Prevention of Legg-Calv-Perthes disease. Transphyseal Neck-Head Drilling. Nuno Craveiro Lopes; Carolina Escalda and Carlo Villacreses.

Orthopedic and Traumatologic Department, Pediatric Orthopedic Unit, Garcia de Orta Hospital, Almada, Portugal ABSTRACT Purpose It is well documented that multiple factors are involved in the pathogenesis of LeggCalv-Perthes disease (LCPD) and that several fractional and sequential ischemic episodes are necessary and that a specific sequence of chained events is needed to trigger the disease in a susceptible child. Within this context, the reinforcement of the arterial blood flow and of the venous drainage of the epiphyseal femoral head, could constitute a way of avoiding the repetition of ischemic episodes thus preventing the onset of LCPD. To determine the effects of transphyseal neck-head drilling (TNHD), we have developed a experimental study and reviewed data from the cases where the procedure was used clinically. Methods Forty-four, White New Zealand rabbits, were used. Drills from 2 to 3.5mm in diameter were used along with a specially made guide, in order to minimize trauma. There were 4 study groups: Group I hips not operated on, used as a control. Group II Drilling of <10% of the total growth plate area. Group III - Drilling of >10% of the total growth plate area. Group IV Metaphyseal drilling, without reaching the growth plate. Clinically, we have been using TNHD for 30 years. We reviewed 205 TNHD procedures done in 96 cases of ischemic disease of the growing hip (IDGH) and 117 cases of Legg-Calv-Perthes disease (LCPD). Results We found that TNHD with the perforation of less than 10% of the growth plate area didnt interfere with the growth of the proximal femur and induces a marked increase of epiphyseal micro-vascularisation, due to the formation of anastomosis between metaphyseal and epiphyseal circulation. Clinically, from the 96 IDGH patients treated with TNHD, 55 have already reached the end of growth. None have progressed to LCPD and no growth disturbances of the affected femur where observed. Studies done with Gadolinium enhanced MRI, showed patent anastomosis between the metaphyseal and epiphyseal circulations. From a group of 20 IDGH patients not subjected to TNHD, 5 on stage III, all developed LCPD, and from 15 on stage II, 3 developed LCPD. Conclusions Epidemiological data from the area of influence of our unit, comparing the incidence of LCPD before and after the implementation of the IDGH detection protocol and LCPD prevention with TNHD, have shown a decrease of LCPD cases from 8.5/100.000 to 1.8/100.000 per year, on the population less than 16 years of age. Significance We confirmed clinically what we have found experimentally: TNHD induces anastomosis of small blood vessels between metaphysis and epiphysis, thus supplementing the epiphyseal unstable supply, preventing new ischemic episodes on a IDGH patient and aborting the evolution to LCPD. INTRODUCTION The multifactorial origin of Legg-Calv-Perthes disease (LCPD) is well documented [6,7,8,20,21,22,23,24,26,27,37,43]. The same is true for the existence of two or more ischemic episodes preceding the onset of the disease [3,4,7,10,21,25,38,41,43,44,49]. After more than 30 years of experimental and clinical data analysis about the initial stage of LCPD [9,10,11,12,13,14], the senior Author (NCL) verified that these episodes are symptomatic. Patients complain of pain and transient limping, and it is possible to detect those ischemic episodes with imaging techniques. The same Author has also found that those episodes represent an autonomous disease, which, if some enchained factors are present, can evolve to LCPD. The Author named this pre-LCPD situation, Ischemic Disease of the Growing Hip (IDGH)[15,16,17,18,19]. To clarify the pathogenesis of LCPD, the senior Author developed an animal model and analysed the data of patients treated with Transphyseal Neck-Head Drilling (TNHD), in the stage of sequential ischemic episodes and initial necrosis[15,16]. Within this context, the reinforcement of the arterial blood flow and of the venous drainage of the epiphyseal femoral head, independent from the reticular network, could constitute a way of avoiding the repetition of ischemic episodes thus preventing the onset of LCPD. The idea of supplementing the unstable epiphyseal blood flow trough the growth plate was attractive but controversial.

