Subacute Osteomyelitis

IntroductionSubacute osteomyelitis is a distinct form of osteomyelitis, and Brodie abscess is one type of subacute osteomyelitis. Subacute osteomyelitis is difficult to diagnose because the characteristic signs and symptoms of the acute form of the disease are absent.1,2,3 The disease has an insidious onset, mild symptoms, and lacks a systemic reaction, and supportive laboratory data are inconsistent. Subacute osteomyelitis may mimic various benign and malignant conditions, resulting in delayed diagnosis and treatment. The most frequently made incorrect diagnosis is that of tumor.1,4,5 In noncontemporary literature, Brodie abscess was referred to as a chronic form of osteomyelitis; however, in almost all contemporary literature references, Brodie abscess is referred to as the most common type of the subacute form of osteomyelitis. For excellent patient education resources, visit eMedicine's Cancer and Tumors Center and Cancer Screening Center. Also, see eMedicine's patient education articles Bone Marrow Biopsy and Cancer: What You Need to Know.

History of the ProcedureSir Benjamin Brodie, a surgeon in St. George's Hospital, London, United Kingdom, first described subacute osteomyelitis in 1832.6 He amputated the leg of a man who had intractable pain for a number of years. On examination of the amputated limb, Brodie found a cavity the size of a walnut filled with dark-colored pus. The bone immediately surrounding the cavity was whiter and harder than the surrounding bone. The inner surface of the cavity appeared to be highly vascular.6 Since then, low-grade pyogenic abscesses of the bone have frequently been referred to as Brodie abscesses. In 1951, Wiles referred to Brodie abscesses as a particular form of chronic osteomyelitis that follows an acute attack, when the virulence of the organism and the resistance of the patient are evenly balanced.7 Little discussion exists in the literature again until Harris and Kirkaldy-Willis described primary subacute osteomyelitis8 ; they were the first to publish a radiograph that demonstrated an abscess of subacute osteomyelitis crossing the epiphyseal plate of the distal tibia. Based on their experience in East Africa, Harris and Kirkaldy-Willis classified primary subacute osteomyelitis, into 2 types, depending on whether a bone abscess is present or not, with the first type being metaphyseal and the second type diaphyseal. Subsequently in 1973, Gledhill proposed a radiologic classification for primary subacute osteomyelitis that consisted of 4 types based on his review of 8 patients, as follows9 :

Type I Solitary lesion with surrounding sclerosis, classic Brodie abscess Type II Metaphyseal radiolucent lesion with an associated loss of cortical bone Type III Diaphyseal cortical hyperostosis without onion-skinning Type IV Diaphyseal lesions associated with onionskin layering

In 1982, Roberts et al modified and expanded Gledhill's classification to 6 forms based on morphology, location, and similarity to neoplasms, as follows10 (see image below):

Modified classification of subacute osteomyelitis. Type I is metaphyseal. Type Ia is a punched-out central metaphyseal lesion. Type Ib is an eccentric metaphyseal cortical erosion. Type II is diaphyseal. Type IIa is a localized cortical and periosteal reaction. Type IIb is a medullary abscess in the diaphysis without cortical destruction but with onionskin periosteal reaction. Type III is epiphyseal. Type IIIa is a primary epiphyseal osteomyelitis. Type IIIb is a lesion that crosses the epiphysis and involves both the epiphysis and the metaphysis. Type IV is a metaphyseal equivalent. Type IVa involves the vertebral body with an erosive or destructive process. Type IVb involves the flat bones of the pelvis. Type IVc involves the small bones, such as the tarsal bones.

Type Ia lesions present as a punched-out radiolucency that is often suggestive of eosinophilic granuloma (see images below). Type Ib lesions are similar to type Ia lesions but have a sclerotic margin and appear as a classic Brodie abscess.

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Anteroposterior radiograph of the distal radius. This image depicts a central metaphyseal lesion (punched-out radiolucency), type Ia.

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Lateral radiograph of the distal radius. This image depicts a central metaphyseal lesion (punched-out radiolucency), type Ia.

Type II lesions erode the metaphyseal cortex and may appear similar to osteogenic sarcoma (see images below).

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Anteroposterior radiograph of the left tibia. This image depicts periosteal reaction of the diaphyseal cortex, type IIb.

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Lateral radiograph of the left tibia. This image depicts periosteal reaction of the diaphyseal cortex, type IIb.

Type III lesions are observed as a localized diaphyseal cortical and periosteal reaction simulating osteoid osteoma (see images below).

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Anteroposterior and lateral radiographs of the distal femur. These images depict a type IIIa epiphyseal lesion.

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Anteroposterior radiograph of the distal tibia. This image depicts an eccentrically located radiolucent lesion crossing the epiphyseal plate, type IIIb.

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Lateral radiograph of the distal tibia. This image depicts an eccentrically located radiolucent lesion crossing the epiphyseal plate, type IIIb.

Type IV diaphyseal lesions most often resemble Ewing sarcoma, with onionskin periosteal reaction (see images below).

