Ehud Lebel

Bone density changes with enzyme therapy for Gaucher disease

Gaucher disease is the most common lysosomal storage disease. Enzyme replacement therapy engenders improvement in hematological and visceral parameters; however, improvement in bone density (BMD) with treatment has not been confirmed. This study presents follow-up of BMD in the first ten patients in Israel treated with low-dose recombinant enzyme for up to 108 months. BMD at femoral neck and lumbar spine was determined by dual-energy X-ray absorptiometry (DEXA) at the start of the trial, after 3–6 months, after 18–24 months, and at the most recent follow-up. BMD in all patients was very low at onset and never normalized. There was a decrease in BMD in all patients at 3–6 months. Older patients (four women, two men; >30 years of age) showed some improvement in BMD during treatment. Younger patients (four females; 18–23 years of age) did not show a statistically significant improvement. These findings might reflect the failure of patients with Gaucher disease to achieve expected peak bone density at appropriate chronological milestones despite treatment. Nonetheless, the z-scores of the older patients were better than those of the younger patients, implying some catch-up period. Yet, some patients with Gaucher disease evince rapid onset of osteoporosis in early adulthood. Enzyme treatment per se, as well as attendant improved well-being and increased physical activity, may induce amelioration in BMD at this later stage. One may consider adding anti-osteoporosis therapy in young adults to induce earlier “catch up” to peak bone mass, and then enzyme replacement in later adulthood to prevent decrements in bone mass related to Gaucher cell infiltration.

Kingella kingae infections in children.

Kingella kingae is a beta-hemolytic gram-negative bacillus. It was first described in the 1960s by EO King and has been reported as a cause of osteo-articular pediatric infections since the early 1980s. We performed a retrospective review of all pediatric cases of invasive K. kingae infection between 1997 and 2002, in order to define the incidence, clinical presentation and outcome of invasive K. kingae infections in a pediatric population. During the study period, a total of 24 pediatric patients with K. kingae infection were identified. There were 15 blood culture isolates of K. kingae, out of a total of 1151 (1.3%) positive blood cultures, and 9 synovial fluid culture isolates out of a total of 76 (11.8%) positive synovial fluids. Fifteen patients had osteo-articular infections and 9 had primary bacteremia without osteo-articular infection. Outcome was favorable in all cases and only in 2 patients with knee joint infection was surgical intervention performed, by means of formal knee arthrotomy. All patients recovered uneventfully, in 7 cases without any intervention and in the others with intravenous or oral antibiotic. In conclusion, invasive K. kingae infection is not uncommon in Israel. It usually has a mild course and thus is not always detected and treated. As K. kingae grows best in blood culture broth, blood and joint fluid should always be inoculated into blood culture bottles in suspected cases. This bacterium is highly sensitive to betalactame antibiotics and infection resolves quickly with antibiotic treatment. Surgical intervention for osteo-articular infection is seldom indicated.

Serum levels of osteoprotegerin and osteoprotegerin polymorphisms in Gaucher disease

Bone involvement in Gaucher disease causes disability and reduced quality of life; loss of function and pain are important indications for enzyme replacement therapy. The purpose of this study was to ascertain whether osteoprotegerin (OPG), which decreases osteoclast activity, is indicative of incipient bone involvement by comparing OPG serum levels to Gaucher disease severity (SSI) and bone mineral density (BMD), and to correlate bone and disease markers to OPG polymorphisms: OPG1‐2(A163G), OPG3‐4(T129C) and OPG5‐6(C1217T). Of 554 patients, 173 Ashkenazi Jewish patients with non‐neuronopathic Gaucher disease were enrolled and 32 healthy Ashkenazi Jews served as controls. Serum OPG levels were detected by enzyme‐linked immunosorbent assay and BMD was obtained by dual X‐ray absorptiometry. OPG polymorphisms were determined in 63 randomly chosen patients. Serum OPG values for patients were not greater than in controls, but showed a statistically significant trend to increase with age (P = 0·057). No correlation existed between OPG levels and BMD or with genotype or other disease markers. A significant correlation was noted between OPG5‐6 genotype and SSI. A significant difference was found between the allele distributions of each OPG polymorphism when compared with Caucasians and Ashkenazi Jews. OPG levels probably do not predict BMD in Gaucher disease and hence are not indicative of osteoporosis in Gaucher disease.

Achilles tenotomy as an office procedure: safety and efficacy as part of the Ponseti serial casting protocol for clubfoot.

