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Critical Care of EV 71 Encephalomyelitis 理 Epidemiology of EV 71 Encephalomyelitis in Taiwan 流行療 France () (1979) Sweden () (1973) Hungary ( 利 ) (1978) Bulgaria ( 利 ) (197) 度 Vietnam () (27) EV 71

1 Critical Care of EV 71 Encephalomyelitis 理 Epidemiology of EV 71 Encephalomyelitis in Taiwan 流行療 France () (1979) Sweden () (1973) Hungary ( 利 ) (1978) Bulgaria ( 利 ) (197) 度 Vietnam () (27) EV 71 outbreaks 流行羅 China () (27-21) Japan ()(1973) Japan ()(1978) Taiwan()(1988) Philadelphia( 律 )(1987) Malaysia ( 來 ) (1997) Australia() ( ) 拉 California () ( ) 陵蘭 New Work ( 紐 )(1972 ) New Work ( 紐 )(1977 ) (1987) EV 71 outbreaks: 流行 Location Season/Year Cases Age distribution Fatalities Clinical features California Throughout yr, % < 3 yrs AM/E New York Summer/fall, % < 7yrs HFMD/AM/E Melbourne, Australia Summer, % < 4 yrs HFMD/AM/polyneuritis Sweden Summer, % < 3yrs HFMD /AM Japan Summer, ,296 71% < 4 yrs Some HFMD/BSEAFP Bulgaria % < yrs 68 AM/E/BSE/AFP New York Summer, % < 3 yrs HFMD/AM/E/AFP New York Summer, Children AM Japan Summer, ,31 6% < 3 yrs Some HFMD/AM/E/BSE/AFP Hungary Summer, , 46% < 6 yrs 4 HFMD/AM/E/AFP Australia 114 HFMD/AM/E France Spring, 1979 Children CNS complications Philadelphia 1987 AFP USA AM/E/AFP Malaysia 1997, HFMD/BSE/PE Taiwan ,16 78 HFMD or HA; E/BSE/AFP/PE Vietnam 27 China AFP=acute flaccid paralysis ; AM=aseptic meningitis ; BSE=brainstem encephalitis E=encephalitis ; HA=herpangina; HFMD=hand-foot-mouth disease 咽 Modified: Samuda GM et al. Pediatr Infect Dis J 1987;6: Ho M J Microbiol Immunol Infect 2;33:2-216 例 1999~21(Aug.) 例數 W12~W34 W21~W2 W38~W 年例年女年率 PS. 率 1() 數 6

2 年例年年例理年年 < 年率年北北率隆 >6. 連栗蘭金蓮林 PS. 率 1 ( ) 數 7 年率 8 Trend of EV in Taiwan, by RODS data -- Updated: 212/3/9 年 3 RODS ) % 2 ( % te % a2 R % n io 1 lta u s n1 o C week 9 1 歷年離 Year\Ran k 2 EV71 (19.7%) CA16 (17.%) ECHO9 CB3 (.%) CB4 (4.%) 21 EV71 (17.7%) CA16 (1.2%) ECHO4 (.9%) ECHO6 CB4 (1.%) (13.4%) (.7%) 22 CA16 (16.%) ECHO6 CB (9.8%) EV71 (8.6%) CA24 (2.9%) (11.%) 23 CA16 (3.7%) EV71 (1.%) ECHO9 ECHO11 CA6 (3.7%) (7.1%) (6.4%) 24 CA4 (16.1%) CB4 (14.9%) CA1 (14.7%) EV71 (9.4%) CB3 (2%) 2 CB3 (3.1%) CA16 (26.6%) EV71 (13.%) CA6 (6.6%) CA (6.%) 26 CA4 (24.1%) CA2 (14.%) ECHO18 CA (1.4%) CB2 (7%) (11.%) 27 CA16 (23.1%) CA6 (22.2%) CA1 (2.4%) CA4 (.8%) ECHO6 28 CA2(3.4) EV71 (29.%) CB4 (11.3%) CB1 (4.3%) CA16 (.3%) (4.%) 例數年例 211( 年 / 1) 例 : 8 / 例 : 3 / Updated: 212/3/12 212(1 ) 例 : 14 例 : '11/ / 年 12

Updated: 212/3/12 Updated: 212/3/12 2 離 EV71 CA CB ECHO NPEV positive rate 1 2 212 年流行 -- RODS data -- 2 8 212 年 1 Isolates 離數 1 1 6 4 2 positive rate 率 (%) 例 1 2.

