*2.3.2 Cardiac sarcoidosis*

Cardiac involvement in sarcoidosis is uncommon (5%) and is associated with very poor prognosis [1], because of many complications of cardiac as follows: ventricular tachycardia, conductional abnormalities, congestive heart failure, and sudden cardiac death. Moreover, cardiac sarcoidosis (CS) is an important prognostic factor in patients with this disease. However, early diagnosis of CS in still

**Figure 2.** *HRCT: coarse linear opacities, architectural distortion, superior hilar retraction, and traction bronchiectasis.*

**Figure 3.** *HRCT: hilar and mediastinal lymph node enlargement, sometimes with calcification.*

really difficult due to the nonspecific clinical manifestations of the disease, inhomogeneous myocardial involvement, and the limited diagnostic yield of diagnostic tests. Therefore, there are no standardized tests for the early diagnosis of cardiac sarcoidosis, although early detection of CS is very important for effective treatment. Besides a history and physical examination, electrocardiography (ECG) and transthoracic echocardiography are useful for cardiac evaluation.

**39**

**Figure 5.**

myocardial wall [14, 15].

*hilar retraction, and traction bronchiectasis.*

CS can be diagnosed using (18) F-FDG-PET/CT (PET) and cardiovascular magnetic resonance (CMRI) that nowadays have been emerged as well for this purpose in recent clinical practice [1]. Imaging modalities that can both identify disease and predict response to therapy are supreme to improve management of cardiac sarcoidosis. (18) F-FDG-PET has many practical advantages in identifying disease activity and monitoring treatment response in patients with CS [1]. In (18) F-FDG, increased uptake, indicating active inflammation, can be seen in CS in the

*HRCT: micronodules and macronodules with perilymphatic distribution, for the most part, symmetrically in the middle zones of the lungs; pulmonary ground glass areas; thickening of the peribronchovascular interstitium; coarse linear opacities and interlobular septal thickening; and architectural distortion, superior* 

*Early Diagnosis of Sarcoidosis*

**Figure 4.**

*DOI: http://dx.doi.org/10.5772/intechopen.90523*

*Scadding stages for staging of pulmonary disease on chest X-rays.*

## *Early Diagnosis of Sarcoidosis DOI: http://dx.doi.org/10.5772/intechopen.90523*


#### **Figure 4.**

*Sarcoidosis and Granulomatosis - Diagnosis and Management*

really difficult due to the nonspecific clinical manifestations of the disease, inhomogeneous myocardial involvement, and the limited diagnostic yield of diagnostic tests. Therefore, there are no standardized tests for the early diagnosis of cardiac sarcoidosis, although early detection of CS is very important for effective treatment. Besides a history and physical examination, electrocardiography (ECG) and

*HRCT: coarse linear opacities, architectural distortion, superior hilar retraction, and traction bronchiectasis.*

transthoracic echocardiography are useful for cardiac evaluation.

*HRCT: hilar and mediastinal lymph node enlargement, sometimes with calcification.*

**38**

**Figure 3.**

**Figure 2.**

*Scadding stages for staging of pulmonary disease on chest X-rays.*

#### **Figure 5.**

*HRCT: micronodules and macronodules with perilymphatic distribution, for the most part, symmetrically in the middle zones of the lungs; pulmonary ground glass areas; thickening of the peribronchovascular interstitium; coarse linear opacities and interlobular septal thickening; and architectural distortion, superior hilar retraction, and traction bronchiectasis.*

CS can be diagnosed using (18) F-FDG-PET/CT (PET) and cardiovascular magnetic resonance (CMRI) that nowadays have been emerged as well for this purpose in recent clinical practice [1]. Imaging modalities that can both identify disease and predict response to therapy are supreme to improve management of cardiac sarcoidosis.

(18) F-FDG-PET has many practical advantages in identifying disease activity and monitoring treatment response in patients with CS [1]. In (18) F-FDG, increased uptake, indicating active inflammation, can be seen in CS in the myocardial wall [14, 15].

#### **Figure 6.**

Sarcoid galaxy sign*: mass-like region from confluence of numerous smaller granulomas with a central core and multiple peripheral nodules (arrows).*

Focal hypermetabolic activity or a focal increase of activity with a diffusely increased background on (18) F-FDG- PET is characteristic for cardiac sarcoidosis but this technique has some limitations. Normal myocardial cells use glucose as one of main energy substrates [14], and so physiologic (18) F-FDG uptake may be found in myocardium of healthy subjects; also papillary muscles and lateral wall of left ventricle may also show normal uptake of (18) F-FDG. Then, special patient preparation is, therefore, needed prior to F-FDG-PET scan in patients with sarcoidosis, with three different approaches: prolonged fasting, dietary modification with high-fat diet and i.v. administration of unfractionated heparin, trying to suppress (18) F-FDG uptake promoting fatty acid metabolism.

