Clinic Rev Allerg Immunol (2015) 49:5462
DOI 10.1007/s12016-015-8475-x
Diagnosis of Sarcoidosis
Thomas E. Wessendorf & Francesco Bonella &
Ulrich Costabel
Published online: 18 March 2015
# Springer Science+Business Media New York 2015
Abstract The diagnosis of sarcoidosis, a systemic gran-
ulomatous disease, is based on a compatible clinicalra-
diological picture and the histological evidence of
noncaseating granulomas. Other diseases mimicking sar-
coidosis, mostly infections and other granulomatoses,
have to be excluded. There is no single test for sarcoid-
osis, and the presence of granulomas alone does not es-
tablish the diagnosis. Symptoms of sarcoidosis are not
specific and can be markedly different according to or-
gan involvement and disease course. Respiratory symp-
toms and fatigue are the most common symptoms at any
stage of disease. Histological confirmation is not needed
for Lfgrens or Heerfordts syndrome and asymptomatic
bihilar lymphadenopathy. The radiological staging sys-
tem is still based on chest radiography, and computed
tomography is not mandatory for routine follow-up.
18
F-fluorodeoxyglucose positron emission tomography
may be of value in special cases. For assessment of lung
involvement and follow-up, pulmonary function tests are
necessary with vital capacity being the most important
single parameter and diffusion capacity the most sensi-
tive. Bronchoscopy with biopsy is the most common
procedure for detection of granulomas, when there is
no easier biopsy site like skin or peripheral lymph nodes.
Endobronchial ultrasonography-guided transbronchial
needle aspiration has replaced mediastinoscopy for eval-
uation of mediastinal and hilar lymph nodes with a high
diagnostic yield. Despite numerous studies, no single
biomarker can be reliably used for correct diagnosis or
exclusion of sarcoidosis. Genetic testing, despite
T. E. Wessendorf (*) : F. Bonella : U. Costabel
Interstitial and Rare Lung Disease Unit, Ruhrlandklinik, University
Hospital, University Duisburg-Essen, Tschener Weg 40,
45239 Essen, Germany
e-mail: thomas.wessendorf@ruhrlandklinik.uk-essen.de
promising advances, has still not been included in rou-
tine care for sarcoidosis patients. The long-term progno-
sis of sarcoidosis depends on the different organ mani-
festations: Cardiac or central nervous involvement, to-
gether with respiratory complications, is critical. A mul-
tidisciplinary approach is necessary for comprehensive
care of the sarcoidosis patient.
Keywords Sarcoidosis . Diagnostic evaluation .
Granulomatous disease
Introduction
Sarcoidosis is a systemic disease with a heterogeneous clinical
presentation. Although pulmonary manifestations typically
dominate the clinical picture and abnormalities on chest radio-
graphs are detected in about 90 % of patients, about half of
patients with sarcoidosis are asymptomatic. The complicated
nature of sarcoidosis and wide range of symptoms at presen-
tation have prompted research on diagnostic tools, particularly
minimally invasive procedures like endobronchial
ultrasonography-guided transbronchial needle aspiration
(EBUS-TBNA) and positron emission tomography (PET).
The definition of diagnostic accuracy of these investigations
is still under debate.
Biomarkers and gene polymorphisms may provide
help in assessing risk for sarcoidosis, predicting disease
outcome or assessing treatment response, but they still
do not have a role in the routine diagnosis of sarcoid-
osis. In the present article, we will review the current
status of establishing the diagnosis of sarcoidosis, focus-
ing on recent developments to diagnose pulmonary, car-
diac, and neurologic organ involvement.
Clinic Rev Allerg Immunol (2015) 49:5462 55

Clinical Evaluation Table 2 Differential diagnosis of granulomatous reaction

The recommended examinations in the initial evaluation of
suspected sarcoidosis are given in Table 1. For diagnosis,
the typical clinicalradiological picture should be supported Lymphogranulomatosis
by the histologic confirmation of noncaseating granulomas.
However, the existence of granulomas alone does not neces-
sarily secure the diagnosis of sarcoidosis [1]. The physician
must carefully consider other etiologies of granuloma forma-
tion, particularly if the history and results of imaging are not
typical (Table 2). Cultures of biopsy material and body fluids
must be negative.