To determine the effects of neck-head drilling across the physeal growth plate, namely the possible reinforcement of the epiphyseal blood flow and the repercussion on the growth of the proximal femur, the Authors have developed a second experimental study [18,19], and latter established a prevention protocol of LCPD based on the early detection of IDGH and its treatment by TNHD. MATERIAL AND METHOD For the first experimental model, 27 White New Zealand rabbits, seven to eight weeks old, were used. This growth stage of the rabbit is equivalent to that of a 5-6 year old child. To try to reproduce the morphologic, radiological and histological aspects of LCPD, an no invasive method was used, consisting on the use of flexible splints to place the legs of the rabbits in extension and internal rotation for 6 hours, promoting an effusion and secondary collapse of the retinacular vessels, without causing their destruction [2]. In the following day micro-trauma was produced on the right hip only, using a vibratory motor for a period of 30 seconds. This sequence was repeated twice a week [15,16]. The image data and histological examinations from 19 patients who presented signs and symptoms compatible with the existence of IDGH under risk of development of LCPD, and 17 patients with LCPD in the initial stage, were analysed. These patients were treated between 1995 and 2006 with TNHD, and had samples for histological examination. For the second experimental study to determine the effect of neck-head drilling across the physeal growth plate, the Authors used forty-four White New Zealand rabbits, aged between 6 and 12 weeks, were used. Drills from 2 to 3.5mm in diameter were used along with a specially made guide, in order to minimize trauma [18,19]. There were 4 study groups: Group I 44 left hips. Not operated on, used as a control. Group II 30 right hips. Drilling of <10% of the growth plate. Single drilling with 2 and 2.5mm drills, using as an entry point the trochanter crossing the neck-head growth plate thru the epiphysis. The perforated area ranged in size from 6% to 10% of the total growth plate area, depending on the rabbits age. Group III - 7 right hips. Drilling of >10% of the growth plate. Single drilling with 3 and 3.5mm drills, using the same technique. The perforated area ranged in size from 12% to 20% of the total growth plate area. Group IV 7 right hips. Metaphyseal drilling. Single drilling with 2.5mm drills on the metaphyseal area of the trochanter and neck of the femur, without reaching the growth plate. The Authors apply a TNHD procedure if the probability of evolution to LCPD is high. As a guide of the probability of evolution to LCPD, the Authors had developed a classification of IDGH considering 3 stages: Stage I, (Fig.1) represents a hip where one can identify sequel of an old ischemic episode; it has a low probability of evolution to LCPD. Stage II, (Fig.2) shows sequel of an old episode with a new ischemic episode in evolution; it is considered to have a moderate probability of evolution. Finally, stage III, (Fig.3) presenting signs of a recent episode with a new one in evolution, situation that is considered to have almost 100% of probability to evolve to Legg-Calv-Perthes disease.

Fig.1 IDGH Stage I Irregular contour(a) Synovitis(b), thick cartilage(c). No actual ischemia (d)

Fig.2 IDGH Stage II Irregular contour(a) Synovitis with effusion(b), Subchond. ischemia(c)

Fig.3 IDGH Stage III Porosis (weakening)(a) Synovitis with effusion(b) Subchond. ischemia(c)

Fig.4 LCPD Stage I Dense, subchond. Fr.(a) Synovitis with effusion(b) Extensive necrosis(c)

Indication for TNHD, includes a child over 5 years old presenting an ischemic episode on the MRI or a Perthes lesion on the necrotic or early fragmentation stage (Fig.4). TNHD is performed with image intensifier control, with a 5mm trephine (perforated area correspond to less than 5% of the growth plate), over a wire guide centred on the ischemic or necrotic area. It is a low risk, 10-minute procedure (Fig.5 and 6).

