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Case presentation בית חולים אסף הרופא

Case presentation בית חולים אסף הרופא. - 50 y/o F. - Causes of admission: short transient speech disturbance and paresthesias of right limbs. - Medical history: Sjogren's disease CRF HTN Arthritis

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Case presentation בית חולים אסף הרופא

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  1. Case presentation בית חולים אסף הרופא

  2. - 50 y/o F. - Causes of admission: short transient speech disturbance and paresthesias of right limbs. - Medical history: Sjogren's disease CRF HTN Arthritis s/p hysterectomy and oopherectomy Childhood PPD+ , TREATED

  3. - Medication: Normiten Vasodip Plaquinil Eprex Salagen (pilocarpine) Vit D + Ca prednisone

  4. Physical examination : Normal BP – 200/115 mmHg HR – 80/ min Temp – 36.6 C Neurological examination : Normal except - Minimal right hyperreflexia

  5. Lab tests Blood count : HGB – 11.7 g/dL (11-16g/dL) HCT – 33.3 % (37-48%) Blood chemistry : ^Urea - 76 mg/dL (10-45 mg/dL) ^Cre – 1.61 mg/dL (0.5-0.9 mg/dL) Est. GFR – 37 ml/min (>60 ml/min) ^CK – 444 U/L (10-145 U/L) ^TP – 85 g/L (64-83 g/L) ^ALT – 34 U/L (4-31 U/L) ^AST – 36 U/L (5-32 U/L) CRP - <3 mg/L (0-5 mg/L) ^ ESR-100

  6. Coagulation : Normal Urine test : Mild proteinuria Mild hematuria

  7. Imaging : EKG - NSR, no ischemic changes Chest X-ray - hilar and periph. lymphadenopathy, subsegmental atelectasias of RML and lingula.

  8. Brain CT -

  9. What's next ?

  10. Chest CT - Multiple peripheral and pleural lymph nodes on both lung with lubsegmenta atelectasis of RML and lingula Abdominal CT - Circumscribed hypodense lesion, 2.5 x 2.5 cm, in the left hepatic lobe. Retroperitoneal ilieacal and inguinal lymph nodes. Echo - Normal LV size and functionLVH Mild left atrial dilatation Carotid doppler - Normal Bone scan- Hyperintense lesions in left and right temporal bones, left scapula, right 8th rib and D7 m/p sclerotic changes.

  11. Additional tests: ACA, LAC – Negative Anti ds DNA- Normal A/P- ANCA -negative C3 – 103 mg/dL (73-93 mg/dL) C4 – 19,8 mg/dL (18-36 mg/dL) CEA-0.4 ug/l (0-3.0 ug/l) Blood electrophoresis- elevate IgG,IgA ,IgM  RF – 1280 IU/mL (<10 IU/mL) ANA-Positive ! Anti Ro, Anti LA -Positive

  12. CSF- 12/3 cells u/l -100% lymphocytes protein – 34.8 mg/dL (20-25 mg/dL) glucose – 49 mg/dL (40-80 mg/dL) cytology - no sign of malignancy Oligoclonal - negative

  13. Events during hospitalization : After 5 days a transient speech disturbance followed by speech arrest, mastication movements and repetative movement of the right arm lasting for 30 sec. The patient received a loading dose i.v. 750 mg of Dantoin. Further examinations : EEG – normal AND ?

  14. Brain MRI : T1 + GAD

  15. Brain MRI : T2 - Flair

  16. The next step : FNB of left lung – No malignancy identified. Culture- including Z/N - no TB DIFFERENTIAL DIAGNOSIS ?

  17. Differential Diagnosis : Antiphospholipid syndrome SLE Sarcoidosis Scleroderma Vasculitis Dermatomyositis Diabetes Mellitus Amyloidosis MS

  18. Epidemiology, Etiopathogenesis, and General Features. • Clinical triad. • xerophthalmia, • xerostomia, • nondeforming arthritis. • It is seen in 0.5 to 2.0 % of the population. • Among the connective tissue diseases, it is second in prevalence only to rheumatoid arthritis. • Most (90%) patients are women. • Onset usually occurs during middle age.

