Autoimmune > Sarcoid

Sarcoidosis:

View cases of sarcoid

Clinical:

The specific etiology of sarcoidosis has not yet been identified, but it likely the result of an interaction between environmental exposures and genetic susceptibility initiating a cell-mediated immune response to as yet unidentified antigens [8,65]. Some authors suggest that propionibacteria and mycobacteria may be associated with the development of sarcoidosis [69]. Familial clustering has been reported in 4-17% of cases and there is a reported 80-fold increased risk of developing sarcoid in monozygotic twins (which supports genetic susceptibility) [65]. Thoracic sarcoidosis is a great mimic of other diseases including lymphoma, tuberculosis, and many causes of chronic pulmonary infiltrates. Sarcoid begins as an alveolitis/ non-granulomatous pneumonitis with a T-cell infiltrate. T-cells release factors which attract macrophages which in turn form giant cells and non-caseating granulomas within the interstitium. The end result is interstitial fibrosis [4].

To confirm the diagnosis, granulomas of known causes and sarcoid-like reactions must be excluded [32]. Granulomatous lesions may result from TB, berylliosis, leprosy, hypersensitivity pneumonitis, and fungal disease [32]. Local sarcoid-like reactions may be seen in lymph nodes that drain a neoplasm or a site of chronic inflammation [32].

Patients generally present between the age of 20 to 40 years. Blacks (African-Americans) are affected more than whites (3 to 15:1) and females more than males (for the black population [9]). First-degree relatives of patients with sarcoidosis are at an increased risk for the disease [68]. Sarcoid is rarely seen in Afrian and South American blacks [9]. Swedes and Danes also seem to have a high prevalence of disease [32]. The disorder is rare in children and when it occurs, usually affects white males. Familial disease is seen much more frequently in blacks (17% of cases) [8]. Sarcoid seems to have an earlier onset and more aggressive clinical course in blacks [8]. Smokers are not an an increased risk for sarcoid, and smoking may have an inverse relationship to the disorder [8]. The development of sarcoid has been seen in association with interferon therapy [16]. Up to 7% of patients receiving interferon may develop sarcoid [16]. Sarcoid associated with interferon therapy manifests mainly as pulmonary (76%) or cutaneous disease with a benign, uncomplicated evolution [31].

Most patients are asymptomatic (25-50%). Among those with symptoms, the most common are non productive cough, exertional dyspnea, and wheezing [54]. Other symptoms include insidious onset fatigue, low grade fever, and night sweats. Less commonly some patients have chest pain (9-19% of cases [69]) or discomfort [54]. Pulmonary function tests typically demonstrate a restrictive ventilatory defect with decreased vital capacity, FRC, and carbon monoxide diffusing capacity [32]. However, other authors indicate that PFT's can reveal either a restrictive or obstructive pattern- interstitial disease results in low lung complicance, while peribronchial lesions can obstruct small airways [9]. Lab analysis in patients with sarcoid reveals an elevated angiotensin converting enzyme (ACE) level in 56-67% of patients with stage I, 72-87% with stage II, and 56-95% of patients with stage III disease [4]. ACE levels may correlate with disease activity- ACE is a product of macrophages and is an indicator of granuloma burden in the body [9]. Other findings include anergy, peripheral lymphopenia (depressed cellular immunity), and hypergammaglobulinemia. Hypercalcemia/ hypercalciuria is found in 2-15% of patients and is secondary increased intestinal absorption of calcium [19]. This results from activated macrophages in sacroid granulomas which are extra-renal sources of 1,25-OH Vit. D. The Kveim-Siltzbach test is positive in 90% of patients with active disease.

A diagnosis of sarcoid is based on clinical and radiologic suspicion, tissue confirmation of noncaseating granulomas, and exclusion of other diseases such as TB, lymphoma, or malignancy [43]. The use of endosonographic nodal aspiration results in a greater diagnostic yield compared to conventional bronchoscopic biopsy (80-90% vs 53%, respectively) [43,54].  BAL fluid will show a CD4+/CD8+ lymphocyte ratio greater than 3.5 (specificity 94%, sensitivity 53% for the diagnosis of sarcoid) and a lymphocyte differential count of more than 15% (sensitivity as high as 90%) [54].

It is important to remember that sarcoid is a systemic process which can involve other organ systems (extra pulmonary manifestations are seen in 30-50% of cases [54]). Pulmonary involvement is found in 90% of patients and mediastinal adenopathy is the most frequent finding [19]. Pulmonary parenchymal involvement is found in about 20% of patients [19]. The liver and spleen are the most commonly involved non-pulmonary viscera- with granulomata noted in 40-80% of patients in autopsy series [18,19]. Liver involvement is found in 24-94% of patients and liver lab abnormalities are seen in 2-60% of cases [18,21]. Symptomatic liver disease is uncommon (fewer than 5% of patients) [18]. Liver involvement is usually infiltrative, and focal liver lesions are uncommon (5% of patients) [21]. When focal involvement is present, the CT findings usually consist of multiple, small (0.5-1.5 cm) hypodense nodules [21]. On splenic biopsy, granulomas can be found in 24-59% of patients with sarcoid [18].

