Nicholas S Kalson

Panagiotis D Gikas
email: pdgikas@doctors.org

Timothy W R Briggs

O n l y Current Strategies for Knee Cartilage Repair

Keywords: Knee, cartilage, injury, microfracture, autologous chondrocyte implantation, mosaicplasty

Defects in knee articular cartilage can cause pain and disability and present the clinician with an extremely challenging clinical situation. This article describes the most up-to-date surgical techniques that aim to repair and/or regenerate symptomatic focal defects in articular cartilage, which include arthroscopic debridement, microfracture bone marrow stimulation and autologous osteochondral allografting, with an emphasis on autologous chondrocyte implantation (ACI). In the future, refinement of tissue engineering approaches promises to further improve outcome for these patients.

Introduction

Knee articular cartilage (AC) defects have long presented a challenge to physicians.

In 1743 the famous English anatomist William Hunter wrote 'an ulcerated cartilage is a trouble-some problem… that, once destroyed, it is not recovered' [START_REF] Hunter | On the structure and diseases of articulating cartilage[END_REF]. Today, more than 250 years later, cartilage damage is still an issue for physicians and patients and there is still no universally accepted and successful treatment approach for damaged AC. However, the result of research into novel surgical therapies developed over the last two decades, described in this article, have the potential to consign this statement to history.

Importance of knee cartilage defects

Articular cartilage lesions are common. In patients undergoing arthroscopic investigation for knee symptoms the incidence of cartilage defects has been found to be 61% [START_REF] Hjelle | Articular cartilage defects in 1,000 knee arthroscopies[END_REF] and 63% [START_REF] Curl | Cartilage injuries: a review of 31,516 knee arthroscopies[END_REF] and the prevalence of work-or sport-related articular lesions has been reported at 22% and 50% [START_REF] Piasecki | Intraarticular injuries associated with anterior cruciate ligament tear: findings at ligament reconstruction in high school and recreational athletes. An analysis of sex-based differences[END_REF][START_REF] Shelbourne | Outcome of untreated traumatic articular cartilage defects of the knee: a natural history study[END_REF]. Furthermore, in patients with anterior cruciate laxity the incidence of articular pathology is as high as 54% [START_REF] Indelicato | A perspective of lesions associated with ACL insufficiency of the knee. A review of 100 cases[END_REF]. Although more common with age, these injuries are also frequent in patients less than 55 years old [START_REF] Curl | Cartilage injuries: a review of 31,516 knee arthroscopies[END_REF][START_REF] Noyes | Arthroscopy in acute traumatic hemarthrosis of the knee. Incidence of anterior cruciate tears and other injuries[END_REF], in whom a prosthetic joint replacement, with a limited lifespan, is not recommended. Therefore alternative treatments are required. Focal AC defects are most often traumatic in origin, resulting from a high-load impact or repetitive shear and torsional loads on the superficial zone of articular cartilage [START_REF] Jones | Autologous chondrocyte implantation[END_REF]. A small proportion of lesions are caused by osteochondritis dessicans (less than 5%) [START_REF] Widuchowski | Articular cartilage defects: study of 25,124 knee arthroscopies[END_REF]. Focal AC defects are separate from osteoarthritis, a chronic degenerative disease, which has distinct clinical, radiological and arthroscopic findings. Hyaline AC is predominantly composed of a unique extra-cellular matrix (ECM), formed from embryonic mesenchyme in a complex and incompletely understood developmental process [START_REF] Morrison | The development of articular cartilage: I. The spatial and temporal patterns of collagen types[END_REF]. The two principal components of AC are proteoglycans, negatively charged glyocsaminoglyan chains that swell and hydrate AC, and collagen type II, a fibrillar collagen that traps the proteoglycans and provides tensile strength. This ECM is specialised to cope with its singular biomechanical environment; to regain a functional joint, cartilage defects would ideally be replaced by tissue of this precise composition.

Natural history of knee cartilage defects

Injury to some musculoskeletal tissues, such as bone, result in recapitulation of embryonic development processes and regeneration of fully functional tissue identical to the pre-injured tissue. However, there are several barriers to intrinsic articular cartilage repair: 1) It is avascular, meaning that the nutrients required for energetic repair processes and the removal of metabolic waste products are limited by diffusion to/from surrounding tissues. 2) It is relatively acellular, therefore few cells are available to effect repair. These obstacles conspire to limit repair of defects to a fibro-cartilaginous substitute tissue with different molecular composition (more type I collagen, less proteoglycan) and biomechanical behaviour (less proteoglycan and collagen type II, more collagen type I), compared to the original hyaline tissue [START_REF] Furukawa | Biochemical studies on repair cartilage resurfacing experimental defects in the rabbit knee[END_REF][START_REF] Cheung | In vitro synthesis of tissuespecific type II collagen by healing cartilage. I. Short-term repair of cartilage by mature rabbits[END_REF]. Despite this clear pathological response to injury the natural history of untreated AC lesions is not fully understood [START_REF] Widuchowski | Isolated full thickness chondral injuries. Prevalance and outcome of treatment. A retrospective study of 5233 knee arthroscopies[END_REF]. [START_REF] Shelbourne | Outcome of untreated traumatic articular cartilage defects of the knee: a natural history study[END_REF] reported a series of patients identified with AC defects discovered at the time of arthroscopic cruciate ligament reconstruction. Patients left with untreated AC lesions had similar subjective patient scores at an average follow up of nine years than control subjects with no AC defects. Interestingly, the authors also noted that a number of patients with significant AC defects have no/mild clinical symptoms [START_REF] Shelbourne | Outcome of untreated traumatic articular cartilage defects of the knee: a natural history study[END_REF]. In another treatment intervention trial patients treated only with debridement and no surgical repair procedure showed spontaneous improvement [START_REF] Dozin | Comparative evaluation of autologous chondrocyte implantation and mosaicplasty: a multicentered randomized clinical trial[END_REF]. Therefore, although some lesions will be asymptomatic, AC defects have the potential to manifest as continued joint pain, impaired movement and functional disability, that will need treating in a carefully selected group of patients. Additionally, it is known that AC defects increase the risk of osteoarthritis, which may require knee replacement [START_REF] Gelber | Joint injury in young adults and risk for subsequent knee and hip osteoarthritis[END_REF]. Therefore, it is desirable to intervene not only to reduce current morbidity but also in order to reduce the likelihood of future joint disorder.

Patient selection and indication for surgery

A wide-range of non-specific symptoms may lead clinicians to consider that an AC defect is the source of a patient's pain, including locking, pain at rest, swelling, pain with activity, instability and retropatellar crepitus [START_REF] Ochi | Articular cartilage repair using tissue engineering technique--novel approach with minimally invasive procedure[END_REF][START_REF] Hangody | Autologous osteochondral mosaicplasty. Surgical technique[END_REF]. Approximately two thirds of patients with chondral defects have associated ligamentous or meniscal pathology and AC damage has been reported in association with 23% of ACL injuries and 54% of knees with chronic anterior cruciate ligament laxity or instability [START_REF] Indelicato | A perspective of lesions associated with ACL insufficiency of the knee. A review of 100 cases[END_REF]. Focal AC defects are distinct from osteoarthritis, which often involves more widespread cartilage damage and prominent subchondral bony changes, is predominantly a disease of old age, and has a chronic, gradually worsening course.

Cartilage lesions are graded I-IV according the International Cartilage Repair Society scale [START_REF]Cartilage Injury Evaluation Package[END_REF]. Grade I lesions are nearly normal with only superficial fissures, grade II lesions extend less than 50% of cartilage depth, grade III are severely abnormal lesions extending more than 50% of cartilage depth, but not into the subchondral bone, and grade IV lesions include the subchondral bone.

Clinical examination is supported by arthroscopic assessment, the gold standard investigation for chondral defects, which allows direct visualisation of the chondral surface. In addition, magnetic resonance imaging (MRI) has a high sensitivity and specificity to detect chondral defects (greater than 95% for grade III lesions [START_REF] Palosaari | Fat suppression gradient-echo magnetic resonance imaging of experimental articular cartilage lesions: comparison between phase-contrast method at 0.23T and chemical shift selective method at 1.5T[END_REF]).

High resolution MRI can provide sufficient information for operative planning, and might in future obviate the need for diagnostic arthroscopy. Most importantly, the commonly occurring asymptomatic AC defect makes it essential that care is taken during clinical examination and investigations to determine that findings correlate with clinical symptoms, therefore ensuring that treatment is not misdirected [START_REF] Shelbourne | Outcome of untreated traumatic articular cartilage defects of the knee: a natural history study[END_REF].

Patient selection and indications for surgery vary according to the treatment type, and are considered further below.

Current treatment options

Orthopaedic surgeons have developed a wide arsenal of treatment options for treating focal knee AC defects [START_REF] Knutsen | A randomized trial comparing autologous chondrocyte implantation with microfracture. Findings at five years[END_REF]. Those most commonly employed today include, but are not limited to: 1) arthroscopic debridement, in which loose cartilage is trimmed, 2) microfracture, in which bone marrow based repair is stimulated, 3) autologous osteochondral grafting, in which bone-cartilage plugs are harvested from non-weight bearing joint sites and implanted directly into the defect, and 4) autologous chondrocyte implantation, a two-stage procedure involving harvest of chondrocytes, growth in vitro, then re-implantation.

