MUDr. Dana Maňasková


Vyhledávání na medicinman.cz
 

nemoci-sympt/PLICNI/sarkoidoza/klinika

Historie

  • First described in 1877 as a skin disease by a dermatologist, Jonathan Hutchinson [6]

Popis

  • Systemic granulomatous disease
  • Undetermined etiology
  • Invariably affecting the lungs and thoracic lymph nodes
  • “immune paradox”
    • Peripheral anergy
    • Exaggerated inflammation at disease sites

Clinical manifestations

  • Sarcoidosis is a systemic granulomatous disease of unknown aetiology
  • Primarily affecting the lungs and lymphatic systems [4]
  • But any organ may be involved.
  • Presentation may be an incidental finding on chest radiology,
  • Or due to symptoms
    • Most commonly cough or breathlessness
    • Or relating to involvement of other organ systems such as the eyes, skin, nervous system or heart. [4]
  • Ocular and rheumatological symptoms
    • Are the other main presentations [4]

Nonspecific symptoms

    • Fatigue, weight loss and fever
      • May be indicative for active sarcoidosis [6]
  • Do not correspond with objective physical evidence of disease
    • Fatigue, fever, anorexia,
    • Arthralgia -occur in 45% of sarcoidosis cases [8]
    • Muscle pain
    • General weakness,
    • Muscle weakness,
    • Exercise limitation
    • Cognitive failure [7]
    • Night sweats [8]
  • Neither lung function test results nor chest radiographs correlate with these nonspecific health complaints [7]
  • There is a positive association between symptoms of suspected small fibre neuropathy (SFN) and fatigue, as well as dyspnoea and fatigue [7]
  • Sarcoidosis patients suffer more from fatigue even in the absence of other symptoms [7]
  • Some sarcoidosis patients are debilitated by the symptoms of their disease and are unable to work; [7]
  • Others are underemployed and incapable of reaching their full potential due to health-related issues [7]
  • Pulmonary complaints such as dyspnea on exertion, cough, chest pain, and hemoptysis (rare) occur in 50% of cases [8]
  • Swelling or soreness of the lymph nodes, weight loss, and reddened, watery, or sore eyes
  • Lumps, ulcers, discolored skin, or skin sores on the back, arms, legs, scalp, and face may occur
  • May also exhibit enlarged liver, spleen, or salivary glands [8]

  • A scaly rash, red bumps on the legs, night sweats, fever, sore eyes, and pain and swelling in the legs [10]

Synonyma

  • Most famous synonym worldwide for sarcoidosis is Besnier-Boeck-Schaumann disease [6]

Heerfordt’s syndrome

  • Another rare syndrome of sarcoidosis
  • Presents with a triad of
    • Facial nerve palsy,
    • Uveitis
    • Parotid gland enlargement [6]
  • Lso known as Heerfordt-Waldenström syndrome or uveoparotid fever
  • Variant of sarcoidosis, comprising of:
    • Fever
    • Parotid enlargement
    • Facial palsy
    • Ocular involvement (anterior uveitis) [13]
  • Prevalence is unknown
  • Only isolated case reports exist
  • Neurologic involvement may occur in cca 5% of patients with sarcoidosis, with facial nerve palsy dominating
  • Rarity sections hold a case with the subsequent development of progressive multifocal leukoencephalopathy PML [13]
  • Complete or incomplete (two out of the last three) [13]
  • no specific imaging characteristics exist
  • Imaging is nonetheless important to show the systemic nature of the disease and/or possible biopsy sites.
  • Enlargement of the parotid gland(s) and enlargement of cervical lymphadenopathy
    • Seem to be typical 2
    • May be observed clinically and by various imaging modalities [13]
  • Constellation of symptoms along with blood samples and biopsy usually allows the diagnosis
  • Prognosis equals the underlying systemic disease
  • Improvement of symptoms often occurs after a few days of immunomodulating therapy, e.g. steroids
  • Possible associated diseases need independent treatment [13]
  • First to describe the constellation of symptoms was the Danish ophthalmologist Christian Frederik Heerfordt (1871-1953) in 1909
  • Association with sarcoidosis was observed by the Swedish internist Jan Gösta Waldenström (1906-1996) in 1937
  • Misdiagnosing facial paralysis as simple Bell palsy
    • Prevents possible treatment of the underlying systemic disorder [13]

Löfgren syndrome

  • Acute presentation of sarkoidosis
    • Acute arthritis, polyarthritis
    • Erythema nodosum
    • Bilateral hilar lymphadenopathy [4]
  • Distinct acute form with a good prognosis [4]
  • Often have an acute presentation consisting of arthritis, erythema nodosum (a rash of red or reddish-purple bumps on the ankles and knees), and bilateral hilar lymphadenopathy (occurring in 9%-34% of patients). [8]
  • Episodes of erythema nodosum can be painful, short-term use of a nonsteroidal anti-inflammatory drug (NSAID) may be beneficial [8]