Other sites of involvement include bone (up to 15%), kidneys (8-19% [18]), CNS (symptomatic disease in 5-9%- basal granulomatous meningitis; hypothalamus; cranial neuropathy), skin/cutaneous (10% to 30%- erythema nodosum, lupus pernio), occular (12-25%- uveitis), the myocardium (up to 25-50% of patients, but only about 5% have clinical evidence of myocardial involvement [19,28]), parotid glands (6%) [19], and the testicles (5% or less of patients [18]). The trachea is involved in 1-3% of cases- most commonly the subglottic region.

Head and neck involvement: Orbital structures are the most commonly involved sites for head and neck sarcoid [55]. Uveitis is the most common occular manifestation of sarcoid with anterior uveitis seen in 65%, posterior uveitis in 30%, and a combination in 10-15% of patients [55]. Patients complain of eye pain, redness, decreased vision, light sensitivity, and dark floating spots in the visual fields [55]. The optic nerve is the second most common affected cranial nerve after the facial nerve (bilateral facial nerve palsy may develop in up to one-third of patients with neurosarcoid [65]) [55]. Optic nerve involvement can present with decreased vision or vision loss, which can be rapid and painful [55]. Involvement of the lacrimal gland occurs in 10% of patients [55] and parotid gland involvement in 5% [65].

Involvement of the nervous system is seen clinically in 5-15% of cases [66], but clinically silent CNS involvement can occur in up to 25% of sarcoid patients [55]. Leptomeningeal involvement is the most common manifestation of CNS sarcoid and can be seen in 40% of affected patients [55]. Leptomeningeal sarcoid has a predilection to involve the basilar meninges, most commonly the suprasellar and frontal meninges [55]. Patients can present with HA, seizure, and symptoms related to cranial nerve invovelment [55]. Dural involvement is reported in up to 34% of patients and can appear as focal or diffuse dural thickening [55]. Cranial nerve involvement can be seen in up to 50% of patients with neurosarcoid [55]. The most commonly affected nerves include the facial (VII), optic (II), trigeminal (V), and oculomotor nerves [55]. Hypothalamic and pituitary manifestations of sarcoid are rare and account for only 1% of lesions found within the sella [55].

Patients with cardiac involvement may demonstrate conduction abnormalities/arrhythmias, valvular dysfunction, and heart failure [33].

Syndromes associated with sarcoidosis:

Erythema nodosum (EN): Most common non-specific skin finding in sarcoid [37]. EN can occur in other nongranulomatous diseases as well [37]. The disorder is a type of panniculitis (inflammation of the subcutaneous fat) that manifests as multiple bilateral tender erythematous nodules with diameters ranging from 1 to 10 cm most commonly on the anterior shins [37].

Lofgren's syndrome refers to an acute febrile illness accompanied by bilateral hilar adenopathy and erythema nodosum in a patient with sarcoid [9,18]. They may also have uveitis or parotitis and arthralgias of large joints. These findings are associated with a favorable prognosis with complete resolution within 2 years of presentation. [4,54]

Heerfordt's syndrome: Consists of parotid gland enlargement/parotiditis, fever, uveitis, and cranial nerve (facial nerve) palsies [18,55]. The condition is usually self-limited and most commonly affects patients in the 2nd to 4th decades of life [19].

Lupus pernio refers to the presence of violaceous (blue-purple) raised skin lesions typically on the cheeks and nose or upper torso in a patient with sarcoid [37]. Lupus pernio occurs more frequently among Puerto Ricans and African Americans [37]. It is associated with a poor prognosis.

In HIV: A number of cases have been described of new onset sarcoid in HIV patients following initiation of antiretroviral therapy with rise in CD4 count [10,12]. This may be related to immune restoration [10,12]. The radiologic features are similar to sarcoid in non-HIV patients [12].

Treatment:

Many patients can be monitored without treatment because spontaneous resolution or stability may occur (up to half of patients with pulmonary sarcoid have spontaneous improvement within the first 6 months) [54]. Steroids can relieve symptoms and suppress inflammation. Indications for steroid therapy include CNS, occular, cardiac and progressive pulmonary involvement, as well as hypercalcemia. Between 50-90% of patients will have a favorable response to corticosteroids, but relapse after discontinuation of therapy is seen in 20-74% of cases [54] and patients should be monitored for at least 3 years after treatment [65].  Initial response to steroid treatment does not preclude progression to pulmonary fibrosis. [9]. When steroids cannot be tapered to 10 mg/d or less, methotrexate or other second line agents may be considered [54[. For the treatment of end-stage lung secondary to sarcoid, lung transplant can be performed. Unfortunately, the disorder recurs in the transplanted lung in up to 35% of cases [14].

Staging:

Staging is based upon the CXR findings (4): Stage 0- Normal CXR; Stage 1- Mediastinal/ Hilar adenopathy; Stage 2- Adenopathy plus parenchymal infiltrates; Stage 3- Lung infiltrates only (adenopathy has resolved); and Stage 4- Fibrosis/ Cystic changes.

At presentation about 5-10% of patients have stage 0 disease; 50% (25-65%) have stage I; 25-30% have stage II; 10-15% stage III; and 5% have stage IV [9,32,65]. The clinical course is variable, but nearly two-thirds of patients will remain stable or experience a remission within a decade of diagnosis [32]. Recurrence after a remission lasting more than 1 year is uncommon (fewer than 5% of patients) [32].

