Introduction
Forms of sarcoidosis | Occurrence (in %) |
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Pulmonary sarcoidosis
| |
Respiratory system
a possible spontaneous remission in stages I–III of SA: stage I—bilateral hilar lymphadenopathy, stage II—lymph-adenopathy and diffuse pulmonary infiltrations, stage III—diffuse pulmonary infiltrations with fibrosis only in lung parenchyma, stage IV—irreversible fibro-cavernous changes in the lungs; bronchial mucosae (30–60 %); alveolar form (snowballs) (1.5 %) | 90 |
Pleura
(bi)lateral fluid, fibers | 0.7–10 |
Extrapulmonary sarcoidosis
| |
Nervous system
| 5–15—symptomatic, 25—on autopsy |
Heart
arrhythmia, sudden death (SA in ventricular septum often affects the cardiac conduction system), myocarditis, pericarditis with/without pericardial effusion, mitral regurgitation, congestive heart failure, myocardial scarring with the formation of ventricular aneurysms | 5—symptomatic, 25—on autopsy |
Eye(s)/orbital
anterior uveitis (50–90 %), intermediate uveitis, posterior uveitis with retinal perivasculitis, periphlebitis, neovascularization, vitreous hemorrhage, proliferative retinopathy, conjunctivitis, orbital mass lesions, extraocular myopathy, cornea involvement, optic neuropathy with disturbed vision or vision loss | 25–90 |
Liver/spleen
| <65 |
Bone/joint
lytic/sclerotic changes in bone (e.g. skull, nasal bones, vertebrae), jungling’s syndrome (cystic spreading of the short bones of the hand and foot), acute and chronic arthritis | 5–40 |
Skin
erythema nodosum, lupus pernio, macules, papules, sub-cutaneous nodules, plaques, ichthyosis, ulcers, pustules, alopecia, in post-operative scars, in tattoos, erythroderma, hypopigmented patches | 25–35 |
Peripheral lymphadenopathy
| 30 |
Calcium metabolism/kidneys
hipercalcemia, hipercalciuria, nephrolithiasis | 2–63 |
Lacrimal glands
keratoconjunctivitis sicca syndrome, proptosis | 15–28, but up to 88 % on Gal67 scanning |
Parotid glands
Heerfordt’s syndrome (fever, uveitis, inflammation of lacrimal and parotid glands, paresis n. VII), Mikulicz’s syndrome (fever, uveitis, inflammation of lacrimal and parotid glands) | 5 |
Reproductive tract
| <4 |
Digestive system
| <1 |
Muscles
| <1 |
Sarcoidosis of the nervous system (neurosarcoidosis—NS)
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Confirmed NS—the clinical picture suggests NS, other causes of neurological symptoms have been excluded, there is a histopathological presence of characteristic granuloma in the biopsy material in the central nervous system.
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Probable NS—the clinical picture suggests NS, other causes of neurological symptoms have been excluded, changes noted in an MRI scan indicate the presence of NS, the presence of an increased level of protein and/or pleocytosis particular lymphocytic, as well as the presence of oligoclonal bands confirmed in the cerebrospinal fluid, where the presence of systemic sarcoidosis has been confirmed histopathologically, or there have been at least 2 imaging results (Gal67 scintigraphy, CXR), there is an increased level of ACE in serum.
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Possible NS—the clinical picture suggests NS and other causes of neurological symptoms have been excluded.
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Confirmed NS—the patient suffering SA presents symptoms of diabetes insipidus, paresis of the facial nerve, an MRI head scan (with gadolinium contrast) confirms changes in the cerebrospinal meninges or the brain stem, in the cerebrospinal fluid are increased levels of cells, particularly, lymphocytes and/or increased protein, a biopsy of nerve tissue reveals granulomas inflammation.
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Probable NS—neuropathy of undefined cause appears in the patient, MRI confirms abnormalities other than those defined above, electrodiagnostic tests show abnormal results.
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Possible NS—a patient suffering multiorgan SA presents with unexplained headaches and/or radiculopathy.
Sarcoidosis of the central nervous system (CNS)
Cerebral NS
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Cranial neuropathy (brain base)—in about 23–73 % [30]
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Paresis of n. VII—usually one-side (in 25–50 %), rarely both sides
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Damage of n. II—blurred vision, abnormal color recognition, disturbed field of vision, papilledema in the fundus of the eye (in 1–10 %)
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Damage of n. VIII—deafness, dizziness (in 7 %)
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Damage of n. IX and X—dysfunction of the throat muscles, palate and vocal chords (in 4 %).