Neurological manifestations

  • Neurosarcoidosis
  • In less than 10% of the patients,
  • Predilection for the base of the brain
  • Any part of the central or peripheral nervous system may be involved
  • Diagnosis of neurosarcoidosis is often very difficult
    • Especially in patients who lack either pulmonary or systemic manifestations of sarcoidosis [6]
  • Cca 50% of patients with nervous system sarcoidosis have facial nerve palsy
  • Peripheral nervous system involvement may cause
    • Muscle weakness
    • Atrophy
    • Sensory disturbance
    • Deep tendon-reflex loss in the distribution of the affected nerve [6]
  • Brain involvement may experience
    • Alterations in memory or mental acuity
    • Strokelike symptoms [8]
  • Signs and symptoms of raised intracranial pressure due to hydrocephalus
  • Cranial nerve palsies
    • Optic nerve involvement (particularly common) 5
    • Facial nerve palsy
  • Endocrine features of hypothalamic/pituitary sarcoidosis 7
    • Diabetes insipidus
    • SIADH
    • Hyperprolactinemia
    • Hypothyroidism
    • Hypoadrenalism
  • Seizures
  • Variable weakness, paresthesias and dysarthria/dysphagia
  • Spinal cord involvement presenting as myelopathy [11]
  • Although it is very rare (range 1-17%) to have isolated neurosarcoidosis (i.e. without systemic disease)
  • Central nervous system symptoms are not uncommonly the first manifestation
    • Such patients are often imaged without the diagnosis of systemic sarcoidosis having yet been made [11]
  • Up to 10% of patients with the systemic disease will demonstrate positive imaging findings
  • Thus not all patients with demonstrable imaging findings of neurosarcoidosis are symptomatic [11]
  • Histologically, central nervous system involvement is seen in ~20% (range 14-27%) of patients with systemic sarcoidosis
    • Although only ~10% (range 3-15%) are symptomatic [11]
  • Headache, seizures, encephalopathy, neuroendocrinological dysfunction, paraesthesia, paraplegia and peripheral neuropathy [16]
  • Cranial neuropathy is a typical manifestation
    • As the basal meninges tend to become infiltrated by disseminated granulomas and plaque formation
    • The facial nerves, in some cases the optic nerves, are most frequently involved
      • Any combination of cranial nerve involvement is possible [16]
  • Facial nerve palsy will usually resolve
  • But optic neuropathy has a poorer prognosis [16]
  • Disease course is also unfavourable in patients with
    • Chronic meningitis,
    • Intracranial mass
    • Spinal cord sarcoidosis
    • Sequelae can be devastating, and mortality rates are approximately 10% [16]
  • Radiculopathy if the spinal cord is affected (in rare cases cauda equina polyradiculopathy may occur)
  • Mononeuropathy,
  • Mononeuritis multiplex,
  • Carpal tunnel,
  • Muscle involvement which may cause proximal myopathy and muscle atrophy [17]
  • Speech difficulties
  • Psychiatric issues
  • Hallucinations
  • Irritability
  • Double vision or other vision issues [19]

Radiographic features of neurosarcoidosis

  • Can be thought of as occurring in one or more of five compartments
    • Skull vault involvement (refer to musculoskeletal manifestations of sarcoidosis)
    • Pachymeningeal involvement
    • Leptomeningeal involvement (seen in up to 40% of cases 1)
    • Pituitary and hypothalamic involvement
    • Cranial nerve involvement
    • Parenchymal involvement (most common) [11]

CT

  • CT is usually the first modality used in the workup of patients with neurosarcoidosis
    • It is not as sensitive or specific as MRI, with up to 60% of patients with subsequently proven neurosarcoidosis having negative CT scans
  • The features will be similar and regions that demonstrate enhancement on MRI may also be seen to enhance on CT, although often less dramatically. [11]
  • On non-contrast scanning lesions, be they pachymeningeal, leptomeningeal or parenchymal, can appear hyperdense [11]
  • Often the only finding is hydrocephalus due to occult leptomeningeal disease [11]

MRI

  • With contrast is the modality of choice for investigating suspected neurosarcoidosis.
  • In general, lesions follow a standard signal intensity
    • T1: iso- or hypointense to adjacent grey matter
    • T2: variable
      • Most are hyperintense
      • Some lesions can be iso- or hypointense
    • T1 C+ (Gd): homogeneous enhancement [11]
  • Pachymeningeal involvement
    • Often takes the form of pachymeningeal thickening with homogeneous enhancement
    • In some cases, the masses can be low on T2 weighted images, which although a helpful clue, is not pathognomonic.
  • Leptomeningeal involvement
    • T1 weighted with contrast
      • Quite prominent changes may be inapparent on other sequences
      • May be focal or generalized leptomeningeal enhancement particularly around the basal aspects of the brain and circle of Willis
        • Nodular or smooth
      • May follow perforating vessels up into the brain (via the perivascular spaces)
        • Sometimes referred to as tongues of fire
        • Can mimic parenchymal lesions
        • Can result in a CNS vasculitis picture, especially if a leptomeningeal disease is subtle elsewhere [11]
      • May lead to hydrocephalus
  • Pituitary and hypothalamic involvement
    • Frequently seen as part of a more extensive leptomeningeal disease
    • May also be encountered in isolation
      • Sometimes with limited disease confined to the infundibulum. [11]
  • Cranial nerve involvement
    • May be involved either as part of a more widespread leptomeningeal disease
    • In isolation
    • Any nerve can be involved
      • Facial nerve and optic nerve are most commonly affected
        • Facial nerve involvement is usually symptomatic but is often normal on imaging
          • The facial nerve is the most common cranial nerve affected, which may mimic Lyme disease. [17]
        • Optic nerve involvement can be anywhere along its course from the globe to the optic chiasm
          • Orbital manifestations of sarcoidosis for a discussion of the non-optic nerve orbital disease spectrum. [11]
  • Parenchymal involvement
    • Most common finding and can be in many forms
      • Extension of leptomeningeal disease up perivascular spaces
      • Periventricular high T2 signal white matter lesions
        • Often indistinguishable from multiple sclerosis or leukoaraiosis
        • May have low T2 signal components (without hemorrhage) due to high cellularity
        • Enhancing masses or nodules [11]
  • Another cranial nerve that may be affected is the vestibulocochlear nerve
    • Causing balance and hearing problems [17]
  • Ataxia, may be present with cerebellar involvement [17]
    • Involvement of the cerebellum and brain stem and the development of an akinetic rigid syndrome similar to Parkinsonism have been reported but are rare. [22]
  • Chronic meningitis with basal meningeal involvement
    • Common manifestation of neurosarcoidosis
    • Meningitis may present with either leptomeningeal or pachymeningeal involvement.
      • It is one of the several important causes of pachymeningitis [17]
  • In gathering a history, the first sign of neurosarcoidosis may be seizures
    • Generally confers a poor prognosis
    • Simple partial or complex partial seizures may have a better prognosis in comparison to generalized tonic-clonic seizures [17]
  • Depending on the location of the disease in the brain, the patient may also present with:
    • SIADH
    • Changes in appetite
    • Somnolence
    • Autonomic impairment
    • Weight gain
    • Impotence
    • Galactorrhea
    • Dementia
    • Impaired cognition [17]