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Lateral radiograph of the lumbosacral spine. This image depicts destruction of bone and disc space, type IVa.

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Computed tomography scan cut of the right lower extremity. This image depicts a sclerotic lesion of the right iliac bone, type IVb.

Type V lesions occur in the epiphysis and appear as a concentric radiolucency. Type VI lesions involve the vertebral body with an erosive or destructive process.

This classification system is the most widely used in the literature, and several reports advocate modifying the classification system to include flat bone involvement, tarsal bones, and lesions affecting both the metaphysis and the epiphysis. Some authors have modified the Roberts's classification system (see Introduction, Clinical, below). In all reported series of primary subacute osteomyelitis, the classic Brodie abscess (central metaphyseal lesion with well-defined sclerotic margins, type Ia according to the authors' new classification system) has comprised the largest number of cases.

ProblemSubacute osteomyelitis is characterized by mild to moderate pain, usually described as a persistent ache; intermittent symptoms; insidious onset; and, often, a long delay between the onset of pain (the most common presenting symptom) and the diagnosis. Usually, symptoms are present for 2 weeks or longer. The course is generally marked by few or no constitutional symptoms and no known previous acute disease.

FrequencyThe incidence of subacute osteomyelitis has increased since antibiotics have been used to treat osteomyelitis. The disease reportedly accounts for 8.8%,11 35%,12 and 42%13 of primary bone infections, although a report by Blyth et al indicates a mild decline in the incidence of both acute and subacute osteomyelitis, with greater decline in the acute form than in the subacute form.14 In East Africa, subacute osteomyelitis is the most common form of osteomyelitis. Onset of subacute osteomyelitis tends to occur in slightly older children than the onset of acute osteomyelitis. Subacute osteomyelitis has been reported in patients as young as 6 months and as old as 39 years, but the common age range is 2-15 years. Sex ratios vary, but in general, males are affected slightly more often than are females.

EtiologySubacute osteomyelitis is one of the many clinical presentations of hematogenous osteomyelitis. The organisms reach the bone from a disrupted site elsewhere in the body that may pose little or no threat of its own accord (eg, skin pustule, furuncles, impetigo, infected blisters and burns). Infection has even been suggested to be the outcome of common events such as normally harmless daily teeth brushing. Factors that may influence the behavior of a septic process in bone may relate to host resistance, virulence of the infecting organism, and adequacy of antibiotic therapy. Moreover, subacute osteomyelitis appears to depend on the interplay between the infecting bacteria and the immune mechanism of the host. True primary subacute osteomyelitis represents a favorable host-pathogen response. In East Africa, where subacute osteomyelitis is the most common form of osteomyelitis, children in bare feet have frequent foot infections and develop a high resistance to staphylococcal infections (the most common causative organism), as pointed out by Harris and Kirkaldy-Willis.8 That trauma results in vascular injury and an area of hypoxia in the metaphyseal region of bone is an attractive theory, but it is difficult to prove as an inciting cause of subacute osteomyelitis. When

the host resistance is insufficient to overwhelm the infection, it is conceivable that subacute osteomyelitis may develop. The pyogenic organisms' initial attack is presumed to be controlled by the host, and presumably, spread to large areas of cancellous tissue or to the subperiosteal region has not occurred. A central area of suppurative necrosis in the metaphyseal region becomes enclosed by a wall of fibrous tissue and granulations, the offending organisms are destroyed, and the pus is usually sterile. The circulation of the epiphysis predisposes to sluggish blood flow through the vascular loops. Possibly, the rich supply of the reticuloendothelial cells located in the epiphysis attenuates the osteomyelitis, leading to the subacute course in this region. The metaphyseal-equivalent regions are defined as the portion of a flat or irregular bone that borders cartilage (apophyseal growth plates, articular cartilage, or fibrocartilage), such as the pelvis, the vertebrae, the clavicle, and the small bones (tarsal bones).15 The vascular anatomy and the mechanism of seeding are analogous to those found in the metaphysis of long bones.

PathophysiologySite of infection Subacute osteomyelitis occurs in a much wider variety of bones than does the acute type, and the disease occurs at various sites within the affected bones. The lower limb is affected much more often than the upper limb, and the tibia is affected relatively more often than is the femur. Subacute osteomyelitis may involve only the epiphysis, which is contrary to the belief that primary bone infection does not occur in the epiphysis (see image below).


The diaphysis is occasionally affected (see first 2 images below), although this occurs more often in adults than in children; the most commonly affected site is the metaphysis (see last 2 images below).





Communication of the lesion between the metaphysis and the epiphysis is also common (see images below).



Other sites in which subacute osteomyelitis is frequently reported are metaphyseal-equivalent locations, such as the pelvis, the vertebrae, the calcaneum, the clavicle, and the talus. When subacute osteomyelitis occurs in tarsal bones, it usually occurs in the subchondral part or on the

border of the apophysis of the calcaneus. Subacute lesions of the spine occur more often in adults than in children (see image below).


