Summary: Strengthening of the quadriceps femoris muscle (QFM) is of great importance in the treatment of the patients with knee osteoarthritis (OA). In this study, we aimed to investigate and compare the effects of neuromuscular electrical stimulation (NMES) and isometric exercises (IsE) on QFM by 99mTc-sestamibi scintigraphy which is a new skeletal muscle perfusion agent. Twenty female patients aged between 41-62 years, diagnosed as having knee OA according to American College of Rheumatology (ACR) criteria were included in the study. Radiograms of the knees were taken, thigh girth and Lequesne index values were obtained in all cases before and after the training activities. After randomization, one QFM of each case was subjected to the procedure of NMES for 23 minutes daily by Compex device which is a computed electrostimulator, whereas the other was applied IsE for 9.5 minutes daily, five times a week for three weeks’ period. 99mTc-sestamibi scintigraphic evaluations were performed 3 days before and after the training programmes and thigh uptake ratios were calculated from the images. Significant increases in thigh uptake ratios were determined in both groups, however this increase did not reach significant difference between the groups. Significant increases were also found in thigh girth values for both groups whereas the mean value of increase was much more apparent in NMES group. The increases in uptake ratios and thigh girth improvement values were significant in cases of stage I when compared with advanced radiological stages. Clinical improvement in Lequesne indices were found to be concordant with scintigraphic increases in all cases. Finally, it was concluded that NMES and IsE training activities seemed to increase muscle perfusion as shown by 99mTc-sestamibi scintigraphy. Muscle strengthening methods were more effective in cases with early radiological stages knee OA. 99mTc-sestamibi scintigraphy can be considered in evaluation of effects of muscle rehabilitation methods on muscle perfusion and mitochondrial fraction as a new, cheap and non-invasive method.

Key Words: Neuromuscular electrical stimulation, isometric exercise, 99mTc-sestamibi scintigraphy.

Introduction

Strengthening of atrophic and weak muscles due to various pathologic conditions is of great importance in the rehabilitation process. Traumas, surgical procedures, immobilization due to degenerative joint disorders, structural pathologies like scoliosis, paresis and paralysis observed in upper motor neuron lesions are the frequent causes known to decrease the strength of muscles(1). Among these factors, the rehabilitation of the weak quadriceps femoris muscle (QFM) due to knee osteoarthritis (OA) is of great importance in the treatment(2).  

Isometric exercises are widely used during acute and chronic phases of knee OA which lead to range of knee motion restrictions(3,4). Neuromuscular electrical stimulation (NMES) is another current method which has place in the strengthening of weak muscles(5). Many studies have been performed about the comparative evaluation of NMES and isometric exercise (IsE) for their abilities to strengthen muscles. However the reports of these studies have been contradictory (5,6,7).

Technetium-99m-sestamibi (methoxy-isobutyl-isonitril) is basically a myocardial perfusion scintigraphy agent. However it has been used as a new skeletal muscle perfusion agent recently(8,9). In this study, we aimed to investigate the effects of both NMES and IsE on QFMs of patients with knee OA by 99mTc-sestamibi scintigraphy. At the same time this investigation would help us determine the usefulness of 99mTc-sestamibi as a possible new, cheap, non-invasive and easily available evaluation method of muscle rehabilitation techniques for their effects on muscle configuration and perfusion. To the best of our knowledge, this study is the first one which the muscle strengthening techniques were evaluated with a muscle perfusion scintigraphic agent.

Materials and Methods

Patient selection: Twenty consecutive female patients with knee OA, aged between 41 and 62 years were included in the study (Table 1). Knee OA was diagnosed according to the criteria of American College of Rheumatology(10). Antero-posterior and lateral knee radiographies of all patients were taken. Patients with radiographic grades between one and three according to Kellegren-Lawrence classification were included in the study. Exclusion criteria were as follows:  Presence of: 1) male sex, 2) grade four Kellegren-Lawrence radiographic changes, 3) acute synovitis, 4) active and regular training in any branch of sports, 5) regular training to strengthen muscles, 6) any disease together with neurologic deficits having impact on lower extremity muscles, 7) any systemic and cardiovascular disease having potential to prevent exercise training.    

Muscle strenghtening methods: The patient was informed about the procedure and signed the written consent. Both QFMs of each patient were included in the study. The dominant sides of all the patients were the right side. After randomisation with simple systematic method (x+1), one QFM of each patient was trained with IsE and the other one with NMES. So, twenty QFMs were trained in each group. The training programmes were applied once a day, five days a week and lasted for three weeks. Totally 15 sessions were performed.