In cardiac sarcoidosis, the combined use of FDG-PET/CT and CMRI may provide optimal detection of the disease by enabling the differentiation between patients with active granulomatous inflammation and those with fibrous lesions. CMRI is a sensitive technique to assess the locations and extent of disease. Myocardial sarcoidosis may present on CMRI as segmental wall motion abnormality, focal wall thickening or thinning, or nodules with a patchy distribution [3].

On CMRI scan, in CS, we can find late gadolinium enhancement (LGE) related to the presence of fibrous granulomatous tissue, areas with an increased signal on T2-weighted sequences consistent with myocardial edema and with hypointensity suggesting fibrosis [10]. Recently, the value of LGE on CMRI, which allows visualization of even minute amounts of myocardial damage, has been emphasized in diagnosing CS, and it might be a promising tool for determining the prognosis of patients with biopsy-proven extracardiac sarcoidosis [1, 16].

However, it is not easy to differentiate between active and inactive sarcoidosis lesions, which is important for patient management. In addition, cardiac MRI is generally contraindicated in patients with pacemakers or implantable cardioverter defibrillators (ICDs).

#### *2.3.3 Neurosarcoidosis*

Nervous system involvement is not an uncommon manifestation of sarcoidosis and can be clinically symptomatic neurosarcoidosis, which occurs in 5–16% of

**41**

*Early Diagnosis of Sarcoidosis*

*DOI: http://dx.doi.org/10.5772/intechopen.90523*

mortality in patients with sarcoidosis.

findings on MRI are often nonspecific.

coidosis still a clinical challenge.

depend on the areas of the nervous system involved.

system involvement, it is really difficult to obtain [3, 18].

patients with sarcoidosis, and subclinical neurosarcoidosis, with an incidence of subclinical disease that may be higher [17–19]. The neurological manifestations

optic nerve presenting with diplopia or impaired visual acuity [3, 19].

The most commonly involved part are cranial nerves, though any part of neuroaxis can be affected. The facial nerve is the most common cranial nerve involved presenting with facial palsy, and the second most common nerve affected is the

Neurosarcoidosis in the brain can present with leptomeningeal and intraparenchymal infiltration of granulomas resulting, for example, in cranial nerve palsies, basal meningitis, and endocrine dysfunction. It can cause also peripheral neuropathies (such as sensorimotor polyneuropathy, radiculopathy, and myopathy) [3]. For all of these reasons, neurosarcoidosis is an important cause of morbidity and

Diagnosis and management of patients with neurosarcoidosis are still challenging because the gold standard is tissue-proven biopsy but, in most cases of nervous

*Contrast-enhanced MRI* for the detection of intracranial and spinal cord lesions is the imaging modality of choice for evaluating neurosarcoidosis. However, the

In central nervous system (CNS) involvement, the hypointensity of signal of the dural and of parenchymal lesions in T2-weighted sequences is useful to identify sarcoidosis. Contrast-enhanced MRI is a sensitive tool in the detection of CNS inflammation but has a low specificity, making the correct diagnosis of neurosar-

The most common imaging finding in T2-weighted sequences are hyperintense parenchymal lesions (gray matter) and in T1-weighted sequences, after intravascular administration of contrast agents, are meningeal enhancement (basilar meningitis involving of cranial nerves is thought to be a common phenomenon), and swelling and/ or enhancement of optic nerves or chiasm maybe with associated visual loss. Other imaging presentations include intracranial masses simulating neoplasms and vasculitic infarcts. Moreover, in a small part of cases, brain MRI can be normal. Cervical or thoracolumbar spine abnormalities, such as spinal cord swelling, meningeal enhancement,

and parenchymal contrast enhancing lesions, can also be detected [20].

neuropathy evaluation, although the findings are not specific.

(18) F-FDG and neurosarcoidosis is very limited.

