**Physiological Manifestation in Pulmonary Sarcoidosis**

### Kentaro Watanabe

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Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/55012

### **1. Introduction**

Sarcoidosis is a granulomatous disease involving multiple organs with unknown cause. More than 90% of patients with sarcoidosis have lung disease [1–3]. However, respiratory function in patients with sarcoidosis often remains normal, even when pulmonary parenchymal involvement is extensive. Not only the lung parenchyma but also the lung airways are involved, which sometimes makes it difficult to evaluate the relationship between functional impairment and morphological/imaging patterns.

Respiratory function impairment in sarcoidosis has not been considered to be a major concern in either clinical or basic research. However, the marked restrictive ventilatory impairment in sarcoidosis with end-stage pulmonary fibrosis is a serious problem in clinical practice.

Obstructive disease is another manifestation of respiratory function impairment in sarcoido‐ sis that is sometimes associated with the end-stage fibrosis of sarcoidosis, with marked reduction of vital capacity and total lung capacity. However, obstructive ventilatory impairment also appears without restrictive disease of sarcoidosis, especially in the early stage of sarcoidosis [4–6].

This chapter will review the functional impairment in patients with pulmonary sarcoidosis, especially restrictive and obstructive ventilatory impairments, taking the histological back‐ ground into consideration.

### **2. Restrictive impairment**

Restrictive impairment is mainly caused by extensive fibrosis secondary to sarcoid granulomas or by interstitial pneumonia coexistent with pulmonary sarcoidosis.

© 2013 Watanabe; licensee InTech. This is an open access article 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, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. 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, provided the original work is properly cited.

Histologically, sarcoidosis manifests itself as multiple nodules of nonnecrotizing granulomas consisting of epithelioid histiocytes and multinucleated giant cells with mononuclear inflam‐ matory cells at the periphery of the nodules. Granulomas are usually situated in the intersti‐ tium (Figures 1, 2), and sometimes in the air spaces (Figure 3) [7–9], thus forming spaceoccupying lesions. Granulomas are typically scattered along the lymphatic routes. Peribronchial and perivascular tissues are richly supplied by lymphatics, where granulomas grow larger (Figures 1, 2). The imaging pattern is, therefore, quite characteristic; that is, opacities are situated along the bronchovascular bundles. High-resolution computed tomog‐ raphy (HRCT) describes well multiple nodules located along airways and pulmonary vascu‐ latures and on the pleura, including the interlobar pleura (Figure 4). Sarcoid granulomas may spontaneously regress or become fibrotic (Figure 5).

sarcoid granulomas are preceded by lymphocytic infiltration or that interstitial pneumonia

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**Figure 3.** An epithelioid cell granuloma located in the peripheral airway. Another granuloma is embedded in the in‐

**Figure 4.** Chest CT scan of a 28-year-old man with pulmonary sarcoidosis. Small nodules are found along the bron‐ chial wall (short arrows) and pulmonary artery (arrowheads). Nodules are also found on the pleural surface, including

**Figure 5.** Nonnecrotizing epithelioid granulomas with giant cells are surrounded by concentric layers of fibrotic bundles.

Here, we present a 49-year-old woman with a nine-year history of progressive pulmonary sarcoidosis with stages from early cellular interstitial pneumonia to late fibrotic interstitial pneumonia. She underwent transbronchial lung biopsy at 40 years of age, when she noticed dyspnea and cough. Chest radiograph revealed bilateral diffuse ground-glass shadows and CT revealed ground-glass opacities along the bronchovascular bundles. The imaging features appeared like nonspecific interstitial pneumonia (Figures 6a and b). A transbronchial lung biopsy specimen collected at that time showed cellular interstitial pneumonia and focal

typically occurs in the early stage of sarcoidosis.

terstitium in the right lower quadrant (69-year-old woman).

the interlobar pleura (long arrows).

It is reasonable to hypothesize that restrictive impairment in sarcoidosis depends on the extent of parenchymal involvement of the granulomas, even if they later become fibrotic [10]. Generally, respiratory function worsens with more advanced disease stages, but the radio‐ graphic stage does not correlate well with the severity of respiratory function impairment [11].

**Figure 1.** Low-magnification view of pulmonary sarcoidosis in a biopsy specimen. Nodular lesions are situated along the bronchovascular bundles. (Courtesy of Dr. Thomas V. Colby, Mayo Clinic, Arizona, USA.)

**Figure 2.** High-magnification view of the specimen shown in Figure 1. Nonnecrotizing epithelioid granulomas sur‐ round a bronchiole. (Courtesy of Dr. Thomas V. Colby, Mayo Clinic, Arizona, USA.)

A mild interstitial mononuclear cell infiltration is said to occur occasionally in pulmonary sarcoidosis, but in practice this is rarely seen [12]. However, some investigators have paid attention to coexistent interstitial pneumonia in patients with sarcoidosis. Interstitial pneu‐ monia or secondary fibrosis in end-stage sarcoidosis may play a more important role in the restrictive impairment of sarcoidosis. Rosen et al. examined interstitial pneumonia in patients with sarcoidosis [13]. They found that the incidence of interstitial pneumonia decreases as the density of parenchymal granulomas increases, and that interstitial pneumonia is significantly more prevalent in patients with sarcoidosis of stage I than stages 2 or 3. They concluded that sarcoid granulomas are preceded by lymphocytic infiltration or that interstitial pneumonia typically occurs in the early stage of sarcoidosis.

Histologically, sarcoidosis manifests itself as multiple nodules of nonnecrotizing granulomas consisting of epithelioid histiocytes and multinucleated giant cells with mononuclear inflam‐ matory cells at the periphery of the nodules. Granulomas are usually situated in the intersti‐ tium (Figures 1, 2), and sometimes in the air spaces (Figure 3) [7–9], thus forming spaceoccupying lesions. Granulomas are typically scattered along the lymphatic routes. Peribronchial and perivascular tissues are richly supplied by lymphatics, where granulomas grow larger (Figures 1, 2). The imaging pattern is, therefore, quite characteristic; that is, opacities are situated along the bronchovascular bundles. High-resolution computed tomog‐ raphy (HRCT) describes well multiple nodules located along airways and pulmonary vascu‐ latures and on the pleura, including the interlobar pleura (Figure 4). Sarcoid granulomas may

It is reasonable to hypothesize that restrictive impairment in sarcoidosis depends on the extent of parenchymal involvement of the granulomas, even if they later become fibrotic [10]. Generally, respiratory function worsens with more advanced disease stages, but the radio‐ graphic stage does not correlate well with the severity of respiratory function impairment [11].

**Figure 1.** Low-magnification view of pulmonary sarcoidosis in a biopsy specimen. Nodular lesions are situated along

**Figure 2.** High-magnification view of the specimen shown in Figure 1. Nonnecrotizing epithelioid granulomas sur‐

A mild interstitial mononuclear cell infiltration is said to occur occasionally in pulmonary sarcoidosis, but in practice this is rarely seen [12]. However, some investigators have paid attention to coexistent interstitial pneumonia in patients with sarcoidosis. Interstitial pneu‐ monia or secondary fibrosis in end-stage sarcoidosis may play a more important role in the restrictive impairment of sarcoidosis. Rosen et al. examined interstitial pneumonia in patients with sarcoidosis [13]. They found that the incidence of interstitial pneumonia decreases as the density of parenchymal granulomas increases, and that interstitial pneumonia is significantly more prevalent in patients with sarcoidosis of stage I than stages 2 or 3. They concluded that

the bronchovascular bundles. (Courtesy of Dr. Thomas V. Colby, Mayo Clinic, Arizona, USA.)

round a bronchiole. (Courtesy of Dr. Thomas V. Colby, Mayo Clinic, Arizona, USA.)

spontaneously regress or become fibrotic (Figure 5).

166 Sarcoidosis

**Figure 3.** An epithelioid cell granuloma located in the peripheral airway. Another granuloma is embedded in the in‐ terstitium in the right lower quadrant (69-year-old woman).

**Figure 4.** Chest CT scan of a 28-year-old man with pulmonary sarcoidosis. Small nodules are found along the bron‐ chial wall (short arrows) and pulmonary artery (arrowheads). Nodules are also found on the pleural surface, including the interlobar pleura (long arrows).

**Figure 5.** Nonnecrotizing epithelioid granulomas with giant cells are surrounded by concentric layers of fibrotic bundles.

Here, we present a 49-year-old woman with a nine-year history of progressive pulmonary sarcoidosis with stages from early cellular interstitial pneumonia to late fibrotic interstitial pneumonia. She underwent transbronchial lung biopsy at 40 years of age, when she noticed dyspnea and cough. Chest radiograph revealed bilateral diffuse ground-glass shadows and CT revealed ground-glass opacities along the bronchovascular bundles. The imaging features appeared like nonspecific interstitial pneumonia (Figures 6a and b). A transbronchial lung biopsy specimen collected at that time showed cellular interstitial pneumonia and focal aggregates of epithelioid cells with giant cells, which is compatible with sarcoidosis (Figures 6c and d). But for the sarcoid granulomas, the histological features would be similar to those of cellular pattern of nonspecific interstitial pneumonia, a subset of idiopathic interstitial pneumonias [14]. The ground-glass opacities on chest CT were attributable to the infiltration of mononuclear cells in the alveolar septa. At that stage, restrictive impairment and gas exchange impairment were prominent (Table 1). The pathophysiological mechanisms under‐ lying the functional impairment described in Figures 6c and 6d are probably similar to those of the cellular interstitial pneumonias described above. In contrast to the decrease in DLco, DLco/VA was normal. The decrease in DLco observed in the patient can be mainly attributed to diffusion impairment caused by thickened alveolar septa.

(d)

(e) (f)

(g)

the 100% level for FVC as predicted for the patient at year 0.

**Figure 6.** Chest radiograph (a) of a woman with sarcoidosis showing diffuse ground-glass opacities in the bilateral lung fields. Chest CT (b) of the same woman showing ground-glass opacities mainly along the bronchovascular bun‐ dles. (c) A transbronchial lung biopsy specimen obtained from the same woman. Alveolar septa are thickened. Granu‐ lomas are sparsely found. (d) A high-magnification view of Figure 6c. Alveolar septa are thickened with mononuclear cell infiltration. Small foci of epithelioid granulomas are found on the right side of the specimen. Thickened alveolar septa may be the barrier to gas exchange. Chest radiograph (e) and CT (f) of the woman with sarcoidosis, which were taken 7.1 years after the first CT (Figure b). Ground-glass opacities disappeared, but many bronchi were densely con‐ centrated in the left lung base, forming traction bronchiectasis. (g) Yearly decline of FVC in the course of the 8.6 years of follow-up of advanced pulmonary sarcoidosis. The annual decline of FVC calculated using linear regression was 38 mL (2.9% of the initial FVC at year 0), which is far milder than that observed in IPF. The top of the vertical axis shows

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Restrictive impairment and gas exchange impairment are serious presentations in ad‐ vanced sarcoidosis, as is the case in IPF. However, honeycomb-like cysts, which are the imaging hallmark of IPF/UIP, are atypical radiographic manifestations in sarcoidosis [11]. Moreover, the most important diagnostic feature in sarcoidosis is the prognosis or the slope of the deterioration of respiratory functions, as seen in Figure 6g. Nardi et al. reported that

At the later stage, the ground-glass opacities disappeared and traction bronchiectasis became the main imaging finding (Figures 6e and 6f), although outer-zone-dominant honeycombing at both lung bases, which is the hallmark of usual interstitial pneumonia (UIP), was absent. Restrictive impairment progressed during the 8.6 years of follow-up, but the annual decrease in FVC was gradual (Table 2 and Figure 6g).

To summarize the disease of this woman, ground-glass opacities at the initial stage were replaced by traction bronchiectasis in the course of 8.6 years of follow-up. It is probable that cellular interstitial pneumonia associated with pulmonary sarcoidosis progressed to fibrosing interstitial pneumonia with gradual decrease in FVC. However, the pulmonary fibrosis in this case did not look like idiopathic pulmonary fibrosis (IPF).

aggregates of epithelioid cells with giant cells, which is compatible with sarcoidosis (Figures 6c and d). But for the sarcoid granulomas, the histological features would be similar to those of cellular pattern of nonspecific interstitial pneumonia, a subset of idiopathic interstitial pneumonias [14]. The ground-glass opacities on chest CT were attributable to the infiltration of mononuclear cells in the alveolar septa. At that stage, restrictive impairment and gas exchange impairment were prominent (Table 1). The pathophysiological mechanisms under‐ lying the functional impairment described in Figures 6c and 6d are probably similar to those of the cellular interstitial pneumonias described above. In contrast to the decrease in DLco, DLco/VA was normal. The decrease in DLco observed in the patient can be mainly attributed

At the later stage, the ground-glass opacities disappeared and traction bronchiectasis became the main imaging finding (Figures 6e and 6f), although outer-zone-dominant honeycombing at both lung bases, which is the hallmark of usual interstitial pneumonia (UIP), was absent. Restrictive impairment progressed during the 8.6 years of follow-up, but the annual decrease

To summarize the disease of this woman, ground-glass opacities at the initial stage were replaced by traction bronchiectasis in the course of 8.6 years of follow-up. It is probable that cellular interstitial pneumonia associated with pulmonary sarcoidosis progressed to fibrosing interstitial pneumonia with gradual decrease in FVC. However, the pulmonary fibrosis in this

(a) (b)

(c)

to diffusion impairment caused by thickened alveolar septa.

case did not look like idiopathic pulmonary fibrosis (IPF).

in FVC was gradual (Table 2 and Figure 6g).