When subacute osteomyelitis occurs in the long bones of adults, the diaphysis is involved as often as is the metaphysis. The patella is rarely involved. Multifocal subacute osteomyelitis is a rare form of subacute osteomyelitis that was reported by Season and Miller and by Rasool.16,17 It is usually associated with a deficient immune system. Bacteriology The causative organism is usually coagulase-positive Staphylococcus (30-60%). Other organisms encountered are Streptococcus, Pseudomonas, Haemophilus influenzae (much less common after widespread vaccination), and coagulase-negative Staphylococcus. An increased prevalence of Kingella kingae, a gram-negative coccobacillus, was noted by Lundy and Kehl, mostly in children younger than 3 years as a cause of all types of osteoarticular infections, including subacute osteomyelitis.18 Patients with sickle cell anemia are predisposed to infections with Salmonella, whereas Pseudomonas aeruginosa is isolated from skeletally mature intravenous drug abusers. However, in almost 25-50% of cases of subacute osteomyelitis, no organism is cultured.

PresentationPresenting symptoms of subacute osteomyelitis include mild to moderate localized pain. Pain is the most consistent complaint in most patients, and it may at times become more intense or remit and is frequently exacerbated following a period of unusual activity. Night pain that is relieved with aspirin is frequently reported. Minimal loss of function is another common symptom (eg, limping in a patient with a lower limb lesion), with no history of systemic toxicity. On clinical examination, localized tenderness may only occasionally be associated with warmth, redness, and soft-tissue swelling with the involvement of subcutaneous bone. This finding seems to increase and subside with activity. Pain may occur with movement of the adjacent joint, and some joint effusion may be present, but the pain and effusion are usually mild. The surrounding muscles may occasionally demonstrate some wasting. Classification Ross and Cole categorized these lesions either as aggressive or as cavities in the area of the metaphysis and epiphysis.19 This categorization helps in the treatment plan, as aggressive lesions

should be treated surgically for diagnosis. Gledhill classified subacute osteomyelitis according to radiologic appearance,9 and this classification scheme has since been modified by Roberts et al.10 The classification scheme is useful for reporting the results of treatment according to the site but is not a prognosis or treatment plan. The authors have modified the latter as follows (see image below):

Modified classification of subacute osteomyelitis. Type I is metaphyseal. Type Ia is a punched-out central metaphyseal lesion. Type Ib is an eccentric metaphyseal cortical erosion. Type II is diaphyseal. Type IIa is a localized cortical and periosteal reaction. Type IIb is a medullary abscess in the diaphysis without cortical destruction but with onionskin periosteal reaction. Type III is epiphyseal. Type IIIa is a primary epiphyseal osteomyelitis. Type IIIb is a lesion that crosses the epiphysis and involves both the epiphysis and the metaphysis. Type IV is a metaphyseal equivalent. Type IVa involves the vertebral body with an erosive or destructive process. Type IVb involves the flat bones of the pelvis. Type IVc involves the small bones, such as the tarsal bones.

Type I is a metaphyseal lesion. o Type Ia is a central metaphyseal lesion that is seen as a punched-out radiolucency, often suggestive of Langerhans cell histiocytosis (see images below).



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Type Ib is a metaphyseal lesion eccentrically located with cortical erosion, which

may give the appearance of osteogenic sarcoma. Type II is a diaphyseal lesion. o Type IIa is a localized cortical and periosteal reaction that simulates osteoid

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osteoma. A type IIb lesion is a medullary abscess in the diaphysis without cortical destruction but with onionskin periosteal reaction that resembles Ewing sarcoma (see image below).


Type III is an epiphyseal lesion. o Type IIIa is a primary epiphyseal osteomyelitis and appears as a concentric radiolucency. This type is usually seen in children younger than 4-5 years (see image below).


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Type IIIb is a subacute infection that crosses the epiphysis and involves both the epiphysis and metaphysis (see images below).



A type IV lesion is a metaphyseal-equivalent lesion, which is defined as the portion of a flat or irregular bone that borders cartilage (apophyseal growth plates, articular cartilage, or fibrocartilage), such as the vertebrae, the pelvis, and small bones (eg, tarsal bones and clavicle).15 o Type IVa involves the vertebral body with an erosive or destructive process (see image below).


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Type IVb involves the flat bones of the pelvis and is mostly sclerotic, with neither erosion nor destructive processes. Ezra et al mentioned this type in 1993 and 1997 (see image below).20,21


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Type IVc involves the small bones (eg, tarsal bones, clavicle).

Duration of symptoms Because the symptoms of subacute osteomyelitis are vague, an accurate diagnosis is usually delayed. The bone lesion may also not be readily apparent on plain radiographs for some time.

