Prebent Titanium Elastic Nailing, Ilizarov Fixation and Bone Grafting for Treating Congenital Pseudarthrosis of the Tibia: Preliminary Outcomes of 15 Cases

Background: To report the preliminary outcome of treating congenital pseudarthrosis of the tibia (CPT) by using titanium elastic nails (TENs) combined with other surgical procedures including pseudarthrosis resection, autogenous iliac bone grafting and Ilizarov technique, with a mean follow-up time of 4.5 (3.3 to 6.3) years. Methods: 15 patients with CPT treated by combined surgery including pseudarthrosis resection, titanium elastic nails (TENs) technique, autogenous iliac bone grafting and Ilizarov xation between 2013 and 2017 were retrospectively investigated. Signs of bone union, limb length discrepancy (LLD), rate of refracture and degree of residual deformities were reviewed. The AOFAS Ankle Hindfoot scale and measurement of ankle movement were used to evaluate ankle function. Results: The mean age at index surgery was 110 (24 to 285) months. 13 (86.7 %) patients obtained union of the pseudarthrosis on the rst attempt (primary union). The average time to primary union was 4.8 (3 to 7) months. The rest 2 cases achieved union after additional surgeries (secondary union). In terms of complications, refracture occurred in 2 patients (13.3%) and 5 (33.3%) patients developed pin infection. The mean limb length discrepancy at the nal follow up was 14.6 (4–41) mm. 3 patients (20 %) had ankle valgus deformities with a mean LDTA of 74.3° (range, 68 to 81°). The average AOFAS score improved from 40.3 (27 to 51) pre-operatively to 76.1 (63 to 87) post-operatively. For the patients who received proximal tibial lengthening, the average healing index (HI) was 65.1 (57.3 to 77.8) days/cm. Conclusions: Titanium elastic nails (TENs) technique is an ideal intramedullary xation method in the surgical treatment of CPT. The combination of TENs technique with bone grafting and Ilizarov xation has the advantages of early bone union, less injury on metaphyseal and early functional recovery.

Currently, the combined treatment including resection of the pseudarthrosis and surrounding hamartomatous tissue, autogenous bone grafting and internal and external xation is the most commonly used techniques (7,(9)(10)(11). Rigid xation is a crucial factor in the treatment of CPT. The use of intramedullary (IM) rodding technique in treating CPT was rst described by Charnley et al. in 1956 and was later modi ed by Williams et al., which helped to decrease the risk of refracture and revolutionized the operative management of these severe deformities (12,13). The retrograde implanted transplantar intramedullary nail provides improved biomechanical stability for bone consolidation, restores the mechanical axis of the limb and reduces the risk of iterative fracture, while at the expense of length discrepancy, joint stiffness and even damage to the articular surface. In addition, children usually have to receive reoperations as the tibiae outgrow their rods, which leads to interruption of childhood and prolonged disability (7,14,15). Telescopic rods can extend during the growth and consequently decrease the number of reoperations. It should be noted, however, that the application of these rods in children is limited by the small shaft diameter of medullary cavity. Moreover, injury to epiphysis may occur as the end of the telescopic rod still requires to be xed through epiphysis (16).
The disadvantages of the commonly used IM rods mentioned above encouraged us to make changes to our treatment procedure. Elastic stable intramedullary nails (ESINs, or Nancy nails) were initially developed in 1980s by a group of pediatric surgeons in France (17). The successful outcome of combining ESINs with external xation for pediatric bone lengthening has led us to improve the existed procedure in treating CPT (18). During the past ten years, the TENs technique, in combination with pseudarthrosis resection, bone grafting and Ilizarov's xation, has been applied to treat patients with CPT patients in our institute. This study presents the preliminary outcomes of this new treating protocol and validates its e cacy with regard to surgical procedure, subsequent complications and the comparison with the results of previously used techniques.

