Interhospital Conference

Ramathibodi hospital20 March 2012

Patient profile

• ผู้��ป่�วยเด็กหญิ�งไทย อาย� 2 ป่� 11 เด็�อน• ภู�มิ�ลำ�าเนา จั�งหว�ด็ นนทบุ�รี!• ส่#งตั�วมิารี�กษา รีพ.รีามิาธิ�บุด็! เมิ�(อว�นท!( 2 ก�นยายน

2554

Chief complaint

• แขนขาข�างขวาอ#อนแรีง 2 เด็�อนก#อนมิารีพ.

Present illness

• 2 เด็�อนก#อนมิารีพ. มิารีด็าส่�งเกตัว#าผู้��ป่�วยรี�องงอแงบุ#อย แขนขวาอ#อนแรีง ขย�บุน�อยลำง ตั#อมิาขาขวาอ#อนแรีง ไมิ#ยอมิเด็�น ไมิ#มิ!ไข� ไป่ตัรีวจัท!( รีพ. ได็�รี�บุการีตัรีวจั CT brain พบุเป่+น subacute hemorrhage Lt parieto-occipital lobe จั,งได็�รี�บุการีรี�กษาโด็ยท�ากายภูาพบุ�าบุ�ด็

Present illness

• 2 ส่�ป่ด็าห.ก#อนมิารีพ. ผู้��ป่�วยมิ!แขนแลำะขาข�างขวาอ#อนแรีงมิากข,0น แลำะเรี�(มิมิ!อาการีอ#อนแรีงแขนขาข�างซ้�ายรี#วมิด็�วย อาการีอ#อนแรีงเป่+นมิากข,0นเรี�(อยๆ ไมิ#พลำ�กคว�(า ไมิ#พ�ด็ ลำ�มิตัาเป่+นพ�กๆ ตั#อมิามิ!อาการีเกรีงแขนขาท�0ง 2 ข�าง ไมิ#มิ!กรีะตั�ก มิ!ไข�ตั�(าๆ มิารีด็าได็�พาไป่รีพ.อ!กแห#งหน,(งแลำะได็�รี�บุการีตัรีวจั MRI brain พบุเป่+น white matter lesion แลำะได็�รี�บุการีตัรีวจัเพ�(มิเตั�มิพบุมิ!การีตั�ด็เชื้�0อทางเด็�นป่5ส่ส่าวะ จั,งได็�รี�บุการีรี�กษาโด็ยให�ยาฆ่#าเชื้�0อ อาการีอ#อนแรีงย�งไมิ#ด็!ข,0น

Present illness

• 3 ว�นก#อนมิารีพ. ได็�รี�บุการีส่#งตั�วมิารี�กษาตั#อท!(รีพ.ป่รีะส่าท อาการีเกรีงเป่+นมิากข,0น ซ้,มิลำง ไมิ#ค#อยลำ�มิตัา MRI brain พบุว#ามิ! progression of white matter lesion ผู้��ป่�วยได็�รี�บุการีรี�กษาด็�วย methylprednisolone 2 ว�น แพทย.ตัรีวจัรี#างกายพบุตั�บุมิ�ามิโตัข,0น CBC: Hct 28%, WBC 3,550/cumm (N 25%, L 43%, M 27%), platelets 52,000/cumm จั,งส่#งตั�วมิารี�กษาตั#อท!( รีพ.รีามิาธิ�บุด็!

Personal history

• บุ�ตัรีคนท!( 4/4, V/E due to poor maternal effort, BW 3600 g, no perinatal complication

• ไมิ#มิ!โรีคป่รีะจั�าตั�ว แขงแรีงด็!ตัลำอด็• ไมิ#มิ!ป่รีะว�ตั�แพ�ยาอาหารี• พ�ฒนาการีป่กตั� พ�ด็เป่+นป่รีะโยค วาด็วงกลำมิได็� ข,0น

บุ�นได็ส่ลำ�บุขา • ว�คซ้!นครีบุตัามิเกณฑ์.