NMES application: Muscular stimulation was provided by a computed neuromuscular stimulator called COMPEXTM. The time and modulation of stimulation programmes were preserved in the hard disc of the device. Main technical properties of the device were listed in Table 2. NMES was applied through three channels by a monopolar, large and negative electrode and four small, positive electrodes on the motor stimulation points of the QFMs. Double electrodes were placed on rectus femoris, vastus medialis and vastus lateralis  as to be one electrode on the widest parts of the muscles and the other on the insertions of the same muscles. These electrodes were applied with gels that increased the impulse transmission. They were fixed with velcro tapes to the thigh. NMES was applied to the patient in sitting position and the thigh of the patient was fixed manually to the table by the physician in order to prevent knee motions during strong contractions. Motor unit stimulation and strong contractions were provided by bipolar and symmetrical square waves. Programmes with frequencies of 75 and 85 Hertz were selected to obtain maximal contractions in fast muscle fibrils. The intensity was increased by motivation of the patient, every after three or four contractions according to the compliance and tolerance of the patient. Impulses with 20-25 amper were used for the beginning and these values were increased up to 50-55 amper until the end of the training set. The programmes specific for strengthening of large muscle groups were selected in the first training week. Programmes with higher impulse frequencies and intensities were applied in the second and third weeks. Each training session consisted of three parts. The first part was for warming and lasted for four minutes. The second part was for training and lasted for 15 minutes. The third part was a four minutes’ period for relaxation. Isometric exercise training: The patients sitted on the examination table with the hips flexed and the knees extended. A roll pillow was placed under the knees of the patient to provide a little knee flexion. Afterwards the patients were motivated to contract selected one of QFMs as maximal as possible. The ankle and the knees of the patients were fixed manually to the table to prevent knee motions provided by strong contractions. In this way the patients were verbally motivated and their performances were observed closely. One exercise session lasted for 9.5 minutes and consisted of 3 sets. Each set consisted of 10 contractions and one minute of rest period between the sets. The contraction duration was six seconds and the resting period between the contractions was nine seconds. 

Thigh girth measurement: Thigh girth was measured around the point ten centimetres proximal to the apex of the patella in each patient by the same physician.

99mTc-sestamibi muscle perfusion scintigraphy: All study patients were fasted and were maintained at rest for at least 30 minutes before the intravenous administration of 99mTc-sestamibi [555MBq]. Scintigraphic images were obtained approximately 60 minutes later. Studies were performed using a large field of view gamma camera (Philips Diagnost Tomo) equipped with a low-energy, parallel-hole, high-resolution collimator, and a 20% energy window centred at 140 keV. Images were acquired in a 128x128 pixel matrix until 400.000 counts/view were obtained or for 5 minutes. The semiquantitative analysis was performed in a blinded fashion one week later. Regular region of interest (ROI) were drawn around muscular thigh and nonmuscular knee areas. The uptake ratios were computed by dividing the mean counts in the muscular ROI by mean counts in the nonmuscular ROI (11,12). Since these ratios could be affected by increases in muscle mass, normalized uptake ratio (NUR) was calculated by dividing these ratios by the patient’s body surface area(13,14). Intraobserver variations were assessed by reanalysing all data one week later.

Analysis: Demographic properties of the patients like age, gender and weight were identified (Table1). Radiographic investigations of the knees were performed. Thigh girth measurements, 99mTc-MIBI muscle perfusion scintigraphic evaluations and Lequesne knee OA severity index questionnaires of the patients were performed three days before and three days after the training and stimulation programme periods. The scintigraphic uptake ratios before and after NMES and IsE programmes were compared to determine whether 99mTc-sestamibi would be able to demonstrate the effects interventions on muscle. Besides any probable superiority of these methods to each other were investigated by comparing the increases in uptake ratios of individual applications. Moreover scintigraphic findings were assessed for probable correlations with thigh girth measurements, radiographic grading system and Lequesne severity index. Comparisons for dependent groups were made by Student t-test. Mann-Whithey U test was used for subgroup comparisons and correlation analysis was made by Pearson correlation test. SPSS version 9.0 was used for the interpretation of the data.

Results

The mean age of the patients participated in the study was 51,9. The age, gender and weight characteristics with radiological grades of the knees of all the patients were shown in Table 1. The application sides of either NMES or IsE programmes were shown in the same table. 