Methods
We retrospectively evaluated the patients with pseudarthrosis of the tibia treated by the same group of senior surgeons at our institute from 2013 to 2017. Combined surgical treatment including pseudarthrosis resection, TENs technique, autogenous iliac bone grafting and Ilizarov xation was set as inclusion criteria. Exclusion criteria included pseudarthrosis of the tibia caused by trauma or infection. A total of 15 patients (9 boys and 6 girls) with CPT were included. Background characteristics is shown in Table 1. All the cases were unilateral, with 6 cases on the right side and 9 cases on the left side. The pseudarthrosis were all located on the distal third of the leg. 13 patients had a bular lesion at the time of the index surgery. According to the Crawford classi cation, 1, 1, 7 and 6 patients were de ned as type I, II, III and IV, respectively (19). Mean age at index surgery was 110 months (range, 24 to 285) months and 5 patients had undergone surgery previously in other hospitals. Preoperative measurements were performed, which included examination of skin condition, bular status and limb length discrepancy. The American Orthopaedic Foot & Ankle Society [AOFAS] ankle-hindfoot scale was also noted for clinical assessment of ankle function before the index surgery (20). No patient was lost to follow-up. Approval was obtained by the research ethics committee at Shanghai Jiao Tong University A liated Sixth People's Hospital. All the patients were informed consent to participate and approved the publication of their data.

Surgical Procedure
All surgeries were performed by the same group of senior surgeons (QL.K.). Iliac crest bone graft was harvested at the beginning of the surgery. Brie y, an incision was made at the anterior superior iliac spine. The outer table of the anterolateral surface of the ilium was exposed subperiosteally and as much cancellous bone as possible was harvested from the supra-acetabular region for subsequent bone grafting. An anterior longitudinal incision was made to expose the affected area of the tibia. The abnormal periosteum and sclerotic bone edges at the pseudarthrosis site were excised. The brous tissue, if present at the bular site in patients with concomitant bular lesion, was excised. An intramedullary k-wire was used to x the osteotomized bula if the tibial fragments were held apart by an intact bula. Two TENs, with an identical diameter at 30-40% of the isthmus of the medullary canal, were selected for internal xation. Before nail insertion, the nails were pre-bent over the length of the bone three times the diameter of the medullary canal. Both nails should be pre-contoured in the same way. The entry points were situated anteriorly on the proximal medial and proximal lateral metaphyseal cortices, 2 cm distal to the proximal physis. The rst nail was inserted into the medullary canal with the nail tip at right angles to the bone shaft, and the nail tip was rotated through 180° with the inserter to align the nail tip with the axis of the medullary canal. Then the nail was advanced up across the resection site towards the level of 1 cm distal to the metaphysis of the tibia. The vertex of the arch should be located at the level of the resection site. The second nail was inserted at the insertion point on the opposite side in the same way. The two nails were situated in a shape like the Eiffel Tower ( Fig. 1, 2b, 3b). Due to the triangular shape of the tibial medullary canal, both nails tend to lie dorsally, which would result in recurvation. Therefore, before hammering the nails in their nal position in the distal metaphysis, the tips of both nails were turned slightly posteriorly in order to achieve the physiological antecurvation of the tibia. Finally, end caps were applied to the nails to reduce the risk of nail migration and soft-tissue irritation, and to facilitate subsequent implant removal. The positions of the nail tips were checked under the image intensi er.
