Retrospective Knee Patient Outcome Results

Retrospective Knee Patient Outcome Results Nicholas Collins and Kaylee Stephenson Introduction: When it comes to chronic pain, knee pain ranks as the second most prominent contributor to these conditions, following back pain. 1 It has been documented by the American Osteopathic Association that over 33% of Americans suffer from knee pain at some point in their lives. 1 While the knee is a large load-bearing joint, it is also prone to many injuries in one s lifetime due to various activities such as sports, or occupations that require intense physical activity. 1 At Premier Regenerative Stem Cell & Wellness Centers, a number of patients that come in seeking relief for knee pain are those that suffer from osteoarthritis or from complications that stem from an injury (many being recreational related). Treatment options for osteoarthritis and other conditions causing knee pain include medication, physical therapy, and surgery if the pain or injury is severe enough. 2 Patients who have exhausted most of their treatment options and want to avoid surgery try stem cell therapy as a method to reduce pain and increase the functionality of their knees. Mesenchymal stem cells (MSCs) are harvested from the patient s own bone marrow and the procedure itself is very minimally invasive, therefore it appeals to many people that don t want the recovery period or invasiveness of a knee replacement or other similar surgery. MSCs are becoming a more renowned treatment option due to their ability to self-repair, induce cell-signaling effects, and differentiate into a number of different cell lineages found in bone, cartilage, and connective tissue. 3 Methods and Materials: 1

Similar to those who receive lumbar and cervical spine treatment, patients coming in for knee injections must also consult with the physician in order to determine whether or not they are a good candidate for stem cell injections. Patient information, consent, and medical history are collected in order to ensure the best care possible be given to the patient. Patients that have undergone a Image 2. Pelvic anatomy including the PSIS. 5 total joint replacement are usually redirected to another form of treatment due to the fact that MSC s cannot proliferate and conduct cellular signaling as well in an inorganic joint. The day of the procedure, the patient is given antibiotics intravenously and then brought to the procedure room to prepare the rest of the way for stem cell injections. The patient is placed in a prone position (image 1) in order for the physician to access the posterior superior iliac spine (PSIS) shown in image 2. The PSIS is the point of insertion of the Jamshidi needle in order to aspirate the appropriate amount of bone marrow. The position of the bone marrow aspiration needle is guided by the fluoroscopic x-ray machine for precision. The bone marrow that is harvested is then processed through centrifugation for 30 minutes in order to separate the buffy coat, which contains the mesenchymal stem cells, from the rest of the bone marrow aspirate. After separation of the stem cells is complete, the patient is ready for the injection of these stem cells into the target area. For knee patients, in order for the physician to access the target area, the patient must be turned over into a supine position (image 1). Once the patient is in this position, the appropriate knee (or both knees for bilateral treatment) is prepped for stem cell injection. The appropriate amount of bone marrow concentrate is then injected into the femoral or intercondylar notch (image 3) of the target knee(s). Injection into the target area is also guided by fluoroscopic x-ray imaging. Image 1. Supine position versus prone position. 4 Image 3. Patellar anatomy including the intercondylar notch. 6 Patient outcome data is acquired through an entirely different form as compared to lumbar and cervical patients. Those who have had stem cell injections in their knee complete 2