  • Nuclear medicine
    • Gallium-67 citrate scan is insensitive to central nervous system involvement -positive in only 5% of cases
      • Helpful in confirming the presence of a systemic disease when neurological manifestations are the presenting complaint
      • Gallium scan is positive in approximately 45%
        • Other inflammatory/white cell abundant diseases may also be positive
          • Tuberculosis and lymphoma [11]

Diferenciální diagnostika nálezů

  • Meingy
    • Meningioma
    • Dural metastases including lymphoma
    • Erdheim-Chester disease
    • Idiopathic hypertrophic cranial pachymeningitis [11]
  • For leptomeningeal involvement consider
    • Tuberculous leptomeningitis
    • Lymphoma/leukemia infiltration
    • Leptomeningeal metastases
    • CNS cryptococcosis
    • Cryptococcal meningitis
      • Rare but life-threatening complication of sarcoidosis
        • Patient's may be misdiagnosed as neurosarcoidosis, which can result in considerable treatment delay and worse outcome
        • CSF cryptococcal antigen tests are advised in patients with sarcoidosis and meningitis [11]
  • For pituitary and hypothalamic involvement consider
    • Langerhans cell histiocytosis
    • Pituicytoma
    • Ectopic posterior pituitary: intrinsic high T1 signal
    • Lymphocytic hypophysitis
    • IgG4-related hypophysitis
    • Metastasis
    • Local masses
    • Meningioma
    • Optic nerve glioma
    • Hypothalamic astrocytoma [11]
  • For cranial nerve involvement consider in addition to all causes of leptomeningeal disease (see above), specific entities:
    • Optic nerve
      • Optic neuritis
      • Optic nerve glioma
      • Optic nerve meningioma [11]
  • For parenchymal involvement consider
    • Multiple sclerosis
    • ADEM
    • Leukoaraiosis: in asymptomatic cases, it is often not possible to distinguish between these and neurosarcoidosis lesions
    • When enhancing other entities to consider include:
      • Cerebral metastases
      • Tumefactive demyelination or acute demyelination
      • Primary brain tumors [11]

  • Neurosarcoidosis is commonly associated with cranial neuropathies, but any portion of the nervous system can be involved.[15]
  • The symptoms of neurosarcoidosis tend to be similar to the symptoms of multiple sclerosis (MS) or transverse myelitis. This is because neurosarcoidosis also damages the myelin coating around the nerve fibers. [19]
  • Spinal cord involvement
    • All parts of the spinal cord may be affected.
    • Most commonly patients present with a cervical cord or conus medullaris involvement, which may be painful.
    • The clinical syndrome varies between mild involvement with numbness
    • Severe, with evidence for transverse myelitis leading to difficulty walking and bladder problems
    • MRI scans show inflammation of the spinal cord and sometimes, like in the brain, it is thought to be a tumour before the diagnosis is made. [22]
  • Involvement of the cauda equina has also been reported.
    • Ascending, often bilateral,
    • Predominantly sensory disturbance with bladder and bowel problems.
    • It tends not to be painful. [22]

Osteoporoza

  • Vlivem rPTH a následně vlivem kortikoidní terapie
  • When corticosteroids are given long term or in high doses
    • We advocate close surveillance of bone density
    • And radiography if clinical signs of spine compression are present
  • Bone protection with
    • Oral bisphosphonates
    • Or infusion of zoledronic acid (5 mg given intravenously once per year) is recommended [16]

Patients at increased risk

  • Decreased bone density
  • Nad 50 years of age
  • Postmenopausal women
  • May be treated prophylactically with oral calcium supplementation
    • If serum and urinary calcium levels are regularly monitored
  • Postmenopausal women should consult a gynaecologist to decide whether oestrogen-replacement therapy is appropriate [16]