The Ilizarov ring xation was then applied to perform realignment and compression osteosynthesis at the pseudarthrosis site, with one ring xed below the site of pseudarthrosis and one ring xed above. If limb length discrepancy (LLD) was over 3 cm and the age of the patient was more than 3 years, proximal tibial lengthening using the Ilizarov technique was performed concomitantly, with another ring added proximal to the corticotomy site, as described by Cho  Bone transport, if needed, was started 7 days after the surgery at the rate of 0.5 mm/day in 4 increments. Active and passive motion of the knee and ankle were advised to prevent joint contracture after the surgery. Union was considered to be achieved with the formation of at least 3 visible bridging cortices in 2 planes under anteroposterior and lateral radiographs. The criterion used Ilizarov frame removal was set as the achievement of bone union both at the distraction gap and the pseudarthrosis site. Long leg cast was then applied for 1-2 months. Hereafter patients were recommended to move under partial weightbearing with the support of a Knee-Ankle-Foot-Orthosis until skeletal maturity. In order to minimize the risk of refracture and abnormal tibia bowing, the TENs were left in situ till skeletal maturity but may be changed for longer and thicker ones when the tip of the nails receded into the distal third of the tibia with growth. Other additional surgeries for addressing residual problems include treatment of refracture, deformity correction with hemiepiphysiodesis or osteotomy, surgery for nonunion, nail change for pin site problem and treatment of joint contracture.

Outcome evaluation
Post-operative radiographs were obtained every month until xator removal to monitor consolidation and limb length; thereafter, follow-ups were continued every half year until the patients achieved skeletal maturity. Bone union rate and time till union were calculated. Primary union referred to bone united after the rst operation without any need for secondary surgeries. Secondary union was labeled when additional surgery was needed to obtain union. Occurrence of refracture was recorded. For evaluation of limb lengthening, healing index (HI) and limb length discrepancy at the nal follow-up were measured. The healing index (HI) de ned by Aldegheri et al., is expressed as the number of days the xator was applied per centimeters of new-formed bone regenerate length (23). Limb length was measured radiographically from proximal physis to distal physis of the tibia. It should be mentioned that LLD measurement was performed after the index surgery as LLD might increase due to impaction of bone ends after excision of pseudoarthrosis. Residual deformities, including tibial malalignment and ankle valgus, were assessed by the anteroposterior and lateral radiographs. Additional surgical interventions during the period of follow-up were noted. The American Orthopaedic Foot & Ankle Society [AOFAS] Ankle Hindfoot scale was used to evaluate ankle function post-operatively. Additional surgical procedures for addressing the subsequent complications and residual deformities were recorded.

Statistical methods
All statistics were calculated using IBM SPSS software (version 22). Paired t-test was used for evaluating the difference between pre-and post-operative AOFAS score (at last follow-up). The Mann-Whitney U test was performed for analysis of LLD post-operation and at the nal follow up. The level of signi cance was set at p < 0.05.

Results
The patients were investigated at a mean follow-up time of 4.5 years (range, 3.3-6.3y) after the index operation. At the nal follow-up, all the patients had their external frame removed and could walk with full weight bearing on the treated limb. The TENs were retained in all 15 patients during the latest follow-up.
All the patients were satis ed with the functional and cosmetic outcomes (Figs. 2 and 3). A total of 24 reoperations were performed to change the undersized TENs at the last follow-up visit ( Table 2).
Union of the pseudarthrosis was achieved in 100% of the cases, with primary union in 13 cases (86.7%). 2 cases of delayed union at the pseudarthrosis site (case 6 and case 10) achieved union after supplemental allogenous bone graft and replacement of elastic nails. One case with nonunion regarding the bone transport site (case 8) received bone graft and prolonged duration of Ilizarov xation ( Table 2). The average time to primary union was 4.8 months (range, 3 to 7 months) and for secondary union it was 10.3 months (range, 7 to 13 months). An average number of 1.3 (range, 1 to 2) surgeries were performed to achieve union ( Table 3).