The average duration of symptoms before diagnosis is 1-6 months, but symptoms may be present longer before the diagnosis. Differential diagnosis Osteomyelitis is a known mimic of various diseases, and subacute osteomyelitis is no exception, having all of the presenting signs and symptoms of many bone tumors, both benign and malignant. The variety of radiographic presentations of subacute osteomyelitis has been emphasized by Gledhill.9 The classic solitary lesion located in the metaphysis surrounded by reactive new bone presents little difficulty in diagnosis. However, extensive erosions of cortical bone, periosteal new bone formation, or both may add a more ominous dimension. Patients with subacute osteomyelitis may occasionally be initially diagnosed with Ewing sarcoma or osteogenic sarcoma. From these observations, the following lesions must be considered among the differential diagnosis of subacute osteomyelitis:

When the lesion is diaphyseal and associated with an onionskin periosteal reaction, it may be confused with Ewing sarcoma, Langerhans cell histiocytosis, or, much less likely, osteogenic sarcoma. When the lesion is epiphyseal, it may be confused with a chondroblastoma, fungal osteomyelitis, or tuberculous osteomyelitis, or with an aneurysmal bone cyst, pigmented villonodular synovitis (PVNS) erosions, giant cell tumor, or gout, depending upon the age of the patient. Metaphyseal eccentric lesions may be confused with the more common nonossifying fibroma, although, typically, the diagnosis of nonossifying fibroma is easily made, as is the diagnosis of chondromyxoid fibroma. Brodie abscesses, osteoid osteoma, and intracortical hemangioma should all be included in the differential diagnosis of an intracortical bone lesion.

IndicationsSubacute osteomyelitis treatment is controversial; however, in patients with characteristic clinical and imaging findings and laboratory results, treatment with antibiotics alone may be undertaken without biopsy, at least in the pediatric age group.3,19,21,22,23,24,25 In the literature, opinion differs as to whether treatment should be surgical or medical for these classic lesions. Failure of symptoms to resolve after an up to 6-week course of antibiotics or worsening of the condition during treatment should lead to reevaluation and a definite tissue and/or bacteriologic diagnosis, followed by surgical treatment and appropriate antibiotics. Other indications for surgery are impending sinus formation or drainage into a synovial joint. Clinical signs of subperiosteal pus or synovitis indicate that the subacute infection has transformed into an acute component, and it must be drained surgically.

Relevant AnatomyInterconnecting subacute osteomyelitis of the epiphysis and metaphysis is readily explainable in infants younger than 18 months, when one considers that vascular communication between the epiphysis and metaphysis is present until age 18 months, as described by Trueta.26 Epiphyseal lesions may also occur in older adolescents when the growth plate becomes attenuated and fails to provide a barrier to epiphyseal infection. Another interesting explanation for the localization of subacute osteomyelitis adjacent to the growth plate cartilage is the finding by Speers and Nade that S aureus has a certain affinity for physeal cartilage.27

The transgression of the epiphyseal plate from osteomyelitis foci has been well documented (see images below). A review of the literature indicates that despite localized transgression of the epiphyseal plate by subacute osteomyelitis, growth plate arrest, stimulation, or development of transepiphyseal bony bars is exceedingly rare.



ContraindicationsContraindications to medical treatment alone for subacute osteomyelitis include the following:

Failure of symptoms to resolve after an up to 6-week course of antibiotics or worsening of the condition during treatment Aggressive lesions (indistinguishable from malignant bone tumors) Impending sinus formation or drainage into a synovial joint Clinical signs of subperiosteal pus or synovitis

No literature exists to support medical treatment in adults, as subacute osteomyelitis mostly affects patients in the pediatric age group. Until medical treatment in adults is described, surgical treatment of subacute osteomyelitis is indicated. No true contraindications to surgical intervention exist, as medical treatment alone without biopsy or curettage is still controversial in the literature.

WorkupLaboratory StudiesThe laboratory workup of subacute osteomyelitis includes the following:

The white blood cell (WBC) count is usually within the reference ranges or occasionally slightly elevated, with a normal differential. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) measurements are usually mildly elevated, but they may be within the reference ranges in 30-50% of patients. Blood culture results are usually negative.

Imaging StudiesRadiologic findings o The various radiologic techniques involved in the diagnosis of subacute osteomyelitis are important and complementary, rather than competitive. Radiologic osseous changes are often present, even in patients with a short history of symptoms (at least >2 wk to fit the diagnosis). Typically, a localized destructive lesion of bone is present, with surrounding sclerosis in the metaphysis (see images below).



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In some cases, a similar lesion with no surrounding sclerosis may be present. The lesion may cross the epiphyseal plate to affect the epiphysis as well (see first 2 images below), or the lesion may affect the epiphysis alone, although the articular cartilage itself is unaffected (see third image below). Soft-tissue swelling overlying the lesion earlier in the course of the disease might be seen. A central bone density is occasionally seen in the presence of a sequestrum, which makes it difficult to differentiate subacute osteomyelitis from osteoid osteoma on plain films.




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On occasion, the lesion appears to become tethered to the growth plate, and the cavity progressively elongates, with growth extending from the epiphysis into the diaphysis in a snakelike fashion (the "serpentine sign" described by Letts.)11 (See images below).

Anteroposterior radiograph of the distal tibia. This image depicts an eccentrically located radiolucent lesion crossing the epiphyseal plate, demonstrating the serpentine sign.