Small fibre neuropathy - SFN

  • The common neurological complication in SC
  • Considered to be the result of the chronic inflammation, and remains significantly understudied [14]
  • Frequently bothersome symptom in a substantial number of sarcoidosis patients
  • Can be linked to fatigue
  • May be difficult to diagnose
  • Identification can lead to possible targeted treatments
    • TNF inhibitors
    • Intravenous immunoglobulin [7]
  • Patients with high TNF levels
    • Increased fatigue and myalgia
  • Successful treatment of active sarcoidosis
    • Will also improve the symptoms of fatigue [7]
  • TNF-a inhibitors can be efficacious in eradicating fatigue [7]
  • Small fiber neuropathy (SFN) appeared to be rather common in sarcoidosis patients [14]
  • There are also anecdotal reports of success with
    • Intravenous immunoglobulin and infliximab [16]
  • The novel peptide ARA 290 was investigated in small fibre neuropathy in a recent study from the Netherlands
    • Modelled on erythropoietin
    • Has anti-inflammatory and tissue repair-activating properties
    • Shown to be effective in the small fibre neuropathy that is seen in diabetes mellitus
    • Double-blind placebo-controlled study of 22 patients with small fibre neuropathy and sarcoidosis
      • Those on active therapy showed significant improvements compared with placebo
        • Including the small fibre neuropathy screening list score that has been developed for use specifically in sarcoidosis-related small fibre neuropathy [16]
  • Granulomas in the nerve within the perineurium and epineurium may cause
    • Axonal damage
      • Result peripheral neuropathy
  • Nerve injury may cause
    • Diffuse polyneuropathy
    • Mononeuritis multiplex
    • Polyradiculopathy due to spinal root sheath involvement
  • Nerve biopsies demonstrate
    • Axonal degeneration with nerve atrophy.
    • Myelin ovoids may be seen as a sign of demyelination [17]
  • Remissions are possible in peripheral neuropathy and myopathy cases
    • However, the course usually is chronic and progressive [17]

Kardiální neuropatie

  • Moreover, about 50% of patients with small fiber neuropathy showed
    • Impaired cardiac sympathetic nerve activity
      • Can be assessed by iodine-123 metaiodobenzylguanidine (I-123 MIBG) [14]

Postižení různých nervů

Vyšetření

  • Cardiac sympathetic nerve function assessed by myocardial SPECT imaging
    • With the use of radiolabeled I-123 MIBG
    • Images demonstrats absent uptake of I-123 MIBG
    • Bulls’ eye quantification shows a defect size
  • A myocardial perfusion SPECT scintigraphy with Thallium-201
    • Shows normal perfusion
  • Echocardiography and MRI of the heart also normal [14]

Kazuistika

  • Sarcoidosis patient with impaired cardiac sympathetic nerve function which improves after carvedilol therapy [15]
  • Small fiber neuropathy presented with cardiac arrhythmia and dizziness [15]
  • carvedilol for five months
    • Clinical condition stabilized
    • no activity of sarcoidosis could be found
    • Did not recall heart rhythm disturbances anymore
    • I-123 MIBG SPECT study showed improvement of the uptake [15]

Kazuistika

  • We report a 42 year-old female who presented with severe lower limb neuropathic pain, asymmetric weakness and sensory impairment
    • Diagnosed with mononeuritis multiplex
  • Biopsy showed a granulomatous vasculitic process with eosinophils, scarce granulomata and axonal neuropathy and granulomatosis with poliangiitis was assumed.
  • Steroids, cyclophosphamide, alemtuzumab, azathioprine, mycophenolate mofetil and rituximab were used
    • All with transient and insufficient response
  • Skin biopsy performed in a further exacerbation allowed sarcoidosis diagnosis
  • Infliximab and, later, adalimumab induced good clinical and laboratorial response
    • But neutralizing antibodies developed to both drugs
  • So etanercept was tried with good clinical response. [21]

Studie TBC x SC a neropatie

  • 2018 – 2019 , included 71 patients
    • Pulmonary sarcoidosis (n=25)
    • Pulmonary tuberculosis (n=21)
    • Healthy subjects (n=25) [15]
  • Clinical verification of the SFN - “Small fiber neuropathy screening list” (SFN-SL) was used
  • Punch biopsy of the skin was performed followed by the enzyme immunoassay analysis with PGP 9.5 antibodies.
  • Up to 60% of sarcoidosis patients and 19% tuberculosis
    • Presence of at least one complaint, which may be associated with SFN
  • Most frequent complaints included:
    • Dysfunctions of the cardiovascular
    • Musculoskeletal system
    • Gastrointestinal tract [15]
  • Statistically significant correlation between the
    • Intraepidermal nerve fiber density (IEND)
    • SFN-SL score in both groups
  • Density of small nerve fibers in the patients with pulmonary sarcoidosis was lower
    • Compared to the patients with tuberculosis [15]