The average limb length discrepancy after index surgery was 50.1 mm (range, 13 to 90 mm). 2 patients (case 7 and case 15) underwent osteosynthesis of the pseudarthrosis alone as the shortening was anticipated to be no more than 3 cm. The other patients underwent tibia lengthening, with an average healing index (HI) of 65.1 d/cm (range, 57.3 to 77.8 d/cm) ( Table 3). The mean limb-length discrepancy at the nal follow-up was 14.6 mm (range, 4-41 mm). Only one patient (case 10) had residual shortening of over 3 cm (41 mm).   (Table 2). Among them, ankle deformity was revealed by anteroposterior weight-bearing radiographs in 4 patients (case 1, 2, 6 and 11). The rate of residual deformity was similar to or better than that reported in earlier series (15,24,25). Other complications include refracture and pin tract infection (Table 2). Refracture occurred in 2 patients (13.3%, case 2 and 14), both after removal of the external xators (3 years and 10 months after index surgery). 1 patient (case 2) refracture had bular pseudarthrosis. In case 2, the refracture was treated with casting. Ilizarov xator to compress at the refracture site and nail reinsertion were also applied in both cases. Pin tract infection was identi ed in 5 patients, with 2 cases of grade-I and 3 cases of grade-II infection. Those with grade I infection were settled with dressing changes and oral antibiotics, while for persistent or grade II infection, wires had to be changed or withdrawn. In total, 44 additional procedures were performed for the entire cohort of 15 patients (mean, 2.9 procedures per patient). There were no cases of neurovascular complications or amputation in our study.

Discussion
The achievement of skeletal maturity with functional utility and anatomic alignment of the bone is the primary goal of treating CPT (3,4). Among various surgical techniques that have been developed to optimize the outcomes in treating CPT, the Ilizarov technique has been proved to be valuable in promoting high rate of union through compression, dealing with limb length discrepancy via diaphyseal transfer and addressing angular deformities concomitantly. However, the prevalence of refracture after removal of the xator is the main concern. Treating with the Ilizarov frame alone is also challenged by tissue intervention due to pins and K-wires passing through muscle compartments and discomfort led by prolonged frame wearing (22,(26)(27)(28).
IM xation was the primary choice in union achievement and protection against refracture, with su cient biomechanical stability provided (15,29). The combination of the Ilizarov technique and intramedullary xation provides adequate xation after surgery and signi cantly cuts the days of frame wearing, which help to avoid the drawbacks and discomfort brought about when utilizing the external frame alone (3). In For a long period, due to the high rate of refracture, pediatric surgeons were compelled to focus on successful osteosynthesis rather than the sequelae of CPT, such as joint stiffness and arthritic change led by trans-ankle xation; metaphyseal irritation and growth failure led by metaphyseal intrusion; and even failure of IM xation due to inadequate space for nail interlocking in pediatric patients (7,14,16,30,31). The disadvantages of the commonly used IM rods mentioned above encouraged us to make changes in our treatment. In our study, two prebent TENs were positioned in an "Eiffel Tower" shape in the medullary canal of the affected tibia, with their respective convexities facing each other. Obviously, this elastic deformation within the medullary canal creates a bending moment within the long bone that is not rigid but stable enough to provide effective support for preventing further refracture and promoting solid union. As shown in Fig. 1a, the "Eiffel Tower" shaped elastic internal frame ensures exural, translational, rotational and axial stability under external forces. In addition, extensive bone formation that ensures stability after removal of the external xator was also reported to occur along the tract of the intramedullary nails (18).