Lateral radiograph of the distal tibia. This image depicts an eccentrically located radiolucent lesion crossing the epiphyseal plate, demonstrating the serpentine sign.

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In diaphyseal lesions, periosteal reaction may occur with a single layer or it may be laminated with or without bony destruction (see image below).


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In spinal lesions (which occur more often in adults than in children), radiographs may show signs of healing by the time the diagnosis is made (see image below). The principal feature that helps to distinguish subacute osteomyelitis from tuberculosis is sclerosis of the vertebral body with a variable degree of destruction of bone and disc space, associated with relatively early new bone formation in the form of bony bridging between adjacent vertebral bodies. A paravertebral abscess may be present, but it is usually much smaller than in tuberculosis infections.


Bone scanning o Findings on technetium (Tc) bone scans are often positive (see images below), but false-negative results or, less likely, false-positive results are also possible. In addition, bone scan findings are nonspecific, simply demonstrating an increased vascularity or metabolic activity within the bone on the delayed image. Close proximity of the focus of infection to the growth plate may render interpretation of bone scans difficult. The sensitivity and specificity of bone scanning have not been studied in subacute osteomyelitis, but they are better than 90% in cases of osteomyelitis of nonviolated bone when a 3-phase bone scan is performed.

Total body scan. This image shows increased radionuclide uptake at the distal left tibia.

Bone scan of both distal legs and feet. This image depicts increased radionuclide uptake at the distal left tibia.

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Because subacute osteomyelitis has such characteristic features on normal radiographic examination, bone scanning is seldom indicated unless the diagnosis is unclear and a bone scan is performed as part of a tumor workup. Also, bone scanning might be of help in delineating the rarely occurring multifocal subacute osteomyelitis. Gallium scans and scans with Indium 111 (111 In)labeled WBCs (WBC scan) have been used in conjunction with the Tc bone scan in the localization of infection, but they also remain nonspecific. Fractures and infarctions can lead to false-positive results with a WBC scan. In addition, these scans are more expensive, take longer to complete, and entail more radiation exposure (high absorbed radiation to the spleen and lymphocytes limit the injected dose in WBC scans) than Tc scans. Insufficient data exist regarding the specificity of the newer scintigraphic agents, Tc-99m (99m Tc) hexamethylpropyleneamine oxime (HMPAO)labeled leukocytes, and nonspecific polyclonal111 In-labeled immunoglobulin G (IgG). Although Roddie et al reported the use of99m Tc HMPAOWBCs in 20 patients with suspected osteomyelitis in general, with a reported sensitivity of 100% and specificity of 93%,28 the use of polyclonal human IgG is not approved in the US despite its use in some European countries. The advantages of polyclonal human IgG include the fact that it has a simple preparation procedure compared with that of111 Inlabeled WBCs, eliminates the need for phlebotomy and laborious labeling methods, and reduces the patient radiation dose. Infecton (Draximage Inc, Kirkland, Quebec, Canada) is another radiopharmaceutical, which is based on ciprofloxacin that is labeled with99m Tc. The sensitivity is reduced for microorganisms with membranes impermeable to ciprofloxacin, but this method allows better differentiation between infection and sterile inflammation. Infecton is not available in the US but it is used in some hospitals in Europe. In spinal infections, single photon emission (SPE) may reveal abnormalities not

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seen on the planar images. Degenerative disc disease is a cause of false-positive bone scan results. Gallium specificity is greater than 90% and is almost equivalent to magnetic resonance imaging (MRI) for spinal infections. WBC scanning, however, is not sensitive to vertebral osteomyelitis (40%). Computed tomography (CT) scanning o Broaching of the physis may not always be apparent on plain radiographs. It is more readily demonstrated by tomography or by CT.

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CT scanning is valuable in detecting lesions in difficult anatomic locations that could not be seen with plain radiographs, as in the pelvis and sacrum (see images below).


Computed tomography scan cut of the right sacrum. This image depicts a round radiolucent lesion with a sclerotic margin.

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CT scanning is also valuable in differentiating subacute osteomyelitis from osteoid osteoma. In osteoid osteoma, the nidus is central to the lesion, round, smooth, and well defined. In subacute osteomyelitis, a sequestrum, which is usually irregular and eccentric with respect to the radiolucent cavity, may occasionally be present.

MRI

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MRI is the most sensitive investigation in the evaluation of bone marrow pathology. Signal intensity is decreased on T1-weighted images of the lesion (see first image below), whereas signal intensity is increased on T2-weighted images (see second image below), with a rim of decreased intensity due to sclerotic bone.

Sagittal T1-weighted (time echo = 10 ms, time repetition = 400 ms) magnetic resonance image of the left ankle. This image depicts a well-defined lesion of decreased signal intensity in the anterior aspect of the distal tibial metaphysis, which extends into the adjacent growth plate and epiphysis.

Axial fast spin echo T2-weighted (time echo = 48 ms, time repetition = 2400 ms) magnetic resonance image through the distal left tibial metaphysis. This image depicts a welldefined lesion of increased signal intensity in the anterolateral aspect of the distal left tibial metaphysis with a rim of decreased signal intensity.