168 Sarcoidosis

**Figure 6.** Chest radiograph (a) of a woman with sarcoidosis showing diffuse ground-glass opacities in the bilateral lung fields. Chest CT (b) of the same woman showing ground-glass opacities mainly along the bronchovascular bun‐ dles. (c) A transbronchial lung biopsy specimen obtained from the same woman. Alveolar septa are thickened. Granu‐ lomas are sparsely found. (d) A high-magnification view of Figure 6c. Alveolar septa are thickened with mononuclear cell infiltration. Small foci of epithelioid granulomas are found on the right side of the specimen. Thickened alveolar septa may be the barrier to gas exchange. Chest radiograph (e) and CT (f) of the woman with sarcoidosis, which were taken 7.1 years after the first CT (Figure b). Ground-glass opacities disappeared, but many bronchi were densely con‐ centrated in the left lung base, forming traction bronchiectasis. (g) Yearly decline of FVC in the course of the 8.6 years of follow-up of advanced pulmonary sarcoidosis. The annual decline of FVC calculated using linear regression was 38 mL (2.9% of the initial FVC at year 0), which is far milder than that observed in IPF. The top of the vertical axis shows the 100% level for FVC as predicted for the patient at year 0.

Restrictive impairment and gas exchange impairment are serious presentations in ad‐ vanced sarcoidosis, as is the case in IPF. However, honeycomb-like cysts, which are the imaging hallmark of IPF/UIP, are atypical radiographic manifestations in sarcoidosis [11]. Moreover, the most important diagnostic feature in sarcoidosis is the prognosis or the slope of the deterioration of respiratory functions, as seen in Figure 6g. Nardi et al. reported that the 10-year survival of patients with stage IV sarcoidosis was 84.1%, which is far better than that of IPF [15].

of end-stage sarcoidosis, and two of these four patients had a pattern that was indistinguish‐ able from the UIP pattern, with fibroblastic foci. Furthermore, these four patients had under‐ gone lung transplantation with a shorter time to transplant than the remaining three patients without interstitial pneumonia. These results raise the possibility that there is a subset of patients with sarcoidosis that progresses to pulmonary fibrosis resembling IPF/UIP with

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Stage IV sarcoidosis might encompass two subsets of end-stage sarcoidosis, as described above: sarcoid granuloma-derived secondary fibrosis and fibrosing interstitial pneumonia,

Although sarcoidosis involving thoracic lymph nodes and pulmonary parenchyma is familiar to most pulmonologists, airway involvement is often overlooked [19]. Airway dysfunction is an important component of the disease, but is often ignored when the interstitial disease is

As sarcoidosis commonly affects the pulmonary parenchyma, one could often misunderstand that airways are less commonly involved and restrictive impairment occurs more frequently than does obstructive impairment. However, airway involvement, as judged based on clinical features, physiological testing, imaging techniques, bronchoscopy, and airway mucosal biopsy, has been observed in two-thirds of patients with sarcoidosis [19]. According to a case– control etiologic study of sarcoidosis consisting of 736 patients [3], the majority of patients (477/736) had normal FVC defined as > 80% of FVC, in contrast to a smaller percentage of normal FEV1/FVC% defined as > 80% of FEV1/FVC% (340/736). As described above, clinicians should notice that airflow obstruction is more frequently encountered than is restrictive impairment and is the commonest physiological abnormality in patients with sarcoidosis in

Airway sarcoidosis occurring over the entire length of the respiratory tract – from the upper airway to the lower airway, including the respiratory bronchioles – causes a broad spectrum of airway dysfunction or obstructive ventilatory impairment [20]. In addition, airway sarcoi‐ dosis causing obstructive impairment and lung parenchymal sarcoidosis causing restrictive

As airway obstruction in sarcoidosis is reported to be associated with increased morbidity and increased mortality risk [21, 22], obstructive impairment, as well as restrictive impairment,

In this section, the trachea is conveniently included in the upper airway. The nose, sinuses, oropharynx, supraglottic structures, larynx, and trachea are less frequently affected with

impairment could modify their physiological manifestations mutually.

should be checked carefully in the routine follow-up.

**2.** Upper-airway sarcoidosis

which is not secondary but coexistent, although it may be rare.

**1.** Obstructive impairment as a minor component of functional impairment?

poorer prognosis [18].

dominant.

clinical practice.

**3. Obstructive impairment**


FVC: forced vital capacity; FEV1: forced expiratory volume in 1 second; TLC: total lung capacity; FRC: functional reserve capacity; RV: reserve volumeDLco: diffusing capacity of carbon monoxide; DLco/VA: diffusing capacity of carbon monoxide/alveolar volume

**Table 1.** Respiratory function data for a 40-year-old woman with sarcoidosis


**Table 2.** Spirometry 8.6 years after the first measurement (Table 1)

In contrast to patients with sarcoidosis associated with interstitial pneumonia, functional impairment in patients with sarcoidosis without interstitial pneumonia may be less extensive, if present. We frequently encounter patients with sarcoidosis who have extensive imaging findings, but almost normal respiratory function. Such differences in functional impairment raise the possibility that interstitial pneumonia could be independently coexistent with pulmonary sarcoidosis [16], although the histological findings in which sarcoid granulomas are embedded in cellular interstitial pneumonia, as shown in Figures 6c and d, suggest that interstitial pneumonia is one of the fundamental histological manifestations of sarcoidosis.

Shigemitsu et al. reviewed the microscopic slides of explanted lungs to examine chronic interstitial pneumonia (interstitial infiltration by lymphocytes and/or plasma cells) in seven patients with end-stage sarcoidosis who ultimately underwent lung transplantation [17]. In their report, four of the seven patients had diffuse interstitial pneumonia, which was atypical of end-stage sarcoidosis, and two of these four patients had a pattern that was indistinguish‐ able from the UIP pattern, with fibroblastic foci. Furthermore, these four patients had under‐ gone lung transplantation with a shorter time to transplant than the remaining three patients without interstitial pneumonia. These results raise the possibility that there is a subset of patients with sarcoidosis that progresses to pulmonary fibrosis resembling IPF/UIP with poorer prognosis [18].

Stage IV sarcoidosis might encompass two subsets of end-stage sarcoidosis, as described above: sarcoid granuloma-derived secondary fibrosis and fibrosing interstitial pneumonia, which is not secondary but coexistent, although it may be rare.

### **3. Obstructive impairment**

the 10-year survival of patients with stage IV sarcoidosis was 84.1%, which is far better than

FVC mL (% pred) 1210 mL (44%)

FEV1 mL (% pred) 870 mL (36%)

TLC mL (% pred) 2510 mL (68%)

FRC mL (% pred) 1160mL (53%)

RV mL (% pred) 810mL (70%)

DLco mL/min/mmHg (% pred) 11.3 (54%)

DLco/VA mL/min/mmHg/L (%pred) 5.49 (103%)

**Table 1.** Respiratory function data for a 40-year-old woman with sarcoidosis

FVC mL (% pred) 970 mL (38%)

FEV1 mL (% pred) 800 mL (37%)

FEV/FVC % 82%

**Table 2.** Spirometry 8.6 years after the first measurement (Table 1)

FVC: forced vital capacity; FEV1: forced expiratory volume in 1 second; TLC: total lung capacity; FRC: functional reserve capacity; RV: reserve volumeDLco: diffusing capacity of carbon monoxide; DLco/VA: diffusing capacity of carbon

In contrast to patients with sarcoidosis associated with interstitial pneumonia, functional impairment in patients with sarcoidosis without interstitial pneumonia may be less extensive, if present. We frequently encounter patients with sarcoidosis who have extensive imaging findings, but almost normal respiratory function. Such differences in functional impairment raise the possibility that interstitial pneumonia could be independently coexistent with pulmonary sarcoidosis [16], although the histological findings in which sarcoid granulomas are embedded in cellular interstitial pneumonia, as shown in Figures 6c and d, suggest that interstitial pneumonia is one of the fundamental histological manifestations of sarcoidosis.

Shigemitsu et al. reviewed the microscopic slides of explanted lungs to examine chronic interstitial pneumonia (interstitial infiltration by lymphocytes and/or plasma cells) in seven patients with end-stage sarcoidosis who ultimately underwent lung transplantation [17]. In their report, four of the seven patients had diffuse interstitial pneumonia, which was atypical

FEV/FVC % 71%

that of IPF [15].

170 Sarcoidosis

monoxide/alveolar volume

**1.** Obstructive impairment as a minor component of functional impairment?

Although sarcoidosis involving thoracic lymph nodes and pulmonary parenchyma is familiar to most pulmonologists, airway involvement is often overlooked [19]. Airway dysfunction is an important component of the disease, but is often ignored when the interstitial disease is dominant.

As sarcoidosis commonly affects the pulmonary parenchyma, one could often misunderstand that airways are less commonly involved and restrictive impairment occurs more frequently than does obstructive impairment. However, airway involvement, as judged based on clinical features, physiological testing, imaging techniques, bronchoscopy, and airway mucosal biopsy, has been observed in two-thirds of patients with sarcoidosis [19]. According to a case– control etiologic study of sarcoidosis consisting of 736 patients [3], the majority of patients (477/736) had normal FVC defined as > 80% of FVC, in contrast to a smaller percentage of normal FEV1/FVC% defined as > 80% of FEV1/FVC% (340/736). As described above, clinicians should notice that airflow obstruction is more frequently encountered than is restrictive impairment and is the commonest physiological abnormality in patients with sarcoidosis in clinical practice.

Airway sarcoidosis occurring over the entire length of the respiratory tract – from the upper airway to the lower airway, including the respiratory bronchioles – causes a broad spectrum of airway dysfunction or obstructive ventilatory impairment [20]. In addition, airway sarcoi‐ dosis causing obstructive impairment and lung parenchymal sarcoidosis causing restrictive impairment could modify their physiological manifestations mutually.

As airway obstruction in sarcoidosis is reported to be associated with increased morbidity and increased mortality risk [21, 22], obstructive impairment, as well as restrictive impairment, should be checked carefully in the routine follow-up.

**2.** Upper-airway sarcoidosis

In this section, the trachea is conveniently included in the upper airway. The nose, sinuses, oropharynx, supraglottic structures, larynx, and trachea are less frequently affected with sarcoidosis than is the lower airway [1, 2, 19, 20, 23]. The presenting symptoms of laryngeal sarcoidosis are dysphagia, hoarseness, dyspnea, stridor, and cough [20, 23]. Hoarseness can occur from the granulomatous lymphadenopathy in the mediastinum compressing recurrent nerve or from polyneuropathy by granulomatous inflammation of the vagus nerve [24–26]. Sometimes, these may cause respiratory distress, requiring tracheostomy.

Obstructive sleep apnea syndrome occurs with increased frequency in patients with laryngeal sarcoidosis. Turner et al. reported that 14 of 83 consecutive patients with sarcoidosis (17%) had sleep apnea, which was significantly more frequent than that observed in the general popu‐ lation [27]. It may be secondary to laryngeal sarcoidosis, or may result from obesity associated with the long-term administration of corticosteroids.

Tracheal stenosis and dystonia are the primary manifestations of tracheal sarcoidosis, although tracheal involvement is rare compared with sarcoidosis of lobar or segmental bronchi. Cough is the main symptom.

The flow-volume curve is quite characteristic. Sarcoid lesions located in the upper airway cause flattening of the inspiratory and/or expiratory loops of the flow-volume curve, although this is not specific to sarcoidosis. In general, fixed airway stenosis caused by upper-airway sarcoidosis, regardless of whether it is extrathoracic or intrathoracic, induces flattening of both the inspiratory and expiratory loops. Variable extrathoracic or intrathoracic stenosis induces flattening of the inspiratory and expiratory loops of the flow-volume curve, respectively [28, 29] (Figures 7a–d).