Prognosis is directly correlated with the patients staging. About 65-70% of patients (up to more than 90% [65]) with stage I disease will demonstrate spontaneous clearing of radiographic abnormalities and only about 7% will progress to stage II (4). About 30-50% of patients with stage II disease and 10-20% of patients with stage III disease have radiographs that return to normal. Overall about 20% of affected patients will progress to chronic lung disease/pulmonary fibrosis [32]. Non-whites tend to have extrathoracic manifestations and an overall poorer prognosis [9]. Other factors associated with a poor prognosis include disease onset after the age of 40 years, hypercalcemia, splenomegaly, osseous involvment, chronic uveitis, and lupus pernio [32]. Early-stage features that are associated with a good prognosis (spontaneous remission rate >85%) are fever, polyarthritis, and erythema nodosum [32]. There is a 5% mortality rate due directly to sarcoid [9].

Complications:

1- Pulmonary fibrosis:

About 10-20% of patients progress to stage 4 disease. The disorder proves fatal in only 4 to 10% of cases, usually the result of pulmonary fibrosis and cor pulmonale.

2- Mycetoma/Aspergilloma:

Fungal superinfection is a complication of stage 4 disease. Although the characteristic finding is that of a fungus ball within an apical cavity, pleural thickening adjacent to a known cystic space may be the earliest indication of Aspergillus superinfection- occuring 2-3 years prior to the appearance of an intracavitary fungus ball. The pleural thickening is often striking and may achieve a thickness of 2 cm or more [5]. The presence of air-fluid levels within sarcoid pseudocavities is another indication of superimposed fungal infection [32]. Because the walls of aspergillomas are supplied by branches of the bronchial arteries, they bleed easily and they can be associated with life threatening hemoptysis [32].

3- Pneumothorax:

Most cases occur in association with diffuse pulmonary parenchymal disease- particularly fibrocystic disease and are probably due to rupture of subpleural bleb. The incidence of pneumothorax is said to be higher in blacks than in caucasians- likely due to the greater likelihood for disease progression in blacks [5].

4- Cardiac involvement/arrhythmias:

At autopsy, cardiac involvement can be found in up to 25-27% of patients with sarcoid (up to 75% of patients in Japan [52]), however, clinical evidence of cardiac involvement is found in only 5-7% of affected patients [27,38,42,45]. Other authors indicate that only 40-50% of patients with cardiac sarcoid at necropsy demonstrate any clinical evidence of myocardial disease [42]. However, cardiac sarcoid accounts for 13-25% of disease related deaths [39]. The most characteristic lesions of cardiac sarcoid are discrete, compact, non-necrotizing, epitheliod granulomas along with patchy areas of fibrosis [67]. The diagnosis of cardiac sarcoid is difficult as blind endomyocardial biopsy has less than 20-25% sensitivity in detecting non-caseating granulomas because of the patchy distribution of the disease [45,66]. In addition to a patchy distribution, the lesions also have a predilection for the subepicardial and mid-wall myocardium [67].

Myocardial sarcoid tends to involve the basal interventricular septum or left ventricular free wall (and can mimic HCM), with papillary muscle or RV involvement less common or only rarely seen [26,27,30,63,70]. Other authors indicate that the most frequently involved area is the ventricular septum (31.5%), followed by the inferior wall, anterior left ventricle, right ventricle, and lateral left ventricle [45,67]. Involvement of the interventricular septum accounts for the high rates of atrioventricular conduction abnormalities seen in affected patients [67]. Endocardial muscular biopsy can confirm the diagnosis, but has a low diagnostic yield (20-50%) due to the patchy nature of the disease and selective tissue sampling from only the right ventricle [34,42,48].

Cardiac involvement is a major adverse prognostic indicator in sarcoidosis [34]. Up to 85% of sarcoid-related mortality results from cardiac sarcoid [52]. Sarcoid involvement may result in global or regional hypokinesis, with systolic dysfunction leading to a reduced LVEF and an increased end-diastolic LV volume [35]. Inflammatory granulomas or post inflammatory scarring can disrupt normal myocardial electrical activity and produce bundle branch block, cardiac arrhythmias, heart block, CHF, and sudden death [22,27,34,45,48,67]. Involvment of the septum favors conduction abnormalities - most frequent is third-degree AV block which appears in 23-30% of cases [45]. Cardiac sarcoid should be considered in patients younger than age 55 years who present with unexplained second or third degree AV block [45]. Ventricular arrhythmias/tachycardia is the most frequent arrthythmia occurring in up to 23-25% of cardiac sarcoid patients, is the second most common clinical finding, and represents the leading cause of sudden cardiac death in CS patients (CHF is the second most frequent cause of cardiac death in CS patients) [45,70]. The incidence of sudden cardiac death from dysrhythmias in the context of cardiac sarcoid is between 12-65% [48].

Cardiac sarcoid should be considered in patients presenting with second or third degree AV block of unknown etiology and in patients under the age of 55 years, monomorphic ventricular tachycardia in the absence of CAD [42]. Approximately 16-35% of patients younger than 60 years who present with unexplained complete AV block or ventricular tachycardia may have cardiac sarcoid as the underlying cause [65].

Treatment: Corticosteroids are the principal treatment for cardiac sarcoid [63]. The early initiation of steroid therapy can be beneficial in recovery of AV nodal function, help to prevent ventricular arthythmias, aid in preserving LVEF, and improve long-term survival by inhibiting the inflammatory response thereby limiting fibrotic formation in the heart [22,52,63,71]. Some experts advocate 6-12 months of therapy, but others recommend consideration of lifelong treatment because of the risk for relapse or sudden death [63].