Which treatment is chosen depends on several factors, including size of lesion, availability of particular treatments and the age and requirements of the patient. Small lesions may be conservatively managed with arthroscopic debridement and careful monitoring [START_REF] Dozin | Comparative evaluation of autologous chondrocyte implantation and mosaicplasty: a multicentered randomized clinical trial[END_REF][START_REF] Levy | Chondral delamination of the knee in soccer players[END_REF], whereas more extensive lesions require greater intervention. The first choice treatment for lesions less than 2.5 cm 2 is bone marrow stimulation by microfracture [START_REF] Jones | Autologous chondrocyte implantation[END_REF][START_REF] Bekkers | Treatment selection in articular cartilage lesions of the knee: a systematic review[END_REF][START_REF] Knutsen | Autologous chondrocyte implantation compared with microfracture in the knee. A randomized trial[END_REF][START_REF] Kreuz | Results after microfracture of fullthickness chondral defects in different compartments in the knee[END_REF]. Larger lesions may be treated by mosaicplasty [START_REF] Hangody | Autologous osteochondral mosaicplasty. Surgical technique[END_REF], this technique is limited by the availability of donor tissue, or by autologous chondrocyte transplantation, which is becoming more widely available [START_REF] Jones | Autologous chondrocyte implantation[END_REF]. Other treatments, such as abrasion chondroplasty and the use of carbon fibre pads, are either less widely practised, or have been superseded, and are therefore not discussed. Small defects in which there are loose, overhanging flaps of cartilage may initially be treated by arthroscopic debridement [START_REF] Dozin | Comparative evaluation of autologous chondrocyte implantation and mosaicplasty: a multicentered randomized clinical trial[END_REF][START_REF] Levy | Chondral delamination of the knee in soccer players[END_REF]. These lesions often present with locking. However, larger, more complex defects, perhaps with no obvious loose body, require more complex procedures, which either stimulate repair tissue (microfracture) or replace damaged cartilage (osteochondral transplantation or autologous chondrocyte implantation).

Arthroscopic debridement

Bone marrow stimulation by microfracture

Bone marrow stimulation by microfracture is widely considered the first choice treatment for small lesions (less than 2.5 cm 2 ) [START_REF] Jones | Autologous chondrocyte implantation[END_REF][START_REF] Bekkers | Treatment selection in articular cartilage lesions of the knee: a systematic review[END_REF][START_REF] Knutsen | Autologous chondrocyte implantation compared with microfracture in the knee. A randomized trial[END_REF][START_REF] Kreuz | Results after microfracture of fullthickness chondral defects in different compartments in the knee[END_REF] (Figure 3). Bone marrow stimulation techniques aim to induce bleeding for the subchondral bone followed by the formation of a fibrin clot, migration and recruitment of bone marrow derived stem cells and the formation of a fibrocartilaginous repair tissue that covers fullthickness chondral lesions. Bony drilling into the defect, first described by Pridie in 1959 [START_REF] Pridie | A method of resurfacing osteoarthritic knee joints[END_REF], was prevalent until the advent of microfracture in the 1990s [START_REF] Blevins | Treatment of articular cartilage defects in athletes: an analysis of functional outcome and lesion appearance[END_REF]. Pridie drilling uses a hand-driven or motorised drill to penetrate the subchondral plate. This is thought to cause heat-related tissue damage, whereas microfracture uses a gentler arthroscopic awl, which does not generate significant heat [START_REF] Mithoefer | The microfracture technique for the treatment of articular cartilage lesions in the knee. A prospective cohort study[END_REF][START_REF] Gill | The treatment of articular cartilage defects using the microfracture technique[END_REF].

Microfracture is now more popular than other bone marrow stimulation techniques (drilling and arthroscopic abrasion arthroplasty [START_REF] Johnson | Arthroscopic abrasion arthroplasty: a review[END_REF]).

Microfracture has demonstrated good or excellent results in 60-80% of patients [START_REF] Mithoefer | The microfracture technique for the treatment of articular cartilage lesions in the knee. A prospective cohort study[END_REF][START_REF] Steadman | Outcomes of microfracture for traumatic chondral defects of the knee: average 11-year follow-up[END_REF][START_REF] Asik | The microfracture technique for the treatment of full-thickness articular cartilage lesions of the knee: midterm results[END_REF]. There is some evidence that MF works best in patients under 40 years old that might have intrinsically superior healing responses to those in older patients [START_REF] Kreuz | Is microfracture of chondral defects in the knee associated with different results in patients aged 40 years or younger?[END_REF]. It benefits from the low-morbidity of an arthroscopic procedure with a relatively quick recovery period and low complication rate [START_REF] Steadman | Outcomes of microfracture for traumatic chondral defects of the knee: average 11-year follow-up[END_REF][START_REF] Minas | Increased failure rate of autologous chondrocyte implantation after previous treatment with marrow stimulation techniques[END_REF].

Treatable lesions are 1-2.5 cm 2 large, and well shouldered with protected edges [START_REF] Jones | Autologous chondrocyte implantation[END_REF].

Microfracture involves debridement of unstable cartilage to bone level to form a stable rim of healthy cartilage around the defect. Specially designed awls are then used to make multiple holes 2-4 mm deep and 3-4 mm apart in the subchondral bone [START_REF] Steadman | Microfracture: surgical technique and rehabilitation to treat chondral defects[END_REF]. Rehabilitation includes continuous passive motion and partial weight bearing for 6-8 weeks. Interestingly, non-human primate models of microfracture show repair tissue to be immature after six weeks, suggesting a longer rehabilitation period might be necessary [START_REF] Gill | Chondral defect repair after the microfracture procedure: a nonhuman primate model[END_REF].

The procedure may be less-well suited to the patello-femoral joint or the tibia, which in one study showed deterioration after 18 months following microfracture [START_REF] Kreuz | Results after microfracture of fullthickness chondral defects in different compartments in the knee[END_REF], or to lesions larger than 4 cm 2 , which have been reported to fair better after treatment with autologous chondrocyte transplantation [START_REF] Bekkers | Treatment selection in articular cartilage lesions of the knee: a systematic review[END_REF][START_REF] Knutsen | Autologous chondrocyte implantation compared with microfracture in the knee. A randomized trial[END_REF]. Complications include degenerative changes in the subchondral area, such as cysts, osseous overgrowth and intra-lesional osteophytes in approximately 33% of cases [START_REF] Kreuz | Results after microfracture of fullthickness chondral defects in different compartments in the knee[END_REF][START_REF] Mithoefer | The microfracture technique for the treatment of articular cartilage lesions in the knee. A prospective cohort study[END_REF]. The significance of these findings has not been proven, but changes to the subchondral plate likely underlie failed MF treatment [START_REF] Minas | Increased failure rate of autologous chondrocyte implantation after previous treatment with marrow stimulation techniques[END_REF].

Microfracture is not a curative treatment, but it can provide relief for a number of years. However, doubts remain over the durability of the repair tissue produced, which is fibrocartilagenous and has inferior biomechanical properties compared to hyaline tissue. [START_REF] Mithoefer | Clinical efficacy of the microfracture technique for articular cartilage repair in the knee: an evidence-based systematic analysis[END_REF] conducted a systematic review examining the clinical efficacy of MF for knee AD defects. They identified six randomised control trails, which all showed improved knee function during the first 24 months postoperation, but the longevity of the initial improvement was not consistent between studies [START_REF] Mithoefer | Clinical efficacy of the microfracture technique for articular cartilage repair in the knee: an evidence-based systematic analysis[END_REF]. Furthermore, a recent report of microfracture used to treat professional athletes concluded that 'from a strict scientific stand point an untreated control group would be valuable to demonstrate that microfracture does not just mirror the natural course of healing' [START_REF] Riyami | Evaluation of microfracture of traumatic chondral injuries to the knee in professional football and rugby players[END_REF]. There are currently no published studies comparing MF (or any other intervention) to an untreated control group. This should be an important future research goal.

Autologous osteochondral grafting / mosaicplasty

Autologous osteochondral allografting, also known as mosaicplasty, most commonly involves transplantation of small (less than 1cm 2 ) cylindrical cartilage plugs harvested from non-weight bearing areas such as the lateral femoral condyle or the trochlea, directly into the defect in a one-stage procedure [START_REF] Hangody | Autologous osteochondral mosaicplasty. Surgical technique[END_REF] (Figure 2). The use of different size plugs allows defect filling of more than 90%, and the graft needs to be perpendicular and flush to the surface to prevent catching with knee motion [START_REF] Hangody | Autologous osteochondral mosaicplasty. Surgical technique[END_REF].

This technique has the advantage of directly implanting hyaline cartilage onto the defect. The procedure may be done open or arthroscopically, and is not recommended in individuals over 50 years old [START_REF] Hangody | Autologous osteochondral mosaicplasty. Surgical technique[END_REF]. Good to excellent results have been reported in 85-95% of treated defects of the femoral condyles, tibial surfaces and patellar/trochlear lesions [START_REF] Ghazavi | Fresh osteochondral allografts for post-traumatic osteochondral defects of the knee[END_REF][START_REF] Szerb | Mosaicplasty: long-term follow-up[END_REF][START_REF] Emmerson | Fresh osteochondral allografting in the treatment of osteochondritis dissecans of the femoral condyle[END_REF][START_REF] Marcacci | Arthroscopic autologous osteochondral grafting for cartilage defects of the knee: prospective study results at a minimum 7-year follow-up[END_REF][START_REF] Tetta | Knee Osteochondral Autologous Transplantation: Long-term MR findings and clinical correlations[END_REF][START_REF] Solheim | Osteochondral autografting (mosaicplasty) in articular cartilage defects in the knee: results at 5 to 9 years[END_REF].

It is important to note that repair using autologous tissue technique is most suited to small (less than 4 cm 2 ) lesions, being limited by the availability of donor tissue and by potential donor-site morbidity [START_REF] Hangody | Autologous osteochondral mosaicplasty. Surgical technique[END_REF][START_REF] Choi | MR imaging of cartilage repair in the knee and ankle[END_REF]. Larger defects may be filled with allogenous cartilage tissue from a cadaveric donor, although this risks immunologic rejection and disease transmission from donor to recipient. Therefore osteochondral allografts are generally reserved for uncontained (not well-defined) lesions greater than 4 cm 2 where there is significant osseous damage [START_REF] Jones | Autologous chondrocyte implantation[END_REF].