The different results of the examinations must fit together
into the whole clinical picture. The most common symptoms
at presentation are cough and dyspnea on exertion. General
symptoms, from which fatigue is the most frequent, are non-
specific. The most frequent extrapulmonary manifestations of
sarcoidosis include the eyes (particularly in Japanese) [2], the
skin, and the peripheral lymph nodes. Lfgrens syndrome as
a special form of acute sarcoidosis is given by the triad of
bihilar lymphadenopathy, bilateral arthritis of the ankle joints,
and erythema nodosum, most common on the lower limbs.
General flu-like symptoms (fever, arthralgias, myalgias) are
common. In Lfgrens, which is more frequent in the Drug induced granulomatosis
Scandinavian countries, histological confirmation is regarded
as not necessary. The same holds true for Heerfordts syn- Histiocytosis
drome (uveitis, parotitis, Bells palsy and fever), which is Common variable immune deficiency
much more uncommon.
Twenty to fifty percent of patients present with asymptom-
atic bihilar lymphadenopathy [1]. As only 1 in 2,000 patients
may eventually turn out to have an alternative diagnosis [3],
careful observation appears to be the appropriate clinical de-
cision. However, when the lymphadenopathy is asymmetrical,
Table 1 Basic diagnostic tests in the initial evaluation of possible
sarcoidosis
History and complete examination
Chest X-ray
Pulmonary function tests (IVC, FEV1, diffusion capacity)
Laboratory values: peripheral blood count, calcium, liver enzymes,
creatinine, angiotensin-converting enzyme (ACE)
Urine analysis
ECG
Ophthalmological examination
Confirmation of granulomatous inflammation by biopsy or aspiration
cytology:
Bronchoscopy with bronchoalveolar lavage, biopsy of the bronchial
mucosa, transbronchial biopsy, and biopsy of mediastinal and hilar
lymph nodes by endobronchial ultrasound (EBUS-TBNA)
Possible other sites for biopsy, e.g., peripheral lymph nodes, skin,
conjunctivae
Microbiological examination of specimens for bacteria, acid-fast bacilli,
and fungi
Sarcoidosis
Inflammatory bowel disease
Granulomatous polyangiitis (Wegeners)
Bronchocentric granulomatosis
Necrotizing sarcoid granulomatosis
Giant cell arteritis
Lupus erythematodes
Polyarteritis nodosa
Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)
Tuberculosis
Non-tuberculous mycobacteriosis
Leprosy
Fungal infections
Parasitic infections
Whipples disease
Cat-scratch-disease
Foreign body reaction
Berylliosis
Exposition to other metals (aluminium, zirkonium)
Silicosis
Hypersensitivity pneumonitis
Sarcoid-like lesions
Blaus syndrome
massive, or associated with large paratracheal manifestation,
biopsy is strongly recommended.
In chronic sarcoidosis, which is regarded as a disease
course of more than 35 years, there are quite often nonspe-
cific symptoms like cough, exertional dyspnea, arthralgia,
night sweats, weight loss, general weakness, or fatigue.
For the assessment of these general symptoms, which may
be difficult to quantify, questionnaires have been developed:
The Kings Sarcoidosis Questionnaire (KSQ) is a modular
multi-organ health status measure for patients with sarcoidosis
and can be used in clinic and research such as evaluation of
therapies [4]. The KSQ consists of consists of five modules
with three to ten items each: general health status, lung, med-
ication, skin, and eye and correlated with other questionnaires
like SGRQ and the SF36, and weakly with pulmonary func-
tion tests. The sometimes disabling symptom of fatigue occurs
in up to 70 % of patients and is not well correlated to impaired
lung function. Treatment side effects, e.g., weight gain or di-
abetes due to corticosteroid therapy, can be additional causes.
It can be measured and monitored with the validated Fatigue
Assessment Scale [5, 6]. Those questionnaires may be
56 Clinic Rev Allerg Immunol (2015) 49:5462

particularly useful in the follow-up of patients or for research

purposes. They are not used routinely for diagnostic
evaluation.