The combination of IM rodding, circular external xation and iliac bone grafting have been generally accepted as an effective procedure in protecting against refracture, promoting alignment control with high fusion rate and contributing to early removal of external xator (7,9,11,25,32). Since 2013, we applied prebent TENs instead of using conventional IM rod for internal xation. Our study has shown favorable results, with primary union obtained in 86.7% patients. An average number of 1.3 (1 to 2) surgeries were performed to achieve solid union for each patient, which is in line with that reported previously (11). Refracture occurred in only 2 (13.3%) of 15 patients. All obtained union of the refracture site after additional surgery. Most other studies show similar or higher refracture rates for various methods (3). 12 refractures (23.2%) occurred in 21 patients treated by a Williams rod (15). Refracture occurred in 13 (23.2%) of 56 patients treated with combined surgery including pseudarthrosis resection, intramedullary Williams rodding, autogenous iliac bone grafting and Ilizarov's xator in the Zhu et al. study (9). In a recent study using combined techniques of hamartoma resection, periosteal grafting, circular external xator application, and intramedullary rodding, 5 (29.4%) of 17 CPT cases were complicated by refractures (10). As additional refractures may occur before patients reach skeletal, nal outcomes should be assessed after all the patients have reached this milestone. Dobbs et al. noted that the frequency of refracture was higher when a bular pseudarthrosis was not treated (15). Cho et al. reported a higher risk of refracture when the bula remained ununited (26). Agashe et al. concluded that undue stress led by the persistent malalignment of the tibia and bula, loss of intramedullary xation and non-compliance with external bracing regimen are three major causes of refracture (7). Although we followed these suggestions carefully, two cases of refracture still occurred. In one patient (case 2), the occurrence of refracture was probably because of persistent ankle valgus deformity and bular pseudoarthrosis. In another patient (case 14), the patient did not wear the brace and refracture occurred after major trauma. Paley de ned the success probability as:

Success probability = Union rate × [1 − Mean refracture rate]
He reported that on average, success probability was 40% in intramedullary rodding, 57% in the Ilizarov method and 58% in intramedullary rodding combined with the Ilizarov method (2). In our study, the success probability was 69.3%.
To prevent refracture, an intramedullary rod was suggested to be maintained in situ until skeletal maturity (7,15). With longitudinal growth of lower extremity, the distal part of the tibia, the ankle, and the foot migrate distally while the rod remains in place. Thus, reoperations are usually required to push the rod across the ankle joint (16,33). Telescopic rods, such as Bailey-Dubow and She eld expandable rods, can elongate as the child grows, which helps to decrease the number of reoperations required for these children. However, knee and ankle arthrotomies are still required for a tibial insertion of 2 telescoping components (31,34). The subsequently developed Fassier-Duval Rod managed to further decrease the reoperation rate and complication rate by making the insertion with a single proximal entry (16,35). Unfortunately, due to the lack of longitudinal and rotational stability, the sole use of Fassier-Duval rod xation in patients with severe underlying bone pathology of CPT end up with discouraging nonunion, collapse ("negative telescoping") and consecutive joint intrusion (16). The high cost also limits its wide acceptance in the developing area, such as mainland China, where public health care is rudimentary. On the contrary, entry points of the TENs were set distal to the proximal physis and were relatively less invasive during further nail changing as the removal and insertion of the nails did not require ankle arthrotomies.
In order to decrease the prevalence of ankle stiffness, Dobbs et al. used the solid two-part Williams intramedullary rod (the rod assembly consists of an indwelling rod and an insertion rod) and recommended surgically advancing the rod out of the ankle joint soon after the pseudarthrosis has healed (15). However, metaphyseal irritation and arthritic change of ankle joint, which results in restricted joint mobility and growth failure, remains as the rod is advanced antegrade across the ankle joint and out through the heel pad during insertion. The ankle joint was usually immobilized by rod trans xation for nearly two years after rod insertion (14,15,29,36). Migration passage of the IM nail through the growth plate may lead to the formation of brous bridge (30). Thus, techniques that require the rod positioned across the ankle and subtalar joint are less desirable. Custom interlocking intramedullary nails may decrease the prevalence of ankle stiffness as it does not trans x the ankle joint. However, it is too large for younger patients and it is not suitable for patients in whom the segment distal to the pseudarthrosis is not long enough to accommodate adequate xation (29). Agashe et al. used the antegrade method of intramedullary nailing which started from the proximal tibia and passed through the "fracture" till the level of the ankle. Ankle motion and achievement of union was satis ed in most of the CPT patients.