Family history

• ป่ฏิ�เส่ธิการีแตั#งงานในเครี�อญิาตั�• บุ�ตัรีชื้ายคนท!( 1 เส่!ยชื้!ว�ตั อาย� 1 ป่� 9 เด็�อน มิ!ไข�

ส่�ง ก�อนท!(คอ ตั�บุมิ�ามิโตั• บุ�ตัรีชื้ายคนท!( 2 แขงแรีงด็! ป่5จัจั�บุ�นอาย� 14 ป่�• บุ�ตัรีคนท!( 3 induced abortion GA 3

months

Physical Examination

V/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 secHEENT: bilateral cervical LN 0.5 cm, no neck mass, pharynx and tonsil not injected

Physical Examination

CVS: normal S1 S2, no murmurLung: clear, no adventitious sound, no retractionAbdomen: soft, no distension, liver 3 cm below RCM, liver span 9 cm, spleen 4 cm below LCMSkin : no lesion

Physical 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

Investigation

6

4321 5

7 8 9

10 11 12 13 14

CBC

• Hb 9.5 g/dL• Hct 28.2%• WBC

2,930/cumm.• PMN 40%• Lymph 51%• Mono 5%• Atyp L 4%• Plt

34,000/cumm.

• RDW 16.9%• MCV 70.5 fL• MCH 23.7 pg• MCHC 33.7 g/dL• Anisocytosis 1+• Microcyte 1+• Hypochromia 1+

Coagulogram

• aPTT 27 sec• PT 13 sec• INR 1.13• TT 11 sec• Fibrinogen 248 mg/dL

Blood chemistry

• Na 129 mmol/L• K 3.2 mmol/L• Cl 94 mmol/L

• CO2 23.5 mmol/L

• Inorganic phosphate 3.5 mg/dL

• Calcium 7.6 mg/dL (correct 8.8)

• Mg 1.8 mg/dL

• BUN 10 mg/dL• Cr 0.51 mg/dL

Liver function test

• AST 25 U/L• ALT 29 U/L• GGT 20 U/L• TP 62.6 g/L• Albumin 25.6 g/L

• ALP 63 U/L• TB 0.2 mg/dL• DB 0.1 mg/dL

CXR

Ferritin

• Ferritin 2,248 ng/mL

Viral studies

• EBV IgG : Positive• EBV IgM : Negative• EBV viral load < 100 copies

Bone marrow aspiration

• Bone marrow aspiration–Hypercellularity 1+–Adequate in number of

megakaryocyte, erythroid, myeloid series–No blast–No abnormal cell–No hemophagocytic activity

Bone marrow biopsy

–Active trilinear hematopoiesis with increase histiocytes with hemaphagocytosis activity–No immunophenotypic evidence of

increased blasts or non-Hodgkin lymphoma–CD68-positive histiocytes are

increased

Lipid profile

• TG 328 mg/dL• Chol 112 mg/dL• LDL 38 mg/dL

LDH

• LDH 164 U/L

CSF profile

• CSF–WBC 3 cell/cumm–RBC not seen–Monocyte 100%–Glucose 58 mg/dL–Protein 93.8 mg/dL–Blood glucose 104 mg/dL

Brain biopsy

–Dense perivascular lymphohistiocytic infiltration with demyelination–CD1a : negative–CD3, CD4, CD8, CD20 : Positive–CD68 : Positive in reactive

histiocytic cell

Brain biopsy (1)

Perivascular cuffs of mononuclear inflammatory cells

Brain biopsy (2)

Microglial activation

Brain biopsy (3)

Infiltrate of foamy histiocytes with reaction astrocytes

PRF1 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 identified–The PRF1 c.822C>T and c.900C>T

which synonymous SNPs

UNC 13 D (Munc 13-4)

–Polymorphism or Mutation of UNC13D IVS4-1 or IVS9-1 was not identified–c.756_757insAC cause a shift in the

reading frame

UNC13D c.756_757insAC

Post-treatment

1 -week 1-month 3-month

Hb (g/dL) 9.4 10.9 12.5

Hct (%) 29 30.9 37.9

WBC (cumm)