Autologous chondrocyte implantation

By 2003 more than 15,000 patients have undergone ACI worldwide [START_REF] Minas | Autologous chondrocyte implantation in the arthritic knee[END_REF] and it is now widely considered the frontline treatment for defects larger than 2 cm 2 [START_REF] Jones | Autologous chondrocyte implantation[END_REF] (Figure 4). The procedure is recommended for ICRS grade III/IV lesions of the femoral condyle or trochlear region, but more recently has been used with success for patellar lesions. The optimum candidate is a highly motivated patient, less than 50-55 years old, with a high functional demand and high potential for compliance with the long-term rehabilitation required (reviewed in [START_REF] Jones | Autologous chondrocyte implantation[END_REF]).

Indications

The size of a lesion best suited to ACI is still debated. Conventional thinking is that lesions less than 2-2.5 cm 2 may be treated initially with microfracture, and that ACI may be used in patients that continue to have pain after microfracture. However, although microfracture was considered a 'non bridge-burning procedure' [START_REF] Minas | Increased failure rate of autologous chondrocyte implantation after previous treatment with marrow stimulation techniques[END_REF], a recent study suggests that previous microfracture reduces the chances of successful ACI by 30% [START_REF] Minas | Increased failure rate of autologous chondrocyte implantation after previous treatment with marrow stimulation techniques[END_REF]. Bone involvement is not a contraindication, but when bone involvement is deeper than 6 -8 mm autologous bone grafting should be undertaken (Petersen 2003). Reciprocal (kissing) lesions are generally a contraindication.

Pre-operative assessment

In pre-operative planning weight loss is central, and a BMI less than 30 kg/m 2 is recommended. Weight loss has been associated with improved activities of daily living scores and SF-36 Physical Component Summary Scores following cartilage repair procedures [START_REF] Mithoefer | The microfracture technique for the treatment of articular cartilage lesions in the knee. A prospective cohort study[END_REF]. Clinical assessment should include knee alignment and associated injuries. Malalignment should be corrected by osteotomy, and knee ligaments reconstructed. Meniscal lesions require repair or resection at initial arthroscopy. Radiographic assessment includes postero-anterior weight bearing views to assess for medial/lateral compartment narrowing, bilateral Merchant views to assess patellar facet wear, subluxation and tilt, and bilateral long-limb standing radiographs to examine the leg axis and potential sites of increased load to the repair site. Magnetic resonance imaging has a high sensitivity and specificity (over 90%) for detecting AC defects, but only lesions that correlate with clinical symptoms should be treated.

Surgical technique

Two separate procedures are required for ACI. First, arthroscopic assessment is performed after physical examination and radiographic studies. If areas of ICRS grade III/IV are found, the lesions are measured. If the reciprocal surface is not severely damaged and the patient is an appropriate candidate for chondrocyte implantation a biopsy is taken. Harvest is from a non-weight bearing area of articular cartilage, such as the medial edge of the trochlear groove. Approximately 200-300 mg of tissue are taken, which corresponds to approximately 300,000 cells. It is important to remove tissue from a healthy area in order that 'normal' chondrocytes are collected. Chondrocytes are cultured for 4-6 weeks in a laboratory compliant with Good Manufacturing Practice guidelines. It is important that chondrocytes are not cultured longer than this, or phenotypic changes emerge. Either a chondrocyte suspension, or chondrocytes seeded on a collagen-based scaffold (matrix assisted autologous chondrocyte implantation -MACI) is then implanted in a second procedure. The defect is prepared by debriding the edges to normal articular cartilage. Damage to the underlying chondral bone is avoided to prevent bleeding into the defect. In ACI, a periosteal graft, which may be harvested from the proximal tibia, is used to cover the implanted cells [START_REF] Brittberg | Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation[END_REF], or chondrocytes can be implanted beneath a collagen membrane (ACI-C). In the MACI technique, cells are seeded on a collagen type I/III scaffold at a precise concentration (1 million cells per cm 2 ). The membrane is placed directly into the defect and secured with fibrin glue, eliminating the need for suturing to surrounding cartilage and use of a cover, which can damage surrounding healthy cartilage.

Rehabilitation

Rehabilitation protocols vary widely, but always involve a long and cautious process, requiring high motivation and patient compliance. When planning rehabilitation it is important to remember that a biological healing process is occurring, which involves cell proliferation (0-6 weeks), matrix production (first 6 months), and matrix remodeling (6 months onward). Most protocols require reduced weight bearing for 10 weeks, aiming to avoid impact loading and twisting or shearing forces which might damage the repair tissue. One protocol uses a plaster of Paris for week one, then toe-touch weight bearing with flexion-extension exercises at weeks two-six [START_REF] Gikas | An overview of autologous chondrocyte implantation[END_REF]. From six weeks partial weight bearing is used, and from ten weeks full weight bearing is allowed. Other regimes use passive movement from day one onwards, which aims to stimulate implanted cells via mechanical signals as early as possible [48]. It ought to be noted that the ideal mobilization protocol aims to optimize the repair process, and it is tailored to the individual case. Well-contained lesions are protected by surrounding cartilage and may begin weight bearing at 4 weeks, whereas large poorly contained lesions should not bear weight fully until 8-12 weeks post-surgery [START_REF] Jones | Autologous chondrocyte implantation[END_REF].

Post-operative assessment

Arthroscopy remains the gold standard for post-operative evaluation, often carried out at one year post-operation, and allows visualisation of the repair and biopsy for histological assessment. Probe indentation stiffness can also be measured, and has demonstrated up to 80% stiffness compared with native articular cartilage [START_REF] Vasara | Indentation stiffness of repair tissue after autologous chondrocyte transplantation[END_REF]. Gikas et al. (2009) demonstrated progressive development from fibrocartilage to hyaline cartilage with increasing time from operation in patients having undergone ACI/MACI. The appearances of the repair tissue can also be investigated with MRI [START_REF] Gikas | A correlation between the timing of biopsy after autologous chondrocyte implantation and the histological appearance[END_REF]. In one series ACI provided better defect filling than microfracture [START_REF] Brown | Magnetic resonance imaging appearance of cartilage repair in the knee[END_REF]. More sophisticated MRI techniques use intravenously administered gadolinium, which can penetrate cartilage, and T1 imaging can estimate glycosaminoglyan content, and T2 mapping allows evaluation of collagen content (for review see [START_REF] Trattnig | MR imaging of cartilage and its repair in the knee--a review[END_REF]).

Clinical results of ACI

Clinical results for ACI have been encouraging. Numerous case-series report positive effectiveness of ACI for treatment of knee AC defects, with follow-up now available more than 10 years post-procedure [START_REF] Peterson | Autologous chondrocyte transplantation. Biomechanics and long-term durability[END_REF][START_REF] Kon | Second generation issues in cartilage repair[END_REF][START_REF] Mandelbaum | Treatment outcomes of autologous chondrocyte implantation for full-thickness articular cartilage defects of the trochlea[END_REF][START_REF] Kon | Arthroscopic second-generation autologous chondrocyte implantation compared with microfracture for chondral lesions of the knee: prospective nonrandomized study at 5 years[END_REF]. Furthermore, there are randomised trials (RCT) comparing ACI to microfracture [START_REF] Knutsen | A randomized trial comparing autologous chondrocyte implantation with microfracture. Findings at five years[END_REF][START_REF] Knutsen | Autologous chondrocyte implantation compared with microfracture in the knee. A randomized trial[END_REF][START_REF] Cole | A randomized trial comparing autologous chondrocyte implantation with microfracture[END_REF] and to mosaicplasty [START_REF] Bentley | A prospective, randomised comparison of autologous chondrocyte implantation versus mosaicplasty for osteochondral defects in the knee[END_REF], and these RCTs have been reviewed in an attempt to determine an optimum treatment for focal AC defects.

A Cochrane Collaboration meta-analysis identified four randomised control trials comparing ACI with microfracture or mosaicplasty that met their eligibility criteria [START_REF] Knutsen | Autologous chondrocyte implantation compared with microfracture in the knee. A randomized trial[END_REF][START_REF] Bentley | A prospective, randomised comparison of autologous chondrocyte implantation versus mosaicplasty for osteochondral defects in the knee[END_REF][START_REF] Horas | Autologous chondrocyte implantation and osteochondral cylinder transplantation in cartilage repair of the knee joint. A prospective, comparative trial[END_REF][START_REF] Basad | Treatment of chondral defects with MACI or microfracture. First results of a comparative clinical study[END_REF][START_REF] Wasiak | Autologous cartilage implantation for full thickness articular cartilage defects of the knee[END_REF]. One of these trials reported superior outcome for ACI versus mosaicplasty [START_REF] Bentley | A prospective, randomised comparison of autologous chondrocyte implantation versus mosaicplasty for osteochondral defects in the knee[END_REF], whilst the other trials did not find a superior treatment. In one study one year after treatment ACI was associated with a tissue regenerate that was superior to that of microfracture [START_REF] Knutsen | Autologous chondrocyte implantation compared with microfracture in the knee. A randomized trial[END_REF]. Overall, they could not find evidence to support ACI over microfracture or mosaicplasty, and concluded that further patients randomised to microfracture or ACI. Follow-up at two years did not show differences in functional outcome [START_REF] Van Assche | Autologous chondrocyte implantation versus microfracture for knee cartilage injury: a prospective randomized trial, with 2-year follow-up[END_REF].

