OPTIMAL INJECTION DEPTH FOR COLLAGENASE CLOSTRIDIUM HISTOLYTICUM DETERMINED BY ULTRASONOGRAPHY IN THE TREATMENT OF DUPUYTREN´S DISEASE

INTRODUCTION

Dupuytren’s disease (DD) is a common, benign, fibroproliferative disease with thickening of the palmar and digital fascia and adjacent soft tissues mainly in the ring finger and the little finger.¹ Normal palmar fascia affected by DD transforms into pathologic nodules and cords, which may form progressive flexion contractures and inhibit normal function of the hand. The mainstay treatment for DD is surgical fasciectomy or fasciotomy.^2,3 The surgical treatment is associated with significant morbidity, with a reported overall complication rate of 17%, including skin complications, hematoma, digital nerve injury, and complex regional pain syndrome.⁴ Despite resection of the pathological lesion, subsequent secondary operations are sometimes required because of recurrence and revision surgery is even more challenging, with a higher rate of complications.⁵ Due to the risks of primary surgery and the challenges of additional surgery on a previously scarred bed, hand surgeons have long been searching for nonsurgical treatments for DD.⁶

An alternative nonsurgical treatment for DD is Collagenase Clostridium Histolyticum (CCH) injection (Auxilium Pharmaceuticals, Inc., Malvern, PA, USA), which was introduced in 2009.^7.8 It relies on enzymatic cleavage of the pathologic cords via local injection of collagenase, followed by delayed manual manipulation.⁹ The efficacy and safety of CCH has been confirmed in clinical studies and CCH subsequently became a therapeutic drug for the minimally invasive treatment of DD. ^7-11 The most common adverse outcomes reported for CCH injection are pain with injection and manipulation, edema, ecchymosis, lymphadenopathy and skin tears that are usually resolved without further surgical therapy.^7-12 However, a serious complication is tendon rupture, requiring technically demanding surgical procedures for secondary reconstruction.^8-12 It is important to minimise the occurrence of such complications, therefore injection to the correct depth by a skilled physician is recommended. In Japan, only hand surgeons board certified by The Japanese Society for Surgery of the Hand (JSSH) are allowed to perform CCH injections.¹¹

The technical instruction leaflet for CCH injection recommends a “2–3 mm depth” of injection;¹³ however, there is little supporting evidence to rationalise the appropriateness of this assertion. We hypothesized that the optimal injection depth is the distance from the surface of the skin to the middle of the cord because we believe that it would produce maximum efficacy and minimise side effects. We note that Leclere et al proposed a an ultrasound (US) guided injection technique¹⁴ as a way to achieve the same result. The aim of this study was to evaluate the use of US to determine the optimal injection depth in different patients with different cord thicknesses.

MATERIAL AND METHODS

A total of 43 patients affected by DD with fixed flexion contracture (FFC) of the metacarpophalangeal (MP) or proximal interphalangeal (PIP) joint were included in this study. There were 40 males and 3 females with a mean age of 71.4 years (range 53–87). Treatment was given to only one finger in each patient. Affected digits were the little (n = 24), the ring (n = 17) and the middle (n =2) fingers. The mean FFCs caused by the palpable cords were of 45 degrees at the MP joint (range 0-80) and 17 degrees at the PIP joint (range 0–65).

We marked three collagenase injection points at 2 mm intervals on the skin above the cord around the MP joint of the involved digit before injection. All points were located not more than 4 mm distal to the palmar crease (Figure 1). Then pulling each finger under tension, we measured the hypothesized “optimal depth”, i.e. the distance from the skin surface to the centre of the cord, by high resolution ultrasonography with long axis images (SNiBLE; Konica Minolta, Tokyo, Japan) with an 18 MHz linear transducer. The linear transducer was applied over the cord with care to prevent compression of subcutaneous soft tissues. We also measured the distance from the skin surface to the superficial aspect of the cord, the width of the cord by long axis imaging and used this to calculate the distance from the skin surface to the centre of the cord (Fig 2). We analyzed the correlation between the FFC of the MP joint and the width of the cord additionally (Pearson’s correlation analysis).