Popisy

  • In patients with pulmonary sarcoidosis
    • Small fiber neuropathy may develop as a result of systemic immune-mediated inflammation
    • Most common symptoms of this complication were dysautonomia and mild sensory dysfunction [15]
  • In tuberculosis patients
    • Clinical and histological symptoms of the small fiber neuropathy were subsequently less prominent
    • May represent the difference between the autoimmune and bacterial inflammation [15]
  • The condition presents as
    • Peripheral pain
    • Disturbances of sensation
    • With abnormal temperature sensation [16]
  • Fibres in the autonomic system may also be affected [16]
  • Quantitative sensory testing in 31 patients with sarcoidosis
    • 81% had reduced temperature sensitivity [16]
  • Punch skin biopsy in seven of these patients with sarcoidosis
    • Reduction in the density of intra-epidermal nerve fibres compared with control subjects [16]
  • Diagnosis may be associated with autonomic dysfunction
    • Might be responsible for life-threatening events and sudden death of unknown cause which are not uncommon in sarcoidosis [16]
  • Prevalence of small fibre neuropathy
    • May be as a high as 60% amongst patients with sarcoidosis [16]
  • More standard nerve conduction studies are usually negative
    • High index of suspicion is needed [16]
  • Small, unmyelinated C and thinly myelinated Adelta nerve fibers mediate autonomic function, nociception, and thermal sensitivity
    • Selectively reduced
    • Or predate large fiber involvement in many diseases [18]
  • A common etiology underlying small nerve fiber loss (SNFL) may be chronic inflammation
  • Sarcoidosis is an orphan disease of immune dysregulation and sustained inflammation
  • Although sarcoidosis often resolves spontaneously, many patients have persistent disease
    • And the majority of these suffer a painful neuropathy associated with SNFL
    • There are no approved therapies to treat the underlying pathophysiology of SNFL and its symptoms remain poorly managed [18]
  • Counter-regulatory mechanism, that limits damage while simultaneously activating tissue repair has been identified
    • Activated by the innate repair receptor (IRR) comprised of beta common (CD131) and erythropoietin receptor subunits
    • Signals via janus kinase-2
    • And via multiple downstream intracellular molecular pathways
  • IRR activation promotes tissue protection and repair in a wide variety of preclinical models - including neuropathy
  • Noncaseating granulomas within the endoneurium
  • With injury primarily affecting large myelinated fibers
  • Granulomas in the epineurium and perineurium associated with periangiitis [20]
  • Direct compression and microvascular insult may both be at play
    • Variability of electrodiagnostic and clinical findings in neurosarcoidosis [20]

Testicular sarcoidosis

  • Have been found in 5% or less of patients at autopsy [11]

Abdominal wall

  • Sarcoidosis can involve the muscles and produce either a nodular, myopathic or myositic appearance
  • Radiographic changes include
    • Nodules extending along the muscle fibers
  • The atrophic myopathic form characterized by
    • Muscular atrophy
    • Fatty infiltration [12]


Cardiac involvement

  • Leading cause of death in sarcoidosis
  • Electrocardiography should therefore be performed at diagnosis
  • Incidence of cardiac sarcoidosis was 2.3% [6]
  • Most frequent cardiac manifestations are
    • Arrhythmias,
    • Sudden death
    • Congestive heart failure [6]
  • But uncommon manifestations have also been reported [6]
  • In the United States more than 10% of patients with sarcoidosis
    • Can result in bradycardia, shortness of breath, and edema [8]

Fatigue

  • Up to 50–70% of sarcoidosis patients
  • Impaired quality of life
  • Usually multifactorial.
  • Can be a consequence of treatment itself
    • As a complication of corticosteroid
  • Granuloma formation and cytokine release may be involved
  • Despite adequate sarcoidosis treatment, many patients continue to experience fatigue [6]
  • Sarcoidosis patients treated with immunomodulating drugs
    • Relationship between fatigue and plasma IL-1b [6]
  • Four areas:
    • Metabolic abnormalities
      • Treatment of anaemia,
      • Diabetes mellitus
      • Thyroid disorders [7]
    • Psychosocial conditions
      • Depression, anxiety and stress [7]
    • Disease-related fatigue
    • Treatment-induced fatigue [7]

Sleep apnoea

  • Six to eight times more common in the sarcoid population compared to the general population [7]
  • Sleep disturbances are often related to SFN and autonomic dysfunction, which may, in part, explain the fatigue [7]
  • Increased OSA was identified in male patients along with patients with
    • Lupus pernio,
    • Upper airway involvement
    • Increased body mass index (BMI) [7]
  • Recognition and treatment of OSA can greatly improve symptoms of fatigue and lethargy [7]
  • Periodic leg movement or restless legs
    • Found in more than half of the sarcoidosis patients [7]
  • Obstructive sleep apnoea in sarcoidosis with its attendant fatigue symptomatology has been described
    • But excess daytime sleepiness, assessed by the Epworth Sleepiness Scale
      • Has also been reported in the absence of sleep apnoea
  • Treatment options for obstructive sleep apnoea are likely to have a positive effect on fatigue
    • Is important to distinguish between these two states [16]

Fatigue and both small fibre neuropathy and muscle weakness

  • Disease-modifying therapy in both worsening and possibly alleviating fatigue also needs to be considered [16]
  • Bilateral phrenic neuropathy with axon loss, suggesting a poor prognosis [19]
    • Case establishes phrenic neuropathy and peripheral polyneuropathy secondary to neurosarcoidosis as a cause of respiratory failure [19]

Comorbidities associated with sarcoidosis

  • Depression,
  • Anxiety,
  • Hypothyroidism
  • Altered sleep patterns
  • May all contribute to fatigue
  • Most patients’ complaints of fatigue are not correlated with clinical parameters of disease activity [6]