  19. Epidemiology, Etiopathogenesis, and General Features. • occurs in isolation in 50 % of cases and in the context of rheumatoid arthritis, SLE, scleroderma, or another connective tissue disease in the remaining patients. • Primary Sjögren's syndrome predominantly affects exocrine glands, with lymphocytic infiltration and fibrosis of lacrimal and salivary glands. • Ocular, oral, and dental complications occur as a result of decreased tear and saliva production.

  20. Epidemiology, Etiopathogenesis, and General Features. • Xerophthalmia can be demonstrated by Schirmer's test, staining of the corneal and conjunctival epithelium by rose bengal dye, or demonstration of epithelial strands by slit-lamp examination. • Xerostomia can be assessed by nuclear scanning of the salivary glands, radiological sialography, or calculation of salivary flow rate. • Biopsy of minor salivary glands, found on the inner aspect of the lower lip, is well tolerated and diagnostic when lymphocytic aggregation is demonstrated.

  21. Etiology • Unknown, • Glandular inflammatory processes appear to be related to cell-mediated immunity or antibody-mediated cytotoxicity. • The association with certain HLA class II antigens suggests a hereditary predisposition. • Immune complex disease does appear to be responsible for rare cases of associated vasculitis.

  22. Extraglandular manifestations • occur in at least 25 % of patients. • Lymphadenopathy • hepatosplenomegaly.

  23. Extraglandular Manifestations • Arthritis of the small joints. • More than 80 % of patients. • Symmetric. • Mild synovitis. • No deformity. • Renal disease. • Interstitial nephritis. • Up to 40 % of cases.

  24. Extraglandular Manifestations • Lungs. • Less common. • Interstitial pneumonitis. • Restrictive or obstructive abnormalities of pulmonary function. • Vasculitis. • Skin. • nonthrombocytopenic. • Purpura. • urticaria. • Peripheral nervous system, • Muscle. • Occurs in up to 20 % of patients. • Lymphoproliferative disorders • increased risk of lymphoma.

  25. CNS Manifestations • Less frequent than peripheral neurological manifestations. • Affective and personality disorders. • Subcortical dementia. • Parkinsonism.

  26. CNS Manifestations • Focal cerebral deficits. • hemiparesis, • hemianopia, • Aphasia, • Simple and complex partial seizures. • Nystagmus, • Ataxia, • internuclear ophthalmoplegia • Spinal cord involvement: • Progressive myelopathy, • Acute transverse myelitis, • intraspinal hemorrhage.

  27. CNS Manifestations • EEG. • Abnormal in nearly one-half of patients with CNS dysfunction, nonspecific. • CT scanning and MRI. • Focal regions of abnormality in patients with clinical evidence of localized pathology.

  28. CNS Manifestations • CSF. • Elevation of protein concentration. • intrathecal immunoglobulin synthesis, • Increased IgG and oligoclonal bands. • Pathological studies. • perivascular inflammation. • Diffuse vasculitis involving the cerebral blood vessels. • Acute necrotizing arteritis of the spinal cord.

  29. Peripheral Neurological Manifestations • 10 to 32 %. • Sensory neuropathy (61%). • sensorimotor neuropathy (17%). • polyradiculopathy (11%). • Mononeuritis multiplex occurs somewhat less commonly. • Entrapment neuropathy, particularly carpal tunnel syndrome. • Cranial nerve involvement. • Trigeminal, • oculomotor, • abducens nerves.

  30. Peripheral Neurological Manifestations • Electrophysiological studies. • demyelination, • denervation, • Both. • The CSF. • Normal. • pleocytosis and an elevated protein concentration.

  31. Peripheral Neurological Manifestations • Peripheral nerve tissue may show demyelination, nonspecific epineurial inflammation, or acute or chronic vasculitis or perivasculitis. • Dorsal root ganglionitis, with lymphocytic infiltration and degeneration of ganglion cells, has also been reported to accompany subacute sensory neuronopathy.