#### **3.** Lower-airway sarcoidosis

As described above, the lower airways are also affected, similarly to the lung parenchyma. As granulomatous lesions also occur in the bronchial mucosa and submucosa [30], endoscop‐ ic examination frequently identifies these submucosal lesions. Endoscopic examination also identifies indirect findings derived from peribronchial lesions, such as extrinsic bronchial compression by enlarged lymph nodes. The morphological characteristics of airway involvement include bronchial stenosis, mucosal nodularity, hypervascularity, and mucos‐ al edema (Figures 8a–d) [19, 20, 23, 31–33]. Some investigators have emphasized the mucosal vessels that run perpendicular to cartilaginous rings as an early manifestation of sarcoido‐ sis (Figure 8c) [31, 32, 34].

Bronchial mucosal biopsy confirms the histological diagnosis (Figure 9). These lesions can lead to respiratory symptoms and signs, such as cough and wheezes in auscultation, which are often misdiagnosed as asthma.

Lower-airway involvement in sarcoidosis may lead to airflow limitation (Figure 10, Table 3). However, bronchial mucosal findings in fiberoptic bronchoscopy are not always correlated with the severity of airflow limitation, because airflow limitation is due not only to proximal airway lesions but also to distal airway lesions that are not visible using conventional fiberoptic bronchoscopy. According to the report of Stjernberg et al., an obstructive spirometry pattern was found in only three patients among 21 patients with bronchial sarcoidosis that was confirmed by bronchoscopy [5].

**Figure 8.** Endoscopic findings of bronchial sarcoidosis. a) Flattened and pale-colored plaques arising from the bron‐ chial mucosa, forming a "cobblestone appearance" (right main bronchus, 38-year-old woman), b) Bronchial lumen is crowded by pale-colored multiple nodules (left upper lobe bronchus, 61-year-old woman), c) Mucosal hypervasculari‐ ty with vessels running perpendicular to cartilaginous rings (left lingular bronchus, 38-year-old man), d) Network for‐ mation of mucosal vessels in the left main bronchus, and mucosal edema of the left second carina (29-year-old man).

**Figure 7.** a) Normal flow-volume curve, b) Variable extrathoracic stenosis, c)Variable intrathoracic stenosis, d)Fixed ex‐

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trathoracic or intrathoracic stenosis.

sarcoidosis than is the lower airway [1, 2, 19, 20, 23]. The presenting symptoms of laryngeal sarcoidosis are dysphagia, hoarseness, dyspnea, stridor, and cough [20, 23]. Hoarseness can occur from the granulomatous lymphadenopathy in the mediastinum compressing recurrent nerve or from polyneuropathy by granulomatous inflammation of the vagus nerve [24–26].

Obstructive sleep apnea syndrome occurs with increased frequency in patients with laryngeal sarcoidosis. Turner et al. reported that 14 of 83 consecutive patients with sarcoidosis (17%) had sleep apnea, which was significantly more frequent than that observed in the general popu‐ lation [27]. It may be secondary to laryngeal sarcoidosis, or may result from obesity associated

Tracheal stenosis and dystonia are the primary manifestations of tracheal sarcoidosis, although tracheal involvement is rare compared with sarcoidosis of lobar or segmental bronchi. Cough

The flow-volume curve is quite characteristic. Sarcoid lesions located in the upper airway cause flattening of the inspiratory and/or expiratory loops of the flow-volume curve, although this is not specific to sarcoidosis. In general, fixed airway stenosis caused by upper-airway sarcoidosis, regardless of whether it is extrathoracic or intrathoracic, induces flattening of both the inspiratory and expiratory loops. Variable extrathoracic or intrathoracic stenosis induces flattening of the inspiratory and expiratory loops of the flow-volume curve, respectively [28,

As described above, the lower airways are also affected, similarly to the lung parenchyma. As granulomatous lesions also occur in the bronchial mucosa and submucosa [30], endoscop‐ ic examination frequently identifies these submucosal lesions. Endoscopic examination also identifies indirect findings derived from peribronchial lesions, such as extrinsic bronchial compression by enlarged lymph nodes. The morphological characteristics of airway involvement include bronchial stenosis, mucosal nodularity, hypervascularity, and mucos‐ al edema (Figures 8a–d) [19, 20, 23, 31–33]. Some investigators have emphasized the mucosal vessels that run perpendicular to cartilaginous rings as an early manifestation of sarcoido‐

Bronchial mucosal biopsy confirms the histological diagnosis (Figure 9). These lesions can lead to respiratory symptoms and signs, such as cough and wheezes in auscultation, which are

Lower-airway involvement in sarcoidosis may lead to airflow limitation (Figure 10, Table 3). However, bronchial mucosal findings in fiberoptic bronchoscopy are not always correlated with the severity of airflow limitation, because airflow limitation is due not only to proximal airway lesions but also to distal airway lesions that are not visible using conventional fiberoptic bronchoscopy. According to the report of Stjernberg et al., an obstructive spirometry pattern was found in only three patients among 21 patients with bronchial sarcoidosis that was

Sometimes, these may cause respiratory distress, requiring tracheostomy.

with the long-term administration of corticosteroids.

is the main symptom.

172 Sarcoidosis

29] (Figures 7a–d).

**3.** Lower-airway sarcoidosis

sis (Figure 8c) [31, 32, 34].

often misdiagnosed as asthma.

confirmed by bronchoscopy [5].

**Figure 7.** a) Normal flow-volume curve, b) Variable extrathoracic stenosis, c)Variable intrathoracic stenosis, d)Fixed ex‐ trathoracic or intrathoracic stenosis.

**Figure 8.** Endoscopic findings of bronchial sarcoidosis. a) Flattened and pale-colored plaques arising from the bron‐ chial mucosa, forming a "cobblestone appearance" (right main bronchus, 38-year-old woman), b) Bronchial lumen is crowded by pale-colored multiple nodules (left upper lobe bronchus, 61-year-old woman), c) Mucosal hypervasculari‐ ty with vessels running perpendicular to cartilaginous rings (left lingular bronchus, 38-year-old man), d) Network for‐ mation of mucosal vessels in the left main bronchus, and mucosal edema of the left second carina (29-year-old man).

Airflow obstruction is reported in 4–63% of patients with sarcoidosis, depending on the spirometry criteria used by different authors [3, 5, 6, 10, 22, 35–40]. Sharma et al. reported that airway obstruction defined as less than 75% of FEV1/FVC was found in 63% of black American nonsmoking patients with sarcoidosis [37]. Airflow obstruction defined as less than 70% of FEV1/FVC, the criterion for COPD, occurs in 9–14% of patients with sarcoidosis [3, 39]. We demonstrated that 21% of patients with sarcoidosis (12/56) had airflow obstruction, which was defined as less than 70% of FEV1/FVC, obtained at least once in repeated spirometry during the entire follow-up period [41].

FVC mL (% pred) 3150 mL (120%) FEV1 mL (% pred) 1990 mL (94%)

TLC mL (% pred) 4540 mL (115%) FRC mL (% pred) 2710 mL (105%) RV mL (% pred) 1240 mL (81%) DLco mL/min/mmHg (% pred) 21.3 (137%) DLco/VA mL/min/mmHg/L (%pred) 5.63 (121%)

FVC: forced vital capacity; FEV1: forced expiratory volunme in 1 second; TLC: total lung capacity; FRC: functional reserve capacity; RV: reserve volume; DLco: diffusing capacity of carbon monoxide; DLco/VA: diffusing capacity of carbon

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As described above, airflow obstruction is frequently encountered in sarcoidosis. Lavergne et al. demonstrated that airway obstruction by sarcoid granulomas in the bronchial mucosa that were histologically confirmed via endobronchial biopsy was partially or completely reversed by steroid treatment, with improved pulmonary symptoms [21]. However, airflow obstruction in sarcoidosis is often refractory to inhaled steroid or bronchodilator therapy in clinical practice [20, 23, 38, 39, 41]. This presentation is not likely to be caused by coexistent asthma or COPD, because of its poor response to inhaled steroids and/or β-agonists. At what level of the airways

Airways with endobronchial lesions that are visible on fiberoptic bronchoscopy are not the only airways that are responsible for airflow obstruction. Small airways or the lung paren‐ chyma may also be involved in airflow obstruction. In general, the extent of decreased attenuation with a mosaic pattern is related to small airway disease, whereas a reticular pattern is considered to be a typical pattern of pulmonary fibrosis on CT. Air trapping, which presents as decreased attenuation exaggerated at expiratory CT, is a common feature of sarcoidosis, and there have been reports examining the correlation between air trapping and airflow obstruction [42, 43]. However, Hansell et al. reported that airflow obstruction is more closely related to a reticular pattern than to the extent of decreased attenuation on expiratory CT [44]. It is possible that progression to fibrosis of granulomatous inflammation adjacent to the small

As described above, obstructive impairment appears at an early stage of sarcoidosis and also with advancing radiographic stage. The efficacy of treatment may depend on the anatomical

sites of sarcoid granulomas, associated fibrosis, and severity of the symptoms.

FEV/FVC % 63%

**Table 3.** Respiratory function data for a 61-year-old woman with sarcoidosis

airways is critically associated with airflow obstruction.

**4. Treatment of obstructive impairment**

monoxide/alveolar volume

does airflow obstruction occur?

Airflow obstruction is often associated with an advanced stage of sarcoidosis or decreased VC and FVC [39], but occurs without any relationship to radiographic stage or restrictive impair‐ ment [6, 37]. Small airway dysfunction is common in early sarcoidosis without restrictive defects [4–6]. The previous investigations described above tell us that airflow obstruction occurs in all stages of sarcoidosis and should always be looked for in patients with sarcoidosis who have respiratory symptoms [38].

**Figure 9.** An epithelioid cell granuloma obtained using bronchial mucosal biopsy.

**Figure 10.** Flow-volume curve of a 61-year-old woman with bronchial sarcoidosis. Her mucosal finding under bron‐ choscopy is shown in Figure 10b. She never smoked and the expiratory flow is reduced, with a downward convex, as observed bronchial asthma. However, FEV1 did not significantly improve after the inhalation of a β-2 agonist (thick line: basal flow-volume curve; thin line: flow-volume curve after inhalation of salbutamol).


FVC: forced vital capacity; FEV1: forced expiratory volunme in 1 second; TLC: total lung capacity; FRC: functional reserve capacity; RV: reserve volume; DLco: diffusing capacity of carbon monoxide; DLco/VA: diffusing capacity of carbon monoxide/alveolar volume

**Table 3.** Respiratory function data for a 61-year-old woman with sarcoidosis

Airflow obstruction is reported in 4–63% of patients with sarcoidosis, depending on the spirometry criteria used by different authors [3, 5, 6, 10, 22, 35–40]. Sharma et al. reported that airway obstruction defined as less than 75% of FEV1/FVC was found in 63% of black American nonsmoking patients with sarcoidosis [37]. Airflow obstruction defined as less than 70% of FEV1/FVC, the criterion for COPD, occurs in 9–14% of patients with sarcoidosis [3, 39]. We demonstrated that 21% of patients with sarcoidosis (12/56) had airflow obstruction, which was defined as less than 70% of FEV1/FVC, obtained at least once in repeated spirometry during

Airflow obstruction is often associated with an advanced stage of sarcoidosis or decreased VC and FVC [39], but occurs without any relationship to radiographic stage or restrictive impair‐ ment [6, 37]. Small airway dysfunction is common in early sarcoidosis without restrictive defects [4–6]. The previous investigations described above tell us that airflow obstruction occurs in all stages of sarcoidosis and should always be looked for in patients with sarcoidosis

**Figure 10.** Flow-volume curve of a 61-year-old woman with bronchial sarcoidosis. Her mucosal finding under bron‐ choscopy is shown in Figure 10b. She never smoked and the expiratory flow is reduced, with a downward convex, as observed bronchial asthma. However, FEV1 did not significantly improve after the inhalation of a β-2 agonist (thick

line: basal flow-volume curve; thin line: flow-volume curve after inhalation of salbutamol).

the entire follow-up period [41].

174 Sarcoidosis

who have respiratory symptoms [38].

**Figure 9.** An epithelioid cell granuloma obtained using bronchial mucosal biopsy.

As described above, airflow obstruction is frequently encountered in sarcoidosis. Lavergne et al. demonstrated that airway obstruction by sarcoid granulomas in the bronchial mucosa that were histologically confirmed via endobronchial biopsy was partially or completely reversed by steroid treatment, with improved pulmonary symptoms [21]. However, airflow obstruction in sarcoidosis is often refractory to inhaled steroid or bronchodilator therapy in clinical practice [20, 23, 38, 39, 41]. This presentation is not likely to be caused by coexistent asthma or COPD, because of its poor response to inhaled steroids and/or β-agonists. At what level of the airways does airflow obstruction occur?