X-ray:

CXR: Plain film CXR abnormalities are found in over 90% of patients with sarcoid at sometime during the course of their disease (1). Bilateral hilar adenopathy is found in 95% of cases, right paratracheal adenopathy in 70%, and AP window adenopathy in 30-50%. Subcarinal nodes can also be involved in up to 25% of patients. The presence of right paratracheal and bilateral hilar adenopathy is referred to as the 1-2-3 pattern or Garland triad [68]. The addition of AP window adenopathy is referred to as the 1-2-3-4 pattern [68].

Lymph node calcifications are found in 3-20% (5). Calcification can be amorphous, popcorn-like, or uncommonly egg-shell in appearance (5%). Calcification of affected nodes is related to duration of disease. Calcification is seen in 3% of cases after 5 years, and in 20% of cases after 10 years [32]. RARE nodal findings include isolated mediastinal adenopathy (anterior, middle, or least commonly- posterior mediastinal adenopathy), or isolated unilateral hilar adenopathy (1-3%) (5). Older patients are more likely to have atypical patterns of adenopathy [9,32].

The interstitial lung disease can have a variety of appearances: a reticulo-nodular pattern is the most common and is typically bilateral and symmetric. An acinar or "alveolar" pattern with small indistinct nodular opacities can be seen. The densities can be discrete or coalesce producing areas of apparent parenchymal consolidation with air bronchograms [19]. The infiltrates can be peripheral and mimic pulmonary infiltrates associated with eosinophilia (1). Despite the appearance of airspace disease, the abnormality is still the result of interstitial disease. Multiple nodules have also been described, particularly in young black females and are usually very responsive to steroid therapy. Pleural effusions are RARE (0-5%), can be uni- or bilateral, are usually small to moderate in size, and are usually straw colored exudates with a lymphocyte predominance (5). A negative gallium scan is a reliable indicator of clinical inactivity.

Computed tomography: CT is more sensitive than CXR in the detection of adenopathy and parenchymal lung disease [9]. Mediastinal adenopathy is easily demonstrated.

HRCT is used to evaluate for parenchymal lung disease. Small 2-4 mm, well circumscribed pulmonary nodules are commonly seen (75-90% of cases) in a perilymphatic distribution [32]. The nodules are seen within the lung parenchyma (usually with a bilateral, symmetric, distribution predominantly in the upper and mid lung zones [32]), along the pleural surfaces, and along the fissures. There can be nodular thickening of the bronchial walls (when identified, this is associated with a very high diagnostic success rate for transbronchial biopsy (80-95%) [3]), along vessels, and along the fissures. These findings are related to the presence of non-caseating granulomas which are distributed within the bronchial mucosa, and along the lymphatics in the bronchovascular bundles, interlobular septa, and subpleural regions. Subpleural nodules (3-10mm in size) are found in 60-80% of cases. Large nodules greater than 1 cm in diameter occur as a result of coalescence of small nodules and are often surrounded by many tiny satellite nodules ("galaxy sign") [17,32]. Larger pulmonary nodules and masses can be seen in 15-25% of patients [32]. The masses may or may not contain air bronchograms [32]. Rarely, the nodules or masses may cavitate (<3% of patients) [32]. Other findings include ill-defined centrilobular nodules which may coalesce.

Nodular or irregular (occasionally smooth) thickening of the perivascular interstitium is also particularly common in sarcoid. The distribution of perivascular interstitial thickening may be patchy. Nodular or irregular thickening of the interlobular septae can be seen. Parenchymal bands can be seen in patients with sarcoid. Endobronchial granulomata in patients with sarcoid may rarely (1% of cases) result in significant airway narrowing [13].

Areas of ground glass attenuation can also be identified in about 40% of patients [32] and reflect the presence of microscopic interstitial granulomas or fibrosis, rather than alveolitis. Air trapping at the level of the secondary lobules has also been described and is felt to be related to narrowing of the small airways as a result of peribronchiolar granulomas [2,11]. The ground-glass opacities commonly have a finely stippled appearance due to the presence of tiny nodules [23].

Air trapping (due to small airways involvement by granulomas or fibrosis) will appear as areas of decreased attenuation on expiratory images- this produces a mosaic attenuation pattern [32]. Air trapping can be seen in up to 95% of patients [32].

Parenchymal opacities/airspace consolidation with air bronchograms may be seen in sacoid (alveolar sarcoid), but are uncommon (although other authors indicate that alveolar or airspace consolidation is seen in 10-20% of patients [32]). The consolidations are usually bilateral symmetric, and predominantly in the middle and upper lung zones [32]. The consolidation reflects the confluence of numerous micronodules that compress the surrounding alveoli or encroach on the alveolar spaces [32]. The extent of abnormalities on CT unfortunately correlate poorly with the patients level of functional impairment.

Pleural involvement in sarcoid is rare (1-4% of patients) [32].

In late stage disease, severe fibrosis results in architectural distortion, traction bronchiectasis, and fibrocavitary changes which is difficult to distinguish from other causes of end-stage lung disease.