*2.3.4 Bone sarcoidosis*

Electromyography (EMG) can be an additional useful tool for peripheral

The usefulness of (18) F-FDG in neurosarcoidosis is poor because of the physiologic uptake of (18) F-FDG activity in normal gray matter. However, granulomatous inflammation shows hypermetabolism, whereas neuronal damage presents as hypometabolism. (18) F-FDG-PET may reveal additional occult lesions amenable to biopsy in some patients with inaccessible intracranial lesions, but the literature on

Bone involvement is a rare manifestation of sarcoidosis usually associated with pulmonary findings. The exact prevalence of bone sarcoidosis is still not known, depending on the studied population and the used diagnostic tools [21]. The prevalence of bone sarcoidosis is between 3% and 5%, above all affecting the phalanges [22].

Both (18)F-FDG-PET/CT and conventional MRI are sensitive in detecting sarcoidosis bone lesions but are not always reliable in differentiating sarcoidosis bone

(18) F-FDG-PET/CT is highly sensitive in detecting granulomatous bone marrow infiltration, but an increased (18) F-FDG uptake can mimic metastatic

lesions from metastatic disease, thus often requiring bone biopsy [17].

#### *Early Diagnosis of Sarcoidosis DOI: http://dx.doi.org/10.5772/intechopen.90523*

*Sarcoidosis and Granulomatosis - Diagnosis and Management*

(18) F-FDG uptake promoting fatty acid metabolism.

patients with biopsy-proven extracardiac sarcoidosis [1, 16].

Focal hypermetabolic activity or a focal increase of activity with a diffusely increased background on (18) F-FDG- PET is characteristic for cardiac sarcoidosis but this technique has some limitations. Normal myocardial cells use glucose as one of main energy substrates [14], and so physiologic (18) F-FDG uptake may be found in myocardium of healthy subjects; also papillary muscles and lateral wall of left ventricle may also show normal uptake of (18) F-FDG. Then, special patient preparation is, therefore, needed prior to F-FDG-PET scan in patients with sarcoidosis, with three different approaches: prolonged fasting, dietary modification with high-fat diet and i.v. administration of unfractionated heparin, trying to suppress

Sarcoid galaxy sign*: mass-like region from confluence of numerous smaller granulomas with a central core* 

In cardiac sarcoidosis, the combined use of FDG-PET/CT and CMRI may provide optimal detection of the disease by enabling the differentiation between patients with active granulomatous inflammation and those with fibrous lesions. CMRI is a sensitive technique to assess the locations and extent of disease.

Myocardial sarcoidosis may present on CMRI as segmental wall motion abnormality, focal wall thickening or thinning, or nodules with a patchy distribution [3]. On CMRI scan, in CS, we can find late gadolinium enhancement (LGE) related to the presence of fibrous granulomatous tissue, areas with an increased signal on T2-weighted sequences consistent with myocardial edema and with hypointensity suggesting fibrosis [10]. Recently, the value of LGE on CMRI, which allows visualization of even minute amounts of myocardial damage, has been emphasized in diagnosing CS, and it might be a promising tool for determining the prognosis of

However, it is not easy to differentiate between active and inactive sarcoidosis lesions, which is important for patient management. In addition, cardiac MRI is generally contraindicated in patients with pacemakers or implantable cardioverter

Nervous system involvement is not an uncommon manifestation of sarcoidosis and can be clinically symptomatic neurosarcoidosis, which occurs in 5–16% of

**40**

**Figure 6.**

*and multiple peripheral nodules (arrows).*

defibrillators (ICDs).

*2.3.3 Neurosarcoidosis*

patients with sarcoidosis, and subclinical neurosarcoidosis, with an incidence of subclinical disease that may be higher [17–19]. The neurological manifestations depend on the areas of the nervous system involved.

The most commonly involved part are cranial nerves, though any part of neuroaxis can be affected. The facial nerve is the most common cranial nerve involved presenting with facial palsy, and the second most common nerve affected is the optic nerve presenting with diplopia or impaired visual acuity [3, 19].

Neurosarcoidosis in the brain can present with leptomeningeal and intraparenchymal infiltration of granulomas resulting, for example, in cranial nerve palsies, basal meningitis, and endocrine dysfunction. It can cause also peripheral neuropathies (such as sensorimotor polyneuropathy, radiculopathy, and myopathy) [3]. For all of these reasons, neurosarcoidosis is an important cause of morbidity and mortality in patients with sarcoidosis.

Diagnosis and management of patients with neurosarcoidosis are still challenging because the gold standard is tissue-proven biopsy but, in most cases of nervous system involvement, it is really difficult to obtain [3, 18].

