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Table e-11. Clinical assessment:The following patient characteristics were collected: age at onset of neurological manifestations, sex, ethnic background, relevant personal and family background, triggers of HLH (i.e. acute EBV infection, HIV, mycobacterium tuberculosis, Still’s disease, autoimmune connective tissue disorders, lymphomas, leukemias and immunosuppressive drugs), CNS signs and symptoms, response to steroids and/or immunosuppressive therapies, number of neurological attacks, weight loss (10% of the initial body weight), mood disorders (according to Diagnostic and Statistical Manual of Mental Disorders -5 criteria), disability at the last follow-up during the relapse free period (modified Rankin scale), duration of follow-up (months).2. Radiological assessment:Patients were examined with a 1.5-Tesla or a 3-Tesla MRI at each CNS attack and at last one time during the relapse free period in order to assess the response to steroids and/or immunosuppressive therapies. Brain magnetic resonance images (MRIs) were obtained using the following sequences in our 12 enrolled patients: precontrast and postcontrast T1-weighted images (WI), T2WI, fluid-attenuated inversion recovery, T2*-weighted gradient-echo images (T2*WI), diffusion-weighted imaging, apparent coefficient diffusion map (ADC), and magnetic resonance angiography (MRA). Spinal MRIs were obtained using the following sequences in our 12 enrolled patients: precontrast and postcontrast T1WI and T2WI. Brain CT scan and digital subtraction angiography were not performed because none of our patients had T2* hypointensities and evidence of vascular involvement on MRI (ie, no brain infarction, haematoma or arterial narrowing on MRA).3. Histological procedure: Brain biopsy was performed in 4 patients. Histological sections were stained with H&E, Bielschowsky stain, Perls’ iron stain, and the following antigens: CD20, CD3, CD4, CD8, granzyme B, CD68, CD 38, CD 138, CD1a, beta-amyloid, neurofilament and glial fibrillar acid protein. A myelin stain (Klu?ver-Barrera) and a proliferation marker (Ki-67) were also used. In situ hybridisation studies were performed for Epstein-Barr virus early RNA-1.4. Ancillary tests: All patients had routine blood tests (including C reactive protein level, serum protein electrophoresis), serum lactate deshydrogenase level and IgE level, serological tests for infections (HIV, hepatitis B virus, hepatitis C virus, Epstein-Barr virus, Lyme and syphilis), serological tests for connective tissue diseases (antinuclear antibodies, (anti-double stranded DNA), extractable nuclear antigens, rheumatoid factor, complement C3 and C4, lupus anticoagulant, anticardiolipin and antiphospholipid antibodies), systemic vasculitis (antineutrophil cytoplasm antibodies and cryoglobulinaemia), sarcoidosis (ACE), demyelinating disorders (aquaporin-4 antibody and anti-myelin oligodendrocyte glycoprotein antibody), antineuronal and antiganglioside antibodies. CSF analysis with immunoelectrophoresis was performed in all patients. Bone marrow biopsy and/or aspiration were performed in 5/12 patients, and Whole body CT and/or PET scan in all patients.5. Systemic signs of HLH according to the HLH-2004 criteria: Five criteria were evaluated in all patients during attacks: 1) fever (temperature ≥ 38.5 °C); 2) splenomegaly; 3) cytopenias, of at least two cell lines: Hb < 9 g/dL; platelet count < 100,000/?L; absolute neutrophil count < 1,000/?L; 4) hypertriglyceridemia (> 265 mg/dL) and/or hypofibrinogenemia (≤ 150 mg/dL); 5) hemophagocytosis in bone marrow, spleen, lymph node, or liver. Three additional criteria were evaluated in some of the patients: low or absent lymphocyte cytotoxic activity, ferritin level > 500 ?g/L and elevated soluble CD25 (soluble IL-2 receptor> 2,400 U/ml). 6. Atypical features for CLIPPERS:Atypical clinical features include: cortical signs and/or symptoms; polyneuropathy; corticosteroid therapy resistance; relapse despite a daily dose of glucocorticoids ≥ 30 mg; and clinical presentation explained by another disease than CLIPPERS. Atypical radiological features include: gadolinium-enhancing lesions without punctate or curvilinear shape, large T2 hyperintensities, diffusion restriction, T2* hypointensities, arterial stenosis on MRA, corticosteroid therapy resistance.Atypical histological features include: vasculitis, demyelinating lesions, granuloma, and lymphoma. ................
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