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Disseminated changes—in 30 % [32]
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Aseptic meningitis—in 8–40 % [30]
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Endocrinal disturbance of the hypothalamus and hypophysis in the course of NS (in 2–26 %) with primarily diabetes insipidus, polydipsia and polyuria, galactorrhoea, and amenorrhoea [30]
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Cerebro-spinal fluid examination—changes are frequent (in about 2/3 cases) but unspecific and appear mainly in cranial neuropathy or meningitis [38]; there is often mild or moderate lymphocytosis with increased index of lymphocytes C4/CD8 > 5, increased protein concentration, a hypoglycorrhachia with CSF glucose less than 50 % of concomitant blood glucose (in 10–20 %), increased level of ACE (in about 50 %), increased IgG level, and uncharacteristic oligoclonal bands (in about 30 %) [19, 21, 34, 37]; pleocytosis and hypoglycemia often appear in the acute phase of the disease [34]; in NS, patients with an isolated cranial neuropathy of nerve VII, cerebrospinal fluid is mostly normal [37].
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Imaging methods (CT, MRI brain scan with gadolinium, Gal67 scintigraphy and FDG-PET) [18, 20, 30, 35, 39‐47]
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MRI—is considered the most sensitive but unspecific test in diagnosis patients with NS (Fig. 2) [23, 36, 38, 39, 45]; the most common brain MRI finding of NS is a basilar leptomeningeal involvement (in about 30–40 %), which is usually occurred as a thickening and diffuse or nodular enhancement; brain NS in MRI can be also present as focal masses or diffuse thickening of dural meninges, persistent pseudotumor changes (in about 14 %); involvement of hypothalamus/pituitary and cranial nerves, which show enhancement and thickening post gadolinium; rarely NS changes in MRI occur as hydrocephalus or in the periventricular region and in the white matter.×
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Gal67 scintigraphy—in 2/3 of patients changes can be revealed, however, in the majority they are unspecific; one characteristic image in scintigraphy, but also in FDG-PET, observed in sarcoidosis of the parotid and lacrimal glands is called a “panda sign” [45].
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FDG-PET—allows for a localization of changes in whole body and finding a characteristic intrathoracic pattern and/or “panda sign” may be highly suggestive for sarcoidosis; isolated NS needs additional diagnostic tests, because FDG-PET does not distinguish the changes in the course of malignancy or TB from NS [16, 40‐47]; recently, it was revealed that a combination multiple fluorodeoxyglucose PET-avid lymph nodes with mild flurothymidine (FLT) PET uptake can be helpful in differentiating granulomatous inflammatory diseases such neurosarcoidosis from malignancy [42]; FDG-PET and FLT-PET are more useful methods in localizing the optimum site for a biopsy than Gal67 scintigraphy and MRI [37, 42].
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Neurophysiological tests—the effectiveness of a visual evoked potentials (VEPs) test is recommended particularly, as an affected optic nerve can be symptomatic of NS, and also auditory evoked potentials (AEPs) with abnormal results suggested NS changes in the brain stem, precursory subclinical or clinical manifestations; equally VEP and AEPs are useful in monitoring the progress of the disease [21, 25]; the advantage of such tests are that they are noninvasive, do not require prior preparation of the patient, are simple to carry out and can be repeated.
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A biopsy of the cerebrospinal meninges or brain remains the gold standard for the diagnosis of NS; in the case of negative results of the biopsy or the existence of contraindication to its use, a tissue diagnosis of sarcoidosis can often be established in an extraneural location, e.g. biopsy of lymph nodes, lungs, conjunctiva or lacrimal/parotid glands (Table 1) [6, 20‐33].
Sarcoidosis of the spinal cord
Peripheral nervous system SA (PNS)
Muscle sarcoidosis
NS treatment
Pharmacologic treatment
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Corticosteroids are considered the drug of choice for the treatment of sarcoidosis with monitoring for potential adverse events, e.g. peptic ulcer diseases, systemic fungal infection, active tuberculosis, hypersensitivity, cataract formation, diabetes mellitus or osteoporosis [reviewed in 1, 20–23, 30, 36, 51, 53, 59]:
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The cranial neuropathy: according to the latest treatment algorithm for NS, proposed by Nozaki et al. (with input from personal communication from Professors Barney Stern and Robert P. Baughman) [36] in 2013, in the case of cranial neuropathy, particularly where nerve VII is affected, prednisone is recommended in a daily dose of 20-40 mg with a decrease of dosage over 1–6 months to the lowest effective dose; if corticosteroids cannot be tapered to less than 10 mg/day of prednisone equivalent within 3–6 months, consideration should be given to higher dose prednisone and/or alternative agents [51]; there was a tendency for recurrence of symptoms at doses of prednisone less than 20–25 mg/day [reviewed in 1, 36, 51].