Recently, [START_REF] Magnussen | Treatment of focal articular cartilage defects in the knee: a systematic review[END_REF] reviewed five randomised control trials comparing ACI/MACI, osteochondral autograft transfer and microfracture. All treatments improved clinical outcome measures compared to pre-operative assessment, but no technique consistently had superior results, and no study used non-operative control groups [START_REF] Magnussen | Treatment of focal articular cartilage defects in the knee: a systematic review[END_REF]. The authors' recommendation is that a large prospective trial be conducted and that non-operated controls be included.

These trials are consistent in reporting clinical improvement following ACI.

Furthermore, economic analysis has demonstrated cost effectiveness of ACI [START_REF] Minas | Chondrocyte implantation in the repair of chondral lesions of the knee: economics and quality of life[END_REF].

There is emerging evidence that that the repair tissue produced in ACI is more hyaline-like and more durable than that following microfracture. [START_REF] Knutsen | A randomized trial comparing autologous chondrocyte implantation with microfracture. Findings at five years[END_REF][START_REF] Saris | Characterized chondrocyte implantation results in better structural repair when treating symptomatic cartilage defects of the knee in a randomized controlled trial versus microfracture[END_REF]. However, there is currently no firm evidence that ACI provides improved patient outcomes compared to either microfracture or mosaicplasty. Furthermore, the quality of trial methodology investigating knee AC defects could be improved by adequately describing randomisation procedures, including untreated control groups, use of validated outcome measures and the use of an independent investigator or outcome assessment [START_REF] Wasiak | Autologous cartilage implantation for full thickness articular cartilage defects of the knee[END_REF][START_REF] Jakobsen | An analysis of the quality of cartilage repair studies[END_REF].

Matrix-assisted/induced autologous chondrocyte implantation

Autologous chondrocyte implantation is considered to be the first widely available and commercially successful cell-based therapeutic intervention. Undoubtedly, in the future more cellular therapies will become available to treat a wide variety of disorders. The pioneering position of ACI at the forefront of medical technology has understandably led to close scrutiny from medical regulatory authorities. [START_REF] Wood | Autologous cultured chondrocytes: adverse events reported to the United States Food and Drug Administration[END_REF] reported that the rate of adverse reactions in patients treated with Carticel, an autologous chondrocyte implant system, was 3.8% (497/7500). Adverse reactions included graft failure (25%), delamination (22%) and tissue hypertrophy (18%) [START_REF] Wood | Autologous cultured chondrocytes: adverse events reported to the United States Food and Drug Administration[END_REF] and most often occurs within 6 months after surgery in approximately 25% cases and can require surgery [START_REF] Kon | Second generation issues in cartilage repair[END_REF].

It is thought that tissue hypertrophy is related to the use of a periosteal graft to cover the implanted chondrocytes, which in addition is technically difficult to harvest and can cause joint stiffness and arthrofibrosis. The technical advantages of scaffoldbased techniques (e.g. MACI), which remove the need for an arthrotomy and the risk of perosteal hypertrophy, have led to some surgeons preferring scaffold techniques [START_REF] Kon | Second generation issues in cartilage repair[END_REF]. Therefore, there has been evolution towards implants in which cells are seeded in a 3D matrix that does not require periosteal cover. Since the late 1990s, when the European Drug Agency licensed the use of collagen and hyaluronan based scaffolds for implantation with cultured autologous chondrocytes, several different matrix based implants have been devised, including Matrix induced autologous chondrocyte implantation (MACI, Verigen Transplantation Service, Copenhagen, Denmark), Hyalograft C (Fidia Advanced Biopolymers Laboratories, Padova, Italy), and CaReS (Ars Arthro, Esslingen, Germany). Mid-long term follow-up is now becoming available [START_REF] Behrens | Matrix-associated autologous chondrocyte transplantation/implantation (MACT/MACI)--5-year follow-up[END_REF], and suggests that MACI gives similar or slightly improved clinical outcome compared to ACI [START_REF] Gikas | An overview of autologous chondrocyte implantation[END_REF] or microfracture [START_REF] Kon | Arthroscopic second-generation autologous chondrocyte implantation compared with microfracture for chondral lesions of the knee: prospective nonrandomized study at 5 years[END_REF]. Biopsy results have also been encouraging, showing the production of hyaline cartilage [START_REF] Gikas | An overview of autologous chondrocyte implantation[END_REF][START_REF] Gikas | A correlation between the timing of biopsy after autologous chondrocyte implantation and the histological appearance[END_REF].

Nevertheless, randomised trials are required to investigate these new procedures [START_REF] Zeifang | Autologous Chondrocyte Implantation Using the Original Periosteum-Cover Technique Versus Matrix-Associated Autologous Chondrocyte Implantation: A Randomized Clinical Trial[END_REF].

Histological analysis of repair tissue following ACI/MACI reveals that approximately 50% of patients have hyaline-like or mixed hyaline and fibrocartilage tissue [START_REF] Knutsen | A randomized trial comparing autologous chondrocyte implantation with microfracture. Findings at five years[END_REF][START_REF] Gikas | A correlation between the timing of biopsy after autologous chondrocyte implantation and the histological appearance[END_REF].

Although this is certainly improved compared to microfracture [START_REF] Saris | Characterized chondrocyte implantation results in better structural repair when treating symptomatic cartilage defects of the knee in a randomized controlled trial versus microfracture[END_REF], why some chondrocyte implants produce hyaline tissue and others fibro cartilaginous tissue is not known. This may be due to specific patient, cell-culture or knee injury factors, and investigation into predicting which patients respond best will be important in the future. [START_REF] Saris | Characterized chondrocyte implantation results in better structural repair when treating symptomatic cartilage defects of the knee in a randomized controlled trial versus microfracture[END_REF] have begun to investigate manipulation of histological outcome by characterising and selecting chondrocytes for implantation by gene expression profile analysis for a number of cartilage marker genes, such as collagen type II. They found that superior structural tissue was formed in the ACI group, which used characterised chondrocytes, compared with microfracture. This is a promising approach, but further study comparing un-characterised cultured chondrocytes is required to determine whether cell-selection results in improved histological outcome [START_REF] Saris | Characterized chondrocyte implantation results in better structural repair when treating symptomatic cartilage defects of the knee in a randomized controlled trial versus microfracture[END_REF].

Future perspectives

Treatment for articular cartilage lesions has pioneered tissue-engineering techniques, illuminating a path that other therapeutic interventions will undoubtedly tread. Improvement in clinical outcome has been demonstrated following ACI treatment, and there are clear routes forward which involve the development of matrix-based implants. Currently minimally invasive procedures such as microfracture are probably best for small defects (less than 2.5 cm 2 ), and ACI for larger lesions. However, it has been said that no treatment has demonstrated longterm efficacy [START_REF] Ochi | Articular cartilage repair using tissue engineering technique--novel approach with minimally invasive procedure[END_REF][START_REF] Wood | Autologous cultured chondrocytes: adverse events reported to the United States Food and Drug Administration[END_REF]. The evidence for ACI providing superior outcomes compared with treatment by microfracture bone-marrow stimulation is not yet well established [START_REF] Wasiak | Autologous cartilage implantation for full thickness articular cartilage defects of the knee[END_REF][START_REF] Jakobsen | An analysis of the quality of cartilage repair studies[END_REF] and improvement in the quality of randomised control trials that are undertaken is required [START_REF] Wasiak | Autologous cartilage implantation for full thickness articular cartilage defects of the knee[END_REF][START_REF] Jakobsen | An analysis of the quality of cartilage repair studies[END_REF].

Chondrocyte implantation holds great promise for future development. The refinement of tissue engineering techniques will include evaluation of different cellscaffold combinations, genetic manipulation of implanted cells, and use of alternative cell sources such as mesenchymal stem cells. In the future, therapies might incorporate mechanical stimulation of the tissue ex vivo prior to implantation (NeoCart), the use of allogenic chondrocyte transplantation (DeNovo ET), use hydrogel or hyaluronic acid-based scaffolds [START_REF] Hettrich | Cartilage repair: third-generation cellbased technologies--basic science, surgical techniques, clinical outcomes[END_REF]. There is also a push to develop single-stage arthroscopic cell-based treatments that use allogenous cells, or autologous cells of non-cartilage origin (e.g. mesenchymal stem cells) cultured and differentiated in vitro prior to implantation. Although none of these procedures yet

  randomised trials are required. Since publication of the Cochrane review (2006) [61], further RCTs have been published. Knutsen et al. (2007) reported no difference in clinical or radiographic 5-year follow up of patients treated with either microfracture or ACI [20]. Saris et al. (2008) report similar short-term clinical outcome was for ACI and microfracture groups [62]. Similarly, Van Assche et al. (2008) reported on 67

  regulatory approval, the scope for future development of chondrocyte implantation techniques will, hopefully, result in superior treatments.Key pointsArticular cartilage defects are a common injury, particularly in the young and active They still present a challenging problem with no universally accepted treatment Whether to treat must be directed primarily by clinical information, not solely by the presence of a lesion Microfracture is a successful temporary repair procedure, recommended for small lesions, which produces fibrous tissue and can provide relief for several years Autologous chondrocyte implantation offers the possibility of regeneration with a hyaline tissue, and is the recommended front-line treatment for larger defects Future research will refine tissue engineering techniques to improve outcome with cell-scaffold treatmentsReview criteriaArticles published in English were identified by searching PubMed in December 2009 using the following search terms: 'cartilage and repair', 'cartilage and regeneration', 'cartilage and articular chondrocyte implantation', 'cartilage and osteochondral autograft', 'cartilage and microfracture', and 'cartilage and periosteal transplantation'.

Figure 1 .

