The musculoskeletal manifestations of Gaucher's disease
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1 The musculoskeletal manifestations of Gaucher's disease Poster No.: C-2179 Congress: ECR 2010 Type: Educational Exhibit Topic: Musculoskeletal Authors: S. M. M. McDonald, M. A. Hopper, P. W. P. Bearcroft; Cambridge/ UK Keywords: Gaucher's disease, Skeletal, Imaging DOI: /ecr2010/C-2179 Any information contained in this pdf file is automatically generated from digital material submitted to EPOS by third parties in the form of scientific presentations. References to any names, marks, products, or services of third parties or hypertext links to thirdparty sites or information are provided solely as a convenience to you and do not in any way constitute or imply ECR's endorsement, sponsorship or recommendation of the third party, information, product or service. ECR is not responsible for the content of these pages and does not make any representations regarding the content or accuracy of material in this file. As per copyright regulations, any unauthorised use of the material or parts thereof as well as commercial reproduction or multiple distribution by any traditional or electronically based reproduction/publication method ist strictly prohibited. You agree to defend, indemnify, and hold ECR harmless from and against any and all claims, damages, costs, and expenses, including attorneys' fees, arising from or related to your use of these pages. Please note: Links to movies, ppt slideshows and any other multimedia files are not available in the pdf version of presentations. Page 1 of 33
2 Learning objectives To review the characteristic musculoskeletal manifestations of Gaucher's disease and illustrate the role of MRI in assessing the common skeletal complications of this multisystem disease. Images for this section: Page 2 of 33
3 Fig. 1: Coronal T1w image illustrating common skeletal features in Gaucher's disease: undertubulation of the distal femora, leading to an Erlenmeyer flask deformity, bilateral medullary osteonecrosis and modelling deformity of the femoral heads due to previous avascular necrosis. Page 3 of 33
4 Background Gaucher's disease is an uncommon autosomal recessive multisystem disease characterised as a lipid lysosomal storage disorder. Pathophysiology A genetic fault in the production of a specific enzyme, #-glucosidase, results in an accumulation of a particular lipid, glucosylceramide, inside the cells of the reticuloendothelial system, predominantly within the liver, spleen and bone marrow. The deposition of abnormal lipid within the lysosomes of reticuloendothelial cells impairs the usual processes of programmed cell death, resulting in immortal "Gaucher" cells that progressively enlarge the liver and spleen (fig. 1) and replace normal bone marrow. Clinical Presentation Three clinical subtypes of the disease are recognised, broadly distinguished by the degree of involvement of the neurological system, age of onset and severity of symptoms. The most common form is type 1, which is a slowly progressive, non-neuronopathic form which usually presents in adolescence or young adulthood. Within this population, skeletal complications account for the majority of disease morbidity (fig. 2). The disease affects individuals of all ethnicities, in part due to a high rate of spontaneous mutation, although there is a much higher prevalance in certain ethnic groups, such as those of Ashkenazi Jewish and Norrbottnian Swedish descent. Clinical Management Current therapy is based on the administration of recombinant macrophage targeted #glucosidase, which has been shown to slow, or even reverse, the otherwise progressive proliferation of Gaucher cells. Imaging, predominantly with MRI, has a key role in assessing the skeletal burden of disease, evaluating the response to treatment and identifying musculoskeletal complications (fig. 3). Page 4 of 33
5 Images for this section: Page 5 of 33
6 Fig. 1: Axial T2w image of a Gaucher's patient with hepatosplenomegaly: liver volume 2.58 litres, splenic volume 1.7 litres. Page 6 of 33
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8 Fig. 2: Skeletal complications account for much of the morbidity in the most common form of Gaucher's disease. This sagittal T1w image shows almost complete vertebral collapse of L1 with consequent kyphosis. There are multiple end plate infarctions elsewhere, resulting in a "H" vertebrae appearance at these levels. Page 8 of 33
9 Fig. 3: Coronal T1w image illustrating common skeletal features in Gaucher's disease: undertubulation of the distal femora, leading to an Erlenmeyer flask deformity, bilateral medullary osteonecrosis and modelling deformity of the femoral heads due to previous avascular necrosis. Page 9 of 33
10 Imaging findings OR Procedure details The majority of patients with Gaucher's disease will have radiological evidence of skeletal abnormality. Although the pattern of skeletal disease may vary greatly between individuals, a number of diffuse and focal abnormalities are commonly observed: Diffuse Diffuse marrow replacement Modelling deformities Osteopenia / Osteoporosis Focal Fracture Medullary osteonecrosis Avascular necrosis Focal expanded lytic lesions Osteomyelitis Diffuse skeletal abnormalities Diffuse abnormalities are common in Gaucher's disease. Marrow replacement, osteopenia and modelling deformities (characteristically metaphyseal undertubulation) are potentially reversible with treatment. Marrow replacement Pattern and Distribution Reversibility and treatment response Pattern and Distribution The replacement of normal bone marrow by abnormal Gaucher cells occurs in a characteristic and predictable pattern, with initial involvement of the axial skeleton (figure 1) followed by centrifugal involvement of the appendicular skeleton. It is not incidental that this pattern is the reverse of the typical sequence of developmental conversion of red to yellow marrow, as abnormal lipid accumulation affects the bone marrow in proportion to the local concentration of haematopoietically active red marrow. Thus, the humerus and femur are involved to a greater extent than the distal appendicular skeleton, and the proximal portions of the long bones are involved more, or earlier, than the distal portions. Page 10 of 33
