23Physical ExaminationV/S: T 37.8°C, PR 120 bpm, RR 40 bpm, BP 96/44 mmHg, BW 14 kg (P50-75th), Ht 95 cm (P50-75th), HC 49 cm (P 50th) GA: a Thai girl, drowsiness, mild pallor, no jaundice, no dysmorphic feature, capillary refill 3 sec HEENT: bilateral cervical LN 0.5 cm, no neck mass, pharynx and tonsil not injected
24Physical ExaminationCVS: normal S1 S2, no murmur Lung: clear, no adventitious sound, no retraction Abdomen: soft, no distension, liver 3 cm below RCM, liver span 9 cm, spleen 4 cm below LCM Skin : no lesion
25Physical Examination Nervous system : drowsiness, pupils 3 mm RTLBE, no stiffness of neck, full EOM by observe, no nystagmus, no facial palsy, corneal reflex positive, gag reflex negative, tongue and uvula in midline, spastic all extremities, motor power: Rt side gr I, Lt side gr II, DTR 3+, BKK: present both sides
34Bone marrow aspiration Hypercellularity 1+Adequate in number of megakaryocyte, erythroid, myeloid seriesNo blastNo abnormal cellNo hemophagocytic activity
35Bone marrow biopsyActive trilinear hematopoiesis with increase histiocytes with hemaphagocytosis activityNo immunophenotypic evidence of increased blasts or non-Hodgkin lymphomaCD68-positive histiocytes are increased
42Brain biopsy (3)Infiltrate of foamy histiocytes with reaction astrocytes
43PRF1 gene mutation analysis PCR amplification and sequencing analysis of PRF1 gene (exon 2 and 3)Interpretation :The mutation of PRF1 exon 2 or 3 was not identifiedThe PRF1 c.822C>T and c.900C>T which synonymous SNPs
44UNC 13 D (Munc 13-4)Polymorphism or Mutation of UNC13D IVS4-1 or IVS9-1 was not identifiedc.756_757insAC cause a shift in the reading frameUNC13D c.756_757insAC
46MRI post treatment 3-month MRI brainMarked decrease white matter lesions which severe white matter volume loss with bilateral ventricles dilatationIncrease choline with decrease NAA at residual periventricular lesions without relative hyperperfusionMRI whole spineRemaining intramedullary lesions entire spinal cord but not enhancementClumping with faint enhancing cauda equina nerve root
53Method Single center (France) retrospective1981 to 1993 34 patients (19 girls, 15 boys) with HLH25 patients with family history (consanguinity or siblings affected same syndrome9 patients without family history, no concomitant infection-induced, recurrence of hemophagocytic syndromeEvaluate : clinical, CSF, neuroradiolological studiesE.Haddad, et al. blood Feb;89:
5520-80 lymphocytes/µL with protein 50-100 mg/dL Meningitis20-80 lymphocytes/µL with protein mg/dL20 with meningitis (mean age 6.9 months)9 with neurological symptoms (mean age 16 months)E.Haddad, et al. blood Feb;89:
568/9 with neurological symptoms Brain imaging9/20 with meningitis4 had abnormal : 2 with pericerebral diffuse subdural dilataion, 2 with white matter lesions8/9 with neurological symptomsMost frequent focal necrosis with parenchyma volume loss and white matter lesionsE.Haddad, et al. blood Feb;89:
5719 patients had severe CNS progression 4 patients repeat imaging 3 with severe brain atrophy1 with enhance cerebellar white matter and parenchyma lossE.Haddad, et al. blood Feb;89:
593 cases perform MRI before and after BMT 7 alive with normal neurological examination, CSF, cognitive development3 cases perform MRI before and after BMT2 had normal MRI (pre/post BMT)1 had white matter lesion before BMT and remain 2 years after BMTE.Haddad, et al. blood Feb;89:
61Large cohort of children (n = 193) Originated from 25 countries Median age at diagnosis 9 months106 (55%) less than 1 year of age at diagnosis43/192 (22%) (no data = 1) familial diseaseConsanguinity 37/186 (20%) cases (no data = 7)11 patients studied specified viral infections at diagnosisA. Horne, et al. BJH Dec;140:327–335.
63Neurological symptoms and relation to abnormal CSF A. Horne, et al. BJH Dec;140:327–335.