Airways with endobronchial lesions that are visible on fiberoptic bronchoscopy are not the only airways that are responsible for airflow obstruction. Small airways or the lung paren‐ chyma may also be involved in airflow obstruction. In general, the extent of decreased attenuation with a mosaic pattern is related to small airway disease, whereas a reticular pattern is considered to be a typical pattern of pulmonary fibrosis on CT. Air trapping, which presents as decreased attenuation exaggerated at expiratory CT, is a common feature of sarcoidosis, and there have been reports examining the correlation between air trapping and airflow obstruction [42, 43]. However, Hansell et al. reported that airflow obstruction is more closely related to a reticular pattern than to the extent of decreased attenuation on expiratory CT [44]. It is possible that progression to fibrosis of granulomatous inflammation adjacent to the small airways is critically associated with airflow obstruction.

### **4. Treatment of obstructive impairment**

As described above, obstructive impairment appears at an early stage of sarcoidosis and also with advancing radiographic stage. The efficacy of treatment may depend on the anatomical sites of sarcoid granulomas, associated fibrosis, and severity of the symptoms.

Upper-airway or tracheal sarcoidosis with airway stenosis needs systemic corticosteroids. In some cases, methotrexate or cytotoxic drugs, such as azathiopurine, may be added. Laryngeal sarcoidosis may cause life-threatening upper-airway obstruction. Surgical intervention is indicated for patients with well-localized, life-threatening lesions. When stridor is present, emergent tracheostomy may be needed [20, 45].

There is no specific therapy for PH associated with sarcoidosis. The management of sarcoidosis with PH mainly relies on supportive therapy (supplemental O2 and diuretics, as needed) [52].

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177

Patients with "out of proportion" pulmonary hypertension (characterized by dyspnea insufficiently explained by lung mechanical disturbances and mean pulmonary artery pressure ≥ 40–45 mmHg at rest) should be referred to expert centers and enrolled in clinical trials of pulmonary artery hypertension-specific drugs [55]. Endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and intravenous epoprosterol, etc., have been tried, and some patients experienced a beneficial effect. However, large-scale prospective clinical trials

Department of Respiratory Medicine, Fukuoka University School of Medicine, Fukuoka,

[1] Hunnighake GW, Costabel U, Ando M, et al. ATS/ERS/WASOG Statement on Sarcoi‐

[2] Hunnighake GW, Costabel U, Ando M, et al. Statement on Sarcoidosis. Am J Respir

[3] Baughman RP, Teirstein AS, Judson MA, et al. Clinical characteristics in a case con‐ trol study of sarcoidosis. Am J Respir Crit Care Med 2001; 164(10 Pt 1): 1885-1889.

[4] Dines D and Stubbs SE. Obstructive disease of the airways associated with stage I

[5] Stjernberg N and Thunell M. Pulmonary function in patients with endobronchial sar‐

[6] Argyropoulou PK, Patakas DA, Louridas GE. Airway function in stage I and stage II

[7] Shigematsu N, Emori K, Matsuba K, et al. Clinicopathologic characteristics of pulmo‐

dosis. Sarcoidosis Vasc Diffuse Lung Dis 1999; 16: 149-173.

Lung transplantation is now an important therapeutic option for these patients [53].

are needed before these therapies can be universally adopted.

Address all correspondence to: watanabe@fukuoka-u.ac.jp

Crit Care Med 1999; 160: 736-755.

sarcoidosis. Mayo Clin Proc 1978; 53: 788-791.

coidosis. Acta Med Scand 1984; 215:121-126.

pulmonary sarcoidosis. Respiration 1984; 46: 17-25.

nary acinar sarcoidosis. Chest 1978; 73: 186-188.

**Author details**

Kentaro Watanabe

Japan

**References**

As the symptoms of bronchial sarcoidosis are, if present, cough and wheezing, and spirometry shows reduced rate of FEV1/FVC, which is misdiagnosed as asthma, inhaled β2-agonists and/ or corticosteroids are often administered. However, we have often experienced unfavorable results in such cases, especially when parenchymal lesions are associated with the condition.

As described above, Lavergne et al. [21] examined the effect of systemic steroid therapy for patients who had histologically proven bronchial sarcoidosis with airflow obstruction (< 70% of FEV1/FVC), but their radiographic stages were 1 to 3. They obtained a favorable result after administration of 0.6 mg/kg of oral corticosteroids initially, and concluded that airflow obstruction by bronchial sarcoidosis without fibrosis-related airway obstruction is treatable.

### **5. Airway hyperreactivity**

The prevalence of airway hyperreactivity, as demonstrated by a positive methacholine or histamine challenge test, is significantly higher in patients with sarcoidosis compared with normal controls [46–49]. It is unclear whether airway hyperreactivity is a physiological manifestation of endobronchial sarcoidosis or is due to concomitant asthma [20]. However, Wilsher et al. examined the prevalence of asthma in patients with sarcoidosis and demon‐ strated that it was the same as that observed in the normal population [50]. Airway hyper‐ reactivity in sarcoidosis and asthma can be distinguished by the response to inhaled corticosteroids and β2-agonists. Airway hyperreactivity associated with asthma is improved by these agents, whereas airway hyperreactivity caused by sarcoidosis requires oral cortico‐ steroids [20, 47, 48].

### **6. Pulmonary hypertension**

Pulmonary hypertension (PH) occurs in 1–28% of patients with sarcoidosis [51–53]. PH is a serious complication in advanced stage VI sarcoidosis and has a poor prognosis. PH is largely attributed to the destruction of the capillary bed by pulmonary fibrosis. As the severity of PH does not always correlate with parenchymal changes, other factors may contribute to the development of PH, such as specific vasculopathy, local increased vasoreactivity, mechanical compression of pulmonary vessels, and portopulmonary hypertension.

According to the Dana Point Classification of 2008 [54], PH in sarcoidosis falls under category 3 (PH owing to lung disease and/or hypoxia) or 5 (PH with unclear multifactorial mechanisms) [53]. There is no specific therapy for PH associated with sarcoidosis. The management of sarcoidosis with PH mainly relies on supportive therapy (supplemental O2 and diuretics, as needed) [52]. Lung transplantation is now an important therapeutic option for these patients [53].

Patients with "out of proportion" pulmonary hypertension (characterized by dyspnea insufficiently explained by lung mechanical disturbances and mean pulmonary artery pressure ≥ 40–45 mmHg at rest) should be referred to expert centers and enrolled in clinical trials of pulmonary artery hypertension-specific drugs [55]. Endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and intravenous epoprosterol, etc., have been tried, and some patients experienced a beneficial effect. However, large-scale prospective clinical trials are needed before these therapies can be universally adopted.

### **Author details**

Upper-airway or tracheal sarcoidosis with airway stenosis needs systemic corticosteroids. In some cases, methotrexate or cytotoxic drugs, such as azathiopurine, may be added. Laryngeal sarcoidosis may cause life-threatening upper-airway obstruction. Surgical intervention is indicated for patients with well-localized, life-threatening lesions. When stridor is present,

As the symptoms of bronchial sarcoidosis are, if present, cough and wheezing, and spirometry shows reduced rate of FEV1/FVC, which is misdiagnosed as asthma, inhaled β2-agonists and/ or corticosteroids are often administered. However, we have often experienced unfavorable results in such cases, especially when parenchymal lesions are associated with the condition.

As described above, Lavergne et al. [21] examined the effect of systemic steroid therapy for patients who had histologically proven bronchial sarcoidosis with airflow obstruction (< 70% of FEV1/FVC), but their radiographic stages were 1 to 3. They obtained a favorable result after administration of 0.6 mg/kg of oral corticosteroids initially, and concluded that airflow obstruction by bronchial sarcoidosis without fibrosis-related airway obstruction is treatable.

The prevalence of airway hyperreactivity, as demonstrated by a positive methacholine or histamine challenge test, is significantly higher in patients with sarcoidosis compared with normal controls [46–49]. It is unclear whether airway hyperreactivity is a physiological manifestation of endobronchial sarcoidosis or is due to concomitant asthma [20]. However, Wilsher et al. examined the prevalence of asthma in patients with sarcoidosis and demon‐ strated that it was the same as that observed in the normal population [50]. Airway hyper‐ reactivity in sarcoidosis and asthma can be distinguished by the response to inhaled corticosteroids and β2-agonists. Airway hyperreactivity associated with asthma is improved by these agents, whereas airway hyperreactivity caused by sarcoidosis requires oral cortico‐

Pulmonary hypertension (PH) occurs in 1–28% of patients with sarcoidosis [51–53]. PH is a serious complication in advanced stage VI sarcoidosis and has a poor prognosis. PH is largely attributed to the destruction of the capillary bed by pulmonary fibrosis. As the severity of PH does not always correlate with parenchymal changes, other factors may contribute to the development of PH, such as specific vasculopathy, local increased vasoreactivity, mechanical

According to the Dana Point Classification of 2008 [54], PH in sarcoidosis falls under category 3 (PH owing to lung disease and/or hypoxia) or 5 (PH with unclear multifactorial mechanisms) [53].

compression of pulmonary vessels, and portopulmonary hypertension.

emergent tracheostomy may be needed [20, 45].

176 Sarcoidosis

**5. Airway hyperreactivity**

steroids [20, 47, 48].

**6. Pulmonary hypertension**

Kentaro Watanabe

Address all correspondence to: watanabe@fukuoka-u.ac.jp

Department of Respiratory Medicine, Fukuoka University School of Medicine, Fukuoka, Japan

### **References**


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**Chapter 8**

**Neurosarcoidosis**

http://dx.doi.org/10.5772/55118

**1. Introduction**

prognosis of the disease.

**2. Epidemiology**

the age of 50 [1].

Mohankumar Kurukumbi, Preema Mehta, Isha Misra and Jayam-Trouth Annapurni

Additional information is available at the end of the chapter

Sarcoidosis is an inflammatory granulomatous disease that can affect multiple organ systems, most commonly the lungs. It can also affect other organs, such as the nervous system and heart. Although the exact etiology of sarcoidosis is unknown, it involves the development of noncaseating granulomas in various organs. Noncaseating epithelioid granulomas are the pathological hallmarks of sarcoidosis and symbolize the inflammatory sign of the disease. granulomas are structured masses of activated macrophages and their derivatives (i.e., epitheloid and giant cells). Neurosarcoidosis is a manifestation of sarcoidosis specifically in the nervous system. It is caused by inflammation and abnormal cell deposits in the central and/ or peripheral nervous system, including the brain, spinal cord, or peripheral nerves. In this chapter, we intend to give a brief overview of the common neurologic manifestations of sarcoidosis, as well as diagnosis and management of these symptoms. We will also discuss management of steroid resistant neurosarcoidosis and atypical cases, as well as the overall

Cases of sarcoidosis have been reported worldwide, with a prevalence of approximately 10-80 cases per 100,000 in North America and Europe. Within the United States, African Americans have a greater lifetime risk of developing sarcoidosis than Caucasians (2.4% vs. 0.85%). Worldwide, females have a slightly greater risk of developing this disease. The incidence of sarcoidosis can be described as having a bimodal pattern, with most cases occurring between the ages of 20-40 years old and a second commonly affected group being females who are over

and reproduction in any medium, provided the original work is properly cited.

© 2013 Kurukumbi et al.; licensee InTech. This is an open access article 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, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. 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,

### **Chapter 8**

## **Neurosarcoidosis**

Mohankumar Kurukumbi, Preema Mehta, Isha Misra and Jayam-Trouth Annapurni

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/55118

### **1. Introduction**

Sarcoidosis is an inflammatory granulomatous disease that can affect multiple organ systems, most commonly the lungs. It can also affect other organs, such as the nervous system and heart. Although the exact etiology of sarcoidosis is unknown, it involves the development of noncaseating granulomas in various organs. Noncaseating epithelioid granulomas are the pathological hallmarks of sarcoidosis and symbolize the inflammatory sign of the disease. granulomas are structured masses of activated macrophages and their derivatives (i.e., epitheloid and giant cells). Neurosarcoidosis is a manifestation of sarcoidosis specifically in the nervous system. It is caused by inflammation and abnormal cell deposits in the central and/ or peripheral nervous system, including the brain, spinal cord, or peripheral nerves. In this chapter, we intend to give a brief overview of the common neurologic manifestations of sarcoidosis, as well as diagnosis and management of these symptoms. We will also discuss management of steroid resistant neurosarcoidosis and atypical cases, as well as the overall prognosis of the disease.

### **2. Epidemiology**

Cases of sarcoidosis have been reported worldwide, with a prevalence of approximately 10-80 cases per 100,000 in North America and Europe. Within the United States, African Americans have a greater lifetime risk of developing sarcoidosis than Caucasians (2.4% vs. 0.85%). Worldwide, females have a slightly greater risk of developing this disease. The incidence of sarcoidosis can be described as having a bimodal pattern, with most cases occurring between the ages of 20-40 years old and a second commonly affected group being females who are over the age of 50 [1].

© 2013 Kurukumbi et al.; licensee InTech. This is an open access article 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, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. 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, provided the original work is properly cited.