3 Updated: 212/3/12 Updated: 212/3/12 2 離 EV71 CA CB ECHO NPEV positive rate 年流行 -- RODS data 年 1 Isolates 離數 positive rate 率 (%) 例 '11/ * Recent detailed data are subject to change; counted by specimen Week received Updated: 212/3/12 Updated: 212/3/ 年流行 -- RODS data 年年 WK 1 例 4 數例 ( ) (%) 例 3 2 北 % 北 % % % % % % Updated: 212/3/12 Updated: 212/3/ ~212 ICD9 743 北北 212 年 EV71 率 ( 1. 1 ). 年北北 % % % % % % % % 年 17 18

4 Definition of critical case with EV 71 infection 年例數 3% Cases with hand foot mouth disease or herpangina or acute illness in an endemic region accompany with the following symptoms: ( 咽例流行 ) (1) Myoclonic jerks and tachycardia or hypertension () (2) Encephalitis () (3) Acute flaccid paralysis () (4) Cardiomyopathy () () Cardiopulmonary failure () 例數 3% 2% 2% 1% 1% % 率 % 例例率 Clinical course in critical EV 71 infection 臨 Day 1-2 () Day 3-4 () Day 4- () Clinical Manifestations of EV 71 Encephalomyelitis 臨 Fever () Skin rashes Oral ulcers ( 咽 ) Myoclonus () Sleep interruption () Vomiting () Flaccid paralysis ( 力 ) Cranial nerves palsy ( 神 ) Opsoclonus ( 亂 ) Tachycardia () Tachycardia () Hypertension () Cold sweating ( 冷 ) Pale looking () Altered level of consciousness ( 識 ) Pulmonary Edema () Pulmonary Hemorrhage () Heart failure () Rapid death () 切狀 Fever, Skin rashes, Oral ulcer Dx: Hand Foot Mouth diseases (,, :) Fever subsided () Case Demonstration ( 例 ) 2 year and 4-month-old girl, healthy previously 女, 良, 7/19 7/2 7/21 7/22 良 PM11: Left arm weakness (11: 力 ) : 8:4 惡立 PICU () Case Demonstration ( 例 ) Blood routine () WBC () : 8, N/L (/ 淋 ) : 7/2, Hgb () : 13.1, PLT () : 26K Biochemical profiles () Electrolytes () -Na () : 137, K () : 4.4, Ca () : 9.1, Renal function () -Cr() :.3 Liver function ( 數 ) - AST : 36, ALT : 26, Bil (T) () :. Blood sugar ( 糖 ) : 199 CRP (C) : <.8 CK () : 47, CKMB ( 異 ) : 12 CSF analysis () IP () : 17mmH2O () WBC () : 12 [N/L (/ 淋 ) :2/8], sugar( 糖 ) : 47, protein () :36 Vesicles() Vesicles()

Case Demonstration ( 例 ) Case Demonstration ( 例 ) 1 st CXR, AM: 11: 2 nd CXR 度 9% ph:7.47 PaO2:194 PaCO2:2.3 HCO3:18.1 ABE: -3.4 SaO2:99.8% ph:7.441 PaO2:13 PaCO2:23.8 HCO3:16.4 ABE:-.1 SaO2:98.

5 Case Demonstration ( 例 ) Case Demonstration ( 例 ) 1 st CXR, AM: 11: 2 nd CXR 度 9% ph:7.47 PaO2:194 PaCO2:2.3 HCO3:18.1 ABE: -3.4 SaO2:99.8% ph:7.441 PaO2:13 PaCO2:23.8 HCO3:16.4 ABE:-.1 SaO2:98.3% Case Demonstration ( 例 ) Case Demonstration ( 例 ) 1 st CXR, AM: 11: 2 nd CXR 度 9% ph:7.47 PaO2:194 PaCO2:2.3 HCO3:18.1 ABE: -3.4 SaO2:99.8% EF:27% (64-83%) FS:12.% (28-44%) ph:7.441 PaO2:13 PaCO2:23.8 HCO3:16.4 ABE:-.1 SaO2:98.3% EF:38% (64-83%) FS:18.8% (28-44%) FiO2 ():7-9% HCO3: * 16.4 HCO3: 18.3 PaO2: PaO2: 81 CPR 念了療念了更 Thanks EF:27% *