Imaging

Standard imaging in the diagnostic work-up should include

chest X-ray (CXR), which is mandatory as the lungs and tho-
racic lymph nodes are involved in 95100 % of cases. CXR is
the basis of radiological staging, which has some implications
for the long-term prognosis.
The original staging of sarcoidosis has been developed
from lung involvement as determined only by X-ray [7, 8]
(see Table 3). It must therefore be emphasized that determina-
tion of lung involvement by high-resolution computer tomog-
raphy (HRCT), which is much more sensitive to detect paren-
chymal involvement, should not be mixed up with this classi-
fication, as the long-term prognosis of the disease was derived
from the original CXR classification.
One can argue that, later in the course of disease with the
possible occurrence of complications, comparison would be
easier if a CT at the time of diagnosis had been made.
However, one should not forget the higher radiation exposure
even with modern CTs: We definitely regard routine follow-up
CT scans as unnecessary. HRCT scan should be performed
when a complicated course of pulmonary sarcoidosis in stage
II-IV is suspected, i.e., bronchiectasis, fibrosis, mycetoma,
infection, or malignancy.
Walsh et al. proposed a clinicoradiological staging system
including the composite physiological index (originally devel-
oped for prognosis in idiopathic pulmonary fibrosis) and two
HRCT variables (large vessel diameter and extent of fibrosis).
In a validation cohort of 252 patients, their staging system test
allowed prognostic separation of patients with pulmonary sar-
coidosis [9]. Whether this is superior to the classical staging in
clinical routine has to be shown.
As the confidence with the diagnosis increases with time, a
series of radiological pictures may be particularly useful,
when atypical parenchymal involvement shows no change
over a longer time course.
18
F-fluorodeoxyglucose positron emission tomography
(FDG-PET) is of value for evaluating systemic inflammatory
Fig. 1 Sarcoidosis IV: In this 64-year-old male, lung function tests were
within the normal range: IVC 82 % pred, TLC 89 % pred. Blood gases were
normal; only the diffusion capacity was slightly impaired (TLCO 65 %)
activity [1, 1012]. Teirstein et al. have demonstrated retro-
spectively in 137 sarcoidosis patients with 139 examinations
that FDG-PET scans can help to detect occult diagnostic bi-
opsy sites and may have some value in assessment of revers-
ible activity in patients with sarcoidosis. The limitation is that
a false-positive uptake in FDG-PET can be observed in pa-
tients with other granulomatous diseases, infections, and neo-
plasms [13].
Pulmonary Function Tests
Lung functions tests are impaired in 20 % of the patients with
stage I and in 4080 % in the stages with parenchymal in-
volvement. However, the correlation of lung function tests
with imaging is weak, as occasionally stage IV may present
with normal lung volumes [14] (s. Fig. 1. The most useful
parameter for monitoring the course of the disease is the vital
capacity, which can be easily determined by spirometry. The
diffusion capacity as a very sensitive parameter may be often
reduced, but variability impairs its usefulness. Respiratory
failure with need for oxygen is very rare and only found in
late stages. In general, restrictive impairment of lung function
can be observed; an obstructive pattern points to involvement

Table 3 Radiological CXR staging system of sarcoidosis [7, 8]

Stage 0 Normal CXR with proven extrapulmonary sarcoidosis

Stage I Bihilar lymphadenopathy without parenchymal disease
Stage II Bihilar lymphadenopathy with parenchymal disease
Stage III Parenchymal involvement without lymphadenopathy
Stage IV Fibrosis

Stage 0 is not included in the original classification Fig. 2 Bronchial mucosa with sarcoidosis (white arrows)
Clinic Rev Allerg Immunol (2015) 49:5462 57

of the airways, which may consist of direct narrowing by Endosonographic biopsy of lymph nodes has superseded
granulomatous tissue, peribronchial fibrosis, compression by mediastinoscopy for evaluation of mediastinal and hilar
lymph nodes, or involvement of the small airways. Instead of lymph nodes. The latter is nowadays only performed when
manifest obstruction, bronchial hyperreactivity is quite often sarcoidosis is not top of the differential. The procedure can
observed in 3050 % of cases and can be responsible for dry be done from the bronchi (EBUS-TBNA) or the esophagus
cough, a common complaint [15, 16]. (EUS-FNA). Both are almost without serious adverse effects
and have a sensitivity of 8093 % for sarcoidosis (see
Table 4). Von Bartheld et al. demonstrated the higher diagnos-
tic yield in endosonographic techniques (80 %) versus TBLB
Endoscopic Evaluation
(53 %) in a multicenter trial in 304 patients [25]. However, this
study is hampered by the fact that the yield of TBLB was
Bronchoalveolar Lavage
unusually low, much lower than in most other studies. In a
recent study, Goyal et al. [26] calculated the diagnostic yield
The characteristic finding in bronchoalveolar lavage (BAL)
for sarcoid granulomas of combined procedures in 161 pa-
for sarcoidosis is a predominance of lymphocytes, usually a
tients: TBLB combined with endobronchial biopsy conferred
normal percentage of eosinophils and neutrophils, and an ab-
the highest diagnostic yield (92.8 %) for those patients with
sence of plasma cells and foamy alveolar macrophages [17].