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A gadolinium-enhanced image depicts a well-circumscribed nonenhancing area with slight rim enhancement (see images below.)

Sagittal postgadolinium-enhanced T1-weighted (time echo = 10 ms, time repetition = 650 ms) magnetic resonance image with fat saturation. This image shows a hypodense lesion centrally (fluid) with a moderately thick enhancement, which extends through the growth plate into the epiphysis.

Coronal postgadolinium-enhanced T1-weighted (time echo = 10 ms, time repetition = 650 ms) magnetic resonance image with fat saturation. This image depicts a hypodense lesion centrally (fluid) with a moderately thick enhancement, which extends through the growth plate into the epiphysis.

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A characteristic but not pathognomonic MRI finding that supports the diagnosis of subacute osteomyelitis and helps to exclude the presence of a tumor is the penumbra sign, which was reported by Grey et al to have 75% sensitivity, 99% specificity, and 99% accuracy29 ; in their experience, the penumbra sign did not appear to occur with any great frequency in other osseous conditions. The penumbra sign is characteristically seen on T1-weighted MRIs (2- to 5-mm thickness) and is due to a thick layer of highly vascularized granulation tissue. (The presence of a layer of granulation tissue lining a cavity is important in the differentiation of an abscess from a tumor.) It is a discrete peripheral zone of marginally higher signal intensity than the abscess cavity and surrounding marrow edema/sclerosis and of

lower signal intensity than the fatty bone marrow. The hyperintensity may be due to the high protein content of the granulation tissue. A similar appearance has been described in the wall of brain abscesses. Gadolinium-based contrast agents (gadopentetate dimeglumine [Magnevist], gadobenate dimeglumine [MultiHance], gadodiamide [Omniscan], gadoversetamide [OptiMARK], and gadoteridol [ProHance]) have been linked to the development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). For more information, see the eMedicine topic Nephrogenic Fibrosing Dermopathy. NSF/NFD has occurred in patients with moderate to end-stage renal disease after being given a gadolinium-based contrast agent to enhance MRI or MRA scans. NSF/NFD is a debilitating and sometimes fatal disease. Characteristics include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the whites of the eyes; joint stiffness with trouble moving or straightening the arms, hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness. For more information, see the FDA Public Health Advisory or Medscape.

Diagnostic ProceduresFine needle aspirations (FNAs) of the subacute osteomyelitis abscess cavity do not usually allow isolation of the organism. Open drainage culture findings are positive in 5075% of patients. Whether the culture-negative abscesses are truly negative or whether they are caused by fastidious organisms remains to be investigated. K kingae, for example, is a relatively new pathogen that has appeared to replace the predominance H influenzae in children younger than 3 years and is known to have a tenuous nature that can make it difficult to isolate on cultures.18 For this reason, K kingae or other similar organisms may be the causative organisms associated with some cases of so called culture-negative osteomyelitis.

Histologic FindingsIn subacute osteomyelitis, the surrounding bone is usually sclerotic, but it is of variable thickness, most often thin rather than dense and thick. For most lesions, granulation tissue lines the abscess cavities, and the presence of fat, fibroblastic response (commonly, a fibrin layer separates bone from granulation tissue), remnant of necrotic bone, and new bone formation is seen. Inflammatory infiltration in the form of acute and chronic cells consisting of polymorphonuclear lymphocytes (PMLs), lymphocytes, and plasma cells are seen (see images below). Pus under pressure is rarely encountered. The fluid content of the cavity may be purulent, oily, or even mucoid.30 In diaphyseal lesions at operation, thickened periosteum with a thickened hard cortex without pus is usually encountered. The histologic appearance is usually that of subperiosteal new bone formation with inflammatory cells (plasma cells, fibroblasts, and PMLs) between the trabeculae of the medulla.

Histologic section of bone. This image depicts subacute osteomyelitis with a mixture of polymorphs and plasma cells in an edematous background. Hematoxylin, phloxine, and safranin (HPS) X 440.

Histologic section of bone. This image shows fibrosis, degenerating bone spicules, and subacute inflammation. Hematoxylin, phloxine, and safranin (HPS) X 10 X 1 X 5.

Histologic section of bone. This image depicts fibrosis, a mixture of plasma cells, and occasional polymorphs. Hematoxylin, phloxine, and safranin (HPS) X 25 X 1 X 5.