Background: Ponseti demonstrated the correction of clubfoot in infants using manipulation followed by the application of well-molded long-leg plaster casts. Percutaneous Achilles tenotomy was recommended to correct residual equinus contracture in approximately 80% of cases. In the current study, we evaluated the safety of this practice for the treatment of clubfoot when performed as an “office procedure” without sedation or general anesthesia during the final stage of the serial casting protocol. Patients and Methods: We retrospectively collected data regarding babies who underwent serial manipulation and casting according to the Ponseti protocol for the treatment of clubfoot. All babies managed in the outpatient clinic between 2006 and 2010 were included. Tenotomy was indicated when the forefoot was completely corrected and if the hind-foot showed rigid equinus. Tenotomy was performed by a single scalpel stab in the outpatient clinic, using topical and local anesthesia (without general anesthesia or sedation). The cast was then applied and kept on for 3 weeks. Babies were discharged home after 1 hour of supervision. Surgical reports regarding Achilles tenotomy were reviewed, and data were collected from postoperative notes. We specifically looked for perioperative complications, recovery unit notes, and hospital readmission. Results: Fifty-six babies (83 feet) were included in the current study. There were 40 males and 16 females, and 27 of them had bilateral clubfoot. Three babies (0.5%) had complex (syndrome-related) clubfoot; familial risk was known in 6 (11%) babies. Forty-one (73%) babies were indicated for Achilles tenotomy. Tenotomy was performed after an average of 5 casts (range, 3 to 9). No adverse events were related to local anesthesia and/or the procedure itself, and there was no delay in discharge in any of the operated babies. One baby was evaluated in the emergency room 3 days after the procedure because of (unfounded) parental concern of swelling inside the cast. All other babies had an uneventful course. Retenotomy was performed in 7 babies (12 feet); 2 of them (4 feet) had complex clubfoot. All of these babies (ie, their parents), except 1, had moderate to poor compliance with the treatment protocol. Conclusions: Tenotomy as an office procedure using topical and local anesthesia is a safe procedure. It does not incur a substantial rate of readmission to the emergency room, either because of parental concern or because of actual complications. The need for retenotomy is related to a low compliance with the treatment protocol. Level of Evidence: Level II.

Poor results of drilling in early stages of juxta-articular osteonecrosis in 12 joints affected by Gaucher disease

Background and purpose Gaucher disease is heterogeneous. One of the most devastating complications is bone involvement, ranging from mild osteopenia to osteonecrosis, but no markers have been discovered to predict onset and/or progression. We describe our experience in a large referral center using drilling for juxta-articular osteonecrosis in young patients with Gaucher disease. Patients and methods We retrospectively reviewed medical data from all patients who were recommended to undergo drilling for osteonecrosis of juxta-articular bone of the femoral head, the humeral head, or upper tibia for acute osteonecrosis at a pre-collapse stage. Results 11 patients (mean age 34 years) underwent drilling of 12 joints with juxta-articular osteonecrosis; 3 (mean age 51 years) refused intervention. 9 joints that were drilled showed advancing joint degeneration within 0.5 to 4 years. 3 joints have undergone replacement. Of the 3 joints that did not undergo drilling, 2 have undergone replacement and 1 has collapsed with osteoarthritis. Interpretation We found equally poor outcome with and without drilling. Effective intervention can only be achieved by improving our understanding of bone physiology and pathophysiology in Gaucher disease.

Histologic findings of femoral heads from patients with Gaucher disease treated with enzyme replacement.

OBJECTIVES To assess correlations of patient demographics, including enzyme replacement therapy (ERT) with bone histology, to facilitate decisions of whether and when to perform hip replacement surgery in patients with Gaucher disease. METHODS We examined the histology of surgically removed femoral heads and categorized findings by the presence or extent of osteonecrosis, Gaucher cell (GC) infiltration, and bone regeneration qualifiers using a tripartite histology-based scoring system. RESULTS Twenty-two patients with 26 bone specimens were evaluated. Seventeen patients (77%) were splenectomized, 16 (73%) received ERT, and 12 (55%) had the putatively milder genotype (N370S/N370S), with the rest putatively at increased risk for skeletal disease (N370S/other). The 3 histology subscores were applicable to all specimens. Osteonecrotic bone was seen in 19 of 26 (73%); osteoarthritis was seen in all cartilage specimens. Gaucher cell infiltration was not correlated with demographics or disease severity. A trend was noted between reduced GC infiltration and ERT (ρ = 0.407), but regeneration qualifiers were not correlated with ERT or other features. CONCLUSIONS Histologic findings of GC infiltration and bone regeneration qualifiers did not correlate with demographics or with exposure to ERT. Most specimens unexpectedly showed good regenerative responses to osteonecrosis despite heavy GC infiltration.

Hip arthroplasty in patients with Gaucher disease.

Patients with Gaucher disease suffering from the consequences of femoral head osteonecrosis deserve a treatment modality that will eliminate pain, preserve ambulation and hopefully will endure long enough to allow satisfactory daily life. Total hip arthroplasty fulfills these 3 objectives. The rate of complications during anesthesia and during surgical procedure is comparable to otherwise healthy population if the Gaucher patients are carefully evaluated pre-surgery and prepared by a medical team familiar with all aspects of the disease. With prompt preparation, meticulous procedure, and careful post-operative care, patients with Gaucher disease may benefit from long-lasting hip prostheses. It is to be hoped that newer types of implants would allow longer revision-free periods even in this young patient population who have developed avascular necrosis, and a greater hope for patients with Gaucher disease would be that early administration of bone-specific therapies may prevent osteonecrosis.