64CSF 101 patients (52%) abnormal CSF Elevated CSF protein 76/188 (40%) Elevated cell counts in 79/189 (42%)Abnormal CSF at onset had sequelae compared to 5/61 (8%) patients with normal CSF (P = 0.024)A. Horne, et al. BJH Dec;140:327–335.
67Mortality and CNS involvement 3-year probability of was 56%67 (61%) transplanted37 (34%) ‘off-therapy’49 patients died before SCT18 of these (37%) CNS involvementNo neurological symptom but abnormal CSF (CNS group 3)A. Horne, et al. BJH Dec;140:327–335.
7192 patients with HLH January 2004 to August 2008 82 patients (89%) active viral infection69/82 patients (75%) EBV infection9 patients not find any underlying diseaseNone of the patients were offspring of consanguineous marriages or history of siblings affected by same syndrome82 were only child in the familyS. Yang, et al. Pediatr Blood Cancer 2010;54:408–415.
72Methods Prior to start therapy, all patients underwent CSF cytology and biochemical assaysBrain CT and/or MRI examinationCSF analysis repeated weekly until normalizeCT or MRI examinationsRepeated at 8-week intervals until treatment stoppedCompleted therapy every 6 months for at least 1 year
73RESULTS43 patients CNS involvement, either clinical, MRI/CT or CSF abnormalities36 (84%) patients had EBV-HLHNo underlying disease found in 5 patientsS. Yang, et al. Pediatr Blood Cancer 2010;54:408–415.
74RESULTS 4 : S+R+C 4 : S+R 2 : S+C 6 : R+C 2 : S 3 : C 22 : R S, symptomsR, neuroradiologyC, CSFS. Yang, et al. Pediatr Blood Cancer 2010;54:408–415.
75Neuroradiological Examinations CT 46 patients, 8 showed abnormalitiesCalcifications (n=2), atrophy (n=2), demyelination (n=2), edema (n=1), and hemorrhage (n=1)MRI 64 patients, 34 showed abnormalitiesHigh signal intensity lesions on T2-weighted and FLAIR MRI images (n=29), atrophy (n=9), hemorrhage (n=5), cerebromalacia (n=4), and calcifications (n=2)S. Yang, et al. Pediatr Blood Cancer 2010;54:408–415.
76Clinical Manifestations 12 patients neurological symptoms at diagnosisEleven of these EBV-HLHSeizures (n=10), hemiplegia (n=3), ataxia (n=3), coma (n=2), cranial nerve palsy (n=2)8 pathological changes in CT/MRI images6 abnormal CSFS. Yang, et al. Pediatr Blood Cancer 2010;54:408–415.
77Cerebrospinal Fluid Tests 15 patients (16%) CSF abnormalities at onset11 patients elevated spinal fluid protein10 patients elevated spinal fluid leukocyte countsS. Yang, et al. Pediatr Blood Cancer 2010;54:408–415.
78CNS Involvement After Start of Therapy 12 patients with neurological symptoms had improved3 discontinued therapy due to progressive systemic symptomsOne patient, presenting with CNS dysfunction preceding systemic HLH disease, improved initially but repeated relapses and progressive CNS symptoms 6 months later15 patients with CSF abnormalities at diagnosisNormal within 6 weeks of therapyS. Yang, et al. Pediatr Blood Cancer 2010;54:408–415.
79CNS Involvement After Start of Therapy Neuroradiological abnormalities showed slow recovery rate,Neurological symptoms resolved quickly36 patients with neuroradiological abnormalities2 patients showed any improvement15 patients lost to follow-up,5 patients still undergoing treatment at the end of studyS. Yang, et al. Pediatr Blood Cancer 2010;54:408–415.
80CNS Involvement After Start of Therapy 16 patients followed post-therapy12 showed some improvement of imaging after 3–12 months5 completely normal CT/MRI scans at follow-upOne progressive changes in the CT/MRI images and relapsed3 patients CT/MRI findings unchangedS. Yang, et al. Pediatr Blood Cancer 2010;54:408–415.
81CNS Involvement After Start of Therapy 42 patients followed after discontinuation of therapy21/42 had at least one manifestation of CNS involvement at diagnosis10/42 recovered completely from CNS involvement3 patients not improve with radiological findings while CSF analysis and clinical examination normalizedS. Yang, et al. Pediatr Blood Cancer 2010;54:408–415.