the Lower Extremity Functional Scale (LEFS), a form that focuses more on the functionality of patients through activities that rely more on the lower extremities such as the hips, knees, or ankles. The functional scale of the LEFS ranges from 0 to 4, where 0 represents an extreme difficulty or inability to perform a certain activity and 4 represents no difficulty in completing that same activity. There are a list of 20 activities and patients rate their ability, 0-4, to complete each of these activities. The sum of the patient s responses is then recorded out of a maximum of 80. The pain scale for knee patients is recorded using the standard pain rating score, where the scale ranges from 0 to 10, 0 representing no pain and 10 representing worst possible pain. Depending on which knee the patient is having injected, they provide a corresponding pain rating for their left, right, or both joints. This pain rating is then multiplied by 10 in order to gain a better visual depiction of the patient s pain level. If a patient had both knees injected, the worse knee, or the knee that with the higher pain rating is used for the data. Before their procedures, the patients filled out the LEFS form and the pain scale as a baseline marker to compare post-procedure follow up intervals with. The patients were then contacted 6 weeks, 3 months, 6 months, and 1 year post-procedure and asked to fill out the same form in order to track their progress and observe how their functionality and pain changed compared to baseline. Only patients who had both their LEFS and pain scores at baseline and the specific follow up interval were included in this data, those who missed a follow-up interval or did not have both response values were excluded from those time-points. Data and Results: LEFS Score Over 1 Year LEFS Score (0-80) 80 60 40 20 0 6 wks* 3 mo* 6 mo* 1 yr* Baseline 0 10 20 30 40 50 60 Time (weeks) Figure 1. Average lower extremity functional scale (LEFS) scores over one year for 137 unique patients. Scores were calculated using the LEFS that asks twenty questions which are graded 0-4 (level of difficulty), where high numbers represent better functionality to perform a certain task. Patients were asked to fill out this form before their procedure and then again at 6 weeks, 3 months, 6 months, and 1 year after their procedure. A dependent t-test was run to compare pre and post-operative LEFS scores. *indicates statistical significance at p<0.01. 3

Pain Score Over 1 Year Pain Rating (0 to 100) 80 60 40 20 0 Baseline 6 wks* 3 mo* 6 mo* 1 yr* 0 10 20 30 40 50 60 Time (weeks) Figure 2. Average knee pain ratings on a scale of 0 to 10 (multiplied by 10) over two years for 137 unique patients. Scores were calculated using 0-10 pain scale, where 0 represents no pain and 10 represents worst possible pain. Patients were asked to identify their pain on this scale before their procedure and then again at 6 weeks, 3 months, 6 months, and 1 year after their procedure. A dependent t-test was run to compare pre and post operative pain scale scores. *indicates statistical significance at p<0.01. Table 1. Average LEFS and pain ratings over two years for 137 unique patients with percent improvement for both categories. Sample Size Average LEFS (0-80) LEFS Improvement from Baseline (%) Average Pain Rating (0-100) Pain Improvement from Baseline (%) Baseline 137 38.7-62.4-6 weeks 33 52.8 36.43 36.8 41.03 3 months 51 56.2 45.22 31.1 50.16 6 months 68 58.9 52.20 29.4 52.88 1 year 37 58.8 51.94 37.0 40.70 Table 2. P-values for LEFS Scores and pain ratings at all time intervals (6 weeks, 3 months, 6 months, 1 year). A dependent t-test was performed using Rstudio in order to obtain these values. A p-value below 0.01 indicates statistical significance at a 99% confidence level. LEFS P-Value Pain Rating P-Value 6 Weeks 2.998e-06 3.204e-05 3 Months 4.08e-10 5.259e-11 6 Months 1.124e-11 <2.2e-16 1 Year 1.113e-06 5.632e-05 Table 3. Average LEFS scores at all time intervals (6 weeks, 3 months, 6 months, and 1 year) including baseline. Follow Up Interval LEFS Score (0-80) Change in LEFS Score From Baseline (Point Differential) Baseline 38.65 -- 4

