the FCU if entire fibers were simply degenerated or degraded, leaving a shorter muscle belly to span the entire length. This would require a fiber stretching similar to that observed here and could occur, for example, during bone growth of the patients with cerebral palsy. Based on the known serial sarcomere number of the FCU 11 of 19,000 and the average 1.4 µm sarcomere length increase, the amount of muscle shortening would have to be 27 mm (19, mm) which is a considerable distance, but within reason given the dimensions of the forearm and the FCU muscle (225 mm). 11 Should this explanation of muscle adaptation be true, appropriate therapeutic measures would be needed to restore muscle length to normal, or to permit fibers to shorten to more favorable lengths for active and passive force generation. Such procedures could include muscle tendon lengthening, tendon grafting, or some newly developed procedure to actually increase muscle length. 6,12 14,16 Future studies are required to measure the mechanical properties of these muscles, tendons as well as their composite fibers, to provide an explanation for the observed data. In addition, intraoperative data taken at various time points after the onset of injury may shed light on the mechanism of the muscle adaptation to spasticity. This work was supported by the Department of Veteran s Affairs, NIH grant 45339, Göteborg University, and Swedish Medical Research Council grant REFERENCES FIGURE 3. Schematic representation of muscle adaptation to spasticity. (A) Normal muscle joint interaction. (B) Adaptation if tendon or muscle length decreases, but moment arm remains the same. (C) Adaptation if sarcomere number and moment arm both increase. (D) Adaptation if sarcomere number and moment arm both decrease. 1. Abrams RA, Tsai AM, Watson B, Jamali A, Lieber RL. Skeletal muscle recovery after tenotomy and 7-day delayed muscle length restoration. Muscle Nerve 2000;23: Burkholder TJ, Lieber RL. Sarcomere number adaptation after retinaculum release in adult mice. J Exp Biol 1998;201: Cutts A. Shrinkage of muscle fibres during the fixation of cadaveric tissue. J Anat 1988;160: Cutts A, Alexander RM, Ker RF. Ratios of cross-sectional areas of muscles and their tendons in a healthy human forearm. J Anat 1991;176: Fridén J, Lieber RL. Physiological consequences of surgical lengthening of extensor carpi radialis brevis muscle-tendon Sarcomere Length in Spastic Muscles MUSCLE & NERVE February

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