  32. Extraoral and Extraocular Manifestations of Sjögren's Syndrome • General: fatigue, malaise, fevers • Ear, nose, and throat: epistaxis,otitis media, conduction deafness, recurrent sinusitis • Gastrointestinal: esophageal dysmotility,esophageal webs, reflux, atrophic gastritis,autoimmune pancreatitis, liver disease • Genitourinary: vaginitis sicca, interstitial cystitis • Hematologic: anemia, leukopenia,lymphopenia, cryoglobulinemia, lymphoma • Lungs: xerotrachea, recurrentbronchitis/pneumonia, lymphocytic interstitial pneumonitis,pulmonary fibrosis, bronchiectasis, BOOP • Neurologic: peripheral neuropathy,cranial neuropathy, central nervous system involvement • Renal: interstitial nephritis, hyposthenuria,renal tubular acidosis (types 1, 2) • Rheumatologic: arthralgias, polyarthritis,myalgias, myositis, Raynaud's phenomenon • Skin: xeroderma, purpura, urticaria, vasculitis

  33. History: · Sicca syndrome · Keratoconjunctivitis - Dry eyes with reduced tear production with gritty or sandy sensation under the lids red eyes; photosensitivity · Xerostomia - Decreased saliva production leading to difficulties with chewing, swallowing, and even speech; abnormality in taste and smell; dental caries; mucosal burning sensation; sensitivity to spicy and acidic foods and beverages; increased risk for oral candidiasis; hoarseness of voice · Musculoskeletal symptoms · Arthralgia, morning stiffness, nonerosive arthritis · Myalgia, muscle weakness · Cutaneous findings · Raynaud phenomenon · Nonthrombocytopenic purpura, especially of lower extremities · Nasal, vaginal, and cutaneous dryness · Gastrointestinal symptoms · Dysphagia, nausea, epigastric pain · Achalasia (in children) · Achlorhydria, chronic atrophic gastritis · Primary biliary cirrhosis · Pulmonary findings · Dyspnea due to mild interstitial disease · Dry cough · Renal findings - Interstitial nephritis · Other symptoms - Fatigue, depression

  34. Physical: · Parotid gland enlargement · Corneal ulceration, vascularization · Vasculitic lesions - Purpura · Lymphadenopathy · Autoimmune thyroiditis · Neuromuscular manifestations · Peripheral sensorimotor neuropathy · CNS disorders, such as movement disorder, transverse myelopathy, encephalopathy, aseptic meningitis, and dementia, have been described in some studies. · Arthritis · Intermittent synovitis · Chronic nonerosive polyarthritis: Jaccoud arthropathy is observed in adults. · Oral cavity · Mild erythema and thinning of the mucosa · Erythema, fissuring, coating, and depapillation of the dorsal tongue · Traumatic erosions and ulcers, angular cheilitis, and chapped lips · Frothy, ropey, and thickened saliva

  35. Causes: Multiple etiological factors likely are involved in the pathogenesis of Sjögren syndrome. · Sex hormone: As with other autoimmune disorders, a female preponderance exists in Sjögren syndrome. This suggests that sex hormones may play a role in shaping the autoimmune response. · Genetics: The association of certain HLAs suggests that genetic factors likely play a role in the pathogenesis of Sjögren syndrome. Patients with HLA-B8, HLA-Dw3, and HLA-DR3 have a high incidence of autoantibody production and extraglandular manifestations. Most patients also have the DQA1*0501 allele, which may have a role in the pathogenesis of this disease. · Environmental factors: Epstein-Barr virus (EBV) replicates in the salivary glands during primary infection and remains latent in these organs. EBV-DNA is recovered from salivary glands and saliva of these patients. Its etiopathological role cannot be proven. HIV, human T-cell leukemia-lymphoma virus type 1 (HTLV-1), and cytomegalovirus (CMV) also are under scrutiny as possible inciting agents that lead to lymphoproliferation observed in the end organs. · Autoantibodies: The presence of anti-Ro (SS-A) and anti-La (SS-B) is associated with earlier onset, longer duration, and more extraglandular manifestations of primary Sjögren syndrome. · Inflammatory reactivity: In situ evidence suggests that proinflammatory cytokines, interleukin (IL-1), interleukin 6 (IL-6), and tumor necrosis factor (TNF) are produced in the salivary glands. These are found in the infiltrating lymphocytes as well as the epithelial cells. This suggests that the infiltrating lymphocytes (ie, predominantly CD4 T cells) play a role in the perpetuation of the disease process.