TreatmentMedical TherapyTreatment of subacute osteomyelitis depends on the diagnosis. Almost one third of cases (the group that was categorized by Ross and Cole as aggressive lesions19 ) are indistinguishable from primary malignant bone tumors. Biopsy and curettage are required for diagnosis in these cases. Once the diagnosis is established, appropriate antibiotics (with the dose adjusted according to the patient's weight and age) based on Gram stain, culture, and sensitivity results should be initially started intravenously for 2-7 days, followed generally by 6 weeks of oral antibiotics. (Consultation with pediatric or adult infectious diseases specialists is recommended for the appropriate antibiotic dose, route, and duration.) Clinical and laboratory (ESR and CRP) monitoring of clinical improvement is appropriate. Ezra et al reported their criteria for changing from intravenous to oral antibiotics to be marked cessation of pain, subsidence of swelling, and functional improvement.20

In cases in which clinical and imaging findings and laboratory results are characteristic (ie, the diagnosis is not uncertain), although controversial, treatment with antibiotics alone may be undertaken as suggested by Bogoch et al,22 Ross and Cole,19 Andrew and Porter,23 Martin,25 Hamdy et al,24 Ezra et al,20,21 and Gonzalez-Lopez et al.3 In the literature, opinion differs as to whether treatment for these classic lesions should be surgical or medical. Although most of the available pediatric orthopedic literature supports medical treatment, no literature regarding treatment in adults is available to support either medical or surgical treatment (apart from recommending biopsy); most orthopedic surgeons treating adults feel more comfortable with surgical treatment. Ross and Cole reported an 87% success rate and Ezra et al reported a 96% success rate with a single course of medical treatment.19,20 Hoffman et al found that medical treatment with only biopsy (no curettage) was successful in every case of diaphyseal subacute osteomyelitis they treated (biopsy was required to exclude malignancy).31 In another study, Ezra et al reported a 90% success rate in medically treating subacute osteomyelitis in tarsal bones.21 Failure of resolution of symptoms after a course of antibiotics of up to 6 weeks or worsening of the condition during treatment should lead to reevaluation and a definite tissue diagnosis, bacteriologic diagnosis, or both, followed by surgical treatment and appropriate antibiotics. Other indications for surgery are impending sinus formation or drainage into a synovial joint. Clinical signs of subperiosteal pus or synovitis indicate that the subacute infection has transformed into an acute component, and it must be drained surgically. If treating empirically, use a broadspectrum antibiotic that covers S aureus first and other pathogens secondarily. Coverage should be considered for H influenzae in young children who have not been immunized adequately. Antibiotics administered orally for osteomyelitis must be given in doses that often are 2-3 times that of those recommended in the agents' package inserts. Patient (or parent) education is essential to maintain the compliance that is required for successful treatment. Absorption of the antibiotic to produce effective concentrations at the site of infection is documented by measuring the concentration of the antibiotic or the antibacterial activity in serum.

Surgical TherapyIn case of the aggressive subacute osteomyelitis lesion which is indistinguishable from a tumor, open biopsy for culture and histology is indicated. Other lesions are incised and drained when indicated, the granulation tissue present in the lesion is curetted and cultured, and antibiotics are started immediately after biopsy. In pediatric patients with typical cavities in the metaphysis, the epiphysis, or in both, surgery is undertaken only for specific indications. When clinical signs of subperiosteal pus are present, incision and drainage is performed. When clinical signs of synovitis are present, with a possibility of pus within a joint, arthrotomy is performed and synovium is sent for culture and histology studies. If metaphyseal or epiphyseal cavities communicate with the joint they are curetted. Curettage of cavities is also indicated if the symptoms and signs of infection persist during conservative treatment or if they recur. Curettage of metaphyseal cavities should be carried out carefully, and perforations in the growth plate should not be curetted, because curettage of the metaphyseal lesion usually decompresses the epiphyseal lesion. Ross and Cole reported all epiphyseal cavities in their study healed with a single course of antibiotics and immobilization without operation.19 However, when drainage was indicated, the procedure was not performed through the growth plate. Green et al described curetting epiphyseal lesions after localization by inserting a needle into the epiphysis and obtaining 2 plane

radiographs, then making a 2- to 3-mm drill hole to avoid the weight-bearing or the articulating portion of the epiphysis.32 In the proximal femoral epiphysis, the drill hole has to be intracapsular as far distally as possible to avoid the portion of the femoral head that articulates with the acetabulum while avoiding the growth plate. In the distal femoral epiphysis, the drill hole also has to be intraarticular but avoid the weight-bearing articular surface coming medially or laterally. Diaphyseal lesions may be difficult to treat surgically. In patients with these lesions, the clinical picture is more likely to resemble a tumor, and a surgical biopsy is necessary for diagnosis, which should include adequate periosteum, cortical bone, and medullary tissue. These usually respond to adequate antibiotic therapy. In those cases with inadequate response to medical treatment, exposure of the whole length of the affected bone is indicated, with excision or exposure of all abscess cavities to remove dead bone. The wound is sutured primarily and antibiotics started.

Intraoperative DetailsIf surgery is undertaken for subacute osteomyelitis lesions that measure more than 3 cm or in cases in which bone is weak and subject to fracture, the cavity could be filled with bone graft or bone graft substitutes (either primary bone grafting,33 if the surgeon was happy about the total excision of the abscess cavity to eliminate the dead space, or, more appropriately, delaying bone grafting until the antibiotic treatment is completed and the infection is believed to have been eradicated based on clinical and laboratory results). Other options include the temporary use of antibiotic cement beads and the use of other alternatives to autologous bone graft, such as antibiotic-laden bone graft substitutes. A drain is generally indicated to avoid hematoma or seroma accumulation, which can lead to recurrent abscess.

