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Neuroradiology Case of the Week

Case 292

Justin Brucker, CC4

Clinical Presentation: Patient is a 42-year old woman who presents with otalgia, dysphagia, cough and headache.

Imaging Findings: The frontal bone demonstrates diffuse thickening of the calvarium with sclerotic and lytic bone changes (Figs. 1&2). There are no orbital deformities and the paranasal sinuses are clear. No intracranial abnormalities are found.

Diagnosis: Paget's disease of bone

Discussion: Paget's disease of bone (osteitis deformans) is a skeletal remodeling disorder, characterized by continuously rapid bone turnover (20 times normal rate [5]). Focal lesions may only involve one site (monostotic), though roughly 60-90% of Paget's cases are polyostotic [5,6]. There is a predilection for occurrence within the axial skeleton, particularly in the lower limb girdle. In descending order, the locations of highest incidence are: pelvis, lumbar spine, femur, thoracic spine, skull, tibia, humerus/shoulder, cervical spine, and ribs [1,5]. Within the skull, the calvaria (followed by the maxilla and mandible) is most frequently affected [6].
     Most patients with Paget's disease are over 50 years old and of Anglo-Saxon descent [3]; disease occurs in 3-5% of patients over 40 and 10-11% of patients over 80 [2,5,6]. Sex distribution is approximately equal [2,5], with a small predominance in males [3]. It has been estimated that 3% of the general population has Paget's disease [5], but this is difficult to confirm since most cases are asymptomatic (70%) and discovered incidentally.
     Symptomatic bone lesions are characterized by pain and deformity on clinical exam. Advanced disease may present with bowed tibias, leonized facies, arthritis, fractures, and in the case of cranial involvement, severe neurologic sequelae. Specific outcomes are location-dependent (cranial nerve palsies/neuralgia, visual changes, conductive/sensorineural hearing loss, altered mental status, ataxia, hydrocephalus, sensorimotor deficits, etc.) and may require neurosurgical intervention [4]. Hypertension, aortic stenosis, cardiac disease, and hyperparathyroidism may also occur with Paget's disease [2,4]. Less than 1% of cases transform into a malignancy (usually osteosarcoma).
     The putative agents in Paget's disease are hyperactive osteoclasts, which demonstrate increased sensitivity (10-100 fold) to activation signals as well as atypical morphology [3]. The underlying cause is thought to be both genetic and environmental, since familial cases of Paget's disease (autosomal dominant) only show incomplete penetrance. A first-degree relative with Paget's disease is found for 15-40% of affected individuals [3], and increases one's risk of being affected 7-10 fold [2]. Several gene mutations (on chromosomes 2, 5, 6, 10, and 18) have been discovered to cause Paget's, one of the most well-known being SQSTM1 (30% of cases), which encodes for a ubiquitin-associated protein that plays a key role in the osteoclast activation pathway [2,3]. The nuclei of these osteoclasts are often found to contain viral proteins, suggesting that chronic infection of myelogenous precursor cells may contribute to osteitis deformans. Although no whole virus has ever been recovered from these cells, the Paramyxoviridae family (measles and canine distemper virus) is recognized as a key player in the pathogenesis [3].
     Paget's disease is thought to progress through three phases: (1) the lytic phase, comprised of rapid bone resorption (by atypical osteoclasts) and robust vascularization; (2) a mixed phase, marked by advancing deposition of disorganized bone matrix ("mosaic") by reactive osteoblasts; and (3) the late sclerosing phase, when the soft, thickened bone is eventually replaced by denser, yet still weak, material with poor corticomedullary differentiation [2-6]. The osteoblasts involved in the latter two phases are largely unremarkable, but as it is with normal bone, their functioning is tightly coupled to osteoclastic activity. Thus, the chaotic bone deposition is driven by the unusually rapid bone resorption.
     Due to the high vascularity and metabolic activity within these lesions, bone scans are sensitive and useful tests for determining the distribution of disease. Care must be taken to distinguish these results from malignancy and infection. Plain films offer more specificity and pathognomonic radiologic findings: In the lytic phase, you may see a wedge-shaped "flame" lesion in the long bones, or "osteoporosis circumscripta" (a well-defined, round, lytic lesion that extends across the cranial sutures). During the mixed phase, the thickened lytic/sclerotic bone matrix may give a "cotton-wool" appearance to the calvarium. If the basilar bones are significantly more ossified than the rest of the skull, you might even see a "head within a head" sign (basilar skull dome shows up within the calvarial dome) later in the disease progression. Generally, CT and MRI are not necessary, although the former will certainly reveal the same characteristically disorganized bone architecture [5]. MR will usually visualize bone as a mixed, low-intermediate signal with non-homogeneous enhancement on all sequences. Foci of sclerotic bone might be seen as round foci of hypointensity. The abundant fat/blood content of the marrow, however, will show up as highly intense on T1W images and moderately intense on T2W images, against an intermediate background [6].
     In addition to history, clinical exam, and radiologic findings, serum and urine chemistries can help establish a diagnosis. An elevated serum alkaline phosphatase (125-150% normal, in the context of a normal 25-hydroxy vitamin D level) and urinary pyridinoline or hydroxyproline are indicative of increased bone deposition and resorption, respectively [2,5]. Calcium and phosphate levels are usually normal, but fractures and primary hyperparathyroidism may lead to increased calcium values.
     Bisphosphonates, the treatment of choice, inhibit osteoclast activity and can retard disease progression for months or years (70% have 50% drop in biochemical markers) [5]. Salmon calcitonin has similar effects, but it does not demonstrate the same potency or lasting benefits. Since these drugs stimulate bone reuptake, calcium and vitamin D supplementation should be taken concurrently. Pain management should also be emphasized in symptomatic patients. Surgical interventions are only warranted in cases of fracture, malignancy, deformity, and severe functional impairments.

References:

1. Guyer PB, Chamberlain AT, Ackery DM, Rolfe EB. The anatomic distribution of osteitis deformans. Clin Orthop Relat Res. 1981 May;(156):141-4. [Medline]
2. Kelepouris N. Clinical manifestations and diagnosis of Paget's disease of bone. UptoDate. February 15, 2007. http://patients.uptodate.com/topic.asp?file=othrheum/2448
3. Roodman GD, Windle JJ. Paget disease of bone. J Clin Invest. 2005 Feb;115(2):200-8. [Medline]
4. Schmidek HH. Neurologic and neurosurgical sequelae of Paget's disease of bone. Clin Orthop Relat Res. 1977;(127):70-7. [Medline]
5. Schneider D, Hofmann MT, Peterson JA. Diagnosis and treatment of Paget's disease of bone. Am Fam Physician. 2002 May 15;65(10):2069-72. [Medline]
6. Som P. Head and Neck Imaging, 4th ed. Mosby. 2003; Vol. 1: 338-339.