Neurostimulants

  • Methylphenidate
    • For the treatment of sarcoidosis-associated fatigue [6]
  • Dexmethylphenidate
    • 10 patients, Lower et al. observed improvement in Fatigue Assessment Scores in response to an escalating dose of dexmethylphenidate up to a maximum of 20 mg day [16]
  • Armodafinil [16]
    • Escalating dose of armodafinil up to 250 mg day-1 in 15 patients
    • Improvements in Fatigue Assessment Scores were seen [16]

Anti-TNF agents

  • If organic disease also troublesome [16]

Kortikoidy

  • Given that inflammatory factors may play a causative role, it would be reasonable to assess the effects of a small dose of corticosteroids
    • no greater than 10 mg day-1
  • Possibly with the addition of hydroxychloroquine
    • For patients with troublesome fatigue without any clinical manifestations of organ involvement [16]

Genitourinary tract

  • Renal involvement is seen in 7-22% of patients
  • In male patients the epididymis and the testis can be involved
  • CECT scan may show signs of interstitial nephritis or less frequently multiple hypoattenuating nodules that resemble lymphoma or metastases [12]
  • If epididymis is involved, MRI shows
    • Heterogeneous and nodular enlargement
    • With a slight increase in signal intensity on the T2-weighted images
  • Sonographically
    • Resultant masses are homogeneously hypoechoic [12]

Gastrointestinal tract

  • Involvement of the gastrointestinal tract is rare
  • When present it is usually associated with pulmonary disease [12]
  • Stomach is the most common site of involvement
  • Radiological signs of the disease are very non-specific
    • Ranging from mucosal thickening (mimicking Menetrier disease) to lesions mimicking gastric ulcers or linitis plastica [12]
  • Intestinal
    • Have been found in 5% or less of patients at autopsy [11]
  • Sarcoidosis is most frequently observed in the antrum of the stomach
    • Ulcers, nodules, polyp formation
    • Sometimes a linitis plastica-type picture may be found
    • Often giving rise to postprandial epigastric pain, nausea and vomiting
    • Sometimes causing protein-losing enteropathy, weight loss
    • Signs of G-I bleeding and obstruction [16]
  • Any part of the G-I tract may be involved
    • Small intestine is often spared making it relatively easy to differentiate from Crohn's disease [16]
  • Other causes of granuloma formation such as tuberculosis, fungal infection and lymphoma should also be excluded
  • Upper and lower G-I endoscopy with multiple random biopsies in the absence of macroscopic findings is recommended as part of the diagnostic procedure. [16]


Liver and spleen

  • Are the most frequently involved viscera
  • Granulomata noted in 40-70% of patients
  • Symptomatic liver disease
    • Occurs in less than 5% of patients with sarcoidosis
  • Laboratory evidence of liver dysfunction is seen in 2-60% of patients
    • With the alkaline phosphatase level being most commonly affected [12]
  • Diameter of granulomatous lesions in the liver is generally do 2 mm
  • Appearance of the larger lesions is probably caused by a coalescence of small granulomas.
  • Some patients with marked hepatosplenomegaly have no lesions
  • Nodular lesions can be seen in patients who have only slight enlargement of the liver and spleen [12]
  • no correlation between nodular hepatosplenic sarcoidosis and advanced pulmonary sarcoidosis [12]
  • Prevalence of hepatic granulomas is much more common in autopsy studies
    • Often being found in more than 70% of patients [16]
    • Prevalence is somewhat lower in biopsy studies
  • Abnormal liver function tests are more commonly reported than hepatomegaly
  • There may be hepatic involvement without signs of sarcoidosis in the lungs
  • Fatigue is a common symptom, and right upper quadrant abdominal pain may occur [16]
    • Seldom pruritus and jaundice [16]
  • Elevation of alkaline phosphatase levels
    • Considered to be a more reliable sign of involvement than increased levels of transaminases, which are often only slightly elevated [16]
  • Sometimes, portal hypertension with accompanying oesophageal varices and hepatomegaly may be a consequence of hepatic sarcoidosis
  • Cholestatic signs may mimic primary biliary sclerosis (PBC) and primary sclerosing cholangitis (PSC) [16]
    • Corticosteroids
      • Does not seem to have a major influence on the disease course and does not prevent portal hypertension [16]

Splenic involvement

  • Has been reported to be common in large Finnish biopsy series
    • Sometimes causing left
      • Upper abdominal quadrant discomfort
      • Peripheral blood cytopenia secondary to hypersplenism [16]
  • Spleen involvement without symptoms does not necessitate treatment
  • But enlargement causing cytopenia may require treatment with corticosteroids
    • Eventually in combination with corticosteroid-sparing agents
  • Occasionally, the sheer size of the spleen causes so much discomfort that splenectomy is recommended
    • Will exclude the risk of sudden life-threatening haemorrhage following rupture, either spontaneously or after blunt trauma [16]

Ascites

  • Caused by sarcoidosis is very uncommon
    • Can occur as a consequence of involvement in the peritoneal serosa
    • Sometimes as a result of portal hypertension or heart failure [16]

Radiographic features

  • Homogeneous organomegaly or nodular infiltration.
  • Usually, some enlargement of the liver (hepatomegaly) and spleen (splenomegaly) is seen
    • Can be depicted with ultrasound, CT and MRI [12]