visible mucosal abnormalities, while EBUS-TBNA achieved
The CD4/CD8 ratio is frequently elevated: A ratio larger than
only 57 % diagnostic yield. However, EBUS-TBNA gives
3.5 (upper limit of normal) shows a specificity of 9396 %
better access to the lymph nodes commonly involved in sar-
with a sensitivity of 5359 %, a ratio above 10 has more than
coidosis than transesophageal ultrasound-guided fine-needle
99 % specificity for sarcoidosis [18, 19]. However, the BAL is
aspiration (EUSFNA) [27, 28].
normal in 15 % of the cases, so that no definite exclusion of
It has been suggested that rapid on-site assessment by an
sarcoidosis can be made: We also do not recommend routine
experienced cytologist provides sufficient diagnostic informa-
BAL during follow-up, as this is not adequate to monitor the
tion, so that the more invasive procedure of transbronchial
activity of the disease [20]. In the initial evaluation of the
biopsies with higher risk of bleeding or pneumothorax may
disease, BAL is usually combined in our institution with
not be necessary [29]. Whether this is feasible in daily clinical
endobronchial mucosal and transbronchial biopsies in the
routine appears to be more a question of logistics and requires
same endoscopic procedure (see below).
further research.
Surgical lung biopsy or liver biopsy may only be indicated
Biopsy Procedures in special cases. When there is no site for biopsy after exam-
ination and routine imaging, FDG-PET may detect possible
The confirmation of granulomas at one site is usually regarded other sites for histological investigation [13].
as sufficient for diagnosis, even when there is clinical
suspected multiorgan involvement. Biopsies from the skin or
peripheral lymph nodes may be technically easy. Earlier in- Laboratory Tests
vestigations like fine-needle aspiration of the spleen [21] or
biopsy of conjunctival noduli [22], which may have a relative- Biomarkers
ly high diagnostic yield and be easier to perform in experi-
enced hands than commonly thought, are nowadays infre- In sarcoidosis, a lot of substances have been investigated in
quently used. serum or BAL fluid as candidate biomarkers for diagnosis,
Erythema nodosum, although typical for acute sarcoidosis, monitoring of activity, or for treatment decision.
is histologically a panniculitis or vasculitis, so granulomas
Table 4 Diagnostic effectiveness of endosonographic biopsy in
cannot be found there. sarcoidosis [25, 27, 6163]
Endobronchial mucosal biopsies (e.g., from the right mid-
dle or upper lobe carina) may yield positive results in 41 Author n Se Sp PPV NPV Prevalence
57 %, even if the mucosa appears macroscopically normal.