Postoperative DetailsIn epiphyseal lesions especially, protection of the joints, either with traction or with splinting, and starting protected motion early is a consideration (with intermittent removal of the splint or traction for early range-of- motion exercises). Due to the proximity of the cavity to the articular surface and the risk of collapse, limitation of weight bearing is indicated until evidence of partial healing of the defect is seen on radiographs.

Follow-upFollow-up in cases of subacute of osteomyelitis should continue for at least 2 years. In the first week, closely monitor for signs of response to treatment (clinical and laboratory). Monitor for compliance with antibiotic therapy for 6 weeks. Clinical response is usually within a few days of initiation of treatment. In the first 6 months, monitor for signs of recurrence. Most recurrences occur within 6 months, but recurrence after up to 18 months has been reported. Radiologic healing is slower than clinical healing and usually occurs within 3-12 months. Metaphyseal and epiphyseal cavities usually disappear or heal, leaving either a small area of sclerosis or a small, indistinct lucency in the cortex. The purpose of follow-up after a year is mainly for assessment of bone growth and alignment, although physeal growth is very rarely affected.

ComplicationsIn pediatric cases of subacute osteomyelitis, 24% of infants younger than 1 year experience complications, compared with 8.5% of older children.13 In epiphyseal or epiphyseal-metaphyseal lesions, due to the proximity of the cavity to the articular surface, risk of collapse exists, as does

risk of pus discharge into the joint; Ross and Cole reported 2 such cases, one of the hip and one of the ankle joint.19 Effusions into the hip joint were also reported by Ross and Cole in 2 patients who had closed cavities in the femoral neck.19 Injury to the growth plate during surgical (curettage) treatment is also a possibility. In large lesions, especially the diaphyseal lesions, the involved bone might become weak and prone to fracture after surgical treatment. Ross and Cole reported recurrence in 3 of 32 patients.19 Ezra et al reported recurrence in 1 of 21 patients treated with antibiotics only20 ; all of their patients responded to curettage and antibiotics. Stephens and MacAuley reported that the age and sex of the patient, size of the abscess, and length of intravenous therapy did not influence the rate of recurrence, but they noted more recurrences in patients who were given a shorter course of antibiotics (2-3 wk) and in patients with an initial high ESR level (mean of 30 mm/h in the recurrence group compared with a mean of 8 mm/h in the group without recurrences).33 Although frequently located adjacent to the epiphyseal plate, subacute osteomyelitis rarely results in retardation or stimulation of growth, with Gonzalez-Lopez et al reporting a single case of 15-mm growth stimulation (these lesions are quiescent lesions and hyperemia is minimal)3 and Ross and Cole reporting a single case in a child with a metaphyseal and epiphyseal lesion of the proximal femur that resulted in growth retardation.19 Despite evidence of penetration of the physis by the abscess, growth impairment is extremely rare. Subacute abscesses that traverse the epiphyseal plate do so in only one small cross-sectional area, which may explain the absence of bony bridging. Growth disturbance, thus, seems unlikely based on all the recorded experience with this condition. That stated, Lindenbaum and Alexander reported a case with varus recurvatum deformity of the knee (a metaphyseal-epiphyseal lesion that was present for more than 3 years before treatment).5 Stephens and MacAuley reported coxa vara in 1 patient, mild shortening (7 mm and 15 mm) in 2 patients, and growth stimulation in 2 patients (7 mm and 10 mm).33

Outcome and PrognosisSubacute osteomyelitis is difficult to diagnose, but, once diagnosed, it is a curable disease with a 100% cure rate. Hamdy et al reported their results in treating 44 patients24 of which 24 were treated with antibiotics only, and 20 had surgical debridement followed by antibiotics. With the exception of 1 patient who received inadequate antibiotic therapy, all patients responded well, regardless of whether treatment was conservative or surgical. At an average follow-up of 18 months, no recurrences and no damage to the physis were reported.24 No good outcome studies have been reported as of yet, but from the available literature (apart from the previously mentioned rare complications), the outcome of subacute osteomyelitis is excellent, and full recovery is the rule in most cases.

Future and ControversiesSubacute osteomyelitis treatment remains controversial. Some investigators agree that a conservative course of antibiotic therapy is preferred. In lesions with an aggressive character in which a tumor cannot be excluded, surgery is indicated to establish the diagnosis. Diagnostic experience and awareness of the condition significantly reduce the indications for surgery from an approach in which biopsies are taken of all lesions, to an approach in which biopsies are taken of only selected lesions.

Development of molecular assays for the direct detection of microorganisms has been an actively growing specialty. Amplification techniques such as those using polymerase chain reaction (PCR) should provide increased sensitivity because of the extensive amplification of target nucleic acid to identify the RNA or DNA of viruses, bacteria, and other microorganisms in patients' blood. At present, however, these techniques are not widely available.

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Subacute Osteomyelitis