Ultrasound:

  • Pattern of either diffuse increased homogeneous or heterogeneous echogenicity
  • Nodules are usually hypoechoic relative to the background liver

CT and MRI:

  • In most patients the liver is homogeneous
  • 10-15% of patients show hypoattenuating/hypointense liver and/or spleen nodules
    • Size from 5-20 mm that correspond with coalescing granulomas [12]
  • Nodules become more confluent with increasing size
  • Contrast-enhanced CT liver nodules
    • Appear as hypoattenuating masses relative to adjacent normal parenchyma [12]

MRI

  • Lesions are hypointense on all sequences
  • Hypoenhancing relative to the background parenchyma [12]

Biliary tree

  • Sarcoid can involve the intra or extrahepatic biliary tree
  • Intrahepatic involvement is granulomatous and produces cholestatic and primary biliary cirrhosis like picture
  • Extrahepatic involvement results in stricture and cholestasis, which appears like cholangiocarcinoma.
  • Enlarged portal nodes may produce cholestasis [12]
  • Biliary sarcoidosis can mimic PSC
    • But the response to corticosteroids is much better in patients with the former condition [16]
  • Ursodeoxycholic acid
    • Stimulates impaired hepatobiliary secretion,
    • Has a mild side-effect profile
    • Reported to have a positive effect on liver enzymes, fatigue and pruritus [16]

Skin involvement

  • In cca 25% of sarcoidosis patients [6, 8]
  • Only sarcoid like lesions on the skin
    • Will mostly be found to develop other evidence of systemic sarcoidosis [6]
  • Common signs of skin involvement are
    • Maculopapular lesions
    • Lupus pernio
    • Cutaneous or subcutaneous nodules
    • Infiltrative scars
    • More common in patients of African descent than in white [6]

Lupus pernio

  • Seems to be associated with chronic sarcoidosis and a worse prognosis [6]

Erythema nodosum

  • Most common nonspecific lesion
  • Occurs in 3% - 34% of patients with systemic sarcoidosis
  • In contrast to lupus pernio
    • Patients with erythema nodosum tend to have a good prognosis and not go on to chronic disease [6]

Lymph nodes

  • Enlarged lymph nodes
  • Usually found in the following areas
    • Porta hepatis
    • Para-aortic region
    • Celiac axis
    • Superior mesenteric artery
    • Gastrohepatic ligament
    • Retrocrural region
  • Up to 30% of patients have moderate abdominal adenopathy
    • 2 or more nodes with a short axis nad 1 cm
    • Or nodes in the retrocrural area with a short axis nad 6 mm [12]
  • Around 10% of patients have extensive adenopathy
    • Nad 2 cm and involvement of more than 4 sites
  • Lymphadenopathy can be demonstrated with ultrasound, CT and MRI [12]

Renal disease

  • Is also infrequent
  • Increased serum urea and creatinine concentrations generally reflect renal impairment
    • Related to longstanding hypercalcemia, hypercalciuria, nephrolithiasis, nephrocalcinosis, or granulomatous interstitial nephritis
  • Renal involvement is seen in 8-19% of patients [11]
  • Hydronephrosis
    • May be caused by compression of the ureters by enlarged retroperitoneal nodes [12]
  • Impaired renal function as a result of
    • Nephrocalcinosis
    • Granulomatous nephritis
    • Nephrolithiasis
  • In patients diagnosed with sarcoidosis should be measured:
    • Serum creatinine (and/or cystatin C)
    • calcium
    • Albumin levels
    • Ionized calcium calculated
    • 24-h urinary calcium excretion should be determined
    • Measurement of clearance (EDTA or iohexol) will provide additional information on renal function [16]

Neurodegerace

  • Chronic inflammatory disorders, including sarcoidosis, cause changes in the central nervous system.
  • TNF alfa increased in the serum of sarcoidosis patients
    • Related to disease severity
    • Induces a range of neurological, haematological, metabolic and endocrine changes,
    • Probably involved in the regulation of sleep
  • Increases in TNF-a, oxidative stress and inflammation-induced changes
    • Can alter neurotransmitter metabolism
    • Lead to cognitive impairment
  • TNF-a regulates synaptic transmission in the brain
    • Involved in spatial memory impairment in mice
  • Neuroinflammation with overexpression of cytokines
    • Characteristic of the brain pathology present in Alzheimer’s disease [7]
  • TNF-a may induce the expression of inducible nitric oxide synthase (iNOS)
    • Overexpression of iNOS was found in the brain of some Alzheimer’s disease patients
  • TNF-a inhibitor thalidomide
  • Was effective in reducing iNOS/peroxynitriterelated pathology
    • By restraining TNF-a increases
    • Without harming the physiological function of iNOS [7]
  • Excess TNF-a in the pathogenesis of cognitive impairment and fatigue in patients with sarcoidosis would explain the favourable effect of anti-TNF-a drugs in some studies. [7]

    • Ocular involvement

    • 10% - 50%
    • Extraocular disorders
      • Lacrimal gland swelling
      • Sicca syndrome [6]
    • Intraocular involvement
      • Uveitis
        • Likely to reduce the vision and to deteriorate the quality of life [6]
    • All patients suspected for sarcoidosis should be referred to an ophthalmologist [6]
    • Uveitis, which can result in significant vision loss if left untreated [8]