6 Weeks 52.8 +14.15 3 Months 56.2 +17.55 6 Months 58.9 +20.25 1 Year 58.8 +20.15 Figure 1 shows the average LEFS scores for knee patients pre-procedure and at 6 weeks, 3 months, 6 months, and 1 year post-procedure. It is important to note that based on LEFS scoring, the larger a patient s total LEFS score, the better able they are to complete certain tasks. Therefore, at 6 weeks post-procedure there is an apparent improvement in the average patient s functionality compared to baseline by 36.43%. At 3 months, patients, on average, are still seeing improvements, not only from baseline, but from their 6 week post-procedure follow up. Compared to baseline, average 3 month LEFS scores improved by about 45.22% and compared to 6 week post-procedure LEFS scores, 3 month LEFS scores improved by 6.44%. At 6 months and 1 year post-procedure, there seems to be a plateau that reflects about a 52% improvement from baseline. Figure 2 shows the average pain scale scores for pre-stem cell injections and post-stem cell injections at 6 weeks, 3 months, 6 months, and 1 year. The pain scale for knee patients reflects the same scale used for lumbar and cervical patients, therefore, a higher number on the pain scale indicates a higher perceived pain level for the patient. At 6 weeks, 3 months, and 6 months, the average patient s pain improved from baseline by 41.03%, 50.16%, and 52.88%, respectively. At 1 year, pain scores reflect a relapse of pain compared to the 6 month time interval; at 1 year the average patient s pain seemed to revert back to the level of pain they were feeling 6 weeks postprocedure. Although this trend is not ideal, the pain level for the average patient at 1 year post-procedure was still 40.70% better than the level of pain they were feeling before the procedure. Image 4. Dependent t-test results comparing average baseline LEFS scores to average 3 month LEFS scores, including p-value. To determine statistical significance, dependent t-tests were run using pre and postbaseline scores for each of the 4 follow-up time intervals for both LEFS scores and pain scale scores. In order to determine if the data for each time interval was significant, the p-values from each test were taken into account and analyzed. Image 4 is a direct image from one of the dependent t-tests run to compare baseline LEFS scores with the 3 month follow-up LEFS scores. Table 2 reflects all of the p-values collected from each of the 8 dependent t-tests run comparing 5

baseline and each of the 4 follow-up intervals (6 weeks, 3 months, 6 months, and 1 year) for both LEFS and pain scores. All p-values fall significantly below 0.01, indicating that all data at each of the time intervals is meaningful and not likely related to chance or coincidence. Setting the p-value threshold to 0.01, gives a confidence level of 99% for the indicated results. Discussion: The measure of clinical significance of the Lower Extremity Functional Scale questionnaire is different than that of the Lumbar Oswestry Index and the Neck Disability Index since the LEFS form is scored much differently than the latter two forms. A clinically significant change in a patient s functionality is indicated by a difference of more than 9 points on the LEFS form between two time intervals. 7 Therefore, patients, on average, were seeing clinically measureable improvements from baseline to each of the four follow-up intervals (table 3). In as little as 6 weeks after stem cell treatment, 63.64% percent of patients (21 out of 33) were seeing clinically measurable improvements in functionality regarding their knees. At 3 months, 6 months, and 1 year, 68.63%, 69.12%, and 67.57% of patients, respectively, continued to see clinically significant improvement compared to baseline indicating a better sense of functionality and ability to complete tasks that largely rely on the use of the knees, such as climbing stairs or walking. Although the average LEFS scores seem to primarily follow a trend of improvement that eventually plateaus, the average pain scale scores seem to follow a different trend that reflects both improvement and regression. On average, patients undergoing stem cell injections in the knee see significant pain relief at 6 weeks, 3 months, and 6 months posttreatment. However, after 6 months, the average patient s pain level seems to regress back to the level of pain the patient was experiencing around 6 weeks post-procedure. Although there is this regression of pain at the 1 year mark, the level of pain, on average, is still 40.70% less than what patients were feeling before their procedure. This trend does indicate that a possible time frame for second knee injections may fall between the 6 month and 1 year time interval after the first injection. This statement is a mere suggestion based off of data thus far and other factors, such as personal pain tolerance and intensity, can still affect the validity of second injection recommendations. It is important to reiterate that this is average data. This data represents the average LEFS and pain scale scores of 137 unique patients, therefore, some patients experienced greater improvement than reflected by this data, some patients experienced less significant results, and some patients experienced no real improvement at all. As with the lumbar and cervical data, only patients that completed follow-up forms for the specific time intervals were included in this study, which, unfortunately, means that there were other patients that received stem cell treatment for their knees whose results are not reflected due to lack of follow up data. With all surveys there comes the unfortunate effects of biases and similar to the spine studies, the knee study is also subject to both nonresponse and voluntary response bias. Nonresponse bias occurs when there are significant numbers of respondents and non-respondents in a study; non-respondents may arise from an inability or a disinterest in filling out follow up forms. 8 Voluntary response bias occurs in those who elected 6