Wong [27] 65 92 100 88 44 98
A typical endoscopic aspect (mucosal nodularity) is shown
Oki [61] 15 93 100 100 50 93
in Fig. 2. The diagnostic yield in such cases with abnormal
Garwood [62] 50 85 100 100 12,5 98
appearing mucosa may reach 90 %. The diagnostic yield of
Tremblay [63] 50 83 100 n.a n.a. 92
transbronchial lung biopsy (TBLB) is about 70 % (range, 40
Von Bartheld [25] 154 80 100 100 30 92
90) [23, 24] and can be performed without the need for fluo-
roscopy, but the potential complications of pneumothorax and Se sensitivity, Sp specificity, PPV positive predictive value, NPV negative
bleeding must be considered. predictive value
58
They are either macrophage- or granuloma-associated
(e.g., calcium, ACE, lysozyme, neopterine, carboxypeptidase,
chitotriosidase), lymphocyte-associated (e.g., beta2-micro-
globulin, sIL-2R, IF-gamma, adenosine desaminase), or extra-
cellular matrix-associated (e.g., procollagen III peptide,
hyaluronan, fibronectin) proteins.
Biomarkers can support the diagnosis of sarcoidosis
but are not equivalent to the histological diagnosis of
granuloma. Traditionally, serum concentration of
angiotensin-converting enzyme (ACE) as a marker of
the granuloma burden had been suggested as a diagnos-
tic test or marker of disease activity for sarcoidosis:
Elevation of ACE is found in approximately 4080 %
of patients [30] but is not specific as a false-positive
ACE may be found in other granulomatous disorders.
The administration of ACE inhibitors suppresses the se-
rum ACE level. Furthermore, genetic polymorphisms
account for the interindividual variability, as several al-
leles of the ACE gene have been identified. This may
lead to misclassification of a significant number of pa-
tients (8.5 %) [31]. Genotype-corrected reference values
may overcome this problem, but this has not been
established in clinical routine.
Other biomarkers have not shown so far significant
superiority to ACE, e.g., the serum soluble interleukin-2
(sIL-2R) reflects the activity of the T cell component and
may play a role to assess disease activity particularly in
extrapulmonary disease but could not predict response to
treatment [32]. Serum chitotriosidase was tested in 232
sarcoidosis patients. It was shown to have comparably
reasonable 89 % sensitivity and 93 % specificity for di-
agnosis and evaluation of treatment [33]. In a cross-
sectional analysis of 36 sarcoidosis patients, the
interferon-inducible chemokines CXCL9 and CXCL10
correlated with measures of a special disease severity
score. Serial measurements of CXCL10 corresponded to
clinical course better than ACE or sIL-2R [34].
Another approach may be the use of markers for specific
organ involvement once the diagnosis had been established,
e.g., cardiac sarcoidosis: Baba et al. found in a small number
of patients with cardiac sarcoidosis high sensitive cardiac tro-
ponin T as a useful marker for evaluating the activity of dis-
ease, determined by FDG-PET [35].
Serum KL-6, a marker of different interstitial lung diseases,
was shown to correlate with parenchymal involvement in sar-
coidosis [36], which could be confirmed with imaging in an-
other study [37]. Furthermore, KL-6 tends to associate with
pulmonary disease outcome [38]. However, this requires fur-
ther investigation.
At the present time, no single biomarker can be reliably
used for correct diagnosis or exclusion of sarcoidosis, to mon-
itor the activity of disease or to make any treatment decisions
in the single patient with sarcoidosis.
Clinic Rev Allerg Immunol (2015) 49:5462
Genetic Testing
Sarcoidosis has a significant genetic susceptibility, which has
been shown from family and casecontrol studies. Sarcoidosis
is associated with a genetic risk profile made up of many
variant genes, so there is no single Bsarcoidosis gene^.
MHC-2 alleles can determine the course of the disease, e.g.,
in Scandinavians HLADRB1* 03 predisposes to disease with
spontaneous resolution [39, 40]. A German study on 947 sar-
coidosis patients found a strong association for a polymor-
phism in the butyrophilin-like 2 gene with the development
of sarcoidosis [41]. Using genome-wide peripheral blood
gene expression analysis, Zhou et al. identified a non-
targeted 20-gene sarcoidosis biomarker signature that was
able to distinguish sarcoidosis from healthy controls (accuracy
of 86 %) and which also served as a molecular signature for
complicated sarcoidosis (accuracy 81 %) [42].
However, at the present time, genetic testing has not been
introduced into clinical routine for diagnosis or for treatment
decision.