LV View M mode LA LV Pathophysiological Mechanism of EV 71

異 ) Opsoclonus ( 亂 ) Pupils size ( 異 ) Upper pons-isthmus () :

cerebellar Peduncle Solitary nucleus Pyramids Med.

motor Nucleus of CN X 1 神 Lower pons () : Cranial nerve palsy[

Ileus ( 異 ) Hypertension () Vomiting () Lower medulla () :

paralysis ( 力 ) Pulmonary edema and/or hemorrhage () EV 71

6 LV View M mode LA LV Pathophysiological Mechanism of EV 71 Encephalomyelitis 理理 Although pulmonary edema improved, she died 12 hours later. ( ) 神神惡切不 Upper mesencephalon () : Upward gaze paralysis ( 異 ) Opsoclonus ( 亂 ) Pupils size ( 異 ) Upper pons-isthmus () : Myoclonus () Upper pons () : Ataxia ( 不 ) Tremor () CNS inflammation ( 神 ) Neuronal damage v.s. Cardiac damage 神 Cardiomyopathy () Olivary nucleus Inf.cerebellar Peduncle Solitary nucleus Pyramids Med. lemniscus Nucleus ambiguus CSP(Central sym.pathway) 神路 Dor. motor Nucleus of CN X 1 神 Lower pons () : Cranial nerve palsy[ 神 (67)] Upper medulla () : Bulbar palsy ( 神異 ) Tachycardia () Ileus ( 異 ) Hypertension () Vomiting () Lower medulla () : Swallowing difficulty () 狀 Spinal cord () : Acute flaccid paralysis ( 力 ) Pulmonary edema and/or hemorrhage () EV 71 infection (71) Chiu YT, Chen YT, Lin NN, Cheng CC, Gong CL, Cheng FC, Hsu SL,, Fu YC. Int J Cardiol 2;1: year and 8-month-old boy Left Ventricular Assist Device(LVAD) 例 Critical management of EV 71 Encephalomyelitis Oct /1 PM:23: 1/16 AM 1:4 FiO2 %, SaO2 99%, PaO2 126% FiO2 %, SaO2 1%, PaO2 29%

EV 71 infection Rhombencephalomyelitis Myoclonus AFP Vomiting HR BP Catecholamine storm 神 Pale suddenly Sweating Coldness of limbs Heart failure(lv) Serial heart sono.

$Neurological stage 神 Sympathetic stage 神 Cardiopulmonary stage Decompensated stage Supportive treatment ( 狀療 ) 1. IVIG ()(?) 2. 療 1. 2. shortening fraction (EF) ejection fraction (FS) 3. Milrinone.$ $量 inotropic equivalent > 2 量 shortening fraction 2% (ejection fraction 4%) 連降若 ECLS (ECLVS or ECMO) 不 ECLS (ECLVS or ECMO) Goal of Critical Management of EV 71 Encephalomyelitis 理 Low mortality 率$