  36. Lab Studies: · CBC count with differential: Mild anemia and leukopenia are present. · Erythrocyte sedimentation rate (ESR): Elevated ESR is observed in 80-90% of patients; however, C-reactive protein (CRP) usually is within the reference range. · Immunoglobulin levels: Hypergammaglobulinemia, up to several grams of immunoglobulin G (IgG), is observed in 80% of patients. · Autoantibodies · Antinuclear antibody (ANA) and rheumatoid factor (RF) - Usually elevated · Anti-Ro (SS-A), anti-La (SS-B) · Other autoantibodies to thyroglobulin, thyroid microsomal, mitochondrial, smooth muscle, and salivary duct · Rose Bengal staining: The dye stains the damaged corneal epithelium and indicates keratoconjunctivitis. Imaging Studies: · Sialography - A sensitive and specific radiographic technique to find evidence of sialectasis · Technetium Tc 99 pertechnetate scintigraphy - Delayed uptake in Sjögren syndrome, and correlates with pathological changes · Magnetic resonance imaging (MRI) - Visualization of the glandular parenchyma, in particular for the evaluation of cystic or solid masses (In addition, the volumetric estimate of the gland size can be determined.)

  37. Other Tests: · In the questionnaire for salivary hypofunction, positive responses to all 4 of the following questions indicate major salivary gland hypofunction (adapted from Fox and others, 1998). · Do you sip liquids to aid in swallowing dry foods? · Does your mouth feel dry when eating a meal? · Do you have difficulties swallowing any foods? · Does the amount of saliva in your mouth seem to be too little? · Sialometry is the quantification of whole saliva or individual gland secretions at unstimulated (resting) or stimulated flow rates. For salivary hypofunction, the flow rate for unstimulated whole saliva is less than 0.1 mL/min, while the rate for stimulated whole saliva is less than 0.5 mL/min. The collection period is a minimum of 5 minutes and often up to 15 minutes. When secretions from the parotid gland are evaluated, the modified Carlson-Crittenden collector is placed over the Stensen duct. Isolation of the salivary gland orifices in the floor of the mouth and gentle suction are used to collect submandibular and sublingual secretions together. Besides demonstrating salivary hypofunction, these methods can be used to evaluate the effectiveness of secretogogue therapy. · On sialochemistry, collected secretions can be chilled; frozen; and evaluated for electrolytes, immunoglobulins, and protein constituents. Although not diagnostic for Sjögren syndrome, a profile has been observed, including an increase in secretory immunoglobulin A, lactoferrin, total protein, and sodium and chloride ions. In addition, decreases in lysozyme and potassium and phosphate ions are found. Although still considered experimental, these changes in salivary constituents may help to predict disease progression and prognosis. · Schirmer tear test: This test is used to evaluate tear production by lacrimal glands. A strip of filter paper is placed beneath the lower lid, and wetting of the paper is measured at 5 minutes. Less than 5 mm of wetting suggests decreased tear production. Procedures: · Salivary gland biopsy · The pathological findings are very useful in diagnosis. · Because of the relative ease and lack of complications, labial minor salivary gland biopsy is preferred over parotid gland biopsy, which can result in facial nerve damage. · In order to ensure that a representative sample has been obtained for histopathologic examination, harvesting 5-10 lobules of minor salivary glands is important. Histologic Findings: The characteristic histopathologic findings of the minor salivary glands include an inflammatory infiltrate adjacent to normal appearing acinar structures. The inflammatory infiltrate consists of primarily lymphocytes and fewer plasma cells. Most of the infiltrating lymphocytes are CD4+ memory T lymphocytes. Initially, a focal periductal pattern is observed with eventual confluence of the inflammatory infiltrate that replaces the acini. Periductal and perivascular hyaline deposits may be observed. Unlike the parotid gland lesions, epimyoepithelial islands are rarely observed in the lymphocytic background. The finding of more than one focus of 50 or more inflammatory cells within a 4-mm2 area of glandular tissue supports the diagnosis of Sjögren syndrome. The greater the number of foci, the greater is the disease correlation. When enlargement of the major glands occurs, a benign lymphoepithelial lesion (BLEL) may develop. The characteristic features include a dense lymphocytic infiltrate that is associated with the destruction of salivary gland acini, while the ductal epithelium persists. Hyperplasia of the ductal epithelium and myoepithelial cells that form epimyoepithelial islands within the lymphoid tissues occurs. Formation of germinal centers may be observed. Determination of monoclonality of the lymphocytic infiltrate by immunohistochemical or gene rearrangement studies may be necessary in order to exclude a low-grade B-cell lymphoma.