Fig.5 - Procedure for TNHT with a 5mm trephine

Fig.6 Sequence of the procedure. a) Wire guide positioning b) Introduction

of the trephine over the wire guide reaching the subchondral bone. c) image control of the position of the trephine with flection-abdution of the lower limb. To identify the ischemic episodes and to detect the cases of IDGH at risk of evolution to LCPD, the Authors have developed a screening protocol. All pediatricians and general doctors of the area of influence of the hospital have been informed of the protocol and advised to send all children who presented hip, thigh or knee pain and limping for more than one day of evolution to the emergency unit. From January 1993 to December 1995, the beginning of the implementation of the prevention protocol, the Authors have observed 123 children, with ages between 3 and 12 years, presenting a painful syndrome of the hip. The Authors did a second prospective comparative study between January 1996 and December 1998 including 110 children of the same age. The study protocol included a standard clinical, radiological and laboratorial examination to detect other diagnosis as epiphisiolysis, septic arthritis, rheuma, trauma, LCPD and other causes and on the remaining cases, it included a first ultrasound screen to determine the existence of criteria of probability of IDGH and a second screening using a nuclear magnetic resonance on those cases, to detected an ischemic episode of IDGH. RESULTS On the first animal model [15,16] we observed that the prolonged and repeated positioning of the legs of the rabbit induced an intra articular pressure level sufficient to produce an ischemic episode at the proximal femoral epiphysis. After this episode, we observed a process of rapid revascularization of the preserved vascular canals with repositioning of myeloid and osteoid tissues by differentiation of endothelial cells in mesenchymal progenitor cells, without distortion of the epiphyseal structure or loss of its mechanical resistance. When a new ischemic episode was produced after the completion of the repairing process, all the reparative sequence was repeated, again without loss of the mechanical resistance of the epiphysis (Fig.7). However, the repetition of an ischemic episode during the reconstruction of a previous episode, lead to an alteration of the reparative response, with osteoclastic hyperactivity in the subchondral zone and formation of a distorted bone structure in the epiphysis by osteoblastic hyperactivity, which leads to a mechanically weak bone structure, similar to that described in LCPD as "woven bone". In these conditions, the existence of trauma or micro-trauma on the right hip, lead to the appearance of a sub-chondral pathological fracture and collapse of the structure of the epiphysis, with formation of a true bone sequestum on that side only. This represents the initial stage of LCPD (Fig.8).

Fig.7 - Experimental Model two week - IDGH Sub-chondral weakening(a), double layer lamellae(b), normal myeloid tissue(c)

Fig.8 - Experimental Model five weeks LCPD. Subchondral fracture(a), woven bone(b) and fibrous tissue proliferation(c)

The analysis of the image data and histological examinations from the patients has shown that patients where IDGH was detected presented histological signals of a recent ischemic event on the osteoid and myeloid or recent ischemia over a remodelled anterior ischemic event (Fig.9). In all the cases where the bone samples showed profuse woven bone and total substitution of the myeloid by fibrous tissue rich in fibroblasts, progressed into LCPD (Fig.10). Such biopsies were consistent with failure of immediate revascularization, as the vascular canals had collapsed.

Fig.9 - IDGH Stage III Ischemic event over a reparative process of a recent necrosis(a). Myeloid tissue begins to be substituted by fibrous tissue(b)

Fig.10 - LCPD Stage I Woven bone(a), substitution of myeloid tissue by fibrous tissue(b)

On the second animal model [18,19] we found that transphyseal neck-head drilling (TNHD) with the perforation of less than 10% of the growth plate area didnt interfere with the growth of the proximal femur and induces a marked increase of epiphyseal micro-vascularisation, due to the formation of anastomosis between metaphyseal and epiphyseal circulation (Fig11).

Fig.11 - Diaphanization of a specimen. Drilling at 4 weeks and sacrifice at 8 weeks. Right hip drilled, left hip control. From the 96 IDGH patients treated with TNHD, 55 have already reached the end of growth and none have progressed to LCPD and no growth disturbances of the affected femur where observed (Fig.12).

Fig.12 Evolution of a case of IDGH after TNHD. a) 10/1989 6 years old IDGH stage III. b) 11/1989 6 years old, one month after TNHD. c) 9/1993 10 years old, 4 years after TNHD. d) 04/2002 19 years old, 13 years after TNHD. Studies done with Gadolinium enhanced MRI, showed patent anastomosis between the metaphyseal and epiphyseal circulations (Fig.13 and 14).

Fig.13 - IDGH Stage III 7 months after TNHT

Fig.14 - Gadolinium enhanced MRI. Vascular anastomosis metaphysis-epiphysis

From a group of 20 IDGH patients not subjected to TNHD, 5 on stage III, all developed LCPD, and from 15 on stage II, 3 developed LCPD (Fig 15 to 18).