7 EV 71 infection Rhombencephalomyelitis Myoclonus AFP Vomiting HR BP Catecholamine storm 神 Pale suddenly Sweating Coldness of limbs Heart failure(lv) Serial heart sono. 4-month-old male infant with ECLS 471 Pul. edema Death Sequelae Normal Abnormal Normal 切聯療, Critical management of EV 71 Encephalomyelitis Staging Treatment ( 療 ) Stage 1 () Stage 2 () Stage 3 () Stage 4 () Stage () Mucocutaneous stage Neurological stage 神 Sympathetic stage 神 Cardiopulmonary stage Decompensated stage Supportive treatment ( 狀療 ) 1. IVIG ()(?) 2. 療 shortening fraction (EF) ejection fraction (FS) 3. Milrinone.2-.g /kg/min Milrinone loading dose 2g /kg2 1. Early intubation () 2. 力降 dobutamine 2-2 g /kg/min milrinone.2-.g /kg/min Milrinone loading dose 2g /kg2 3. 療 4. 量 inotropic equivalent > 2 量 shortening fraction 2% (ejection fraction 4%) 連降若 ECLS (ECLVS or ECMO) 不 ECLS (ECLVS or ECMO) Goal of Critical Management of EV 71 Encephalomyelitis 理 Low mortality 率 Low sequelae 降 Consistency 療 Demographic data ( 料 ) Predictors of Unfavorable outcomes in EV 71 infection Fatalities v.s. Survivors ( 不良 ) Age( 年 ) 6m-3y6m Clinical symptoms Heart rate (17 24) ( 臨狀 ) () Pulmonary edema (chest X-ray) (X) Initial sbp 1 mmhg (1mmHg) Duration of hypotension 4 h (4) Viral isolation ( 離 ) EV71infection (71) Comparison between past and present, stage 3a and stage 3b cohort data: Demographic, initial laboratory features and outcomes of patients with critical EV71- related cardiopulmonary failure 料數療療料 Laboratory data ( 數 ) Blood sugar ( 糖 ) (?) Troponin 1 ng/dl ( Inotropic equivalent 3 ( 量 3) Echocardiogram () Ejection fraction (EF;37 11) ( 率 ) Fraction shortening (FS;19.4 7) ( 率 ) Mitral regurgitation ( 流 ) LV dysfunction ( 不 ) Jan SL, et al Chin Med J (Taipei) 2;63: Fu YC, et al. Pediatr Pulmonol 23;3: Hsia SH et al. Pediatr Infect Dis J 2;24: Huang YF et al. J Inf 23;46: Jan SL Intensive care Med 21;36:2-27

TE 94 TR 4 22. 3.17 2.9 24. 6.29 28. E C M O 24. 7.2 21.2 2. 1.

24 Table 1 Initial clinical features and long-term neurological outcomes of EV 71 rhombencephalitis after ECLS Table 1 Initial clinical features and long term neurological outcomes of EV 71

D4 D3 D Clinical features (Day) Symptoms of enterovirus infection Fever D1 D1 D1 D1 D1 D1 D1 D1 D1 D1 Oral ulcer D2 D2 D2 No D1 D2 D1 D2 No D3 Skin rashes D1 D2 D2 No D1 No No D2 D1 D3 Signs of

No Consciousness change D4 No D3 D3 No D D3 No No D Signs of autonomic system Tachycardia D4 D3 D4 D3 D2 D D2 D4 D3 D Cold sweating D4 D3 No No No D No No No D Hypertension D4 D3 D4 D3 D4 D D2-3 D4

$fraction of LV 27% 37% 37% 31% 26% 2% 18% 34% 28% 1% Disease stage IIIa IIIa IIIa IIIa IIIa IIIa IIIa IIIa IIIb IIIb Lee HF & et al., doi:1.116/j.pediatrneurol.212.2.8 [In Press] Table 1 Initial clinical features and long term neurological outcomes of EV 71 rhombencephalitis after ECLS (II) Patient 1 2 3 4 6 7 8 9 1 Fig.$