    Pancreas

    • Sarcoid involvement of the pancreas is uncommon.
    • Imaging manifestations of pancreatitis resulting from sarcoidosis are indistinguishable from those of pancreatitis caused by other conditions [12]
    • Have been found in 5% or less of patients at autopsy [11]


    Plíce

    • Majority of patients have lung and intrathoracic lymph node involvement
    • In most cases sarcoidosis is subacute and self-limiting
    • Lung is involved in the majority of patients and symptoms
      • Dyspnea and cough usually implies active disease
    • Depending on the severity of the inflammation in the lung
      • Pulmonary function tests may reveal
        • Restricted lung volumes and/or
        • Impaired diffusion capacity [6]
    • Estimated 90% of patients with sarcoidosis have pulmonary sarcoidosis
      • Decreased diffusion capacity (the most common abnormality found on pulmonary-function testing
      • Often accompanied by restrictive ventilatory dysfunction and the presence of obstructive airway disease - cca in 30% of patients [8]
    • 5% of patients with sarcoidosis are asymptomatic
      • Disease is detected incidentally by chest radiography performed to detect a different condition, such as pneumonia or another respiratory tract infection [8]
    • Pulmonary hypertension [8]
    • Normal lung tissue becomes peppered with fibrous tissue
      • Looses its elasticity
        • Resulting in loss of lung function
    • Large percentage of patients recover with minimal to mild loss of lung function
    • Many have more severe damage, requiring the use of oxygen and even a respirator [10]
    • Pulmonary and mediastinal manifestations (staging)
      • Alveolar sarcoidosis
      • Necrotizing sarcoid granulomatosis
      • Cavitatory pulmonary sarcoidosis [11]

    Plicní hypertenze

    • In a retrospective analysis of 22 patients treated with a variety of agents for pulmonary hypertension
      • Bosentan and sildenafil, New York Heart Association classification improved after a median of 11 months treatment in 50% [16]
    • Other studies of endothelin pathway blockade have investigated bosentan
      • One case report of improvement on therapy
      • One study of five patients, one of whom was treated with epoprostenol in addition to bosentan, in which mean pulmonary arterial pressures improved
      • Study of seven patients, four also on epoprostenol, showing haemodynamic improvement particularly in those with relatively well-preserved lung volumes [16]
    • Prostacyclin analogues
      • Retrospective study of seven patients
        • Six showed an acute response to intravenous epoprostenol
        • Five of the six continued long-term epoprostenol therapy with improvement in symptomatology [16]
    • Another study, inhaled prostacyclin administered to 22 patients
      • Resulted in an improvement in pulmonary vascular resistance in 20% of the cohort [16]
    • Studies of nitric oxide therapy, including phosphodiesterase type-5 inhibitors
      • Inhaled nitric oxide therapy reduced mean pulmonary arterial pressures and pulmonary vascular resistance
      • Following the acute response, sildenafil was administered with no response even though a previous study from the same group had shown improvements in haemodynamic indices following sildenafil treatment [16]
        • Asi podobný efekt jako s nitroglycerinem u anginy pectoris ? Spotřebování SH zbytků ? Nutné dodání pro obnovení účinku ?


    Prognóza

    • Disease is usually self-limiting
    • Some individuals experience unremitting inflammation
      • May progress into pulmonary fibrosis and death [4]
    • Overall, the prognosis for sarcoidosis is good
    • More than 70% of patients eventually showing no evidence of disease activity,
      • Although residual changes maybe seen on pulmonary radiology [4]
    • Minority develop long term disease
      • Which may prove difficult to manage with later development of lupus pernio and other complications [4]
    • Sarcoid granulomas can disappear leaving no evidence of their former presence
    • The granulomas may persist for several years without becoming fibrotic, apparently still capable of resolution;
      • But if they fail to resolve, they generally undergo hyaline fibrosis [5]
    • In this fibrosis, there may eventually be little or no recognizable remnant of the original epithelioid cell granuloma [5]
    • Necropsy findings at this very late stage of the disease may be non-specific or inconclusive [5]
      • Even though correlation with the observed clinical course may leave no reasonable doubt of the diagnosis [5]
    • Mortality rate of sarcoidosis is approximately 5% [6]
    • More than 50% of the patients a spontaneous remission is seen within three years [6]
    • Recovery - within 10 yrs for two-thirds with few or no consequences [7]
    • Up to one-third of patients have persistent disease, leading to significant impairment of quality of life [7]

    Classified in five stages

    • Scadding system with chest X-rays [6]

    Stage 0

    • Normal appearance [6]

    Stage I

    • Bilateral hilar lymphadenopathy alone [6]
    • Cca 45-80% of the patients will recover [6]
    sarcoidosis,

    Stage II

    • Bilateral hilar lymphadenopathy and parenchymal shadowing [6]
    • Recovery in 30-70% in stage II [6]

    Stage III

    • Parenchymal shadowing alone [6]
    • Recovery in 10-20% in stage III [6]

    Stage IV

    • Fibrosis
    • The remission rate is related to the radiographic stage
      • But may vary due to the different ethnic backgrounds [6]
    • 0% recovery in stage IV [6]

O úroveň výše

Poslední aktualizace: 18. 12. 2022 3:12:59