anaesthesia for total hip replacement in Gaucher's disease

EDITOR: Gaucher’s disease, the most common lysosomal storage disorder, is an enzymatic defect with consequent accumulation of undegraded glucocerebroside in cells of the monocyte–macrophage system [1]. Most patients present with enlargement of the spleen and liver resulting in hypersplenism, with thrombocytopaenia generally more significant than anaemia. Skeletal involvement, particularly osteonecrosis of large joints and pathological fractures, invariably is the most significant cause of morbidity and decreased quality of life. In spite of enzyme replacement therapy, osteopaenia and osteonecrosis continue to be clinically important. The need for total hip replacement (THR), and subsequent revision, is relatively common in these patients at a relatively young age. With regard to the anaesthetic management for orthopaedic surgery in patients with Gaucher’s disease, only one case report appears in the literature of an adult with a sub-capital hip fracture who underwent subarachnoid anaesthesia [2]. We wish to report the anaesthetic management of all cases seen in our institution for THR or revision from 1990 to 2005. Patient characteristics and perioperative data are summarized from the clinical records and presented in Table 1. There were 14 patients, 10 males and 4 females, who underwent THR. Five of these underwent a revision. Six patients (43%) were homozygous for the mild N370S (1226) mutation; eight patients (57%) had been splenectomized; and six patients (43%) had pulmonary hypertension at the time of surgery. Fiftythree percentage of patients underwent general anaesthesia. Five of the operations (21%) were performed with preoperative platelet counts 80 103mm 3. Perioperative blood product transfusion was required in 68% of the operations. All patients with general anaesthesia were orally intubated utilizing direct laryngoscopy and ventilated with tidal volume 6–8 mL kg 1 and respiratory rate of 10–16 min 1. There were no difficulties in airway management. All patients were given preoperative antibiotic prophylaxis mainly with cefamezine; nonetheless, 37% experienced postoperative wound infections presenting significantly higher rates compared to similar patients in our institution (2%) and the rate reported in medical literature (0.3–2%) [3]. A wound infection was defined as one of the following: wound redness, excessive pain, tissue necrosis, local oedema, purulent discharge from the operation wound and maximal temperature 38.5 and/or white cell count 10000. Other complications included one inadvertent spinal, one failed spinal and one patient with severe postoperative thrombocytopaenia (21 103mm 3). Joint replacement for patients with Gaucher’s disease is an important therapeutic intervention that dramatically reduces pain, improves functionality and increases quality of life. For patients with Gaucher’s disease, the preoperative evaluation of haematological Correspondence 265

Bone Mineral Density in Gravida: Effect of Pregnancies and Breast-Feeding in Women of Differing Ages and Parity

Changes of bone during pregnancy and during lactation evaluated by bone mineral density (BMD) may have implications for risk of osteoporosis and fractures. We studied BMD in women of differing ages, parity, and lactation histories immediately postpartum for BMD, T-scores, and Z-scores. Institutional Review Board approval was received. All women while still in hospital postpartum were asked to participate. BMD was performed by dual-energy X-ray absorptiometry (DXA) machine at femoral neck (FN) and lumbar spine (LS) by a single technician. Of 132 participants, 73 (55.3%) were ≤30 years; 27 (20.5%) were primiparous; 36 (27.3%) were grand multiparous; 35 (26.5%) never breast fed. Mean FN T-scores and Z-scores were higher than respective mean LS scores, but all means were within the normal limits. Mean LS T-scores and Z-scores were highest in the grand multiparas. There were only 2 (1.5%) outliers with low Z-scores. We conclude that, in a large cohort of Israeli women with BMD parameters assessed by DXA within two days postpartum, mean T-scores and Z-scores at both the LS and FN were within normal limits regardless of age (20–46 years), parity (1–13 viable births), and history of either no or prolonged months of lactation (up to 11.25 years).

Acupuncture for symptoms of Gaucher disease

OBJECTIVE The purpose of this study was to examine the effect of acupuncture on bone/joint pain, headache and fatigue, as well as quality of life in patients with Gaucher disease (GD), within the framework of an integrated treatment programme. METHODS Patients with GD suffering from any of the above symptoms were offered a series of 10-12 weekly acupuncture treatment sessions. Prior to initiation of treatment, participants were asked to score the severity of pain, as well as to complete the Functional Assessment of Chronic Illness Therapy-Fatigue measure (FACIT-F) and the Medical Outcomes Study (MOS) Short-Form (SF) questionnaire. These tools were evaluated again at the end of the treatment period. RESULTS A total of 12 patients were evaluated. While the only pain outcome reduced by acupuncture was knee pain, a significant improvement was observed with respect to nearly all FACIT-Fatigue measures, including the Physical Well Being (PWB) subscales and the SF-12 Physical Composite Score (PCS), though not for the Mental Composite Score (MCS). Patients reported satisfaction with the treatment process, and no significant side effects were reported. CONCLUSION Acupuncture may play a beneficial role for patients with GD when used in conjunction with conventional therapy, reducing fatigue and improving physical function. The preliminary finding of this observational study should encourage further research.