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The mild or moderate NS, usually initiate with 20–60 mg/day (prednisone or prednisone equivalent) with a decrease of dosage to the lowest effective dose; if corticosteroids cannot be tapered to less than 10 mg/day of prednisone equivalent within 3–6 months, consideration should be given to higher dose prednisone and/or alternative agents [reviewed in 20, 36].
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The severe NS (e.g. altered sensorium, visual loss, or weakness), cases not responding to oral agents, and refractory NS: the administration of intravenous methylprednisolone is advised, at 1 g daily for 3–5 days followed by 1 g per week or daily prednisone orally with a decrease of dosage to the lowest effective dose [reviewed in 36].
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Immunomodulating and cytotoxic agents such as methotrexate, cyclosporine, cyclophosphamide, or azathioprine
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Methotrexate (MTX)—is used as a first-line corticosteroid-sparing agent and allows tapering of prednisone dose to 10 or 20 mg/day in more than one-third of NS cases [reviewed in 36, 51]; it is also reported a beneficial response to MTX in approximately one-fifth of NS patients, who failed prednisone monotherapy [52]; a combination of corticosteroids and MTX has resulted in a favorable outcome in patients with severe CNS involvement [reviewed in 36]; the effectiveness of MTX, given orally, mostly in an initial dose of 7.5 mg/per week and then 10–20 mg/week is noted in about 60 % of NS patients [27]; it requires monitoring for adverse events, e.g. hepatotoxicity, renal insufficiency, pneumonitis, teratogenicity, bone marrow suppression; an administration of folinic acid may reduce toxicity [reviewed in 36].
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Azathioprine—has been used for corticosteroid-refractory NS with potential adverse effects, like neutropenia, abnormal liver function tests, pancreatitis or allergic reactions [reviewed in 30, 55–57]; usual oral dose of azathioprine is 2–3 mg/kg [reviewed in 57].
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Cyclosporine—it was beneficial in some patients, who failed prednisone monotherapy; others worsened in spite of a combination of cyclosporine and corticosteroid therapy [28]; it can be started at 4 mg/kg/day in divided doses and requires monitoring for adverse events, e.g. hypertension, renal failure, hypomagnesemia, and neurotoxicity [reviewed in 30].
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Cyclophosphamide—due to its high toxicity and significant side effects (bone marrow suppression, teratogenicity and carcinogenicity), the use of it is usually limited to severe NS, when TNF-α antagonist cannot be obtained, in NS refractory to other agents; it is also corticosteroid-sparing agent in NS and allows tapering of prednisone dose to 10 mg [52, 53]; according to authors [53, 54], dose of cyclophosphamide is 500–1000 mg intravenously over 30–60 min every 2–4 weeks or 0.5 g/m2 of body surface area intravenously every 4 weeks depending on age, leukocyte count or renal function; given orally, an initial dose 25–50 mg/day is increased by 25 mg increments to ensure adequate immunosuppression; the maximum oral dose is 150 mg/day; intravenous administration of cyclophosphamide is preferred over oral administration due to a lesser side effects [54].
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Mycophenalate mofetil—immunosuppressant as an analog of methotrexate is considered for patients with central NS, though not effective in NS of the muscles [reviewed in 36].
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Anti-malarial agents, like chloroquine and hydroxychloroquine have anti-inflammatory effects and they are also effective in sarcoidosis, especially in patients with NS and sarcoidosis-induced hypercalcemia and/or sarcoid skin lesions; its standard oral dosage is 250–750 mg daily; hydroxychloroquine has lower risk of ocular toxicity than chloroquine, but is less effective than chloroquine; because hydroxychloroquine reduces serum glucose levels, it may be useful for NS patients with steroid-induced hyperglycemia; its standard dosage is 200–400 mg daily orally [20, 21, 36, 57, 59].
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A tumor necrosis factor alpha (TNF-α) inhibitor—e.g. infliximab, adalimumab, thalidomide, pentoxifylline: infliximab is commonly used for neurosarcoidosis that is refractory to other agents and/or corticosteroid-induced complications; in a recent case series of 29 patients with spinal cord neurosarcoidosis, infliximab was the second most frequently used immunosuppressive agent after corticosteroids [49]; it is also useful for therapy of SFN [30, 50, 51]; infliximab 3–5 mg/kg intravenously every 4–8 weeks; often, patients receive an initial loading dose of 3–5 mg/kg intravenously at weeks 0, 2, and 6 [reviewed in 36]; adalimumab and teratogenic thalidomide are effective especially for spinal forms of NS [30, 36, 50, 51, 58]; pentoxifylline have been shown to be effective for various types of organ involvement from systemic sarcoidosis, however, their role in the treatment of neurosarcoidosis is unknown [reviewed in 36, 57]; several major toxicities are encountered with the anti-TNF therapies, but one of the more serious concerns is the increased risk of tuberculosis and similar infections [36, 49, 57].
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Treatment of associated conditions