 1 Figure 1. Schematic of a focal knee cartilage defect. (A) A fibrillated cartilage lesion. (B) Debridement of the defect to healthy cartilage with smooth vertical borders. Reproduced with permission from [71].

Figure 2 .

 2 Figure 2. Arthrotomy mosaicplasty. (A) Miniarthrotomy mosaicplasty on the medial femoral condyle for the treatment of a chondral defect. Three osteochondral plugs can be seen implanted in the defect. (B) Mosaicplasty on the medial talar dome to treat an osteochondritis dessicans defect. Images kindly provided by Laszlo Hangody.

Figure 3 .

 3 Figure 3. Bone marrow stimulation by microfracture. (A) Small holes 3-4 mm apart are created in the bone of the defect. Bleeding is induced, which results in healing by production of fibrocartilagenous tissue. (B) Femoral condyle defect that has been filled with newly formed fibrocartilagenous tissue. Reproduced with permission from Lutzner et al. (2009) [72].

Figure 4 .

 4 Figure 4. Autologous chondrocyte implantation. (B) A focal cartilage defect that has been debrided to healthy cartilage. (B) Autologous cultured chondrocytes have been implanted into the defect, over which a periosteal flap will be sutured. Reproduced with permission from Gikas et al. (2009) [47].


MD E Ernst

PhD Fmedsci Fsb

Frcp Frcped

PhD R Terry

Assessments of complementary and alternative medicine: the clinical guidelines from NICE

Keywords: Complementary/alternative medicine, NICE, clinical guidelines, evidence

Background:

The National Institute for Health and Clinical Excellence NICE is renowned for its rigorous evaluations of medical interventions.

Aim:

To assess the evaluations of complementary/alternative medicine (CAM) by NICE clinical guidelines.

Method:

The NICE website was searched, all clinical guidelines were reviewed and their contents compared to our own evaluations of CAM.

Results:

We found 84 guidelines of which 37 included evaluations of CAM. Some guidelines failed to mention evidence on CAM where such evidence was available. Other guidelines that did mention CAM were not complete.

Conclusions:

The evaluations of CAM in NICE clinical guidelines seem neither systematic nor rigorous.

We located all clinical guidelines available on the NICE website in August 2009. We searched the text of each guideline for any reference to CAM, extracted the type of CAM that was mentioned and the recommendations regarding CAM use. Where possible, we then compared this information with our own evaluations of CAM as published in two recent critical, comprehensive and systematic assessments of the available evidence from controlled clinical trials [START_REF] Ernst | The Desktop Guide to Complementary and Alternative Medicine[END_REF][START_REF] Ernst | Complementary therapies for pain management[END_REF] . These assessments were conducted according to clear, published methodologies which involved systematic searches, pre-defined inclusion-exclusion criteria and critical evaluation of the located primary studies. They related to a broad range of over 50 different diseases [START_REF] Ernst | The Desktop Guide to Complementary and Alternative Medicine[END_REF][START_REF] Ernst | Complementary therapies for pain management[END_REF] . For the purpose of this review, we used a broad definition of CAM.

NICE sometimes employed terminology such as 'holistic care' instead of CAM. Other guidelines included interventions such as diet and exercise, all of which we decided to include in our analysis.

Results

In total, 84 clinical guidelines were located, and 37 of them referred to some form of CAM, while 47 did not mention CAM at all (Tab 1). For the majority of these 47 documents, CAM was not relevant to the topic at hand. However, several other of these 47 guidelines e.g. the ones relating to diabetes, hypertension and stroke did not mention CAM, even though several clinical trials of CAM interventions were available 2,3 (Tab 2).

In 14 cases, the evaluations by NICE could be directly compared to our own assessments [START_REF] Ernst | The Desktop Guide to Complementary and Alternative Medicine[END_REF][START_REF] Ernst | Complementary therapies for pain management[END_REF] (Tab 1). Several NICE guidelines were found to be less than comprehensive. In particular, the guidelines relating chronic heart failure, anxiety, depression, obesity, chronic fatigue syndrome, osteoarthritis, diabetes, familial hypercholesterolemia, rheumatoid arthritis and non-specific low back pain omitted parts of the available evidence on CAM. For instance, appropriately, and that it will be feasible for the NHS to implement the recommendations.

Finally, expert peer reviewers carry out statistical and health economics reviews.

Given this seemingly rigorous procedure, our findings are somewhat disappointing. Some types of CAM have been included in 37 of the 84 clinical guidelines. Recommendations by NICE tend to be cautious and usually stress the lack of available evidence regarding CAM.

This attitude seems laudable in view of the paucity of evidence in this area and has contributed to an awareness that more rigorous CAM research is required. However, one might question why a sizable proportion of the guidelines omits CAM modalities for which (positive and negative) evidence does exist. An example are the recent guidelines on chronic back pain. Table 1 shows that this document fails to mention several CAM options while Not enough evidence to allow recommendations for 'neutracuticals'.

"The use of glucosamine or chondroitin products is not recommended" (p160).

Capsaicin and TENS should be considered as an adjunct.

Exercise should be a core treatment.

Lack of evidence for fish oil, ginger, magnets No adverse effects of manual therapy "Given that there is no evidence on harm caused by laser, ultrasound or pulsed electromagnetic fields, the GDG have not made a negative recommendation on these" (p116 People with IBS should be discouraged from eating insoluble fibre. If an increase … is advised, it should be soluble fibre such as ispaghula powder or foods high in soluble fibre (for example, oats). Flax can reduce bloating Evidence limited for biofeedback and relaxation Some herbal preparations may be clinically effective. However, too many uncertainties regarding type and dose of herbal medicines to make recommendations. "Referral for psychological interventions (including hypnotherapy and/or psychological therapy) should be considered for people with IBS who do not respond to pharmacological treatments after 12 months and who develop a continuing symptom profile" (p464).

Peppermint oil for long-term maintenance therapy

People with IBS who choose to try probiotics should be advised to take the product for at least 4 weeks while monitoring the effect. Poor-quality evidence shows that acupuncture may reduce nocturia and both stress and urge incontinence in the short term

F

There is limited evidence that hypnotherapy for women with UI secondary to detrusor overactivity offers some benefit over the short term (up to 6 months).

There is a lack of evidence on herbal medicines for UI or OAB. The GDG recognises that, despite the limited and poor-quality evidence available, some women may wish to explore complementary therapies for their incontinence

  therapy are, according to the results of several clinical trials, safe and effective treatments for anxiety[START_REF] Ernst | The Desktop Guide to Complementary and Alternative Medicine[END_REF] . Yet, the guidelines fail to mention these options.DiscussionTopics for clinical guidelines may be suggested to NICE by anyone. The suggestions are then filtered using selection criteria established by the Department of Health. The final decision regarding which topics to address is made by the Secretary of State for Health. One of the National Collaborating Centres (NCCs) is then commissioned by NICE to coordinate the guideline development. These centers bring together expertise from the Royal Colleges, NHS trusts, professional, patient and carer organizations. A Patient and Public Involvement Program (PPIP) works alongside the guidance production teams and the NCCs to ensure adequate involvement of patients, carers and the public. Guideline Review Panels then comment on the draft, ensure that stakeholder comments have been responded to

TABLE 1 : COMPARISONS BETWEEN NICE GUIDELINES AND OUR OWN EVALUATIONS 2,3

 1

					Formatted: Font: Bold
					Deleted: DTG
					Formatted: Superscript
					Formatted: Superscript
					Formatted: Superscript
					Formatted: Font: Bold
	Clinical Guideline,	Type of CAM mentioned	NICE recommendations	CAM for which according to
	number, title			our own assessements trial
				evidence exists 1
				(direction of evidence)
	CG5, Chronic heart	Co-enzyme Q10	Apart from a recommendation for exercise, not	Acupuncture (*)
	failure	Hawthorn	enough evidence to make recommendations.	Ayurvedic (+)
		L-cartinine	Warning of potential interactions between	Co-enzyme Q10 (*)
		Vitamin E	prescription drugs and CAM	Ginseng (*)
		Myrobalan (Terminalia		Hawthorn (+)
		arjuna)		L-arginine (+)
				Milk vetch (+)
		Lifestyle advice and other		MyoVive (*)
		therapies (homeopathy,		Vitamin E (-)
		reflexology, hydrotherapy,
		crystal therapy and
		acupuncture) are metioned
		in Apdx
	CG8, Multiple	Cannabis	Reflexology/massage,	Cannabis (*)
	sclerosis	Feldenkrais	Fish oil,	Feldenkrais (*)
		Fish oil	Magnetic field therapy,	Fish oil (-)
		Imagery	Neural therapy,	Imagery (*)
		Linoleic acid	Massage/bodywork,	Linoleic acid (*)
		Magnetic field therapy	Tai chi,	Magnetic field therapy (*)
		Massage	Multimodal therapy	Massage (*)
		Neural therapy	may provide some benefit	Music therapy (*)
		Reflexology		Neural therapy (*)
		Tai chi	Imagery should be considered for patients who	Reflexology (+)
		Traditional Chinese	have musculoskeletal pain only if the person has	Vitamin D (*)
		medicine	sufficiently well-preserved cognition to	Yoga (*)
			participate actively.
			People with MS should be advised that linoleic
			acid 17-23 g/day may reduce progression of
			disability.
	CG22, Anxiety, panic	Biofeedback	"Once the picture is clearer … information [from	Acupuncture (*)
	disorder, with or	Exercise	clinician] might include the availability of ….	Aromatherapy (*)
	without agoraphobia,	Guided imagery	certain complementary interventions." (p29)	Autogenic training (*)
	and generalised	Relaxation		Biofeedback (*)
	anxiety disorder	Relaxation training	Relaxation is more effective than waiting list	Chamomile (*)
			control.	Chiropractic (-)
				Electrostimulation (*)
			"…results indicate that exercise alone is	Exercise (+)
			associated with significant treatment gain and	Flower remedies (-)
			may be a particularly useful treatment in those	Guided imagery (*)
			patients who either do not wish or cannot take	Homeopathy (*)
			medication" (p98)	Hypnotherapy (*)
				Kava (+)
			No support for the use of the following	Lemon balm (*)
			interventions:	Massage (+)
			Hypnotherapy	Meditation (*)
			Neurolinguistic programming	Music therapy (+)
			Progressive muscular relaxation	Passionflower (*)
				Reiki (+)
			Anxiety management training, relaxation and	Relaxation (+)
			breathing therapy are more effective than no	Therapeutic touch (*)
			intervention	Valerian (-)
					Deleted: 27/04/2010
	CG23, Depression:	Exercise	"Patients of all ages with mild depression should	Acupuncture (*)	Deleted: 21/04/2010

  ).