Mesenteric and retroperitoneal adenopathy can be seen in approximately 30% of patients [40]. Liver involvement most commonly produces hepatomegaly, but focal nodules can be found in 5-19% of patients with liver disease [18,19]. When nodules are found, they are typically innumerable, diffusely distributed, and range in size from 1-2 mm to several centimeters [18]. The nodules appear hypodense on contrast enhanced CT imaging [18]. Hypodense splenic nodules can be found in about 6% to 35% of patients with sarcoid [18]. The splenic nodules are usually innumerable and diffusely distributed [18]. Intra-abdominal adenopathy can be found in up to 30% of patients [18].

Osseous involvement occurs in 1-13% of patients [65]. Skeletal lesions tends to involve the small bones of the hands and feet (in particular the distal and middle phalanges of the second and third digits [65]) and there is usually associated skin changes- soft tissue thickening referred to as "sausage dactylitis" [65]. Findings include a reticular trabecular pattern, a lace-like pattern of osteolysis, a mottled appearance, or cyst-like lesions [19,65]. The lesions are hot on bone scan and will also show tracer uptake on FDG PET imaging [20].

Cardiac involvement can appear as areas of myocardial thinning on CT.

Neurosarcoid typically involves the leptomeninges (leptomeningeal enhacement is most common in the suprasellar and frontal basal meninges) and basal midline structrues, including the optic chiasm, hypothalamus, and pituitary gland [40]. Cranial nerve involvement can also be seen- most commonly the optic nerve, and presents as an enlarged, enhancing nerve trunk [40].

MRI:

The appearance of cardiac sarcoid depends on the stage of the disease [26]. Initial edema is followed by granulomatous infiltration that eventually leads to post-inflammatory scarring [30]. The inflammatory phase is characterized by focal wall thickening due to infiltration or edema, combined with wall motion abnormalities on T1 cine images, increased signal on T2 images, and early gadolinium enhancement [22,45]. DIR-FSE T2 images will demonstrate edema as areas of foci of nodular high signal within the myocardium preferentially affecting the mid wall and sparing the subendocardium [26,30,67]. Active granuloma may manifest as focal nodular areas on cine images, appear bright on DIR-FSE T2 images, and will show delayed enhancement on post contrast imaging (therefore LGE alone cannot determine phase of disease) [30,60].

Foci of delayed enhancement have been reported in 25% of cases with biopsy proven disease and localize to the mid-myocardial zones [34]. Involved areas can show enhancement on delayed T1 contrast enhanced images- the delayed enhancement may be mid-wall, subepicardial, or transmural, rather than subendocardial [19,22,24,26,27,29] most commonly in the basal and lateral aspects of the left ventricle [29,57]. Other authors indicate that involvement is most commonly transmural, and if non-transmural the involvement is often subepicardial or midmyocardial  [48]. Sarcoid has a particular predilection for the basal or midventricular septum and lateral LV wall and does not parallel the vascular territories [34,35]. However, subendocardial hyperenhancement along the right aspect of the interventricular septum was observed in 67% of cardiac sarcoid patients in one study [35]. On cine MR, areas of involvement may show segmental contraction abnormalities [22]. Delayed hyperenhancement and myocardial thickening may resolve following steroid treatment (although T2 hyperintensity usually persists) [26]. MR has a sensitivity of 75-100% and specificity of 77-78% for the diagnosis of cardiac sarcoid [48,52,57]. Among patients who are on already on steroid therapy, both CMR and FDG PET may have reduced sensitivity, but CMR may perform better in these patients [67].

In patients with cardiac sarcoid, delayed enhancement is associated with adverse events, arrhythmias sustained ventricular tachycardia, and cardiac death [45,48,57]. Sarcoid patients with areas of delayed enhancement have a 11.5 to 20 times higher likelihood of experiencing cardiac death compared to patients without enhancement [57]. The presence of LGE should be considered in clinical decision making for cardioverter-defibrillator implantation [67].

Late in the disease, scarring will appear as focal areas of wall thinning with associated hypokinesis and delayed enhancement in a non-vascular territory affecting the subepicardial layer [30].

Nuclear Medicine/PET in sarcoid:

FDG PET imaging will demonstrate tracer accumulation at sites of active sarcoid involvement, can be used to detect occult disease, and can also be used to monitor treatment response [25,66].

PET imaging is more accurate and depicts extra-pulmonary involvement better than gallium scintigraphy [25]. Mediastinal lymph nodes are most commonly visualized (39% of patients), followed by extrathoracic nodes (19%), and pulmonary parenchyma (15%) [36]. FDG uptake is variable with SUVmax measurements from 2.5 to 15.8 [36].

For evaluation of treatment response, in a small prospective study, sarcoid patients with a metabolic response following treatment with systemic corticosteroids had significantly fewer relapses compared to patients without a metabolic response [66].

PET imaging of Cardiac Sarcoid:

The diagnosis of cardiac sarcoid is challenging - approximately half of the affected patients are intially asymptomatic and endomyocardial biopsy has a sensitivity of only 20-30% because of the hetreogeneous myocardial involvement [52]. Gallium is specific for cardiac sarcoid, but has a sensitivity of less than 40% [52].

FDG PET can also be used to evaluate for the presence of cardiac sarcoid [41]. Unlike delayed enhancement on MRI which represents cardiac damage, but can also represent scarring/fibrosis (chronic disease), FDG uptake represents active inflammation [45,56]. A limitation of FDG for the evaluation of cardiac sarcoid is the unpredictable physiologic cardiac tracer uptake even during fasting conditions (particularly in the inferolateral and basal myocardium [45]) that can interfere with detection of active disease [41]. Cardiac uptake tends to be higher in male patients, patients under the age of 30 years, patients who fast less than 5-6 hours, patients with heart failure, and patients receiving benzodiazepines [45,58].