About 5-16% of patients with sarcoidosis have neurologic involvement. The most frequent neurologic abnormality includes cranial and peripheral neuropathy, followed by mononeurop‐ athy, myopathy, psychiatric disorders, cerebellar ataxia, hydrocephalus and papilledema. Neurosarcoidosis is also more prevalent in people of African descent and uncommon in people of Chinese descent and Southeast Asians. It is estimated that isolated neurosarcoidosis, without clinical evidence of systemic sarcoidosis, occurs in less than 1% of sarcoidosis patients [2].

system sarcoidosis is difficult to diagnose, which may delay treatment. The neurological symptoms make it a serious and commonly devastating complication of sarcoidosis [6].

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Neurosarcoidosis is seen in approximately 5% of sarcoidosis patients. Of these patients, some may have neurological findings on initial presentation, while others present de novo with neurological signs and symptoms that are consistent with a diagnosis of sarcoidosis [7]. Onset of neurosarcoidosis is most common in the fourth or fifth decades, and typically occurs after

Cranial mononeuropathies frequently occur in neurosarcoidosis. In 2009, Joseph and Scolding conducted a study of 30 new cases of sarcoidosis, and reported cranial neuropa‐ thies in 80% of the patients [8]. The 7th cranial nerve is often affected. In fact, peripheral facial nerve palsy has been noted in up to 50% of patients with neurosarcoidosis. Often‐ times, Bell palsy is found to be the first manifestation of sarcoidosis and may resolve prior to development of additional symptoms. While facial neuropathies may arise due to basilar meningitis, some cases can be attributed to granulomatous inflammation of the extracrani‐

Recent studies have found optic neuropathy to be a more common manifestation than previously thought. Patients can present with myriad complaints, ranging from blurry vision and papilledema to retro-bulbar pain and pupillary abnormalities. Palsies of the 8th cranial nerve also occur, leading to auditory and vestibular problems. Extra-ocular movements can become impaired due to involvement of the 3rd, 4th, and 6th cranial nerves. Olfactory involvement is rare, but has been reported in some cases, leading to anosmia

Neuroendocrine dysfunction is often seen in neurosarcoidosis patients, causing them to present with polyuria, changes in thirst, sleep, appetite, temperature, or libido. The hypothalamus and pituitary gland are also often affected, leading to thyroid, gonadal, and adrenal- related symptoms. This usually occurs as a result of subependymal granuloma‐ tous infiltration of the 3rd ventricle [9]. Other common symptoms include impaired taste and smell, slurred speech, weakness of trapezius and sternocleidomastoid muscles, and tongue deviation and atrophy. Additionally, carpal tunnel syndrome appears to occur more often in sarcoidosis patients, than in the general population. Occasionally, patients may present with the rare Heerfordt syndrome, characterized by fever, uveitis, parotid gland

**5. Clinical manifestations of neurosarcoidosis**

patients have had systemic symptoms for some time.

**5.1. Cranial nerve findings**

al part of the nerve [9].

and impaired taste.

**5.2. Neuroendocrine manifestation**

swelling, and facial nerve palsy [10].

#### **3. History**

Sarcoidosis was first clinically described in 1878 by a dermatologist Dr. Johnathan Hutchinson, who called the disease 'Mortimer's Malady', in reference to his patient's name [3]. He wanted to prove it by a biopsy but the patient refused. Then in 1889, Dr. Ernest Besnier described a similar case which he called lupus pernio due to the "chillblain-like swelling" of the nose and the lupus-vulgaris appearance of the fingers. Besnier also did not have histologic findings. It was not until 1892, Tenneson showed a second case of lupus pernio accompanied by histo‐ logical studies showing lesions which contained epithelioid cells and giant cells. This was the first description of a sarcoid granuloma. Cesar Boeck, in 1899, called it `Multiple Benign Sarkoid of Skin' which later gave birth to the term 'sarcoidosis'. A few years later, central nervous system (CNS) involvement by sarcoidosis was recognized in 1905 by Winkler [3].

#### **4. Etiology and pathogenesis**

Currently, the etiology of sarcoidosis is unknown. There have been hypotheses made including infectious agents, occupational/environmental factors, genetic factors and autoimmune disorders. There has not been a specific pathogen or pathogenic agent linked to the disease. One thought is that the inflammatory response in sarcoidosis, which is characterized by large numbers of activated macrophages and T lymphocytes bearing the CD4-helper phenotype, along with cytokine production is most consistent with a Th1-type immune response com‐ monly triggered by antigens [4]. Also, seeing the trends of blacks and family clusters having increased numbers of the disease, there is a possibility that it is genetic. Many patients with sarcoidosis have the HLA-Factor B 8 (on chromosome 6) and DR 3. Another theory includes inhalation of an antigen that causes granulomatous inflammation in mediastinal lymph nodes and then extends to the lungs and other tissues.[5] Environmental factors involve infections, such as *Mycobacterium tuberculosis* and *Propionibacterium acnes* or *P. granulosum* and noninfectious environmental exposures, such as pesticides and insecticides, pine pollen, silica or talc, metal dusts, and man-made mineral fibers. Exposure to these factors can cause diseases that are histologically and clinically indistinguishable from sarcoidosis [4].

Neurosarcoidosis and multiple sclerosis can present with similar symptoms, such as optic neuritis. It is important to be able to differentiate the two, due to different responses to management and therapy. Since sarcoidosis is often a multisystem disease, solitary nervoussystem sarcoidosis is difficult to diagnose, which may delay treatment. The neurological symptoms make it a serious and commonly devastating complication of sarcoidosis [6].

### **5. Clinical manifestations of neurosarcoidosis**

Neurosarcoidosis is seen in approximately 5% of sarcoidosis patients. Of these patients, some may have neurological findings on initial presentation, while others present de novo with neurological signs and symptoms that are consistent with a diagnosis of sarcoidosis [7]. Onset of neurosarcoidosis is most common in the fourth or fifth decades, and typically occurs after patients have had systemic symptoms for some time.

#### **5.1. Cranial nerve findings**

About 5-16% of patients with sarcoidosis have neurologic involvement. The most frequent neurologic abnormality includes cranial and peripheral neuropathy, followed by mononeurop‐ athy, myopathy, psychiatric disorders, cerebellar ataxia, hydrocephalus and papilledema. Neurosarcoidosis is also more prevalent in people of African descent and uncommon in people of Chinese descent and Southeast Asians. It is estimated that isolated neurosarcoidosis, without clinical evidence of systemic sarcoidosis, occurs in less than 1% of sarcoidosis patients [2].

Sarcoidosis was first clinically described in 1878 by a dermatologist Dr. Johnathan Hutchinson, who called the disease 'Mortimer's Malady', in reference to his patient's name [3]. He wanted to prove it by a biopsy but the patient refused. Then in 1889, Dr. Ernest Besnier described a similar case which he called lupus pernio due to the "chillblain-like swelling" of the nose and the lupus-vulgaris appearance of the fingers. Besnier also did not have histologic findings. It was not until 1892, Tenneson showed a second case of lupus pernio accompanied by histo‐ logical studies showing lesions which contained epithelioid cells and giant cells. This was the first description of a sarcoid granuloma. Cesar Boeck, in 1899, called it `Multiple Benign Sarkoid of Skin' which later gave birth to the term 'sarcoidosis'. A few years later, central nervous system (CNS) involvement by sarcoidosis was recognized in 1905 by Winkler [3].

Currently, the etiology of sarcoidosis is unknown. There have been hypotheses made including infectious agents, occupational/environmental factors, genetic factors and autoimmune disorders. There has not been a specific pathogen or pathogenic agent linked to the disease. One thought is that the inflammatory response in sarcoidosis, which is characterized by large numbers of activated macrophages and T lymphocytes bearing the CD4-helper phenotype, along with cytokine production is most consistent with a Th1-type immune response com‐ monly triggered by antigens [4]. Also, seeing the trends of blacks and family clusters having increased numbers of the disease, there is a possibility that it is genetic. Many patients with sarcoidosis have the HLA-Factor B 8 (on chromosome 6) and DR 3. Another theory includes inhalation of an antigen that causes granulomatous inflammation in mediastinal lymph nodes and then extends to the lungs and other tissues.[5] Environmental factors involve infections, such as *Mycobacterium tuberculosis* and *Propionibacterium acnes* or *P. granulosum* and noninfectious environmental exposures, such as pesticides and insecticides, pine pollen, silica or talc, metal dusts, and man-made mineral fibers. Exposure to these factors can cause diseases

Neurosarcoidosis and multiple sclerosis can present with similar symptoms, such as optic neuritis. It is important to be able to differentiate the two, due to different responses to management and therapy. Since sarcoidosis is often a multisystem disease, solitary nervous-

that are histologically and clinically indistinguishable from sarcoidosis [4].

**3. History**

184 Sarcoidosis

**4. Etiology and pathogenesis**

Cranial mononeuropathies frequently occur in neurosarcoidosis. In 2009, Joseph and Scolding conducted a study of 30 new cases of sarcoidosis, and reported cranial neuropa‐ thies in 80% of the patients [8]. The 7th cranial nerve is often affected. In fact, peripheral facial nerve palsy has been noted in up to 50% of patients with neurosarcoidosis. Often‐ times, Bell palsy is found to be the first manifestation of sarcoidosis and may resolve prior to development of additional symptoms. While facial neuropathies may arise due to basilar meningitis, some cases can be attributed to granulomatous inflammation of the extracrani‐ al part of the nerve [9].

Recent studies have found optic neuropathy to be a more common manifestation than previously thought. Patients can present with myriad complaints, ranging from blurry vision and papilledema to retro-bulbar pain and pupillary abnormalities. Palsies of the 8th cranial nerve also occur, leading to auditory and vestibular problems. Extra-ocular movements can become impaired due to involvement of the 3rd, 4th, and 6th cranial nerves. Olfactory involvement is rare, but has been reported in some cases, leading to anosmia and impaired taste.

#### **5.2. Neuroendocrine manifestation**

Neuroendocrine dysfunction is often seen in neurosarcoidosis patients, causing them to present with polyuria, changes in thirst, sleep, appetite, temperature, or libido. The hypothalamus and pituitary gland are also often affected, leading to thyroid, gonadal, and adrenal- related symptoms. This usually occurs as a result of subependymal granuloma‐ tous infiltration of the 3rd ventricle [9]. Other common symptoms include impaired taste and smell, slurred speech, weakness of trapezius and sternocleidomastoid muscles, and tongue deviation and atrophy. Additionally, carpal tunnel syndrome appears to occur more often in sarcoidosis patients, than in the general population. Occasionally, patients may present with the rare Heerfordt syndrome, characterized by fever, uveitis, parotid gland swelling, and facial nerve palsy [10].

#### **5.3. Other CNS findings**

In addition to the hypothalamus and pituitary gland, central nervous system involvement can affect the cerebral cortex, cerebellum, and occasionally the spinal cord. This can occur due to granulomatous inflammation in a perivascular pattern. Granulomas in various parts of the brain parenchyma have even been known to mimic brain tumors such as gliomas, meningio‐ mas, and schwannomas.

**6. Diagnosis**

and fibroblast proliferation [3].

Neurosarcoidosis has no pathognomonic sign, therefore it is a diagnosis of exclusion. This presents a great challenge, especially when the patient does not previously have a confirmed diagnosis of systemic sarcoidosis. The differential diagnosis encompasses a diverse number of pathologies such as Bell's palsy due to Lyme disease, optic neuropathy due to MS, tuber‐ culosis, carcinomatous or lymphomatous meningitis causing multiple cranial nerve palsies. Additional pathologies include metastatic lesions, encephalopathy via syphilis or CNS vasculitis, peripheral neuropathy, or parenchymal lesions such as astrocytomas. Therefore, it

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If neurosarcoidosis is suspected, the patient should be evaluated for evidence of extraneural disease due to the difficulty of obtaining nerve tissue for evaluation. It is imperative to check the skin, lymph nodes and lungs. Other tests that may be useful include ophthalmologic examination, endoscopic nasal and sinus examinations. Radiological tests include neuroimag‐ ing (discussed later) and chest x-ray or CT scan to search for hilar adenopathy or parenchymal changes consistent with pulmonary sarcoidosis, serum angiotensin converting enzyme (ACE) assays (nonspecific) and lumbar puncture to analyze CSF. CSF findings may show an increased opening pressure, protein up to 250mg/dL, mononuclear pleocytosis, IgG elevation, oligoclo‐ nal bands, glucose normal or low; and CSF ACE is possibly elevated. CSF ACE levels have a relative low sensitivity. Although most studies do not mention immunoglobulins levels in CSF, there is evidence that elevation of immunoglobulin IgG with a high CSF to serum IgG index may be common in CNS sarcoidosis [13]. CSF eosinophilia has also been reported as a consequence of neurosarcoidosis, [14] but may also be present in other infections, inflamma‐ tory, and neoplastic conditions, including lepto-meningeal spread of gliomas [15]. Of note, always be cautious of doing a LP in a patient that possibly has increase intracranial pressure. If this is suspected, check for papilledema by using a fundoscope and MRI imaging preceding the LP [8]. Routine laboratory tests may show hyperglobulinemia, hypercalcemia or elevation of alkaline phosphatase [16]. Hypercalcemia occurs in approximately 13-20% of cases due to

high levels of 1,25-dihydroxy-vitamin D causing hyperabsorption of calcium [17,18].