  38. American-European Criteria for the Classification of Sjögren's Syndrome* • 1. Ocular symptoms (any 1 of 3)Dry eyes > 3 monthsTear use > 3 times dailyForeign body sensation • 2. Oral symptoms (1 of 3)Dry mouth > 3 monthsSwollen salivary glandsNeed liquids to swallow • 3. Ocular signs (1 of 2)Unanesthetized Schirmer's </= 5 mm/5 min in both eyesPositive vital dye staining • 4. Oral signs (1 of 3)Abnormal salivary scintigraphyAbnormal parotid sialographyAbnormal sialometry (unstimulated salivary flow </= 0.1 mL/min) • 5. Positive lip biopsyFocal lymphocytic sialadenitis (focus score >/= 1/4 mm²) • 6. Positive anti-SSA and/or anti-SSB antibodies • *Modified from Vitali C et al.[6] Exclusions: hepatitis C, graft-vs-host disease, anticholinergic medications, etc. Diagnosis of primary Sjögren's syndrome (SS) requires 4 of 6 criteria including item 5 or 6 above. Diagnosis of secondary SS requires established connective tissue disease, 1 sicca symptom (item 1 or 2), plus 2 of 3 objective tests for dry eyes and dry mouth (items 3-5). Diagnosis of SS can be made in patients who have no sicca symptoms if 3 of 4 objective criteria are fulfilled (items 3-6).

  39. Treatment: Cholinergic agonists -- Stimulate salivary secretion. Pilocarpine (Salagen) -- Muscarinic M3 receptor agonist. 5 mg PO tid/qid; may titrate up to 10 mg tid Immunosuppressive agents -- Used to treat extraglandular disease (ie, interstitial pneumonitis, glomerulonephritis, vasculitis, pseudolymphoma, malignancy). Prednisone Corticosteroid with salt-retention properties used for its potent anti-inflammatory effects. Up to 60-80 mg PO qd

  40. Nonsteroidal anti-inflammatory drugs (NSAIDs) -- Use of NSAIDs similar to those used for juvenile arthritis may be used to treat polyarthritis associated with Sjögren syndrome. Naproxen (Aleve, Naprosyn, Naprelan) -- For relief of mild to moderate pain. Inhibits inflammatory reactions and pain by decreasing activity of cyclooxygenase, which is responsible for prostaglandin synthesis. 250-500 mg PO bid (Naprosyn); may increase to 1.5 g/d for limited periods.

  41. Disease-modifying antirheumatic drugs (DMARDs) -- Used for polyarthritis not controlled with NSAIDs. Methotrexate (MTX) has been shown to be effective in managing polyarthritis. Other DMARDs (eg, hydroxychloroquine, sulfasalazine, D-penicillamine) may be synergistic when coadministered with methotrexate. Methotrexate (Folex PFS, Rheumatrex) -- Unknown mechanism of action in treatment of inflammatory reactions (although may involve adenosine receptors); may affect immune function. Ameliorates symptoms of inflammation (eg, pain, swelling, stiffness). Adjust dose gradually to attain satisfactory response. 7.5 mg/wk or 2.5 mg PO/IM bid for 3 doses qwk.

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