Cardiac Evaluation
Cardiac sarcoidosis (CS) is a potentially serious manifestation.
The guidelines by the Japanese Ministry of Health and
Welfare [43] distinguish between CS histologically proven
and clinically suspected. Myocardial biopsy has only a sensi-
tivity of less than 25 % due to sampling error as granulomas
can be found in a patchy fashion in the free wall of the left
ventricle, which is not easily accessible. Therefore, in most
cases, the diagnosis of CS must be made clinically.
The uncertainty in this field may be reflected by the fact
that, among sarcoidosis experts, no clinical manifestation for
involvement of the heart was classified Bhighly probable,^
meaning that fewer than 70 % of experts thought the manifes-
tation as diagnostic for CS [44].
In a recent consensus statement of the Heart Rhythm
Society, one or more of the following manifestations were
considered adequate to establish a clinical diagnosis of CS in
case of histological proven extracardiac sarcoidosis:
treatment-responsive cardiomyopathy or nodal AV block, un-
explained reduced left ventricular function <40 % or sponta-
neous or inducible ventricular tachycardias in the absence of
other risk factors, Mobitz type II or third-degree block, patchy
uptake on cardiac PET, late gadolinium enhancement on car-
diac magnetic resonance imaging (MRI), or a positive gallium
uptake (the last three with patterns consistent with CS). Other
causes must be excluded [45].
In addition, in patients <60 years with otherwise unex-
plained higher-degree heart block (Mobitz II or third-degree
block), it is suggested to look for CS with HRCT or advanced
cardiac imaging (MRI or FDG-PET). If suggestive, extra-
Clinic Rev Allerg Immunol (2015) 49:5462
cardiac, or, if not feasible, otherwise endomyocardial biopsy
should be performed [45].
The actual organ involvement of 25 %, as documented in
autopsy, is much higher than clinical apparent, when clinical
symptoms only arise in about 5 %. The definitive diagnosis of
CS is therefore difficult, and sarcoid patients with cardiac
dysfunction or ECG aberrations and no alternative etiology
should be presumed to have cardiac involvement.
The authors suggest a stepwise pragmatic approach: The
basic routine examination in every patient should be an elec-
trocardiogram (ECG). For easy assessment of left ventricular
function, echocardiography could be done. Echocardiography
is particularly useful in the follow-up of patients with de-
creased left ventricular function, when the ejection fraction
appears to be the easiest target parameter to obtain for moni-
toring treatment decisions.
Twenty-four-hour Holter monitoring and exercise ECGs
can detect abnormalities (e.g., arrhythmias, or conduction ab-
normalities) even when the basic ECG is normal. Any abnor-
mality must be further evaluated by further imaging:
The older radionuclide techniques including thallium scin-
tigraphy and gallium scintigraphy have been superseded by
either cardiac MRI or FDG-PET/CT. MRI can reveal myocar-
dial scarring, where glucose uptake by PET/CT can be used as
a surrogate parameter of the activity of inflammation.
The ranges of sensitivity and specificity are comparable
between the two with higher specificity for the cardiac MRI
Fig. 3 Diagnostic scheme
(adapted from Baughman [64];
BHL bihilar lymphadenopathy)
59
and higher sensitivity for the PET [46]: In a meta-analysis for
diagnosis of CS with the PET/CT [47], estimates demonstrat-
ed a sensitivity of 89 % and specificity of 78 %. The latter is
explained by physiological uptake of 18FDG in healthy people
and nonspecific uptake in other cardiomyopathies. The sensi-
tivity of gadolinium-enhanced MRI for cardiac sarcoidosis
ranges from 75 to >95 %, with specificities of approximately
75 to 80 %.