			Acupuncture (+)
			Arthritis relief plus (+)
			Avocado (*)
			Balneotherapy (*)
			Boswellia seratta (+)
			Capsaicin (+)
			Chondroitin (+)
			Devils claw (*)
			Duhuo jisheng wan (+)
			Eazmov (*)
			Ginger (*)
			Gitadyl (+)
			Glucosamine (+)
			Green lipped mussel (*)
			Homeopathy (*)
			Hyben vital (*)
			Magnets (*)
			Micronutirent beverage (+)
			Phytodolor (+)
			Reumalex (*)
			Sk1306x (+)
			S-adenosylmethionine (+)
			Soy (*)
			Stinging nettle (+)
			Tai chi (+)
			Tipi (-)
			Vitamin E (-)
			Willow bark (+)
	CG 61, Irritable bowel	Acupuncture	Acupuncture should not be encouraged.
	syndrome	Aloe vera	Healthcare professionals should discourage the
		Biofeedback	use of aloe vera.
		Fibre
		Flax
		Herbal medicine (including
		Chinese)
		Hypnotherapy
		Peppermint oil
		Pre-and probiotics
		Psyllium
		Reflexology

Table Deleted :

 Deleted Tables perhaps which should be excluded if there are table/word length limitations ¶

			International Journal of Clinical Practice	Page 16 of 19
			12 16
				Selenium (*)	Deleted: CAM referred to in the
		Page 15: [1] Deleted		Marie-Laure Despres	Spa therapy (*) Spiritual healing (*) 4/21/2010 11:31:00 AM NICE guideline but not by included in the DTG
	CG84, Non specific low back pain	Supplements (*) Tai chi (+) Thunder god vine (+) Tong luo kai bi (*) Uncaria tomentosa (*) Willow bark (*) Acupuncture (*) 4/21/2010 11:32:00 AM Deleted: Clinical Guideline, number, title ... [4] Deleted: ¶ Formatted Deleted: 1 CG34, Hypertension: the management of adults in primary care: pharmacological CG15, Type 1 diabetes in adults Acupuncture Alexander technique Exercise "Offer one of the following treatment options, taking into account patient preference: an exercise programme, a course of manual therapy (THIS GUIDELINE IS IN TABLE 2) Page 15: [2] Deleted Marie-Laure Despres Alexander technique (*) Devil's claw (*) update
		Manual therapy/ Spinal	or a course of acupuncture. Consider offering	Exercise (*)
		manipulation Massage (THIS GUIDELINE IS IN TABLE 2) another of these options if the chosen treatment does not result in satisfactory improvement".	Hydrotherapy (*) Massage (*)
	o r P e e r R e v i e w O n l y F o r P e e r R e v i e w O n l y Prolotherapy (*) Page 15: [3] Deleted Marie-Laure Despres 4/21/2010 11:32:00 AM Spinal manipulation (*) Water injections (*) Yoga (*) (+) = evidence for effectiveness strongly positive (-) = evidence for effectiveness strongly negative (*) = controlled clinical trials are available but evidence for effectiveness is neither strongly positive nor strongly negative Deleted: 27/04/2010 Deleted: 21/04/2010 F o r P e e r R e v i e w O n l y F o r P e e r R e v i e w O n l y F o r P e e r R e v i e w O n l y Deleted: CG15, Type 1 diabetes in adults ¶ ¶ (THIS GUIDELINE IS IN TABLE 2) Deleted: CG34, Hypertension: the management of adults in primary care: pharmacological update ¶ ¶ (THIS GUIDELINE IS IN TABLE 2) Deleted: CG68, Stroke ¶ (THIS GUIDELINE IS IN TABLE 2) Deleted: 27/04/2010 Deleted: 21/04/2010 ... [2] ... [1] ... [3] F CG68, Stroke (THIS GUIDELINE IS IN TABLE 2) F Page 16: [4] Deleted Marie-Laure Despres 4/27/2010 10:35:00 AM o r Clinical Guideline, number, title Type of CAM included Recommendation by NICE o CG11, Fertility Prayer People who are concerned about their r P e Selenium fertility should be informed that the effectiveness of complementary therapies for P fertility problems has not been properly evaluated and that further research is needed e before such interventions can be e recommended. r e CG13, Caesarean Acupuncture Raspberry leaf may affect other things but r R e v i e section Aromatherapy Blue cohosh not chances of Caesarean section (CS) R Castor oil Chinese medicine For the others treatments, the effects on the likelihood of CS have not been properly e Evening primrose Hypnotherapy evaluated and further research is needed v i Raspberry leaf (in labour) e CG21, Falls Tai chi The evidence for effectiveness of group exercise interventions remains limited, apart from the w Tai Chi w O n intervention CG26, Post-Anxiety management Non-trauma-focused interventions such as O traumatic stress disorder Hypnotherapy Relaxation relaxation or non-directive therapy, which do not address traumatic memories, should n not routinely be offered to people who l present with chronic PTSD. No convincing evidence for hypnotherapy y CG27, Referral for Use of complementary None relating to CAM l suspected cancer medicines was a y significant predictor of Deleted: 27/04/2010 treatment delay Deleted: 21/04/2010 CG28, Depression Diet … harm and benefit profiles of these
		in children and	PC3EW\STAFF\Rohini\RecommCAMClinGuidNICE-v15 PC3EW\STAFF\Rohini\RecommCAMClinGuidNICE-v15 Exercise treatments have not been convincingly 28/04/2010 28/04/2010
		young people	Fish oil	established and it is a largely unregulated
			Magnesium	industry.
			Relaxation
			Selenium
			St Johns wort
			International Journal of Clinical Practice

Page 17 of 19 International Journal of Clinical Practice International Journal of Clinical Practice

			Yoga
	CG31, Obsessive		Homeopathy	Insufficient evidence to support use of
	compulsive disorder	Hypnotherapy	hypnotherapy or homeopathy
			Yoga
	CG35 Parkinsons		Exercise	Recommended for various Parkinson
				syndromes
	CG37, Postnatal		Acupuncture (for	None relating to CAM
	care		headache)
			Biofeedback (for
			postpartum headache)
			Diet (eg herbal tea) (for
	infant colic) Electrotherapy Homeopathy Lavender oil (for perineal discomfort) r F o Relaxation
	disorder CG38, Bipolar	overlapping care r complementary, comprehensive and non-e service providers providing genuine e Spinal manipulation statutory and voluntary P Co-operation between	None relating to CAM
	CG 39, Anaemia management in chronic kidney disease CG 40, Urinary incontinence		Vitamin supplements R e None specific to CAM Acupuncture Herbal medicines v w e i Hypnotherapy
				O n
				l y

Page 18 of 19 International Journal of Clinical Practice International Journal of Clinical Practice

		Homeopathy		Massage with emollients may improve
		Honey beeswax	eczema. Patients should be informed of
		Hypnotherapy	safety issues
		Gamma linolenic acid
		(an essential fatty acids)	Children with atopic eczema and their
		Massage		parents or carers should be informed that the
		Olive oil		effectiveness and safety of complementary
				therapies such as homeopathy, herbal
				medicine, massage and food supplements for
				the management of atopic eczema have not
				yet been adequately assessed in clinical
	CG 70, Induction of F labour o r Acupuncture Castor oil Herbal supplements Homeopathy Hot baths	studies No evidence for herbal supplements they should not be offered. Evidence insufficient to determine effectiveness of acupuncture in cervical priming; should not be recommended.
	P		Evidence for homeopathy was poor and insufficient to make recommendations. Castor oil and hot baths should not be
	CG72, Attention disorder (ADHD) deficit hyperactivity	e Supplements r Diet Relaxation e Massage	offered; more research needed. Balanced diet, nutrition and exercise. Dietary fatty acids not recommended.
	CG 73 Chronic kidney disease personality disorder CG77, Antisocial	Yoga Diet Exercise Relaxation	None specific to CAM w e i v R e None specific to CAM
	CG42, Dementia	Animal assisted therapy Aromatherapy Art therapy Massage	O n Should be available but evaluated for cost effectiveness l y
	CG 48, Secondary	Beta carotene		Fish oil and exercise recommended
	prevention of	Exercise
	myocardial	Fish oil		Beta carotene, vitamin E or C or folic acid
	infarction	Vitamin E or C	not recommended
	CG49, Faecal	Psyllium		Very little high quality evidence or research
	incontinence			upon which to base recommendations
	CG 57, Atopic	Aromatherapy	Insufficient evidence for any to make
	eczema in children	Black seed oil	recommendations.
		Chinese herbal medicine

Page 19 of 19 International Journal of Clinical Practice International Journal of Clinical Practice

PC3EW\STAFF\Rohini\RecommCAMClinGuidNICE-v1528/04/2010

"The GDG felt that the evidence for any complementary therapy or medicines being effective was lacking; the GDG was disappointed by this given the overall popularity of these treatments" (p 202). Some CAMs may provide short term symptomatic benefit. … no strong evidence that arthritis will benefit from changes in diet. However, could be encouraged to follow a Mediterranean diet.