2410 9020 9190

Neutrophil (%)

21 13 51

Platelets (cumm)

118000 500000 257000

MRI post treatment 3-month

• MRI brain –Marked decrease white matter

lesions which severe white matter volume loss with bilateral ventricles dilatation– Increase choline with decrease NAA

at residual periventricular lesions without relative hyperperfusion

• MRI whole spine–Remaining intramedullary lesions

entire spinal cord but not enhancement–Clumping with faint enhancing

cauda equina nerve root

Method

• Single center (France) retrospective1981 to 1993

• 34 patients (19 girls, 15 boys) with HLH–25 patients with family history

(consanguinity or siblings affected same syndrome–9 patients without family history, no

concomitant infection-induced, recurrence of hemophagocytic syndrome

• Evaluate : clinical, CSF, neuroradiolological studies

E.Haddad, et al. blood. 1997 Feb;89:794-800.

Results

E.Haddad, et al. blood. 1997 Feb;89:794-800.

• Meningitis – 20-80 lymphocytes/µL with protein

50-100 mg/dL• 20 with meningitis (mean age 6.9 months)• 9 with neurological symptoms (mean age 16 months)

E.Haddad, et al. blood. 1997 Feb;89:794-800.

• Brain imaging–9/20 with meningitis • 4 had abnormal : 2 with pericerebral diffuse subdural dilataion, 2 with white matter lesions

–8/9 with neurological symptoms •Most frequent focal necrosis with parenchyma volume loss and white matter lesions

E.Haddad, et al. blood. 1997 Feb;89:794-800.

• 19 patients had severe CNS progression

• 4 patients repeat imaging –3 with severe brain atrophy–1 with enhance cerebellar white

matter and parenchyma loss

E.Haddad, et al. blood. 1997 Feb;89:794-800.

E.Haddad, et al. blood. 1997 Feb;89:794-800.

• 7 alive with normal neurological examination, CSF, cognitive development

• 3 cases perform MRI before and after BMT–2 had normal MRI (pre/post BMT)–1 had white matter lesion before

BMT and remain 2 years after BMT

E.Haddad, et al. blood. 1997 Feb;89:794-800.

• Large cohort of children (n = 193)• Originated from 25 countries• Median age at diagnosis 9 months• 106 (55%) less than 1 year of age at

diagnosis• 43/192 (22%) (no data = 1) familial disease• Consanguinity 37/186 (20%) cases (no data

= 7)• 11 patients studied specified viral infections

at diagnosisA. Horne, et al. BJH. 2007 Dec;140:327–335.

A. Horne, et al. BJH. 2007 Dec;140:327–335.

Neurological symptoms and relation to abnormal CSF

A. Horne, et al. BJH. 2007 Dec;140:327–335.

CSF

• 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. 2007 Dec;140:327–335.

A. Horne, et al. BJH. 2007 Dec;140:327–335.

Neuroradiology

• Performed 115/193 patients (60%)• 35/115 patients (30%) reported

abnormal–Generalized cerebral atrophy (n =

16)–White matter lesions and

demyelination (n = 5)–Non-specific inflammatory changes

(n = 4),– Intracerebral bleeding (n = 2) and

brain edema (n = 1)–Cerebellar involvement (n=5)

A. Horne, et al. BJH. 2007 Dec;140:327–335.

Mortality and CNS involvement

• 3-year probability of was 56%–67 (61%) transplanted–37 (34%) ‘off-therapy’

• 49 patients died before SCT–18 of these (37%) CNS involvement–No neurological symptom but

abnormal CSF (CNS group 3)

A. Horne, et al. BJH. 2007 Dec;140:327–335.

A. Horne, et al. BJH. 2007 Dec;140:327–335.

Neurological symptoms at follow-up

Transplanted patients• 102 patients undergone SCT, 67 (66%) were

alive• Most common sequelae–Neurodevelopmental retardation (n = 7) –Epilepsy (n = 4)–ADHD (n = 2) –Hearing loss (n = 2)–minimal cerebral palsy and hemiplegia (n

= 1 each)A. Horne, et al. BJH. 2007 Dec;140:327–335.