*Contrast-enhanced MRI* for the detection of intracranial and spinal cord lesions is the imaging modality of choice for evaluating neurosarcoidosis. However, the findings on MRI are often nonspecific.

In central nervous system (CNS) involvement, the hypointensity of signal of the dural and of parenchymal lesions in T2-weighted sequences is useful to identify sarcoidosis. Contrast-enhanced MRI is a sensitive tool in the detection of CNS inflammation but has a low specificity, making the correct diagnosis of neurosarcoidosis still a clinical challenge.

The most common imaging finding in T2-weighted sequences are hyperintense parenchymal lesions (gray matter) and in T1-weighted sequences, after intravascular administration of contrast agents, are meningeal enhancement (basilar meningitis involving of cranial nerves is thought to be a common phenomenon), and swelling and/ or enhancement of optic nerves or chiasm maybe with associated visual loss. Other imaging presentations include intracranial masses simulating neoplasms and vasculitic infarcts. Moreover, in a small part of cases, brain MRI can be normal. Cervical or thoracolumbar spine abnormalities, such as spinal cord swelling, meningeal enhancement, and parenchymal contrast enhancing lesions, can also be detected [20].

Electromyography (EMG) can be an additional useful tool for peripheral neuropathy evaluation, although the findings are not specific.

The usefulness of (18) F-FDG in neurosarcoidosis is poor because of the physiologic uptake of (18) F-FDG activity in normal gray matter. However, granulomatous inflammation shows hypermetabolism, whereas neuronal damage presents as hypometabolism. (18) F-FDG-PET may reveal additional occult lesions amenable to biopsy in some patients with inaccessible intracranial lesions, but the literature on (18) F-FDG and neurosarcoidosis is very limited.

#### *2.3.4 Bone sarcoidosis*

Bone involvement is a rare manifestation of sarcoidosis usually associated with pulmonary findings. The exact prevalence of bone sarcoidosis is still not known, depending on the studied population and the used diagnostic tools [21]. The prevalence of bone sarcoidosis is between 3% and 5%, above all affecting the phalanges [22].

Both (18)F-FDG-PET/CT and conventional MRI are sensitive in detecting sarcoidosis bone lesions but are not always reliable in differentiating sarcoidosis bone lesions from metastatic disease, thus often requiring bone biopsy [17].

(18) F-FDG-PET/CT is highly sensitive in detecting granulomatous bone marrow infiltration, but an increased (18) F-FDG uptake can mimic metastatic disease, reducing the specificity of (18) F-FDG-PET/CT when both sarcoidosis and a tumor, which may develop bone metastases, occur in the same patient. Bone assessment in sarcoidosis patients is also performed using MRI, commonly relying on T1-weighted and T2-weighted images. However, routine MRI is not reliable in differentiating sarcoidosis bone lesions from metastatic disease [17].

Multifocal skeletal sarcoidosis may present as a false positive for bone metastases on (18) F-FDG PET/CT since granulomatous bone marrow infiltration may have an uptake of (18) F-FDG, which mimics that of metastatic disease. When false positive findings on (18) F-FDG PET/CT cannot be totally excluded, biopsy or MRI may represent the second choice to achieve diagnosis. Since conventional MRI may not be accurate in distinguishing between sarcoidosis and metastatic bone lesions, it is possible to perform diffusion whole-body MRI: T1-weighted, T2-weighted STIR, and diffusion-weighted imaging (with different *b* values) [17]. The latter is able to evaluate microscopic tissue water motions average at the millimeter scale of MR images. The ADC value reflects the degree of freedom of water movement at the cellular level, which is determined by architectural tissue properties such as cellular density, cellular arrangements, vascularity, extracellular space tissue viscosity, and nuclear/cytoplasmic ratio. Water movement is impeded in many tumors because of their high cellular density and T2 relaxation times, resulting in high signal intensity on diffusion-weighted images and low ADC values [1].

On conventional imaging the pelvic bone lesions appeared with a signal pattern not specific for sarcoidosis bone lesions or metastatic disease (low signal on T1-weighted images and high signal on STIR images). On diffusion-weighted imaging the pelvic bone lesions showed high signal, which is often seen in bone metastases, but the ADC (<700 µm2 /s) was too low to be suspicious for metastases from breast cancer [1], which enables to differentiate normal bone marrow from malignant marrow [17, 23, 24].