11 There is sparing of the epiphyses until very late in the disease process (figure 2), which mirrors the early developmental conversion from red to yellow marrow that occurs at these sites. Reversibility and Treatment Response The progressive replacement of normal marrow elements by Gaucher cells may be slowed, arrested or reversed by enzyme therapy. Effective treatment can improve skeletal symptoms and reduce the incidence of focal skeletal complications. In addition, changes in bone marrow burden correlate well with changes in splenic volume, which is a well accepted marker of the severity of systemic disease. Appropriate and reproducible imaging of bone marrow burden is therefore an important measure of the severity of both skeletal and systemic disease, whilst serial imaging allows an assessment of treatment response. An assessment of treatment response is extremely important in Gaucher's disease due to the great expense of recombinant enzyme therapy, which renders careful dosage adjustment particularly necessary. Response can be assessed by serial measurement of vertebral body fat fraction on MRI, using the Dixon quantative chemical shift technique. However, although this method is well validated and sensitive, it requires special protocols and is not available on all MR systems. As a validated alternative, semiquantative bone marrow burden scores can be recorded using standard MR protocols, and used to assess treatment response. Modelling deformities Bone modelling occurs prior to physeal closure, in contrast to bone remodelling, which occurs throughout life. Modelling results in the characteristic appearance of individual bones, and reflects a complex balance of osteoblastic and osteoclastic activity. Osteoclast function in Gaucher's disease is impaired, resulting in undertubulation of the metaphyses. It is undertubulation of the femoral distal metaphysis that accounts for the Erlenmeyer flask deformity that is characteristic of, though not specific for, Gaucher's disease (figure 3). Undertubulation of the proximal humeral metaphysis is also frequently observed. Generalised osteopenia/ osteoporosis Page 11 of 33
12 Generalised reduction in bone density is a common feature in Gaucher's disease, which may be ameliorated by enzyme therapy. Primary or secondary fracture prevention with bisphosphonates may be necessary. Focal Skeletal Abnormalities Fracture Osteonecrosis Focal lytic lesions Osteomyelitis Fracture Generalised reduction in bone density results in a high incidence of pathological fracture (figure 4). Impaired osteoclast function in Gaucher's disease leads to poor bone remodelling following fracture and a propensity to non-union (figure 5). Osteonecrosis Osteonecrosis is a very common feature in Gaucher's disease, encompassing both medullary infarction (figure 6) and avascular necrosis of articular bone (figures 7 & 8). Multiple areas of medullary osteonecrosis are common (figures 9 & 10), in which case the frequency and distribution of infarcts reflects the usual pattern of bone marrow replacement: predominant involvement of the axial and proximal appendicular skeleton, along with epiphyseal sparing (figure 11). Avascular necrosis most frequently affects the femoral heads (figure 12), often leading to subchondral collapse, femoral head remodelling and, potentially, joint replacement. Focal lytic lesions Localised proliferation of Gaucher cells in the bone marrow causes focal medullary expansion and cortical thinning, ultimately resulting in discrete, expanded, lytic lesions known as "Gauchomas" (figures 13 & 14) Osteomyelitis Page 12 of 33
13 Individuals with Gaucher's disease are more susceptible to infection due to the pancytopenia that commonly exists as a consequence of marrow replacement and hypersplenism. In addition, focal abnormalities of bone, such as an ununited fracture, serve as potential foci for deep infection. The appearances of infection in Gaucher's disease are the same as those of osteomyelitis in normal individuals, although the context of Gaucher's disease may increase the radiological index of suspicion for infection in appropriate cases. Images for this section: Page 13 of 33
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15 Fig. 1: Sagittal T1w image showing heterogenous vertebral bone marrow signal due to replacement of normal bone marrow by proliferating Gaucher cells. There are multiple end plate infarcts. Fig. 2: Coronal T1w image. There is severe confluent medullary osteonecrosis within both femora, and less severe osteonecrosis within the tibial diametaphysis bilaterally. The epiphyses are spared, with an abrupt transition between normal and abnormal bone occurring at the physeal scar. This reflects the typical pattern of marrow replacement in Gaucher's disease, in which the epiphyses are only affected late in the disease process. Page 15 of 33
16 Fig. 3: Coronal T1w image showing a bilateral Erlenmeyer flask deformity of the distal femora. This deformity results from undertubulation of the long bones, though to be secondary to deficient osteoclast function and impaired bone resorption during skeletal development. Page 16 of 33