Sarcoid lesions in the CNS do not differ from those encountered in other organs. Most cases of CNS sarcoidosis diagnosed by histology have shown variable degrees of menin‐ goencephalomyelitic infiltration, either localized or widespread. This results in focal or disseminated meningeal nodules or plaques, and affecting particularly the basal mening‐ es. Although sarcoid lesions can occur almost anywhere in the central nervous struc‐ tures, most often they are located perivascularly, with varying degrees of associated gliosis

One may need to use other tests such as EEG, evoked potentials, and angiography to exclude other causes. Another test, the Kveim-Siltzbach, is not standardized and is not available universally. However, it can show positive granuloma results 4-6 weeks after injecting part of a spleen from a patient with known sarcoidosis into the skin. According to a study by C K Liam and A Menon, the Kveim-Siltzbach test can show false negative results when done in

is important to think of all the possibilities and rule them out [8].

Meningeal symptoms have been reported in a substantial number of patients; and can cause many of the aforementioned symptoms. Examination of the cerebrospinal fluid typically shows a mononuclear infiltrate and elevated protein. Cognitive and behavioral problems, along with focal neurologic deficits can occur. If the spinal cord is affected, myelopathies and radiculopathies can occur, and the cauda equina may be affected. Communicating and noncommunicating hydrocephalus have been seen in these patients, and sudden death can also occur due to an acute obstruction of CSF flow. Seizures may also occur due to a variety of causes. They are seen as an initial finding in 10% of patients. Sudden death can also occur with involvement of the brainstem leading to central hypoventilation [9].

#### **5.4. Peripheral neuropathy and myopathy**

Patients can present with various types of peripheral neuropathies, including, but not limited to mononeuropathy, sensory polyneuropathy, and acute and chronic inflammatory polyneur‐ opathy. Nerve biopsy typically shows noncaseating granulomas, but necrotizing vasculitis may also be seen. Muscle involvement is commonly seen, and is typically secondary to granulomas in the perimysium; however, only a very small number of patients are actually symptomatic. Onset of myopathy usually occurs later in the course of the disease, after involvement of other organ systems has already been noted. Patients may present with acute myopathy, in a similar manner to polymyositis, or may have more chronic symptoms with associated muscle wasting [9].

#### **5.5. Atypical presentations**

Sarcoidosis has been shown to affect many parts of both the central and peripheral nervous systems, and patients present with a wide variety of neurological symptoms. Often this can cause difficulties in making a diagnosis, as the reported symptoms are diverse and can mimic several other disease processes, such as Guillain-Barre Syndrome, Multiple Sclerosis, and even psychiatric diagnoses. In April 2012, Spiegel et al noted psychiatric manifestations, such as delirium and psychosis, in about 20% of neurosarcoidosis patients, which is equivalent to approximately 1% of all patients with sarcoidosis. Although this is a rare occurrence, these patients can experience striking auditory and visual hallucinations and delusions [11].

Patients have also reportedly presented with hypersomnolence and hyperphagia consistent with Kleine-Levine-Critchley syndrome [12]. In sum, as neurosarcoidosis can present in many ways, clinicians should maintain a high index of suspicion for the disease, especially in those patients who are not known to have sarcoidosis prior to presenting with neurological mani‐ festations. The disease can be very severe and often life-threatening.

### **6. Diagnosis**

**5.3. Other CNS findings**

186 Sarcoidosis

mas, and schwannomas.

In addition to the hypothalamus and pituitary gland, central nervous system involvement can affect the cerebral cortex, cerebellum, and occasionally the spinal cord. This can occur due to granulomatous inflammation in a perivascular pattern. Granulomas in various parts of the brain parenchyma have even been known to mimic brain tumors such as gliomas, meningio‐

Meningeal symptoms have been reported in a substantial number of patients; and can cause many of the aforementioned symptoms. Examination of the cerebrospinal fluid typically shows a mononuclear infiltrate and elevated protein. Cognitive and behavioral problems, along with focal neurologic deficits can occur. If the spinal cord is affected, myelopathies and radiculopathies can occur, and the cauda equina may be affected. Communicating and noncommunicating hydrocephalus have been seen in these patients, and sudden death can also occur due to an acute obstruction of CSF flow. Seizures may also occur due to a variety of causes. They are seen as an initial finding in 10% of patients. Sudden death can also occur with

Patients can present with various types of peripheral neuropathies, including, but not limited to mononeuropathy, sensory polyneuropathy, and acute and chronic inflammatory polyneur‐ opathy. Nerve biopsy typically shows noncaseating granulomas, but necrotizing vasculitis may also be seen. Muscle involvement is commonly seen, and is typically secondary to granulomas in the perimysium; however, only a very small number of patients are actually symptomatic. Onset of myopathy usually occurs later in the course of the disease, after involvement of other organ systems has already been noted. Patients may present with acute myopathy, in a similar manner to polymyositis, or may have more chronic symptoms with

Sarcoidosis has been shown to affect many parts of both the central and peripheral nervous systems, and patients present with a wide variety of neurological symptoms. Often this can cause difficulties in making a diagnosis, as the reported symptoms are diverse and can mimic several other disease processes, such as Guillain-Barre Syndrome, Multiple Sclerosis, and even psychiatric diagnoses. In April 2012, Spiegel et al noted psychiatric manifestations, such as delirium and psychosis, in about 20% of neurosarcoidosis patients, which is equivalent to approximately 1% of all patients with sarcoidosis. Although this is a rare occurrence, these patients can experience striking auditory and visual hallucinations and delusions [11].

Patients have also reportedly presented with hypersomnolence and hyperphagia consistent with Kleine-Levine-Critchley syndrome [12]. In sum, as neurosarcoidosis can present in many ways, clinicians should maintain a high index of suspicion for the disease, especially in those patients who are not known to have sarcoidosis prior to presenting with neurological mani‐

festations. The disease can be very severe and often life-threatening.

involvement of the brainstem leading to central hypoventilation [9].

**5.4. Peripheral neuropathy and myopathy**

associated muscle wasting [9].

**5.5. Atypical presentations**

Neurosarcoidosis has no pathognomonic sign, therefore it is a diagnosis of exclusion. This presents a great challenge, especially when the patient does not previously have a confirmed diagnosis of systemic sarcoidosis. The differential diagnosis encompasses a diverse number of pathologies such as Bell's palsy due to Lyme disease, optic neuropathy due to MS, tuber‐ culosis, carcinomatous or lymphomatous meningitis causing multiple cranial nerve palsies. Additional pathologies include metastatic lesions, encephalopathy via syphilis or CNS vasculitis, peripheral neuropathy, or parenchymal lesions such as astrocytomas. Therefore, it is important to think of all the possibilities and rule them out [8].

If neurosarcoidosis is suspected, the patient should be evaluated for evidence of extraneural disease due to the difficulty of obtaining nerve tissue for evaluation. It is imperative to check the skin, lymph nodes and lungs. Other tests that may be useful include ophthalmologic examination, endoscopic nasal and sinus examinations. Radiological tests include neuroimag‐ ing (discussed later) and chest x-ray or CT scan to search for hilar adenopathy or parenchymal changes consistent with pulmonary sarcoidosis, serum angiotensin converting enzyme (ACE) assays (nonspecific) and lumbar puncture to analyze CSF. CSF findings may show an increased opening pressure, protein up to 250mg/dL, mononuclear pleocytosis, IgG elevation, oligoclo‐ nal bands, glucose normal or low; and CSF ACE is possibly elevated. CSF ACE levels have a relative low sensitivity. Although most studies do not mention immunoglobulins levels in CSF, there is evidence that elevation of immunoglobulin IgG with a high CSF to serum IgG index may be common in CNS sarcoidosis [13]. CSF eosinophilia has also been reported as a consequence of neurosarcoidosis, [14] but may also be present in other infections, inflamma‐ tory, and neoplastic conditions, including lepto-meningeal spread of gliomas [15]. Of note, always be cautious of doing a LP in a patient that possibly has increase intracranial pressure. If this is suspected, check for papilledema by using a fundoscope and MRI imaging preceding the LP [8]. Routine laboratory tests may show hyperglobulinemia, hypercalcemia or elevation of alkaline phosphatase [16]. Hypercalcemia occurs in approximately 13-20% of cases due to high levels of 1,25-dihydroxy-vitamin D causing hyperabsorption of calcium [17,18].

Sarcoid lesions in the CNS do not differ from those encountered in other organs. Most cases of CNS sarcoidosis diagnosed by histology have shown variable degrees of menin‐ goencephalomyelitic infiltration, either localized or widespread. This results in focal or disseminated meningeal nodules or plaques, and affecting particularly the basal mening‐ es. Although sarcoid lesions can occur almost anywhere in the central nervous struc‐ tures, most often they are located perivascularly, with varying degrees of associated gliosis and fibroblast proliferation [3].

One may need to use other tests such as EEG, evoked potentials, and angiography to exclude other causes. Another test, the Kveim-Siltzbach, is not standardized and is not available universally. However, it can show positive granuloma results 4-6 weeks after injecting part of a spleen from a patient with known sarcoidosis into the skin. According to a study by C K Liam and A Menon, the Kveim-Siltzbach test can show false negative results when done in

As mentioned previously, cranial nerve palsies are the most common presentation in neuro‐ sarcoidosis, which can be seen on MRI with inflammation along with spinal cord involvement as well [20]. There have been studies done in which enhanced CT was shown to be normal, but the enhanced MRI was abnormal, implying greater sensitivity of MRI for detection

Neurosarcoidosis

189

http://dx.doi.org/10.5772/55118

In neurosarcoidosis, leptomeningeal disease is a common pattern of involvement, which may be localized or widespread. Less commonly, granulomatous masses can be found within the cerebral parenchyma. There have been cases showing patients with cranial nerve palsies demonstrating clear evidence of focal meningeal disease on gadolinium-DTPA enhanced MRI brain scans. Neurosarcoidosis is difficult to diagnose when patients have no evidence of granulomatous disease outside the nervous system because of the difficulty of obtaining tissue for histological examination. Therefore, primarily neurological evaluation, neuroimaging and lumbar puncture are done. However, diffuse meningeal infiltration particularly in the skull base region is frequently found at necropsy. Two cases presented by Khaw et al showed Gadolinium-DTPA enhanced MRI's in patients with cranial nerve palsies; one with solely cranial nerve palsies and the other along with gynecologic manifestations. In both of these cases, the meninges were affected by the disease and patients presented with multiple lower

cranial nerve palsies, which was not picked up by CT or non-contrast MRI [22].

According to Pawate et al, a study done on 54 cases of neurosarcoidosis, the majority (23%) were found to have intraparenchymal T2 hyperintense lesions on brain MRI. 19% were found to have meningeal involvement seen with gadolinium enhanced MRI. Few of these cases showed intracranial masses, normal brain or solely spinal cord involvement on MRI [23].

When the CNS is involved, brain enhanced MRI and CSF studies are sensitive in the detection of CNS inflammation, however they lack specificity. This continues to make diagnosing

While sarcoidosis is a progressive autoimmune disease and there is currently no cure, symptomatic treatment is available. Corticosteroids have become the treatment of choice for neurosarcoidosis. The dosage and duration of therapy varies based upon the type and severity of the symptoms. For instance, patients who present with peripheral facial nerve palsy or meningeal symptoms are given about 0.5mg/kg/day of prednisone for two weeks. On the other hand, a patient with myopathy is given the same dosage for four weeks, and a patient with a mass lesion or symptomatic hydrocephalus is given two to three times this amount for four weeks. Very severe cases of neurosarcoidosis benefit from IV methylprednisone 20mg/kg/day

for three days, followed by 1-1.5mg/kg/day of prednisone for two to four weeks [24].

The exact mechanism by which corticosteroids have benefited patients with neurosarcoidosis is unclear, but is generally believed to be secondary to its anti-inflammatory and immunomo‐ dulatory effects. Corticosteroids are known to prevent leukocytes from gaining access to sites

neurosarcoidosis lesions [21].

neurosarcoidosis a clinical challenge.

**8. Management of neurosarcoidosis**

**Figure 1.** Noncaseating granuloma in parietal lobe showing the granuloma surrounded by epithelioid cells and nodu‐ lar inflammatory infiltrates (hematoxylin and eosin, 10x). [35]

conjunction with corticosteroid use possibly due immunosuppressive effects. There is also concern that HIV and hepatitis transmission could occur through this technique [8].