to respond to the follow up forms. 8 These patients are likely to have extreme opinions, positive or negative, about their experience and can therefore skew the results to one extreme or another. 8 Both biases can work together to create errors in a study, not always severe, but enough to where it makes it difficult to say with certainty how a patient will feel posttreatment, or if the treatment will even be of benefit to them. Increasing the sample size of the knee patients would likely reduce this bias and improve the study as increasing the number of patients would likely increase the number of responses for each of the follow-up intervals. An increase in the number of total responses may also allow for responses from patients that fall between the two extremes of significant improvement and significant relapse or stagnation. As always with these stem cell studies, the completion of a double-blind study with the appropriate variables would help to improve the collective understanding of MSCs by providing an unbiased basis for both physician and patient. Eliminating this bias would help in focusing on the variables that make a significant difference in determining whether stem cells are the right treatment option for a patient wanting relief from joint pain and frailty. Conclusion: The reported patient data for stem cell injections in the knee represents both clinical and statistical significance for both LEFS and pain scale scores for all follow-up time intervals. In terms of functionality, the average patient seems to experience significant improvement in their knees compared to their baseline, reaching a maximum of about 52% improvement at both 6 months and 1 year. The average patient also seems to feel a significant relief in terms of joint pain at all time intervals compared to baseline, noting, however, the small regression of pain at the 1 year mark back to that of the 6 week mark. However, due to the fact that this data is average data, it is difficult to definitively state whether stem cells are right for everyone experiencing knee pain that does not yet require a more aggressive treatment approach, such as surgery. Factors such as genetics, lifestyle, and mentality may contribute to the efficacy of stem cells and, at this point, the correlation of these variables with stem cell treatments are difficult to study. Though additional data would help in reaching conclusive recommendations for each prospective stem cell patient, the presented data does offer clinically and statistically relevant information that can provide a strong foundation for the development of stem cell therapy as a treatment option for many patients. 7

Works Cited: 1 "Chronic Knee Pain." American Osteopathic Association. American Osteopathic Association, n.d. Web. 26 Dec. 2016. 2 "Osteoarthritis Treatment." Arthritis Foundation. Arthritis Foundation, n.d. Web. 27 Dec. 2016. 3 Via, Alessio Giai, Antonio Frizziero, and Francesco Oliva. "Biological properties of mesenchymal Stem Cells from different sources." Muscles, Ligaments and Tendons Journal. CIC Edizioni Internazionali, 16 Oct. 2012. Web. 27 Dec. 2016. 4 Supine position and prone position. N.d. Wikipedia. Web. 27 Dec. 2016. https://en.wikipedia.org/wiki/supine_position 5 Iliac Crest Pain. N.d. New Health Guide. Web. 26 Dec. 2016. http://www.newhealthguide.org/iliac-crest-pain.html 6 Intercondylar Notch Size. N.d. Anterior Cruciate Ligament Ruptures. Web. 26 Dec. 2016. http://aclinformation.weebly.com/etiology.html 7 Hanson, Emily, Naomi O'Reilly, and Evan Thomas. "Lower Extremity Functional Scale (LEFS)." Physiopedia. Physiopedia, n.d. Web. 26 Dec. 2016. 8 Bias in Survey Sampling. Survey Sampling Bias. Stat Trek, 2016. Web. 22 Dec. 2016. 8

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