Physiologic cardiac uptake is most likely to be minimized when plasma free fatty acid levels are elevated (physiologic FDG uptake is best inhibited when the FFA level is more than 760 uEq/L) [51]. A combination of fasting and diet modification can be used for patient preparation in order to elevate FFA levels and suppress physiologic FDG uptake by normal myocytes. The consensus recommendation is that patients should consume at least two high fat (>35 gm), low carbohydrate (<3 gm) protein permitted meals the day before their exam and then fast for at least 4-18 hours [33,35,39, 41,42,45,47,51,58,63,64,70]. For patients that cannot follow dietary recommendations, a fast of 18 hours or more is recommended [63,64]. However, even when a HFLC diet is used, diffuse homogeneous cardiac uptake can still be seen in 3-7% of patients and focal uptake in the papillary muscles can be seen in 15-19% of patients [41]. Other authors suggest that despite efforts to suppress myocardial activity, up to 30% of patients can still have unsatisfying myocardial FDG uptake [70].

Injection of unfractionated heparin before FDG injection (in conjunction with fasting and a low carbohydrate diet) can also be performed to improve suppression of cardiac activity [42,53]. Unfractionated heparin increases plasma free fatty acid levels (an up to 5 fold increase [53]) through activation of lipoprotein lipase (thereby elevating plasma FFA levels and suppressing glucose metabolism) and the effect occurs at a dose that is significantly lower than that required for anticoagulation [42,45,51]. A dose of 10 IU/kg (700-1000 IU) IV given in divided doses 30 and 15 minutes prior scanning can be used (if there are no contraindications) [42]. Other authors suggest using 50 IU/kg of body weight 15 minutes before FDG adminstration [45,53]. Although the use of unfractionated heparin will acutely increase FFA levels, some authors feel it does not have a significant role in reducing physiologic LV FDG uptake compared to a prolonged fast [51]. One potential concern with the use of heparin is the uncommon, but potentially life threatening risk of heparin-induced thrombocytopenia and no dose of heparin is too low to cause this complication [59].

Intracellular calcium acts as a stimulus for cardiac glucose uptake and the use of calcium channel blockers has also been suggested as a means to decreased cardiac activity [47]. However, this does not appear to be a useful addition to a standard high-fat low carbohydrate meal followed by a 12 hour fast [47].

The consensus recommendation is that unfractionated heparin may be considered, but it's actual impact on myocardial glucose metabolism is uncertain [63].

Patients should be urged to avoid strenuous exercise for 12-24 hours prior to the exam [58]. Vigorous exercise and the resulting catecholamine stimulation increase myocardial glucose uptake by augmenting transporter recruitment and glucose utilization via oxidation [58].

Consensus recommendations are that imaging should be performed only at centers that have experience with cardiac sarcoid protocols [62]. Results of the FDG exam should be interpreted in conjunction with a rest myocardial perfusion exam- either 82Rb or 13N-NH3 PET or resting perfusion SPECT using a 99mTc-agent or 201Tl [63,70]. Findings in cardiac sarcoid include focal or diffuse cardiac uptake (although other authors suggest diffuse uptake is more likely non-specific [64]) [33]. A patchy pattern of focal uptake is most suggestive of cardiac sarcoid [45].

Early in the disease, the focal aeras of FDG uptake are not associated with perfusion abnormalities, but typically there will be a perfusion metabolism mismatch - area of FDG accumulation with an associated resting perfusion defect (as also seen in areas of hibernating myocardium and the pattern has been described in myocarditis) [49,50,67]. On the other hand, resting perfusion defects may be present in patients with cardiac sarcoid that has no significant inflammatory component - therefore, the absence of FDG activity should be interpreted as a sign of "no active myocardial inflammation," but cannot exclude the presence of cardiac sarcoid [67]. More diffuse uptake can occur if physiologic myocardial suppression was insufficient [45].

Perfusion
Normal
Normal
Normal
Abnormal
Abnormal
Abnormal
FDG
Normal
Diffuse
(non-specific)
Focal increase
Focal increase same area
Focal increase
(different area)
Normal
Interpretation
Negative
Non-specific
Early disease
Mismatch pattern
(positive)
Scar and inflammation
Scar/No active
inflammation

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(3) J Thorac Imag 1995, 10: p.236-254 (p.239)

(4) Chest 1983; DeRemee RA. The roentgenographic staging of sarcoidosis: Historic and contemporary perspectives. 83 (1): 128-133

(5) AJR 1985; Rockoff SD, et al. Unusual manifestations of thoracic sarcoidosis. 144: 513-528 (Review article)

(6) ACR Syllabus #40:p.395-398

(7) Chest 1973; Sharma OP, et al. Nodular sarcoid: An unusual radiographic appearance. 64 (2): 189-192 (No abstract available)

(8) Semin Respir Infect 1998; Rybicki BA, et al. Epidemiology, demographics, and genetics of sarcoid. 13 (3): 163-173

(9) Radiographics 1995; Miller BH, et al. Thoracic sarcoidosis: Radiologic-pathologic correlation. 15: 421-437