Fig.15 - 04/1995 - IDGH Stage III Porosis, wider medial space

Fig.16 - 04/1995 - IDGH Stage III Sub-chondral ischemia

Fig.17 - 10/1995 Lost from follow-up. 6 months later - LCPD Stage I

Fig.18 - 10/1995 LCPD Stage I Extensive necrosis

What concerns the prevention prospective comparative studies, on the first period, from January 1993 to December 1995, in 123 children, 32 cases (26%) had a diagnosis, including epiphisiolysis (3), septic arthritis (3), rheuma (3) trauma (2) LCPD (18) and other causes (3). On the remaining 91 cases a first ultrasound screen determine the existence of criteria of probability of IDGH stage II or III in 43 cases. The second screening made with a nuclear magnetic resonance on those cases, detected an ischemic episode in 6 of patients (5% of all cases). So, on the first study period from 1993 to 1995 we have detected 18 cases of LCPD and 6 cases of IDGH on stage II and III. On the second period, from January 1996 and December 1998 including 110 children of the same age, we have diagnosed only 5 cases of LCPD and 7 cases of ischemic disease. DISCUSSION The first signs on the importance of multiple ischemic episodes were brought up in experimental research performed in dogs by Freeman [4], on rabbits by Sanchis [41] and later by Bencano[1]. They were able to simulate the disease through repeated, total surgical section of the vascular network to the femoral head. Vegter [54] through the use of intra-articular injection of serum under pressure on the hip of a rabbit, demonstrated the importance of the repeated fractional necrosis, provoked by the increase of intraarticular pressure on the onset of the disease, indicating that the probable cause of the deformity of the head, is a reduction of its mechanical resistance due to superposing new necrotic episodes over a reconstruction process in progress. Eyring [22], Soto-Hall [46], Kallio [32], Vegter [55] and Schoenecker [45] demonstrated that the in vivo positioning of lower limbs in prolonged and repeated medial rotation and extension, is sufficient to increase the joint pressure on the hip and that it reached values superior to the systolic pressure when there was a simultaneous intra-articular effusion, even if small. Mckibbin [33], Inoue [33] and Catterall [7] presented histological studies performed on femoral heads of patients with LCPD. These patients revealed images of necrosis superposed to zones of bone

regeneration of a prior ischemic insult, confirming the theory of the repetitive ischemic episodes in the origin of LCPD. Our experimental research on the hips subject to repeated posture in medial rotation and extension showed us that the first signs of simple necrosis to the epiphyseal nucleus appeared after repeated positioning on both hips and signs of LCPD only on the hips subjected to microtrauma. Those findings wich are in accordance with the mentioned Authors, seems to confirm that the repeated isquemic events wekens the epiphyseal bone structure and that a trauma or microtrauma is necessary to develop the subchondral fracture that begins LCPD. Our clinical data confirmed the repetitive ischemic episode theory proposed by the mentioned Authors, namely that there are a period of fractional and sequential ischemic episodes before the onset of Perthes disease that leads to the fragility of the epiphyseal structure by sub-chondral osteoclastic hiperactivity and epiphyseal abnormal osteoblastic hyperactivity; Then if a trauma or microtrauma occours, a sub-chondral fracture and epiphyseal collapse begins LCPD. What concerns the TNHD procedure, The effect of the surgical perforation of the growth plate, have been studied by several authors in the past.[5,24,28,31,35,40,46], These researchers observed that multiple pin hole perforations or single perforations of small diameter did not cause alterations to bone growth, however, the perforations of larger diameter caused a significant delay or a complete growth arrest through the formation of a rigid bone bridge. In our present research, we were able to determine that the central perforation of an area less than 10% of the femoral neck-head growth plate area does not hinder growth. This conclusion is based on the direct and the radiological examinations and on the statistical evaluation of the numerous parameters measured. By those data, we may even deduce that with that perforation, there was an increase in the sphericity of the head of the femur. The histological examination of these specimens showed normal growth plate thickness and organization, except immediately next to the perforated area. In agreement with other authors[5,24,54]. We observed in the histological specimens, signs that a small caliber perforation creates a bone bridge whos tensile strength is inferior to the mechanical growth forces in the un-perforated portion of growth plate. This fact permits the progressive elongation of the bone bridge, with a dragging and thinning effect over the growth plate borders in the direction of the metaphysis. Also, in agreement of such authors, we observed that the perforation of larger dimensions, leads to a distortion of the proximal femur, such as, a shorter neck with a prominent trochanter, a vertical tilting of the neck-head growth plate and flattening of the epiphyseal nucleus. These alterations were coupled with a decrease in the thickness of the growth plate and a more or less marked structural disorganization. We noted still that the resulting growth delay and deformity was bigger when the larger perforation was performed in younger rabbits (younger than 9 weeks of age), corresponding to a 6 -7 year old child [14,29]. The idea of improving the vascular conditions in the epiphyseal nucleus via the perforation of the femoral neck-head growth plate is not new. Harriss research 29, using rabbits, confirmed histologically the penetration of cancellous bone through the perforations in the growth plate and a faster bone regeneration in the epiphyseal nucleus after bone necrosis provoked by surgical vascular section. Sifferts research[45], showed histological preparation of femoral hips of rabbits, where he observed the vascular and bone trabecular continuity between the metaphysis and the epiphysis after the perforation of the growth plate. In our work, besides the histological confirmation of the observations performed by other Authors, we demonstrated the existence of an accentuated and constant increase of small blood vessels in the epiphysis of the head of the femur after perforation of the growth plate, which was maintained until the end of the bone growth in rabbits (26 weeks). This result was not accomplished when only the metaphyseal zone was perforated. This increase in epiphyseal blood circulation was due to the reinforcement of the vascular network formed through the perforation of the growth plate and not due to the hemodynamic changes on the retinacular vessels, which had not changed when compared with the Control Group. The perforation of the femoral neck-head growth plate was first performed by Ferguson [23], as a treatment for severe Legg-Calve-Perthes disease in children. Those cases were done in an advanced