As a last resort, a biopsy is done of the meninges, brain, or spinal cord. Biopsies from extra‐ neural tissue are recommended as it is less risky, but if it is highly suspected and a person with known sarcoidosis with neurologic involvement is deteriorating despite therapy, the neural tissue can be sampled [19]. Most common sites include the meninges and mass lesions.

### **7. Neuroimaging**

Neurosarcoidosis does not have a specific finding on imaging that can assure the diagnosis. However, neuroimaging along with neurologic evaluation, CSF analysis, biopsy and others can aid in making the diagnosis. Oftentimes, it is a brain contrast-enhanced MRI and CSF analysis that gives the presumptive diagnosis. Contrast MRI allows one to visualize meningeal or parenchymal involvement of active inflammation with disruption of the blood brain barrier as well as masses and hydrocephalus.

As mentioned previously, cranial nerve palsies are the most common presentation in neuro‐ sarcoidosis, which can be seen on MRI with inflammation along with spinal cord involvement as well [20]. There have been studies done in which enhanced CT was shown to be normal, but the enhanced MRI was abnormal, implying greater sensitivity of MRI for detection neurosarcoidosis lesions [21].

In neurosarcoidosis, leptomeningeal disease is a common pattern of involvement, which may be localized or widespread. Less commonly, granulomatous masses can be found within the cerebral parenchyma. There have been cases showing patients with cranial nerve palsies demonstrating clear evidence of focal meningeal disease on gadolinium-DTPA enhanced MRI brain scans. Neurosarcoidosis is difficult to diagnose when patients have no evidence of granulomatous disease outside the nervous system because of the difficulty of obtaining tissue for histological examination. Therefore, primarily neurological evaluation, neuroimaging and lumbar puncture are done. However, diffuse meningeal infiltration particularly in the skull base region is frequently found at necropsy. Two cases presented by Khaw et al showed Gadolinium-DTPA enhanced MRI's in patients with cranial nerve palsies; one with solely cranial nerve palsies and the other along with gynecologic manifestations. In both of these cases, the meninges were affected by the disease and patients presented with multiple lower cranial nerve palsies, which was not picked up by CT or non-contrast MRI [22].

According to Pawate et al, a study done on 54 cases of neurosarcoidosis, the majority (23%) were found to have intraparenchymal T2 hyperintense lesions on brain MRI. 19% were found to have meningeal involvement seen with gadolinium enhanced MRI. Few of these cases showed intracranial masses, normal brain or solely spinal cord involvement on MRI [23].

When the CNS is involved, brain enhanced MRI and CSF studies are sensitive in the detection of CNS inflammation, however they lack specificity. This continues to make diagnosing neurosarcoidosis a clinical challenge.

### **8. Management of neurosarcoidosis**

conjunction with corticosteroid use possibly due immunosuppressive effects. There is also

**Figure 1.** Noncaseating granuloma in parietal lobe showing the granuloma surrounded by epithelioid cells and nodu‐

As a last resort, a biopsy is done of the meninges, brain, or spinal cord. Biopsies from extra‐ neural tissue are recommended as it is less risky, but if it is highly suspected and a person with known sarcoidosis with neurologic involvement is deteriorating despite therapy, the neural tissue can be sampled [19]. Most common sites include the meninges and mass lesions.

Neurosarcoidosis does not have a specific finding on imaging that can assure the diagnosis. However, neuroimaging along with neurologic evaluation, CSF analysis, biopsy and others can aid in making the diagnosis. Oftentimes, it is a brain contrast-enhanced MRI and CSF analysis that gives the presumptive diagnosis. Contrast MRI allows one to visualize meningeal or parenchymal involvement of active inflammation with disruption of the blood brain barrier

concern that HIV and hepatitis transmission could occur through this technique [8].

**7. Neuroimaging**

188 Sarcoidosis

as well as masses and hydrocephalus.

lar inflammatory infiltrates (hematoxylin and eosin, 10x). [35]

While sarcoidosis is a progressive autoimmune disease and there is currently no cure, symptomatic treatment is available. Corticosteroids have become the treatment of choice for neurosarcoidosis. The dosage and duration of therapy varies based upon the type and severity of the symptoms. For instance, patients who present with peripheral facial nerve palsy or meningeal symptoms are given about 0.5mg/kg/day of prednisone for two weeks. On the other hand, a patient with myopathy is given the same dosage for four weeks, and a patient with a mass lesion or symptomatic hydrocephalus is given two to three times this amount for four weeks. Very severe cases of neurosarcoidosis benefit from IV methylprednisone 20mg/kg/day for three days, followed by 1-1.5mg/kg/day of prednisone for two to four weeks [24].

The exact mechanism by which corticosteroids have benefited patients with neurosarcoidosis is unclear, but is generally believed to be secondary to its anti-inflammatory and immunomo‐ dulatory effects. Corticosteroids are known to prevent leukocytes from gaining access to sites

of inflammation, interfere with their function along with that of endothelial cells and fibro‐ blasts, and suppress production of various humoral factors [25]. It is always important to keep in mind, however, that as with all medications, corticosteroids are not without side effects. Common side effects of corticosteroids include cognitive and personality changes, weight gain with central obesity, development of striae, diabetes mellitus, cataracts and predisposition to various infections. Cardiovascular effects are also known to occur, such as hypertension, dyslipidemia, and increased risk of myocardial infarction and stroke. Patients receiving long term corticosteroid therapy are at risk for osteoporotic fractures, especially in the setting of other general risk factors such as being over age 60 or having osteoporosis prior to corticoste‐ roid treatment. Additionally, avascular necrosis, especially of the hip, has been known to occur in a number of patients [1]. Therefore, it is important to carefully monitor the dosage, and to always use the lowest possible effective dose. If treatment with corticosteroids is to be discontinued, it is essential to decrease the dose gradually. Abrupt discontinuation of corti‐

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Several therapies have been proposed for those patients in whom corticosteroid treatment is unsuccessful, or in those who have contraindications to treatment. Many of these studies have shown methotrexate to be an effective treatment. Methotrexate has been successful in twothirds of sarcoidosis patients regardless of the organ systems that are affected. In one study, EE Lower et al observed 554 sarcoidosis patients, of which 71 had neurosarcoidosis. They found that treatment with methotrexate and cyclophosphamide was associated with higher

In 2007, TF Scott et al used aggressive therapy with corticosteroids and alternative immuno‐ suppressants in 48 patients. Over half of these cases had favorable outcomes [27]. Later, in 2011, G Androdias et al observed a small group of patients with neurosarcoidosis, and found evidence suggesting that Mycophenolate mofetil was effective in treatment of CNS symptoms. The agent was also found to have a steroid sparing effect and was better tolerated than several other immunosuppressive agents [28]. Additional studies have shown anti-TNF agents such as infliximab to be effective; and cytokine modulators such as thalidomide and pentoxifylline

Surgical resection of CNS mass lesions is usually not recommended, unless the mass persists or continues to enlarge despite appropriate immunomodulatory therapy. If the patient presents with symptomatic hydrocephalus, a ventriculoperitoneal shunt can be placed. It is important to continue immunosuppressive treatment following placement of the shunt as inflammation can lead to obstruction. Cranial or spinal irradiation is suggested in refractory cases if no response is seen with corticosteroids and at least two other agents [30]. Additionally, symptom-specific treatment may be needed, such as hormone replacement therapy for

costeroid therapy can cause adrenal insufficiency.

**8.1. Alternative therapies for refractory neurosarcoidosis**

response rates than treatment with corticosteroids only [26].

have also been used in a limited number of cases [29].

hypopituitarism, and antipsychotics for patients with psychosis.

**8.2. Other treatments**

**Figure 2.** Neurosarcoidosis involving the pituitary-hypothalamic axis. T-1 gadolinium-enhanced Axial (a) and coronal (b) views shows an area of abnormal enhancement involving the sellar, suprasellar regions and the interpeduncular cistern. The diagnosis was confirmed by a biopsy [3].

**Figure 3.** Meningeal neurosarcoidosis. Axial (a) and coronal (b) MRI T-1 weighted images post infusion of gadolinium DTPA in a patient with systemic sarcoidosis show thickening and enhancement of the dura surrounding the left hemi‐ sphere [3].

of inflammation, interfere with their function along with that of endothelial cells and fibro‐ blasts, and suppress production of various humoral factors [25]. It is always important to keep in mind, however, that as with all medications, corticosteroids are not without side effects. Common side effects of corticosteroids include cognitive and personality changes, weight gain with central obesity, development of striae, diabetes mellitus, cataracts and predisposition to various infections. Cardiovascular effects are also known to occur, such as hypertension, dyslipidemia, and increased risk of myocardial infarction and stroke. Patients receiving long term corticosteroid therapy are at risk for osteoporotic fractures, especially in the setting of other general risk factors such as being over age 60 or having osteoporosis prior to corticoste‐ roid treatment. Additionally, avascular necrosis, especially of the hip, has been known to occur in a number of patients [1]. Therefore, it is important to carefully monitor the dosage, and to always use the lowest possible effective dose. If treatment with corticosteroids is to be discontinued, it is essential to decrease the dose gradually. Abrupt discontinuation of corti‐ costeroid therapy can cause adrenal insufficiency.

#### **8.1. Alternative therapies for refractory neurosarcoidosis**

Several therapies have been proposed for those patients in whom corticosteroid treatment is unsuccessful, or in those who have contraindications to treatment. Many of these studies have shown methotrexate to be an effective treatment. Methotrexate has been successful in twothirds of sarcoidosis patients regardless of the organ systems that are affected. In one study, EE Lower et al observed 554 sarcoidosis patients, of which 71 had neurosarcoidosis. They found that treatment with methotrexate and cyclophosphamide was associated with higher response rates than treatment with corticosteroids only [26].

In 2007, TF Scott et al used aggressive therapy with corticosteroids and alternative immuno‐ suppressants in 48 patients. Over half of these cases had favorable outcomes [27]. Later, in 2011, G Androdias et al observed a small group of patients with neurosarcoidosis, and found evidence suggesting that Mycophenolate mofetil was effective in treatment of CNS symptoms. The agent was also found to have a steroid sparing effect and was better tolerated than several other immunosuppressive agents [28]. Additional studies have shown anti-TNF agents such as infliximab to be effective; and cytokine modulators such as thalidomide and pentoxifylline have also been used in a limited number of cases [29].

#### **8.2. Other treatments**

(a) (b)

(a) (b)

sphere [3].

190 Sarcoidosis

cistern. The diagnosis was confirmed by a biopsy [3].

**Figure 2.** Neurosarcoidosis involving the pituitary-hypothalamic axis. T-1 gadolinium-enhanced Axial (a) and coronal (b) views shows an area of abnormal enhancement involving the sellar, suprasellar regions and the interpeduncular

**Figure 3.** Meningeal neurosarcoidosis. Axial (a) and coronal (b) MRI T-1 weighted images post infusion of gadolinium DTPA in a patient with systemic sarcoidosis show thickening and enhancement of the dura surrounding the left hemi‐ Surgical resection of CNS mass lesions is usually not recommended, unless the mass persists or continues to enlarge despite appropriate immunomodulatory therapy. If the patient presents with symptomatic hydrocephalus, a ventriculoperitoneal shunt can be placed. It is important to continue immunosuppressive treatment following placement of the shunt as inflammation can lead to obstruction. Cranial or spinal irradiation is suggested in refractory cases if no response is seen with corticosteroids and at least two other agents [30]. Additionally, symptom-specific treatment may be needed, such as hormone replacement therapy for hypopituitarism, and antipsychotics for patients with psychosis.