(10) Society of Thoracic Radiology Annual Meeting 2000 Course Syllabus; Haramati LB. Emerging infections in AIDS. 117-119

(11) AJR 2000; Arakawa H, et al. Expiratory high-resolution CT: Diagnostic value in diffuse lung disease. 175: 1537-1543 (No abstract available)

(12) Radiology 2001; Haramati LB, et al. Newly diagnosed pulmonary sarcoidosis in HIV-infected patients. 218: 242-246

(13) AJR 2001; Marom EM, et al. Diffuse abnormalities of the trachea and main bronchi. 176: 713-717 (No abstract available)

(14) Radiology2001; Collins J, et al. Frequency and CT findings of recurrent disease after lung transplantation. 219: 503-509

(15) AJR 2001; Ravenel JG, et al. Sarcoidosis induced by interferon therapy. 177: 199-201 (No abstract available)

(16) AJR 2001; Wittram C, et al. Immune restoration syndrome manifested by pulmonary sarcoid. 177: 1427 (No abstract available)

(17) AJR 2002; Nakatsu M, et al. Large coalescent parenchymal nodules in pulmonary sarcoidosis: "sarcoid galaxy" sign. 178: 1389-1393

(18) AJR 2004; Warshauer DM, Lee JK. Imaging manifestations of abdominal sarcoidosis. 182: 15-28 (No abstract available)

(19) Radiographics 2004; Koyama T, et al. Radiologic manifestations of sarcoidosis in various organs. 24: 87-104

(20) AJR 2004; Aberg C, et al. FDG positron emission tomography of bone involvement in sarcoidosis. 182: 975-977 (No abstract available)

(21) AJR 2004; Jung G, et al. MRI of hepatic sarcoidosis: large confluent lesions mimicking malignancy. 183: 171-173

(22) AJR 2005; Vignaux O. Cardiac sarcoidosis: spectrum of MRI features. 184: 249-254

(23) AJR 2005; Miller WT, Shah RM. Isolated diffuse ground-glass opacity in thoracic CT: causes and clinical presentations. 184: 613-622

(24) AJR 2005; Tadamura E, et al. Effectiveness of delayed enhancement MRI for identification of cardiac sarcoidosis: comparison with radionuclide imaging. 185: 110-115

(25) J Nucl Med 2006; Nishiyama Y, et al. Comparitive evaluation of 18F-FDG PET and 67Ga scintigraphy in patients with sarcoidosis. 47: 1571-1576

(26) AJR 2007; Lim RP, et al. Non-ischemic causes of delayed myocardial hyperenhancement on MRI. 188: 1675-1681

(27) AJR 2007; Hansen MW, Merchant N. MRI of hypertrophic cardiomyopathy: Part 2, differential diagnosis, risk stratification, and post treatment MRI appearances. 189: 1344-1352

(28) J Nucl Cardiol 2008; O'Hanlon R, et al. Evaluation of non-ischemic cardiomyopathy using cardiovascular magnetic resonance. 15: 400-416

(29) AJR 2008; Ichinose A, et al. MRI of cardiac sarcoidosis: basal and subepicardial localization of myocardial lesions and their effect on left ventricular function. 191: 862-869

(30) Radiographics 2009; Sparrow PJ, et al. CT and MR imaging findings in patients with acquired heart disease at risk for sudden cardiac death. 29: 805-823

(31) Radiographics 2009; Kim YK, et al. Thoracic complications of liver cirrhosis: radiologic findings. 29: 825-837

(32) Radiographics 2010; Criado E, et al. Pulmonary sarcoidosis: typical and atypical manifestations at high-resolution CT with pathologic correlation. 30: 1567-1586

(33) J Nucl Cardiol 2011; Brancato SC, Arrighi JA. Fasting FDG PET compared to MPI SPECT in cardiac sarcoid. 18: 371-374

(34) AJR 2011; Hoey ETD, et al. Cardiovascular MRI for assessment of infectious and inflammatory conditions of the heart. 197: 103-112

(35) Radiographics 2011; James OG, et al. Utility of FDG PET/CT in inflammatory cardiovascular disease. 31: 1271-1286

(36) Radiographics 2011; Maurer AH, et al. How to differentiate benign versus malignant cardiac and paracardiac 18F FDG uptake at oncologic PET/CT. 31: 1287-1305

(37) Radiographics 2011; Kanne JP, et al. Beyond skin deep: thoracic manifestations of systemic disorders affecting the skin. 31: 1651-1668

(38) Radiology 2012; O'Donnell DH, et al. Cardiac MR imaging of nonischemic cardiomyopathies: imaging protocols and spectra of appearances. 262: 403-422

(39) J Nucl Med 2012; Youssef G, et al. The use of 18F FDG PET in the diagnosis of cardiac sarcoidosis: a systematic review and metaanalysis including the Ontario experience. 53: 241-248

(40) Radiographics 2013; Bhavsar AS, et al. Abdominal manifestations of neurologic disorders. 33: 135-153

(41) J Nucl Cardiol 2013; Soussan M, et al Clinical value of a high-fat and low-carbohydrate diet before FDG-PET/CT for evaluation of patients with suspected cardiac sarcoidosis. 20: 120-127

(42) J Nucl Cardiol 2013; The role of of 18F-fluorodeoxyglucose positron emission tomography in guiding diagnosis and management in patients with known or suspected cardiac sarcoidosis. 20: 297-306