RESULTS

At US examination in the sagittal plane all cords could be visualized as a mixture of isoechoic or hypoechoic lesions. The average distance from the skin surface to the cord was 1.0 mm (range: 0.4–2.0) and the average width of the cord was 2.7 mm (range: 1.5–3.8). The average optimal depth, i.e. distance from the skin to the middle of the cord, was 2.4 mm (range: 1.5–3.0) (Table 1). Interestingly, 4 cases were less than the 2 mm of minimum recommendation. No correlation between the FFC of MP joint and the width of the cord was found (R2 = 0.183) (Table 2).

DISCUSSION

CCH injection has been approved as a minimally invasive non-surgical procedure to treat DD for more than 10 years in various countries.^{11, 13-15} Its efficacy and safety has been reported in clinical settings. ^{7, 11, 16, 17} Although the technical instruction leaflet for CCH injection recommends a “2–3 mm-in depth injection within 4 mm distal to the palmar digital crease”¹⁴, there is still room for error owing to the different thicknesses and depths of the cords. Furthermore, there is little guidance with objective evidence in the literature regarding the optimal depth for the CCH injection. Physicians tend to inject CCH shallowly to avoid the serious complication of flexor tendon ruptures and this might exacerbate the occurrence of adverse events such as bruising, swelling and skin laceration. These adverse events are mild or moderate and resolved without intervention within a median duration of 10 days. ^8,18 Patients’ satisfaction is superior to that of needle fasciotomy ¹⁹ despite this disadvantage. Verheyden et al. suggested injecting CCH into the centre of the cord in an effort to maximize CCH efficacy and to avoid the greater potential for spread of the enzyme to nearby flexor tendons or pulleys.²⁰ We agree with the authors and believe that injection into the middle of the cord might reduce the rate of the aforementioned complications.

Meals et al. reported their intraoperative findings underlining that the superficial aspect of the cords is located 2 to 4 mm from the skin surface, and cord thickness is rarely more than 4 to 5 mm.²¹ In our study, the average width of the cord was 2.7 mm (range; 1.5–3.8), which was smaller than their findings. We suppose that candidates for surgery may have thicker cords affected by more long-lasting conditions than those selected for non-surgical therapy or alternatively that surgical specimens are free from in-vivo anatomical pressure when measured.

Our US-findings are comparable to previous reports^22,23 but we further investigated the widths of the cord and skin thickness in DD patients. We were able to determine the injection depth by direct measurement and demonstrated that FFC of the MP joint could not be used to determine the injection depth as it did not correlate with the width of the cord. However, the skin thickness may help in predicting the propensity for skin laceration after manipulation. Further research is necessary to define the exact usefulness of US in these procedures. Uehara et al.²⁴ reported US evaluation of the relationship between the cords and neurovascular bundles, utilizing a short axial image. We selected a long axial image because it was easier to detect and measure the anatomical characteristics of the cords and to elucidate the three injection points at the 2 mm intervals. Moreover, pragmatically, it is difficult to hold the probe on the convex surface of the cord for a short axial image because the contact point is smaller compared to the long axis image.

The limitations of this study are: (a) the small number of enrolled patients and (b) the lack of investigation of the spiral, lateral digital and retrovascular cords in the digital forms. This study is mainly focused on the palmar forms with the MP joint main involvement only. The improvement of FCC as a result of this procedure is to be reported elsewhere and is not included here.

CONCLUSION

In this study, we confirmed that “2–3mm in depth” for CCH injection was appropriate in most circumstances.However, 4 cases (9.3%) showed a cord located at less than 2 mm in depth, which could have resulted in delivery of CCH underneath the cord. Experienced surgeons know the anatomy of DD and the nodules but we conclude that measuring the injection depth by US would be beneficial.

To inject the planned depth, the 1.2 mm bevel at the needle tip helps estimate the depth of insertion ²¹ or a silicone tube interposition to adjust needle length is practical for precise injection.²⁵

Acknowledgments: We thank Dr. Marco Guidi for technical assistance with the graphics presented in this work and Dr. W. McPherson for English language assistance.

Declaration: All procedures were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. Informed consent was obtained from all patients included in this study.

Role of authors: All authors have been actively involved in the planning, preparation, analysis and interpretation of the findings, enactment and processing of the article with the same contribution.

Conflict of interest: None.

Corresponding author:

Stefano Lucchina, MD

Locarno Hand Center,

Via Ramogna 16, 6600 Locarno

Switzerland

E-mail: info@drlucchina.com