Robert J Simister Mrcp

Karl Ng Fracp

PhD + Bethan Lang

Michael Beckles

David Chao

PhD Dominick J H Mccabe
email: dominick.mccabe@amnch.ie

Sequential fluctuating paraneoplastic ocular flutter-opsoclonus-myoclonus syndrome and Lambert-Eaton myasthenic syndrome in small cell lung cancer

Keywords: Paraneoplastic opsoclonus-myoclonus syndrome, Lambert-Eaton myasthenic syndrome, anti-voltage gated calcium channel antibodies, small cell lung cancer Simister

Paraneoplastic cerebellar degeneration may occur in association with Lambert-Eaton myasthenic syndrome (LEMS), but to our knowledge, the co-occurrence of paraneoplastic opsoclonus-myoclonus syndrome and LEMS has not been previously reported.

A 67-year-old woman presented with a complex partial seizure and evolving ocular flutter, opsoclonus, myoclonus, and 'cerebellar' signs, all of which improved spontaneously within six weeks. Approximately eight weeks after symptom onset, the patient became encephalopathic, she had a further complex partial seizure, and she became areflexic with potentiation of deep tendon reflexes. Radiological, bronchoscopic and histological investigations revealed small cell lung cancer, and neurophysiological investigations confirmed a diagnosis of LEMS. High titre anti-P/Q-type voltage gated calcium channel antibodies were identified in the serum, which increased as the signs of opsoclonus and myoclonus resolved. The encephalopathy and clinical features of LEMS responded dramatically to chemotherapy and radiotherapy.

Spontaneous improvement of paraneoplastic opsoclonus-myoclonus syndrome may occur, and this syndrome may occur in association with LEMS. Anti-voltage gated calcium channel antibodies are not implicated in the pathogenesis of paraneoplastic opsoclonus-myoclonus syndrome.

Paraneoplastic opsoclonus-myoclonus (POMS) syndrome is a rare paraneoplastic syndrome in adults that has been reported in association with a variety of tumours. [START_REF] Bataller | Clinical outcome in adult onset idiopathic or paraneoplastic opsoclonus-myoclonus[END_REF] Anti-neuronal antibodies are only occasionally identified in POMS. [START_REF] Bataller | Autoantigen diversity in the opsoclonus-myoclonus syndrome[END_REF] Lambert-Eaton myasthenic syndrome (LEMS) may occur in patients with lung neoplasia, and most patients with LEMS will have anti-P/Q type voltage gated calcium channel (VGCC) antibodies in the serum. [START_REF] Voltz | Paraneoplastic neurological syndromes: an update on diagnosis, pathogenesis, and therapy[END_REF] LEMS may co-occur with other paraneoplastic syndromes, but to our knowledge, has not previously been reported in association with POMS.

Case Report

A 67 year old right handed Caucasian woman had a ten day history of lethargy, a five day history of nausea and vomiting, and a one day history of vertigo, jerky truncal tremor on standing and unsteadiness of gait. She subsequently had a complex partial seizure that prompted referral to hospital. She had had symptoms suspicious of a complex partial seizure six months prior to admission, but did not seek medical attention. There was no other relevant past medical history although she had smoked 40 cigarettes per day for 30 years. On admission, general examination was normal.

Neurological examination revealed truncal myoclonus on spinal flexion and on standing, but was otherwise normal. Over the following 3 days, the patient developed increasing nausea, xerostomia and unsteadiness. Further neurological assessment at that stage revealed ocular flutter with occasional opsoclonus, hypometric vertical saccades, saccadic intrusions into pursuit eye movements, and gaze-evoked horizontal nystagmus on right lateral gaze. Intravenous high dose thiamine and multivitamins (pabrinex ® I and II) were administered twice a day for 5 days, followed by 300 mg of thiamine daily without any clinical response. Over the next two weeks, she developed prominent opsoclonus and upper limb incoordination. The persistent nausea and Simister et al -5truncal myoclonus prohibited any attempt to mobilize. A trial of clonazepam 0.5 mg BD had to be discontinued after two days because of extreme drowsiness; the nausea subsequently responded to treatment with ondansetron and domperidone.

Approximately six weeks after symptom onset, the eye movement abnormalities, ataxia, and truncal myoclonus began to spontaneously resolve. Eight weeks after symptom onset, the patient became encephalopathic and had a further complex partial seizure. Repeat bedside cognitive examination revealed evidence of frontal executive, dominant temporal and mild biparietal dysfunction. Cranial nerve examination, including careful eye movement assessment, was normal. Limb tone and power were normal. There was mild limb and gait ataxia. Deep tendon reflexes were now absent at rest, but there was potentiation following voluntary muscle contraction. Sensory Seven months after completion of her treatment and twelve months after initial symptom onset, the patient had no residual neurological symptoms or signs. Antivoltage gated calcium channel antibody titers had fallen to 147 pM, with negative repeat anti-nuclear antibodies. She has remained in remission three years after completion of chemotherapy and radiotherapy.

Discussion

Paraneoplastic opsoclonus-myoclonus syndrome is a rare complication of underlying malignancy in adults which is characterized by the presence of opsoclonus, action myoclonus of limbs, trunk, or head, and occasionally cerebellar dysfunction. [START_REF] Bataller | Clinical outcome in adult onset idiopathic or paraneoplastic opsoclonus-myoclonus[END_REF][START_REF] Anderson | Opsoclonus, myoclonus, ataxia, and encephalopathy in adults with cancer: a distinct paraneoplastic syndrome[END_REF] As the syndrome progresses, encephalopathy and death may subsequently ensue. Resolution of the neurological findings usually requires treatment of the underlying tumour, [START_REF] Bataller | Clinical outcome in adult onset idiopathic or paraneoplastic opsoclonus-myoclonus[END_REF] although spontaneous improvement prior to definitive anti-neoplastic therapy has occasionally been described. [START_REF] Anderson | Opsoclonus, myoclonus, ataxia, and encephalopathy in adults with cancer: a distinct paraneoplastic syndrome[END_REF][START_REF] Dropcho | Paraneoplastic opsoclonus-myoclonus. Association with medullary thyroid carcinoma and review of the literature[END_REF][START_REF] Furman | Spontaneous remission of paraneoplastic ocular flutter and saccadic intrusions[END_REF][START_REF] Nausieda | Opsoclonic cerebellopathy: A paraneoplastic syndrome responsive to thiamine[END_REF] Furman et al. reported two patients with ocular flutter Simister et al -8and cerebellar signs who improved spontaneously before being diagnosed with breast adenocarcinoma and small cell lung cancer, respectively. [START_REF] Furman | Spontaneous remission of paraneoplastic ocular flutter and saccadic intrusions[END_REF] Nausieda et al. described a further patient who developed opsoclonus and cerebellar ataxia without myoclonus in association with an undifferentiated bronchogenic carcinoma. [START_REF] Nausieda | Opsoclonic cerebellopathy: A paraneoplastic syndrome responsive to thiamine[END_REF] Rapid resolution of the opsoclonus, but not the ataxia, was reported within twenty hours of treatment with 200mg of intravenous thiamine.

In our case, the clinical features of ocular flutter, opsoclonus and myoclonus did not respond to thiamine, but subsequently spontaneously improved, despite evolution of the illness with development of a mild encephalopathy, clinical, neurophysiological and immunological features of LEMS, and occurrence of a second seizure. This suggests that the autoimmune response to presumed neuronal antigens in the mid brain and pons resolved, with subsequent autoimmunity to cortical autoantigens above the brain stem and an increase in anti-VGCC antibody titres. Chemotherapy and subsequent radiotherapy resulted in regression of the lung malignancy as well as resolution of the neurological findings of encephalopathy and LEMS, mirrored by a decrease in anti-VGCC antibody titres. Paraneoplastic cerebellar degeneration is described in patients with LEMS, 8 but to our knowledge, the co-occurrence of paraneoplastic ocular flutter-opsoclonus-myoclonus and LEMS has not been previously reported. Voltage gated calcium channels are abundant in the cerebellum, and anti-voltage gated calcium channel antibodies have been suggested to play a role in the pathogenesis of paraneoplastic cerebellar degeneration syndromes. [START_REF] Mason | Small-cell lung cancer, paraneoplastic cerebellar degeneration and the Lambert-Eaton myasthenic syndrome[END_REF] POMS has been described in association with a variety of auto-antibodies, including anti-Ri, anti-Hu, anti-amphiphysin, anti-purkinje cell, [START_REF] Bataller | Clinical outcome in adult onset idiopathic or paraneoplastic opsoclonus-myoclonus[END_REF][START_REF] Voltz | Paraneoplastic neurological syndromes: an update on diagnosis, pathogenesis, and therapy[END_REF] Simister et al -9and anti-mitochondrial antibodies, [START_REF] Blaes | Adult paraneoplastic opsoclonus-myoclonus syndrome associated with antimitochondrial autoantibodies[END_REF] but has never been reported in association with anti-VGCC antibodies. The fact that the anti-VGCC antibody titres increased as the opsoclonus, myoclonus and ataxia resolved strongly argues against a potential role for these antibodies in the pathogenesis of POMS.