(43) JAMA 2013; von Bartheld MB, et al. Endosonography vs conventional bronchoscopy for the diagnosis of sarcoidosis. The GRANULOMA randomized clinical trial. 309: 2457-2464

(44) J Nucl Med 2014; Schatka I, Bengel FM. Advanced imaging of cardiac srcoidosis. 55: 99-106

(45) J Nucl Med 2014; Schatka I, Bengel FM. Advanced imaging of cardiac sarcoid. 55: 99-106

(46) J Nucl Cardiol 2014; Osborne MT, et al. Reduction in 18F-fluorodeoxyglucose uptake on serial cardiac positron emission tomography is associated with improved left ventricular ejection fraction in patients with cardiac sarcoidosis. 21: 166-174

(47) J Nucl Med 2014; Demeure F, et al. A randomized trial on the optimization of 18F FDGmyocardial uptake suppression: implications for vulnerable coronary plaque imaging. 55: 1629-1635

(48) Radiographics 2015; Jeudy J, et al. Cardiac sarcoidosis: the challene of radiologic-pathologic correlation. 35: 657-679

(49) J Nucl Cardiol 2015; Blankstein R, et al. Proceedings of the ASNC cardiac PET summit meeting, May 12, 2014, Baltimore MD. 22. 4. Novel applications of cardiovascular PET: 720-729

(50) J Nucl Cardiol 2015; Sperry BW, et al. Infectious myocarditis on FDG-PET imaging mimicking sarcoid. 22: 840-841

(51) J Nucl Cardiol 2016; Manabe O, et al. The effects of 18-h fast with low carbohydrate diet preparation on suppressed physiological myocardial 18F-fluorodeoxyglucose (FDG) uptake and possible minimal effects of unfractionated heparin use in patients with suspected cardiac involvement sarcoidosis. 23: 244-252

(52) J Nucl Cardiol 2016; Bois JP, Chareonthaitawee P. Optimizing radionuclide imaging in the assessment of cardiac sarcoidosis. 23: 253-255

(53) J Nucl Med 2016; Scholtens AM, et al. Additional heparin preadministration improves cardiac glucose metabolism suppression over low-carbohydrate diet alone in 18F-FDG PET imaging. 57: 568-573

(54) Mayo Clin Proc 2016; Carmona, EM, et al. Pulmonary sarcoidosis: diagnosis and treatment. 91: 946-954

(55) AJR 2017; Chapman MN, et al. Sarcoidosis in the head and neck: an illustrative review of clinical presentations and imaging findings. 208: 66-75

(56) J Nucl Cardiol 2017; Lee PI, et al. The role of serial FDG PET for assessing therapeutic response in patients with cardiac sarcoid. 24: 19-28

(57) J Nucl Cardiol 2017; Manoushagian SJ, et al. Multimodality imaging in the diagnosis and management of cardiac sarcoidosis. 24: 29-33

(58) J Nucl Cardiol 2017; Osborne MT, et al. Patient preparation for cardiac fluorine-18 fluorodeoxglucose positron emission tomography imaging of inflammation. 24: 86-99

(59) J Nucl Cardiol 2017; Bhambhvani P. Challenges of cardiac inflammation imaging with F-18 positron emission tomography. 24: 100-102

(60) Radiographics 2017; Hashimura H, et al. Radiologic-pathologic correlation of primary and secondary cardiomyopathies: MR imaging and histopathologic findings in hearts from autopsy and transplantation. 37: 719-736

(61) J Nucl Cardiol 2017; Ahmadian A, et al. The response of FDG uptake to immunosuppressive treatment on FDG PET/CT imaging for cardiac sarcoidosis. 24: 413-424

(62) J Nucl Med 2017; Ohira H, et al. Inter- and intraobserver agreement of 18F-FDG PET/CT image interpretation in patients referred for assessment of cardiac sarcoid. 58: 1324-1329

(63) J Nucl Med 2017; Chareonthaitawee P, et al. Joint SNMMI-ASNC expert consensus document on the role of 18F-FDG PET/CT in cardiac sarcoid detection and therapy monitoring. 58: 1341-1353

(64) J Nucl Cardiol 2017; Chareonthaitawee P, et al. Joint SNMMI-ASNC expert consensus document on the role of 18F-FDG PET/CT in cardiac sarcoid detection and therapy monitoring. 24: 1741-1758

(65) Radiographics 2018; Ganeshan D, et al. Sarcoidosis from head to toe: what the radiologist needs to know. 38: 1180-1200

(66) Radiographics 2018; Akaike G, et al. PET/CT in the diagnosis and workup of sarcoidosis: focus on atypical manifestations. 38: 1536-1549

(67) J Nucl Med 2019; Ramirez R, et al. Advanced imaging in cardiac sarcoid. 60: 892-898

(68) AJR 2020; Lee GM, et al. Sarcoidosis: a diagnosis of exclusion. 214: 50-58

(69) Radiographics 2020; Naeem M, et al. Noninfectious granulomatous diseases of the chest. 40: 1003-1019

(70) AJR 2020; Yang M, et al. Advanced nuclear medicine and molecular imaging in the diagnosis of cardiomyopathy. 215: 1208-1217

(71) Radiographics 2020; Hotta M, et al. Radionuclide imaging of cardiac amyloid and sacoidosis: roles and characteristics of various tracers. 40: 2029-2041

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