### **9. Prognosis of neurosarcoidosis**

While many patients with neurosarcoidosis have a monophasic illness, relapsing-remitting and progressive disease patterns are also seen. RA Luke et al followed 25 patients with neurosarcoidosis for a minimum of 5 years or until death. 68% of the patients were found to have the monophasic pattern and 32% had a relapsing pattern [31]. The authors also noted that relapses were more common in patients with cerebral symptoms and in those presenting with hydrocephalus. Furthermore, relapses occurred more frequently in those who were taking smaller doses of corticosteroids (10mg or less).

process. Many patients do not experience neurological symptoms until the disease has progressed for some time, and systemic symptoms are present. Other patients have neuro‐ logical manifestations of the disease at the time of initial presentation. Overall, however, neurosarcoidosis only represents a small portion of the total population of patients with a diagnosis of sarcoidosis - about 5%. If patients present with neurological symptoms, with no prior diagnosis of sarcoidosis, it might prove difficult for clinicians to make a diagnosis. This is because these symptoms are quite general and can be seen with a multitude of other diseases. Patients have been reported to have not only general cranial nerve palsies and peripheral neuropathies, but also have been known to present with meningeal symptoms, hydrocephalus,

Neurosarcoidosis

193

http://dx.doi.org/10.5772/55118

Since the exact cause of neurosarcoidosis is not known, it is important to be aware of any clinical signs early on. It is also important to differentiate it from other diseases with similar manifes‐ tations, such as multiple sclerosis due to differences in management and treatment. There are many clinical and lab tests available, as well as imaging that can help determine if one has neurosarcoidosis. Although there is no pathgnomonic sign, brain contrast MRI is a vital tool along with CSF analysis that can give a presumptive diagnosis. They are highly sensitive, although lack specificity, which makes it difficult to definitively diagnose it. Gullapalli and Phillips found a sensitivity of brain MRI of about 82–97% for MS; for CSF abnormality and CSF ACE, sensitivity was 50–80% and 50%, respectively [34]. The most definitive diagnosis can be made from histological analysis of neural tissue via biopsy if there is still doubt despite the other tests or at autopsy. However, it is used as a last resort due to being the most invasive

As with other sarcoidosis patients, corticosteroids are the main treatment for neurosarcoidosis. However, some manifestations are more responsive to steroids than others. Additionally, many patients taking corticosteroids for an extended period of time often experience serious side effects; and there are also several contraindications to taking these medications. For this reason, several alternative therapies have been proposed for sarcoidosis patients, and several studies have found methotrexate and cyclophosphamide to be especially effective in treatment of neurological symptoms. Many other immunomodulatory medications have also been

While many studies have been conducted with regards to the long term outcomes of neuro‐ sarcoidosis patients, no definitive conclusions can be made as yet. However, the prognosis for these patients is mainly dependent on the neurological manifestations they experience. Patients with cranial nerve palsies, and particularly optic neuropathies, have been shown in many cases to respond well to corticosteroid treatment. More serious symptoms on the other hand, such as seizures and spinal cord involvement generally suggest a poor prognosis. However, one must also keep in mind, that various disease patterns have been reported in neurosarcoidosis patients. Neurosarcoidosis may present as a monophasic, relapsing-remit‐ ting, or chronic progressive pattern. Thus, additional studies need to be conducted before any conclusive statements can be made regarding the outlook for patients with neurosarcoidosis.

shown to be effective along with various symptom- specific treatments.

seizures, and even psychosis.

method.

Although the long term outcomes in neurosarcoidosis patients have not yet been clearly defined in studies, some general conclusions can be made. Patients with peripheral facial nerve palsy often show improvement within 2-4 weeks. Some patients with optic neuropathy show improvement, while others with a more progressive disease pattern can become blind. In 1999, G.A. Christoforidis et al conducted a retrospective study of 461 patients with sarcoidosis, confirmed on biopsy. These researchers reported that patients with optic nerve involvement often did not respond as well to corticosteroid treatment as those with other CNS manifesta‐ tions did. The researchers suggest that because the other cranial nerves are surrounded by Schwann cells, they can regenerate more easily than the optic nerve, whose myelin sheath is produced by oligodendrocytes [32].

Symptoms such as peripheral neuropathy and myopathy also tend to follow a more chronic and progressive pattern. Aseptic meningitis usually improves within a few weeks, yet CSF abnormalities (asymptomatic chronic pleocytosis) can persist for some time after. Mass lesions often persist for some time, but can also resolve on occasion. Additionally, patients with encephalopathy often exhibit a progressive pattern. Typically immunomodulatory medica‐ tions are not helpful in patients with endocrinopathies, and these patients need to be treated with hormonal replacement therapy. Also, a series of 68 patients were followed by JP Zajicek et al in 1998, who noted spinal cord involvement in 28% of the patients [33]. The authors concluded that spinal cord disease had a poorer prognosis, as a significant percentage of these patients were found to have deteriorated at follow-up. Patients with seizures have historically been shown to have a poorer prognosis, but more recent studies have disproved this [8].

In general, as the outcome in patients with neurosarcoidosis depends on the severity and types of neurological symptoms, it is difficult to make a conclusive statement regarding the prog‐ nosis of the disease. Reportedly, about 10% of patients with neurosarcoidosis die of the disease, typically secondary to CNS parenchymal involvement, hydrocephalus, or other severe symptoms; or due to immune-compromise secondary to treatment.

#### **10. Concluding remarks**

Neurosarcoidosis can range from mild to life threatening; and can affect any part of the central and peripheral nervous systems. It can present at any point during the course of the disease process. Many patients do not experience neurological symptoms until the disease has progressed for some time, and systemic symptoms are present. Other patients have neuro‐ logical manifestations of the disease at the time of initial presentation. Overall, however, neurosarcoidosis only represents a small portion of the total population of patients with a diagnosis of sarcoidosis - about 5%. If patients present with neurological symptoms, with no prior diagnosis of sarcoidosis, it might prove difficult for clinicians to make a diagnosis. This is because these symptoms are quite general and can be seen with a multitude of other diseases. Patients have been reported to have not only general cranial nerve palsies and peripheral neuropathies, but also have been known to present with meningeal symptoms, hydrocephalus, seizures, and even psychosis.

**9. Prognosis of neurosarcoidosis**

192 Sarcoidosis

smaller doses of corticosteroids (10mg or less).

produced by oligodendrocytes [32].

**10. Concluding remarks**

While many patients with neurosarcoidosis have a monophasic illness, relapsing-remitting and progressive disease patterns are also seen. RA Luke et al followed 25 patients with neurosarcoidosis for a minimum of 5 years or until death. 68% of the patients were found to have the monophasic pattern and 32% had a relapsing pattern [31]. The authors also noted that relapses were more common in patients with cerebral symptoms and in those presenting with hydrocephalus. Furthermore, relapses occurred more frequently in those who were taking

Although the long term outcomes in neurosarcoidosis patients have not yet been clearly defined in studies, some general conclusions can be made. Patients with peripheral facial nerve palsy often show improvement within 2-4 weeks. Some patients with optic neuropathy show improvement, while others with a more progressive disease pattern can become blind. In 1999, G.A. Christoforidis et al conducted a retrospective study of 461 patients with sarcoidosis, confirmed on biopsy. These researchers reported that patients with optic nerve involvement often did not respond as well to corticosteroid treatment as those with other CNS manifesta‐ tions did. The researchers suggest that because the other cranial nerves are surrounded by Schwann cells, they can regenerate more easily than the optic nerve, whose myelin sheath is

Symptoms such as peripheral neuropathy and myopathy also tend to follow a more chronic and progressive pattern. Aseptic meningitis usually improves within a few weeks, yet CSF abnormalities (asymptomatic chronic pleocytosis) can persist for some time after. Mass lesions often persist for some time, but can also resolve on occasion. Additionally, patients with encephalopathy often exhibit a progressive pattern. Typically immunomodulatory medica‐ tions are not helpful in patients with endocrinopathies, and these patients need to be treated with hormonal replacement therapy. Also, a series of 68 patients were followed by JP Zajicek et al in 1998, who noted spinal cord involvement in 28% of the patients [33]. The authors concluded that spinal cord disease had a poorer prognosis, as a significant percentage of these patients were found to have deteriorated at follow-up. Patients with seizures have historically been shown to have a poorer prognosis, but more recent studies have disproved this [8].

In general, as the outcome in patients with neurosarcoidosis depends on the severity and types of neurological symptoms, it is difficult to make a conclusive statement regarding the prog‐ nosis of the disease. Reportedly, about 10% of patients with neurosarcoidosis die of the disease, typically secondary to CNS parenchymal involvement, hydrocephalus, or other severe

Neurosarcoidosis can range from mild to life threatening; and can affect any part of the central and peripheral nervous systems. It can present at any point during the course of the disease

symptoms; or due to immune-compromise secondary to treatment.

Since the exact cause of neurosarcoidosis is not known, it is important to be aware of any clinical signs early on. It is also important to differentiate it from other diseases with similar manifes‐ tations, such as multiple sclerosis due to differences in management and treatment. There are many clinical and lab tests available, as well as imaging that can help determine if one has neurosarcoidosis. Although there is no pathgnomonic sign, brain contrast MRI is a vital tool along with CSF analysis that can give a presumptive diagnosis. They are highly sensitive, although lack specificity, which makes it difficult to definitively diagnose it. Gullapalli and Phillips found a sensitivity of brain MRI of about 82–97% for MS; for CSF abnormality and CSF ACE, sensitivity was 50–80% and 50%, respectively [34]. The most definitive diagnosis can be made from histological analysis of neural tissue via biopsy if there is still doubt despite the other tests or at autopsy. However, it is used as a last resort due to being the most invasive method.

As with other sarcoidosis patients, corticosteroids are the main treatment for neurosarcoidosis. However, some manifestations are more responsive to steroids than others. Additionally, many patients taking corticosteroids for an extended period of time often experience serious side effects; and there are also several contraindications to taking these medications. For this reason, several alternative therapies have been proposed for sarcoidosis patients, and several studies have found methotrexate and cyclophosphamide to be especially effective in treatment of neurological symptoms. Many other immunomodulatory medications have also been shown to be effective along with various symptom- specific treatments.

While many studies have been conducted with regards to the long term outcomes of neuro‐ sarcoidosis patients, no definitive conclusions can be made as yet. However, the prognosis for these patients is mainly dependent on the neurological manifestations they experience. Patients with cranial nerve palsies, and particularly optic neuropathies, have been shown in many cases to respond well to corticosteroid treatment. More serious symptoms on the other hand, such as seizures and spinal cord involvement generally suggest a poor prognosis. However, one must also keep in mind, that various disease patterns have been reported in neurosarcoidosis patients. Neurosarcoidosis may present as a monophasic, relapsing-remit‐ ting, or chronic progressive pattern. Thus, additional studies need to be conducted before any conclusive statements can be made regarding the outlook for patients with neurosarcoidosis.

### **Nomenclature**

CNS: central nervous system

CD4: cluster of differentiation 4

Th1: type 1 helper cells

HLA: human leukocyte antigen


### **Author details**

Mohankumar Kurukumbi1 , Preema Mehta2 , Isha Misra2 and Jayam-Trouth Annapurni1 [2] Smith JK, Matheus MG, Castillo M. Imaging manifestations of neurosarcoidosis. AJR

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195

http://dx.doi.org/10.5772/55118

[3] Vinas F, Rengachary S. Diagnosis and Management of Neurosarcoidosis. Journal of

[4] Hunninghake GW, Costabel U, Ando M, et al. ATS/ERS/WASOG statement on sar‐

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[6] Hoitsma E. Neurosarcoidosis: a clinical dilemma. Lancet Neurol. 2004 Jul;3(7):

[7] Burns TM. Neurosarcoidosis. Arch Neurol 2003; 60:1166. Stern BJ, Krumholz A,

[8] Joseph FG and Scolding NJ. Neurosarcoidosis: a study of 30 new cases. J Neurol

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[11] Speigel DR et al. Neurosarcoidosis and the Complexity in its Differential Diagnoses.

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[13] Fried ED, Landau AJ, Sher JH, Rao C. Spinal cord sarcoidosis: a case report and re‐

[14] Scott TF. A new cause of cerebrospinal fluid eosinophilia: Neurosarcoidosis. Am J

[15] Defendini R, Hunter SB, Schlemingi EB, Leifer E, Rowland LP. Eosinophilic meningi‐

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1249-1255.

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\*Address all correspondence to: mohan311@gmail.com


### **References**

[1] Fitzgerald PA. Chapter 26. Endocrine Disorders. In: McPhee SJ, Papadakis MA, Ra‐ bow MW, eds. CURRENT Medical Diagnosis & Treatment 2012. New York: McGraw-Hill; 2012.

[2] Smith JK, Matheus MG, Castillo M. Imaging manifestations of neurosarcoidosis. AJR 2004; 182:289-95.

**Nomenclature**

194 Sarcoidosis

CNS: central nervous system CD4: cluster of differentiation 4

HLA: human leukocyte antigen

ACE: angiotensin converting enzyme

MRI: magnetic resonance imaging HIV: human immunodeficiency virus

DTPA: diethylene triamine pentaacetic acid

, Preema Mehta2

2 Howard University College of Medicine, Washington, DC, USA

1 Department of Neurology, Howard University Hospital, Washington, DC, USA

\*Address all correspondence to: mohan311@gmail.com

, Isha Misra2

[1] Fitzgerald PA. Chapter 26. Endocrine Disorders. In: McPhee SJ, Papadakis MA, Ra‐ bow MW, eds. CURRENT Medical Diagnosis & Treatment 2012. New York:

and Jayam-Trouth Annapurni1

EEG: electroencephalogram CT: computed tomography

TNF: tumor necrosis factor

Mohankumar Kurukumbi1

McGraw-Hill; 2012.

Mg: milligrams Kg: kilograms IV: intravenous

**Author details**

**References**

Th1: type 1 helper cells

MS: multiple sclerosis

CSF: cerebrospinal fluid LP: lumbar puncture


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**Section 4**

**Diagnosis**

**Section 4**