However, the direction of nailing is relatively dependent on the location of the CPT, since the extremely distal location of the pseudarthrosis, may still require a transplantar nail and end up with poor ankle function (7). In our study, entry points of the elastic nails were set distal to the proximal physis and the ends of the nails were at the level of 1 cm distal to the metaphysis of tibia, which protects the ankle joints from being jeopardized by classical rodding through the ankle. Range of motion in tibiotalar and subtalar joints was optimal in 12 (80%) patients. Only 3 patients in our study developed subtalar and tibiotalar stiffness, probably due to multiple operations for attainment of union (case 6 and case 8), retrograde intramedullary rodding in the previous failed surgery (case 8 and case 15) and relatively distal location of pseudoarthrosis (case 15). Similar to previous reports, ankle valgus deformities remained to be the most common residual deformities in our study, which occurred in 3 of 15 patients (20%) and all of them had received surgeries on bular lesions. There seems to be a trend toward an increased rate of ankle valgus deformity postoperatively in the patients who had a bular pseudarthrosis, which may due to a high position of the bular distal epiphysis and an asymmetric growth of the distal tibial physis that grows more medially than laterally (29,32). In addition, proximal migration of the distal bula causes the talus to move follow the bula, which contributes to ankle valgus and lateral subluxation of the ankle joint. The resultant instability of the ankle increases the risk of refracture (2,7,15,37). Thus, re-establishment of the integrity of the bula is essential for CPT treatment. The distal tibio bular synostosis is useful in bular healing, deformity control and refracture treatment, as described by Thabet et al (5). According to our clinical experience, hemi-epiphysiodesis is the easiest method to correct ankle valgus in CPT children with enough growth potential, as hemi-epiphysiodesis is less invasive and can reduce the risk of nonunion brought by corrective osteotomy. In our study, timely and additional procedures such as medial distal hemi-epiphysiodesis, tibio bular synostosis and supramalleolar osteotomy with external xation showed good outcomes in addressing ankle valgus deformity over 5°, which is also reported in previous reports (2,5,8). At the last follow-up, all three patients did not report any clinical symptoms such as pain or The small number of patients is the limitation of this study. As CPT is a rare disease, more multicenter studies with larger numbers of patients included should be carried out for more meaningful conclusions.
Follow-up period is not long enough to document the outcomes of these younger patients until skeletal maturity. The true success of treating CPT in a growing child can be con rmed only by following the children until maturity. In all, a well-designed prospective study is required in the future to fully investigate the advantages and drawbacks of the titanium elastic nailing technique.
In conclusion, this study demonstrated that the application of prebent titanium elastic nails (TENs), combined with bone grafting and application of circular external xator, is a viable option for CPT in achieving and maintaining union. The advantages of the present surgical procedure lie in providing good stability and protection against refracture. The readily availability is another factor that makes it an alternative rst-line surgical option for young children in the developing world. Moreover, compared with other rodding techniques, the TENs technique poses less injury to ankle joint and metaphysis, which effectively avoids ankle stiffness and reduces negative impact on tibia growth. It is necessary to follow up more patients until skeletal maturity and to evaluate its long-term outcome.
Abbreviations ROM: Range of motion, LLD: Limb length discrepancy, Congenital pseudarthrosis of the tibia: CPT, intramedullary rod: IM rod, Titanium elastic nail: TEN Figure 2 Case 6, a girl with neuro bromatosis who presented with a Crawford type-IV lesion with bula affected.
She received previous surgeries but sustained refracture at 22 years old (a). Pseudarthrosis resection, bone graft, prebent TENs technique and Ilizarov external xation were performed at 23. The LLD after index surgery was 8.7cm (b). 2 months later, the patient underwent bone lengthening at proximal tibia and bula (c). 6 months after the index surgery, no evidence of union at the pseudarthrosis site.
Additional procedures composed of bone grafting and nail changing were performed. Medial distal closewedge osteotomy was also performed for the correction of residual valgus deformity of the knee (d).
Secondary union achieved at the pseudarthrosis site 5 months after the additional surgery. Notice the bone generate at the distraction site (e). External xations were removed 16 months after index surgery.
The length gain was 9.5 cm and the LLD was 7mm. Tendon lengthening of the Achilles was performed due to the contracture of the Achilles tendon during tibial lengthening. The patients also received calcaneal osteotomy for residual deformity correction (f).