Significant increases in the scintraphic uptake ratios were observed in both intervention groups after NMES and IsE regimes. However no significant difference was found between the mean uptake increase ratios of the groups. The uptake ratios of QFMs as shown by 99mTc-sestamibi scintigraphy in NMES and IsE group before and after the interventions were demonstrated in Table 3. The increase ratios were also shown in the same table. Thigh girth increases in both groups reached statistical significance after interventions. Mean thigh girth increase was significantly higher in NMES group. The girth values and increase ratios were also shown in Table 3. Significant positive correlation was observed between thigh girth increase ratios and scintigraphic uptake increase ratios in NMES group (r=0.45, p=0.04). This significant relation was more prominent  in IsE group (r=0.71, p=0.002).

Radiological evaluation revealed 12 grade one, 19 grade two and 9 grade three knee OA according to Kellegren-Lawrence classification. 99mTc-sestamibi scintigraphic uptake increase percentages were observed to be 36.6% in grade one, 18.5% in grade two and 8% in grade three knees. The differences among knees with various grades reached statistical significance between grade one and grade two (p=0.007), between grade one and grade three (p=0.0002) (Table 3). In NMES group, scintigraphic uptake ratios decreased in a consistent manner as the radiological grades increased (38.3%, 22.7%, 6.7% in grades one, two and three consecutively). The similar type of relation was valid for the exercise group (31.6%, 14.37%, 8.1% in grades one, two and three consecutively). The difference between uptake increases in each radiological grades were not significant for NMES and IsE group (p>0.05). Thigh girth increases were similarly greater in patients with low radiological grades. The girth increase ratios were 2.35%, 1.5% and 1.41% for grade one, two and three respectively in NMES group. In exercise group increase ratios were 2.06%, 1.45% and 1.42% respectively. Significantly different girth increases were observed between grade one and grade two, between grade one and grade three, in both groups (p<0.05).

Mean Lequesne index score were 9.9 points in the patients before NMES and IsE interventions. This mean score decreased to 5.6 points after interventions. The improvement in the clinical status of the patients was 45.35% and this value reached statistical significance (p<0.05). Lequesne index improvements were in correlation with scintigraphic uptake ratios in NMES group (r=0.77, p=0.0005) and in exercise group (r=0.41, p=0.04).

Discussion

Isometric exercises of QFM is generally chosen for the prevention of atrophy and muscle strengthening. Studies have shown that IsE has muscle strengthening, pain reduction and range of motion increasing effects (15,16). Neuromuscular electric stimulation is another muscle education technique, used either alone or with IsE in strengthening of muscles following immobilisation after knee operations (17,18). To the best of our knowledge no comparative data exist on the quantitative effects of NMES and IsE  in the prevention or the treatment of the QFM pathologies in patients with knee OA. Some of the existing studies related to the strengthening of healthy QFMs favoured IsE (6,7) and some other NMES (19). There are also studies having found no difference between these two muscle education techniques (20,21).

The strengthening effects of NMES and IsE can be evaluated by many different evaluation methods. Isokinetic dynamometry (Cybex) can be used for the evaluation of the strength of muscles, EMG for the evaluation of motor unit potentials, basal metabolism measurements for the evaluation of the strength exerted and partial oxygen consumption for the evaluation of the blood supply of the muscle. Additionally manual muscle strength testing and some clinical scoring scales can be used. In this study, we used 99mTc-sestamibi muscle perfusion scintigraphy, an unusual evaluation method, which compares the effects of NMES and IsE in muscle cell level.

For an objective comparison, the factors probably effecting the results of the strengthening of muscles were carefully assessed for the comparability of the groups. For example, Soo et al. reported that the strength of quadriceps muscle could be increased in a percentage of 47% in healthy males, while this percentage was only 8% in healthy females, suggesting the effect of sex(22). Romero reported the percentage of strength increases to be 21% in dominant leg and 31% in non-dominant leg(23). Ageing is another factor leading to muscle strength decreases caused by the decrease in type-2 myofibrils just as it is the case for the periarticular atrophy in patients with knee osteoarthritis(24). We did not use control group in the study. The NMES and IsE treatment sessions were applied to the various legs of the same patient. We selected only female patients to the study for two reasons: to eliminate the effect of sex differences and for the lack of individual fibril type variations in female patients(25,26).  One stipulation of the inclusion to the study was right side dominance. The patients with right side dominance were randomised afterwards to provide comparability between intervention groups. Since the body mass index values of the patients were used for normalisation of scintigraphic uptake ratios in quadriceps muscle there was no need to match the patients for this property. Also the patients were selected from the population of 40 years of age and older. The mean age was found to be 51.6.