Both investigations have been suggested for follow-up of
CS: The affected segments on MRI correlated with duration of
sarcoidosis in patients as well as LVEF and LV diastolic vol-
ume [48]. Serial MRI may be not possible in case of implanted
pacemakers or defibrillators, but newer MRI-compatible de-
vices may overcome this problem. As PET/CT represents in-
flammatory activity, this modality may be useful in monitor-
ing disease activity: Blankstein et al. demonstrated, over
a median follow-up of 1.5 years in 118 patients, that
PET findings were predictive of adverse events like
ventricular arrhythmias and sudden deaths; the presence
of both a perfusion defect and abnormal 18FDG update
was associated with a hazard ratio of 3.9 (p<0.01) and
remained significant after adjusting for LV ejection frac-
tion and clinical criteria [49]. In addition, the PET/CT
may be combined with MRI to diagnose cardiac sar-
coidosis (hybrid imaging technique), but so far no pro-
spective studies regarding additional utility of PET/MRI
have been published.
60
Neurosarcoidosis
Involvement of central or peripheral nervous system can be
found in 515 % of sarcoidosis patients [50, 51]. However,
clinical diagnosis is made only in 50 % of autopsy proven
cases [52].
Three different clinical scenarios are possible: (1) a patient
with neurological symptoms and active sarcoidosis of other
organs, histologically proven; (2) a patient with new neuro-
logical symptoms and a history of otherwise inactive sarcoid-
osis; and (3) a patient with possible neurosarcoidosis but no
evidence of sarcoidosis elsewhere in the body.
Every part of the nervous system can be affected, which is
what makes differential diagnosis difficult. Common manifes-
tations include all cranial nerves (most common Bells palsy),
the hypothalamus, and the hypophysis [53]. Other manifesta-
tions are papillary edema, aseptic meningitis, hydrocephalus,
intracerebral lesions, seizures, or psychiatric symptoms.
Peripheral nervous system may present as mononeuropathy,
polyradiculopathy, or polyneuropathy of either sensoric or
motoric type, or both.
Small fiber neuropathy has been described relatively fre-
quent in sarcoidosis leading to sensoric symptoms
(hypesthesia, paresthesia, or pain) or autonomic disturbances,
which may cause disabling symptoms [5457]. The com-
mon symptom of fatigue may be partially explained by
sleep disturbances as a result of restless legs syndrome
due to neuropathic pain [54].
The diagnosis is based on neuroimaging studies, particu-
larly MRI. Whole-body FDG-PET may show in a patient with
neurological symptoms other potential sites for biopsy, when
sarcoidosis is suspected. Examination of the cerebrospinal
fluid usually shows nonspecific changes. CSF ACE is elevat-
ed in more than half of patients with neurosarcoidosis and may
reflect the clinical course [58, 59].
In the first clinical scenario (see above), treatment trial is
justified, and only in case of treatment failure is reassessment
including nervous system biopsy necessary. In the other two
scenarios, nervous system biopsy is crucial and must be
weighed against the risks of a treatment trial.
Assessment of Disease Activity and Recommendations
for Follow-up
The term Bactivity of the disease^ is not without problems as
activity does not necessarily imply worse prognosis or strict
indication for treatment. We recommend careful observation
and follow-up with analysis of symptoms, course of the CXR,
and the lung function. Active disease has not come to rest
meaning either persistence of disease or progress of disease
(which is not the same). Currently, no serum marker exists for
exact description of activity.
Clinic Rev Allerg Immunol (2015) 49:5462
Wasfi et al. developed an objective disease severity scoring
system that incorporates data on demographics, pulmonary
function, and organ involvement to produce a whole-body
sarcoidosis assessment [60], but, due to complexity, it has
been used only for research. More sophisticated investigations
like the FDG-PETmay therefore be reserved for patients with
unexplained and persistent, disabling symptoms, particularly
of extrapulmonary location. Whether this effort is superior to
careful clinical observation and may result in different thera-
peutic consequence has still to be shown.
Conclusion
The principle diagnostic approach to sarcoidosis is shown in
Fig. 3: Compatible clinical radiological data must fit with the
histological confirmation of non-caseating granulomas. The
diagnostic evaluation includes the assessment about the in-
volvement of different organs. When possible alternative di-
agnoses can be excluded with reasonable clinical certainty, the
diagnosis of sarcoidosis is very likely. Sarcoidosis remains
one of the big Bchameleons^ in internal medicine.
Conflict of Interest T.E. Wessendorf, F. Bonella, and U. Costabel de-
clare that they have no conflict of interest.
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