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18 Fig. 4: Sagittal T1w image showing almost complete vertebral collapse of L1 with consequent kyphosis. There are multiple end plate infarctions elsewhere, resulting in a "H" vertebrae appearance at these levels. Fig. 5: Coronal T1w image showing bilateral ununited proximal femoral fractures. Fractures are common in Gaucher's disease, reflecting the generalised osteopenia that accompanies the condition. There is an increased risk of fracture non-union due to impaired osteoclast function. Note the focal "Gauchoma" centered on the right iliac wing. Page 18 of 33
19 Fig. 6: Axial STIR image showing bilateral iliac medullary osteonecrosis. Page 19 of 33
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21 Fig. 7: Coronal T1w image showing heterogenously reduced signal within the distal femur and proximal tibia due to yellow marrow replacement by proliferating Gaucher cells. There is medullary osteonecrosis and severe avascular necrosis, which has led to collapse of the articular surface of the tibia. Fig. 8: Bilateral avascular necrosis of the femoral heads is a common complication of Gaucher's disease. Page 21 of 33
22 Fig. 9: Sagittal fat saturated proton density image of the knee showing striking geographical areas of signal abnormality within the femur, tibia and patella, indicative of active osteonecrosis. Page 22 of 33
23 Fig. 10: Sagittal fat saturated T2w image showing medullary osteonecrosis within the distal femur and the proximal tibia. There is increased signal around the tibial lesion on the fluid sensitive sequence, suggesting that the tibial focus is either active or recent. Page 23 of 33
24 Fig. 11: Coronal fat saturated proton density image showing bilateral medullary osteonecrosis, both above and below the knee. Typically, the proximal long bones are most affected, reflecting the centrifugal pattern of marrow replacement in Gaucher's disease. Page 24 of 33
25 Fig. 12: Coronal T1w image showing bilateral avascular necrosis of the femoral heads. On the right, there has been marked subchondral collapse and pathological remodelling of the femoral head. Page 25 of 33
26 Fig. 13: The hands in Gaucher's disease. There is medullary expansion of the metacarpals due to marrow infiltration and a focal lucency within the right middle finger metacarpal signifying localised accumulation of Gaucher cells. Note the ununited left distal radius and ulna fracture. Page 26 of 33
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28 Fig. 14: Coronal T1W image of a Gauchoma. The distal femur is markedly expanded due to a localised proliferation of Gaucher cells Page 28 of 33
29 Conclusion Skeletal complications account for much of the chronic morbidity in the most common form of Gaucher's disease. Timely and appropriate imaging, predominantly with MRI, permits accurate evaluation of the extent of skeletal disease and reproducible assessment of the marrow response to enzyme treatment. MRI is also the most appropriate method of assessing common focal complications of the disease, such as osteonecrosis, fracture and infection. Images for this section: Page 29 of 33
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31 Fig. 1: Skeletal complications account for much of the morbidity in the most common form of Gaucher's disease. This sagittal T1w image shows almost complete vertebral collapse of L1 with consequent kyphosis. There are multiple end plate infarctions elsewhere, resulting in a "H" vertebrae appearance at these levels. Fig. 2: Coronal T1w image showing bilateral medullary osteonecrosis, both above and below the knee. Typically, the proximal long bones are most affected, reflecting the centrifugal pattern of marrow replacement in Gaucher's disease. MRI is the most useful method of assessing the skeletal complications of Gaucher's disease. Page 31 of 33
32 Personal Information S.M.M McDonald, M.A. Hopper, P.W.P. Bearcroft, Department of Radiology, Addenbrooke's Hospital, Hills Road, Cambridge, UK References Henry J Mankin, Daniel I Rosenthal, Ramnik Xavier, Current Concepts in Gaucher Disease, New Approaches to an An Ancient Disease, Journal of Bone & Joint Surgery, Volume 83-A, No. 5, May 2001 Mario Maas, Cornelis van Kuijk, Jaap Stoker, Carla E.M. Hollak, Erik M. Akkerman, Johannes F.M.G Aerts, Gerard J den Heeten, Quantification of Bone Involvement in Gaucher Disease: MR Imaging Bone Marrow Burden Score as an Alternative to Dixon Quantitative Chemical Shift MR Imaging - Initial Experience, Radiology, Volume 229, No. 2, pp M Maas, L W Poll, M R Terk, Imaging and quantifying skeletal involvement in Gaucher disease, British Journal of Radiology, 75 (Suppl. 1) (2002), A13-A24 L W Poll, M Maas, M R Terk, M Roca-Espiau, B Bembi, G Ciana, N J Weinreb, Response of Gaucher bone disease to enzyme replacement therapy, British Journal of Radiology, 75 (Suppl. 1) (2002), A25-A36 Robert F. DeMayo, Andrew H. Haims, Matthew C. McRae, Ruhua Yang, Pramod K. Mistry, Correlation of MRI-Based Bone Marrow Burden Score with Genotype and Spleen Status in Gaucher's Disease, American Journal of Roentgenology, Volume 191, July 2008, pp M Maas, L W Poll, M R Terk, Imaging and quantifying skeletal involvement in Gaucher disease, British Journal of Radiology, 75 (Suppl. 1) (2002), A13-A24 R J Wenstrup, M Roca-Espiau, N J Weinreb, B Bembi, Skeletal aspects of Gaucher disease: a review, British Journal of Radiology, 75 (Suppl. 1) (2002), A2-A12 Page 32 of 33
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