• 92 patients with HLH January 2004 to August 2008

• 82 patients (89%) active viral infection–69/82 patients (75%) EBV infection

• 9 patients not find any underlying disease• None of the patients were offspring of

consanguineous marriages or history of siblings affected by same syndrome–82 were only child in the family

S. Yang, et al. Pediatr Blood Cancer 2010;54:408–415.

Methods

• Prior to start therapy, all patients underwent –CSF cytology and biochemical

assays –Brain CT and/or MRI examination

• CSF analysis repeated weekly until normalize

• CT or MRI examinations –Repeated at 8-week intervals until

treatment stopped –Completed therapy every 6 months

for at least 1 year

RESULTS

• 43 patients CNS involvement, either clinical, MRI/CT or CSF abnormalities

• 36 (84%) patients had EBV-HLH• No underlying disease found in 5

patients

S. Yang, et al. Pediatr Blood Cancer 2010;54:408–415.

RESULTS

• 4 : S+R+C• 4 : S+R• 2 : S+C• 6 : R+C• 2 : S• 3 : C• 22 : R

S, symptomsR, neuroradiologyC, CSF

S. Yang, et al. Pediatr Blood Cancer 2010;54:408–415.

Neuroradiological Examinations

• CT 46 patients, 8 showed abnormalities–Calcifications (n=2), atrophy (n=2),

demyelination (n=2), edema (n=1), and hemorrhage (n=1)

• MRI 64 patients, 34 showed abnormalities –High 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.

Clinical Manifestations

• 12 patients neurological symptoms at diagnosis

• Eleven of these EBV-HLH• Seizures (n=10), hemiplegia (n=3),

ataxia (n=3), coma (n=2), cranial nerve palsy (n=2)

• 8 pathological changes in CT/MRI images

• 6 abnormal CSF S. Yang, et al. Pediatr Blood Cancer 2010;54:408–415.

Cerebrospinal Fluid Tests

• 15 patients (16%) CSF abnormalities at onset–11 patients elevated spinal fluid

protein –10 patients elevated spinal fluid

leukocyte counts

S. Yang, et al. Pediatr Blood Cancer 2010;54:408–415.

CNS Involvement After Start of Therapy

• 12 patients with neurological symptoms had improved

• 3 discontinued therapy due to progressive systemic symptoms

• One patient, presenting with CNS dysfunction preceding systemic HLH disease, improved initially but repeated relapses and progressive CNS symptoms 6 months later

• 15 patients with CSF abnormalities at diagnosis–Normal within 6 weeks of therapy

S. Yang, et al. Pediatr Blood Cancer 2010;54:408–415.

CNS Involvement After Start of Therapy

• Neuroradiological abnormalities showed slow recovery rate,

• Neurological symptoms resolved quickly• 36 patients with neuroradiological

abnormalities• 2 patients showed any improvement• 15 patients lost to follow-up, • 5 patients still undergoing treatment at

the end of study

S. Yang, et al. Pediatr Blood Cancer 2010;54:408–415.

CNS Involvement After Start of Therapy

• 16 patients followed post-therapy

• 12 showed some improvement of imaging after 3–12 months

• 5 completely normal CT/MRI scans at follow-up

• One progressive changes in the CT/MRI images and relapsed

• 3 patients CT/MRI findings unchanged

S. Yang, et al. Pediatr Blood Cancer 2010;54:408–415.

CNS Involvement After Start of Therapy

• 42 patients followed after discontinuation of therapy

• 21/42 had at least one manifestation of CNS involvement at diagnosis

• 10/42 recovered completely from CNS involvement

• 3 patients not improve with radiological findings while CSF analysis and clinical examination normalized

S. Yang, et al. Pediatr Blood Cancer 2010;54:408–415.

THANK YOU FOR YOUR ATTENTION