## **3. Conclusions**

Imaging gives an important contribution to the assessment of prognosis and follow-up in sarcoidosis. FDG-PET/CT is routinely used for the diagnosis, staging, and therapeutic assessment of several malignancies and becomes nowadays a relevant tool for the management of several infectious and inflammatory diseases, such as sarcoidosis. PET can also be a useful tool for the diagnosis of sarcoidosis by identifying potential biopsy sites in organs that might be accessible. FDG-PET/CT plays a crucial role in sarcoidosis disease, especially for the diagnosis of potentially rare extrapulmonary involvement, and is also an interesting tool for assessing therapeutic efficacy of inflammatory diseases and for management of patients.

#### **Conflict of interest**

The author declares no conflict of interest.

### **Thanks**

Dedicated to all people who made my dreams come true.

To my beloved parents for the unwavering faith that I would have achieved all the goals I had set for myself.

To those who love me, and loved me, and believed in me, giving me the strength to always go ahead and never give up, standing by my side even when things became difficult.

**43**

**Author details**

Marica Tina Maccarone

provided the original work is properly cited.

AUSL Pescara—Radiology Division, Spirito Santo Hospital Pescara, Italy

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: maccaronemarica@hotmail.com

*Early Diagnosis of Sarcoidosis*

*DOI: http://dx.doi.org/10.5772/intechopen.90523*

Often against the wind, but never against my heart.

*Early Diagnosis of Sarcoidosis DOI: http://dx.doi.org/10.5772/intechopen.90523*

*Sarcoidosis and Granulomatosis - Diagnosis and Management*

disease, reducing the specificity of (18) F-FDG-PET/CT when both sarcoidosis and a tumor, which may develop bone metastases, occur in the same patient. Bone assessment in sarcoidosis patients is also performed using MRI, commonly relying on T1-weighted and T2-weighted images. However, routine MRI is not reliable in

Multifocal skeletal sarcoidosis may present as a false positive for bone metastases on (18) F-FDG PET/CT since granulomatous bone marrow infiltration may have an uptake of (18) F-FDG, which mimics that of metastatic disease. When false positive findings on (18) F-FDG PET/CT cannot be totally excluded, biopsy or MRI may represent the second choice to achieve diagnosis. Since conventional MRI may not be accurate in distinguishing between sarcoidosis and metastatic bone lesions, it is possible to perform diffusion whole-body MRI: T1-weighted, T2-weighted STIR, and diffusion-weighted imaging (with different *b* values) [17]. The latter is able to evaluate microscopic tissue water motions average at the millimeter scale of MR images. The ADC value reflects the degree of freedom of water movement at the cellular level, which is determined by architectural tissue properties such as cellular density, cellular arrangements, vascularity, extracellular space tissue viscosity, and nuclear/cytoplasmic ratio. Water movement is impeded in many tumors because of their high cellular density and T2 relaxation times, resulting in high signal intensity on diffusion-weighted images and low ADC values [1]. On conventional imaging the pelvic bone lesions appeared with a signal pattern not specific for sarcoidosis bone lesions or metastatic disease (low signal on T1-weighted images and high signal on STIR images). On diffusion-weighted imaging the pelvic bone lesions showed high signal, which is often seen in bone metastases, but the ADC

/s) was too low to be suspicious for metastases from breast cancer [1], which

enables to differentiate normal bone marrow from malignant marrow [17, 23, 24].

Imaging gives an important contribution to the assessment of prognosis and follow-up in sarcoidosis. FDG-PET/CT is routinely used for the diagnosis, staging, and therapeutic assessment of several malignancies and becomes nowadays a relevant tool for the management of several infectious and inflammatory diseases, such as sarcoidosis. PET can also be a useful tool for the diagnosis of sarcoidosis by identifying potential biopsy sites in organs that might be accessible. FDG-PET/CT plays a crucial role in sarcoidosis disease, especially for the diagnosis of potentially rare extrapulmonary involvement, and is also an interesting tool for assessing therapeutic efficacy of inflammatory diseases and for management of patients.

To my beloved parents for the unwavering faith that I would have achieved all

To those who love me, and loved me, and believed in me, giving me the strength to always go ahead and never give up, standing by my side even when things became

differentiating sarcoidosis bone lesions from metastatic disease [17].

**42**

**Thanks**

difficult.

(<700 µm2

**3. Conclusions**

**Conflict of interest**

the goals I had set for myself.

The author declares no conflict of interest.

Dedicated to all people who made my dreams come true.

Often against the wind, but never against my heart.