Unlike the contradictory results in the strengthening of healthy muscles, NMES was found to be more favourable than IsE after knee operations, patella dislocations, tibia fractures, and arthroplasty. NMES was suggested to prevent atrophy and extensor muscle strength decreases, to provide more satisfactory function and to decrease the hospital stay more successfully than exercise regimens(17,18,27). In our patients significant increases in ratios of thigh uptake were determined in both NMES (23.3%), and IsE groups (18.6%)  by 99mTc-sestamibi scintigraphy. However this increase did not reach to statistically significant difference between both groups. We could not compare our results with a previous study, since our study was the first to use the 99mTc-sestamibi as the evaluation method. The major limitation of our study was that we could not correlate the muscle strength values measured by a dynamometry with the scintigraphic uptake ratios. However it is wise to assume that muscle strength must be increased as many previous study pointed so.

Tc-99m-sestamibi, a myocardial and skeletal muscle perfusion agent, can be used to demonstrate the viability of muscle cell, mitochondrial fraction of the cell, the muscle fibril perfusion and the ischemia. Thus we thought that the uptake increases seen in our patients after interventions must be due to capillary density, capillary/fibril ratio and mithocondrial fraction increases in the muscles(8,9). There exist many study reports supporting these claims(28,29). The most prominent result of strengthening exercises is that they lead to hypertrophy and/or hyperplasia in muscles. The protein synthesis, capillary proliferation, capillary density per fibril, aerobic capacity, oxidative enzymes and mitochondrial fraction in human skeletal muscle increase as consequences of strengthening exercises(30,31,32). On the other hand the similar muscle metabolism changes can be observed with NMES application in healthy subjects. In a study muscle hypertrophy and  nucleus amount and fibril dimension increases as well as mitochodrial fraction increases were observed especially in muscle fibrils, after 19 21 days NMES application(33,34). Twenty-one days of NMES applica tion to triceps surae muscle was observed to result in capillary amount, capillary density and capillary/fibril ratio increases(35). Also NMES can change the biochemical properties of the skeletal muscle by increasing succinate dehydrogenase activity with protein synthesis and decreasing myofibrillary ATP-ase activity(6,36).

The previous studies suggested that these physiological and metabolic changes started after the 4-7th days of NMES application(37,38). The application duration of NMES to our patients seemed  to be sufficient according to these studies. Type 2 fibrils prominently change to type 1 fibrils which are more rich for mitochondrial content, capillary density and oxydative enzyme capacity after NMES application, while the hypertrophy and hyperplasia in type 2 fibrils are more prominent after IsE sessions(33,34,35). The greater uptake that was observed after NMES to quadriceps muscle in our study may be due to this effect. Moreover NMES can train all  the motor units of a specific muscle group in longer duration periods than a voluntary contraction. 

We observed more excessive uptake ratio values in QFMs of the patients with grade 1 radiographic changes of knee OA when compared to the ones with grade 2 or 3 changes. The patients with early OA grades were younger in our study group and it is a known fact that atrophy can not improve in older patients as much as it can in younger ones(31). And also fibrous tissue replaces with the muscle tissue in the advanced stage of knee OA that makes the hypetrophic effect of interventions limited(12). The less thigh girth improvements observed in our old patients supports this claim.

Thigh girth improvements were more prominent in patients treated with NMES. Scintigraphic uptake ratios correlated positively with girth improvements. Although it is well known that NMES and IsE leads to hypertrophy and hyperplasia, many authors reported different girth improvement values due to the differences in application types and duration. Some reported(23) no thigh girth increase despite the strength improvements while others could find extremity diameter increases with NMES applications(39). In a study which compared NMES and IsE in QFM, the thigh girth increase values were found to be 1.87% with NMES and 1.19% with exercise treatment which are parallel findings with our study(40).

Lequesne Indexes showed improvements after interventions. Scintigraphic uptake ratios were in positive correlation with Lequesne index improvement values and this correlations were more prominent in NMES group. Since a patient in our study received both NMES and IsE therapies we could not discriminate the individual effect of these applications.  

As a conclusion NMES and IsE training activities both seemed to increase the muscle perfusion and metabolism probably leading to strength increases with no significant difference. Strengthening methods were more effective in cases with early radiological stages of knee OA. 99mTc-sestamibi scintigraphy can be considered in evaluation of effects of muscle rehabilitation methods on muscle perfusion and mitochondrial fraction as a new method.

Correspondence: Yrd. Doç. Dr. Murat Birtane, Trakya Üniversitesi Tıp Fakültesi Fiziksel Tıp ve Rehabilitasyon AD; 22030-EDİRNE Tel.(0284)2357641-1080, Fax (0284)2359187 Elektronik Posta: mbirtane@trakya.edu.tr
Kabul Tarihi: Mart 2001

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