fragmentation stage when the author did not get good responses using traditional treatment methods. The perforation of the neck-head growth plate technique, had its advocates, but was dropped when new techniques, such as, the re-centering osteotomies were developed which had better results. The current research indicates that the neck-head tunnelling could be essential in the prevention of Legg-Calve-Perthes Disease (LCPD) if this technique is used in the pre-radiological ischemic stage indicated by repetitive hip pain and that can be detected through a cold spot on the nuclide or MRI bone scan [3,21,38,44,49]. In this stage, under the hemodynamic point of view, this condition is comparable to the coronary ischemic heart disease with repetitive angina that precedes a myocardial infarction[7,10,43] and the intent of the tunnelling procedure is to create a reinforcement of the blood flow similar to the one created in coronary bypass surgery. Tunnelling can also be useful in the early treatment of the LCPD, when at the initial necrotic (condensed) stage, where it will speed up the evolution to fragmentation, as it permits penetration of blood flow to the center of the necrotic zone and re-absorption of the sequestrum by the cutting cones from inside to outside, as it has also been verified by the first users of this method [23]. After the fragmentation phase has started, this method is no longer useful. The Authors have 96 patients where TNHD was aplied with the diagnosis of IDGH stage II and III, 55 of them have already reached the end of growth and no one progressed to Perthes disease or showed growth disturbance of the proximal femur. No other complications as fractures, infections, etc, was reported on those cases. Control of patency of the anastomosis using a MRI in T1 sequence with Gadolinium, comproved that the anastomosis induced by the drilling procedure is a long lasting one. A control group of 20 patients diagnosed as ischemic disease, which were not subjected to the drilling procedure, 3 cases in 15 of Stage II developed Perthers disease (20%), and 5 cases of stage III, all developed Perthes disease. Epidemiological data from the area of influence of our unit, comparing the incidence of LCPD before and after the implementation of the IDGH detection protocol and LCPD prevention with TNHD, have shown a decrease of LCPD cases from 8.5/100.000 to 1.8/100.000 per year, on the population less than 16 years of age. CONCLUSIONS The results of the first experimental model suggests the existence of a pathologic entity, prior to LCPD, characterized by the existence of successive ischemic events at the level of the femoral proximal epiphysis, that in certain circumstances can develop into LCPD. We call this entity Ischemic Disease of the Growing Hip (IDGH). The clinical study confirms the existence of a period of fractional and sequential ischemic episodes before the onset of LCPD. These ischemic events lead to weakening of the epiphyseal bone structure at two levels: subchondral cortical bone weakening by osteoclastic hyperactivity and epiphyseal cancellous bone weakening by osteoblastic hyperactivity and woven bone formation. If a trauma or microtrauma happens at that timing, then a pathologic subchondral fracture triggers the beginning of Legg-CalvPerthes disease. The second experimental model have shown that TNHT induces a increase of micro-vascularization, on the epiphisis due to the formation of a bone bridge trought the growth plate, and with it vascular structures transvese from the methaphysis to the epiphysis creating an anastomosis between the two networks. They found that growth arrest or slowing due to the tunnelling procedure is a mather of dimension; when less than 10% of the area of the growth plate, the resistance of the bone bridge is much less than the growth force of the remaining growth plate, and growth continues normally. When the drilled area is bigger than 20%, the resistance of the bone bridge is higher than the force of the growth plate and there are an arrest. In between those two numbers some slowing of growth happens. The Authors conclude that it is possible to identify the fractional and transitory ischemic events that precede the beginning of Legg-Calv-Perthes disease, and to define a group of cases at risk of evolution to LCPD. On those cases, TNHD induces anastomosis of small blood vessels between metaphysis and epiphysis, thus supplementing the epiphyseal unstable supply, preventing new ischemic episodes on a IDGH patient and aborting the evolution to LCPD.

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