POMS may be associated with an improved prognosis in children with neuroblastoma, [START_REF] Altman | Favorable prognosis for survival in children with coincident opso-myoclonus and neuroblastoma[END_REF] and LEMS may be associated with prolonged survival [START_REF] Wirtz | P/Q-type calcium channel antibodies, Lambert-Eaton myasthenic syndrome and survival in small cell lung cancer[END_REF] and clinical remission [START_REF] Newsom-Davis | Lambert-Eaton myasthenic syndrome[END_REF] in adults with small cell lung carcinoma. Further follow-up is required to determine whether the co-occurrence of two independent paraneoplastic syndromes, which could confer an enhanced anti-tumour autoimmune response, will impact on the long-term prognosis in our patient who has been in remission for three years following initial chemotherapy. The observation that this lady made a complete neurological recovery following chemotherapy and radiotherapy supports the hypothesis that an unidentified pathogenic paraneoplastic autoantibody interfered with the function of the omnipause neurons in the pons, without irreversible destruction of the neural structures proposed to be involved in the pathogenesis of this movement disorder.

  examination was normal. She was then commenced on 200 mg of sodium valproate BD. Full blood count, ESR, CRP, glucose and calcium were normal. She had intermittent hyponatremia (lowest sodium level 127 mmol/L [normal range 135-145]), with low serum and urine osmolalities consistent with volitional hypervolemia, caused by excessive water intake to relieve her symptoms of dry mouth. Autoantibody screening revealed a positive anti-nuclear antibody titre of > 1/1000 (nuclear membrane and cytoplasmic pattern), but negative anti-double stranded DNA, extractable nuclear antigens, anti-nuclear cytoplasmic antibodies, anti-Ri, anti-Yo and anti-Hu antineuronal antibodies, and normal complement levels. High titre serum anti-VGCC antibodies were identified on several occasions: 446 + 60 (SEM) picomoles/litre (pM) at presentation, rising to 781 + 28 pM when assayed at the time of development of Simister et al -6areflexia, and 235 + 34 pM after resolution of the opsoclonus and myoclonus (normal < 45 pM; Figure). MRI of brain with gadolinium revealed minimal small vessel disease in the deep white matter and subcortical regions of both cerebral hemispheres, with no inflammatory changes in the brain stem or cerebellum and no evidence of metastases. Cerebrospinal fluid (CSF) was acellular, with normal protein and glucose, but there was intrathecal synthesis of oligoclonal bands. CSF viral polymerase chain reaction testing was negative for herpes simplex, varicella zoster, cytomegalovirus and Epstein Barr virus. Computed tomography of the thorax showed paratracheal and sub-carinal lymphadenopathy, but no evidence of more widespread disease. Subsequent bronchoscopy revealed an endobronchial lesion, and histological examination of a biopsy specimen confirmed a diagnosis of small cell lung cancer. Mammography was normal. Nerve conduction studies performed after the onset of the areflexia revealed generally small amplitude resting compound muscle action potentials. Repetitive stimulation of the right ulnar nerve was performed at the right wrist with the recording surface electrode on abductor digiti minimi. The initial maximum resting compound muscle action potential amplitude was 7.9mV, which increased to 13mV immediately after sustained maximal isometric contraction for 15 seconds. Single fiber electromyography of right extensor digitorum communis revealed massive jitter and blocking in eight out of nine fiber pairs examined, consistent with a diagnosis of LEMS. Electroencephalogram revealed slowing of the background rhythm, with poorly localized sparse sharp waves over the left more than right hemisphere, but no definite epileptiform changes. A diagnosis of paraneoplastic opsoclonus-myoclonus syndrome in combination with mild paraneoplastic cerebellar dysfunction and LEMS was established. The patient was then treated with one cycle of single agent etoposide, followed by three cycles of etoposide and carboplatin chemotherapy as standard first line management. Follow-up assessment two months after completion of chemotherapy revealed a mild reduction in categorical fluency with normal bedside cognitive testing otherwise. Reexamination revealed normal cranial nerves, mild upper limb ataxia, deep tendon reflexes had returned to normal, and she had no myoclonus or other focal limb findings. Repeat CT imaging of thorax showed regression of the thoracic lymphadenopathy, and the patient underwent a course of mediastinal radiotherapy.

Figure 1 :

 1 Figure 1: Bar chart of anti-voltage gated calcium channel titers (in picomoles of


Judith W P M Oomen

Bart W Smits

Dorine W Swinkels

Willem Schreurs

Bastiaan R Bloem

Mathijs P Hendriks

A toxic shot from the hip

A toxic shot from the hip

Word count 589

Characters in title 25

Number of references 6

Numbers of figures 1

Disclosure

The authors report no disclosures.

Abstract

None

A 26-year-old man presented with progressive pain in the right groin. Since one year, he also experienced mental slowing, a weaker voice, 'shaking hands' with decreased dexterity. He denied abdominal pain, nausea or vomiting. Medical history included a gunshot wound in his right thigh two years earlier, which was left untreated. General physical examination revealed painful and restricted movements of the right hip in all directions. Abdominal investigation was normal. Upon neurological examination he was bradyphrenic, with a frontal dysexecutive syndrome. There was a symmetrical postural, action and intention tremor of the hands, but no rest tremor (an accompanying video is available upon request). In addition, he showed polyminimyoclonus and dystonic posturing of the hands, as well as a slight cogwheel rigidity of the arms. His gait was bradykinetic, with small steps, a stooped posture, and a bilaterally reduced arm swing. Moreover, his gums showed a remarkable distinct blue discoloration around the teeth (Burton's lines, figure 1A).

Pelvic X-ray showed bullet fragments in the right femoral head at the articular surface with intra-capsular spreading (figure 1B). Cerebral magnetic resonance imaging was completely normal. Laboratory tests revealed a blood hemoglobin of 7.4 g/dl (normal: 13.0-17.2) with a mean corpuscular volume of 79 fl (normal: 85-100) and erythrocyte protoporphyrin of 5892 nmol/l (normal: < 560). Basophilic staining of the erythrocytes was observed (figure 1C). Iron levels, serum electrolytes, creatinine, liver function and hepatic enzymes were normal.

Based on the combination of parkinsonism, gingival Burton's lines, microcytic anemia with basophilic staining of erythrocytes, porphyria, and persisting bullet fragments in the hip joint, we considered the possibility of chronic lead poisoning. This was confirmed by a high serum lead level of 9.55 µmol/L (normal < 0.72 µmol/L; adult toxicity > 1.93 µmol/L). Surgical excision of the femoral head, capsule and synovial tissue was performed. The articular surface of the femoral head contained a bullet fragment that was 'polished' by movements of the hip (figure 1D). Oral chelating therapy with succimer (2,3"-"dimercaptosuccinic acid) was started after surgery. One week postoperatively, lead levels had decreased considerably to 3.51 µmol/L and further decreased to two 2.5 µmol/L, after two months. Neurological examination after three months revealed only minimal mental slowing and slight intention tremor of the hands. Gait had normalized completely.

Lead poisoning is a rare, delayed complication of persisting intracorporeal bullet fragments.

Fewer than 100 patients have been reported. [START_REF] Coon | Lead toxicity in a 14-year-old female with retained bullet fragments[END_REF][START_REF] Mahan | Increased blood lead levels in an adolescent girl from a retained bullet. A case report[END_REF][START_REF] Mcquirter | Change in blood lead concentration up to 1 year after a gunshot wound with a retained bullet[END_REF] Lead poisoning is uncommon in patients with persisting bullet fragments in soft tissues, since these fragments are usually encapsulated, thus preventing lead absorption. In our patient, lead poisoning may nevertheless have occurred because the bullet fragments persisted in the large hip joint where the acidic environment of the synovial fluid and local arthritis -caused by mechanical friction -could have promoted the absorption of lead. Moreover, lead absorption was likely promoted by the increased surface area caused by bullet fragmentation. [START_REF] Peh | Lead arthropathy: a cause of delayed onset lead poisoning[END_REF] The neurological symptoms and signs of our patient resolved impressively shortly after surgical removal of the remaining bullet fragments. This is remarkable since lead induced neurotoxicity is usually considered to be irreversible. Possibly, chelating therapy was partly responsible for this favorable outcome, although there are no controlled clinical trials that support the efficacy of chelating medications in lead poisoned adults. [START_REF] Coon | Lead toxicity in a 14-year-old female with retained bullet fragments[END_REF][START_REF] Grandjean | Chronic lead poisoning treated with dimercaptosuccinic acid[END_REF] In conclusion, we recommend screening for lead intoxication in patients with signs of parkinsonism who have a history of gunshot wound, especially with persisting bullet fragments large joints. Atypical parkinsonism can be a sign of a delayed lead toxicity, and removal of bullet debris plus early chelating therapy may lead to a remarkable resolution of neurological disability.

  Judith W.P.M. Oomen, MD, Bart W. Smits, MD, Dorine W. Swinkels, MD, PhD, Berend W. Schreurs, MD, PhD, Bastiaan R. Bloem, MD, PhD and Mathijs P. Hendriks, MD From the Department of Orthopaedic Surgery (J.O., B.Sch.), Department of Neurology, (B.Sm., B.B.), Department of Clinical Chemistry (D.S.) and Department of Internal Medicine, (M.H.), Radboud University Nijmegen Medical Centre, The Netherlands Correspondence to: Dr. Berend Schreurs Department of Orthopedic Surgery 357 Radboud University Nijmegen Medical Centre PO Box 9101, 6500 HB Nijmegen The Netherlands Tel: +-31-24-3613918 Fax: +-31-24-3540230 e-mail:b.schreurs@orthop.umcn.nl Search terms Tremor, Gait disorders/ataxia, Basal ganglia, Other toxicology, Lead encephalopathy

Acknowledgments

We thank dr. Kees Kramers (department of Internal Medicine, Radboud University Nijmegen Medical Centre, The Netherlands) and dr. Wim van der Meer (department of Clinical Chemistry, Radboud University Nijmegen Medical Centre) for toxicological review and technical support. Prof. Bloem was supported by a ZonMw VIDI research grant (number 016.076.352).