8 TE 94 TR E C M O 切 Long term follow-up () Table 1 Initial clinical features and long-term neurological outcomes of EV 71 rhombencephalitis after ECLS Table 1 Initial clinical features and long term neurological outcomes of EV 71 rhombencephalitis after ECLS (I) Patient Gender M F F M M M F M M M Age at dz onset 2 mo mo 27 mo 4mo 4 mo 9 mo 16 mo 9 mo 14 mo 21 mo Admission day at dz onset D4 D3 D4 D3 D4 D4 D3 D4 D3 D Clinical features (Day) Symptoms of enterovirus infection Fever D1 D1 D1 D1 D1 D1 D1 D1 D1 D1 Oral ulcer D2 D2 D2 No D1 D2 D1 D2 No D3 Skin rashes D1 D2 D2 No D1 No No D2 D1 D3 Signs of neurological system Vomiting D3 No No D2 No No No D3 D3 No Myoclonic jerks D4 D2 D2 No D2 D D2-3 No No No Gaze paresis No No No No No No No D4 No No Acute flaccid paralysis D3 No D3 No No No No D4 No No Consciousness change D4 No D3 D3 No D D3 No No D Signs of autonomic system Tachycardia D4 D3 D4 D3 D2 D D2 D4 D3 D Cold sweating D4 D3 No No No D No No No D Hypertension D4 D3 D4 D3 D4 D D2-3 D4 No No Hypotension No No No No No No No No D3 D Extraneurologic symptoms Foamy discharge Yes Yes Yes No Yes No Yes No Yes Yes Pulmonary edema by CXR Yes Yes Yes No Yes No Yes No Yes Yes Ejection fraction of LV 27% 37% 37% 31% 26% 2% 18% 34% 28% 1% Disease stage IIIa IIIa IIIa IIIa IIIa IIIa IIIa IIIa IIIb IIIb Lee HF & et al., doi:1.116/j.pediatrneurol [In Press] Table 1 Initial clinical features and long term neurological outcomes of EV 71 rhombencephalitis after ECLS (II) Patient Fig. 1 Brain MRI of Case 3 Disease stage IIIa IIIa IIIa IIIa IIIa IIIa IIIa IIIa IIIb IIIb Mediations and treatment IVIG Yes Yes No Yes No No Yes Yes Yes Yes Milrinone Yes Yes Yes Yes No Yes No Yes Yes Yes CPR No Yes No No No No No No Yes Yes b ECLS mode ECLVS ECMO ECMO ECMO ECMO ECMO ECLVS ECLVS ECMO ECMO EF > % (h) Total ECLS (h) ICU stay(days) Total admission stay(days) Abnormalities on brain MRI Pons Yes No Yes No No No Yes Yes Yes Yes Medulla oblongata Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Spinal cord Yes No Yes No No Yes Yes Yes Yes Yes Cerebral cortex Yes No No No No Yes HIE HIE HIE HIE a c Cerebral infarction Yes No No No No Yes No No No No Others No SDE No No No No No No No No Lee HF & et al., doi:1.116/j.pediatrneurol [In Press] Lee HF & et al., doi:1.116/j.pediatrneurol [In Press] Table 1 Initial clinical features and long term neurological outcomes of EV 71 rhombencephalitis after ECLS (III) Patient Disease stage IIIa IIIa IIIa IIIa IIIa IIIa IIIa IIIa IIIb IIIb Morbidities Bulbar dysfunction Yes Yes Yes No Yes No Yes Yes Yes Yes Respiratory failure Yes No Yes No Yes No Yes Yes Yes Yes Seizure Yes Yes Yes No No Yes Yes No No No Hemiplegia Yes No No No No Yes No No No No Flaccid quadriparesis No No No No No No Yes Yes Yes Yes Follow-up period 11yr 2m 1yr m 7yr m 7yr 3yr 8m 3yr 6m 1yr 11m 1yr 3m 6yr m m Outcome Alive Alive Alive Alive Alive Alive Alive Alive Died Died Seizure No No No No No Yes Yes Yes No No Hemiplegia No No No No No Yes No No No No Motor clumsiness Yes No Yes No Yes No No No No No Duration for decannulation NG or gastrostomy tube 1yr 8m 2m 4yr Nil 11m Nil Never Never Never Never Tracheostomy tube 2yr 1m Nil 4yr Nil 2yr 6m Nil Never Never Never Never Age at cognitive 12y 6mo 1y 6mo 9y 7y y 11mo 3y 1mo 11y 11mo 1y 8mo 7y 7mo 2y 2mo assessment Fig. 2 a Brain MRI of Case 6 b c IQ test (VIQ/PIQ/FIQ) 78/87 /7 83/87 /84 81/4 /6 121/18/ /119 /124 Motor delay Bed-ridden Bedridden status status Bedridden status Bedridden status Lee HF & et al., doi:1.116/j.pediatrneurol [In Press] Lee HF & et al., doi:1.116/j.pediatrneurol [In Press]

9 EV 71 infection clinical stages CDC Stage 1 HFMD/Herpangina () / 咽 Stage 2 () Stage 3 () 3A (A ) 3B (B ) Stage 4 () Staging in critical EV 71 infection () Encephalomyelitis Cardiopulmonary failure Hypertension Hypotension Convalescence 復力糖 WBC EV 71 infection clinical stages (TCVGH) Stage 1 Mucocutaneous stage () Stage 2 Neurological stage () 神 Stage 3 Sympathetic stage () 神 Troponin( 1ng/dl) EFFSLV Stage 4 Cardiopulmonary stage () BP<1 Duration 4h Inotrope equivalent 3 Troponin( 1ng/dl) EF(<4%) 倫理 EF 1%? Stage Decompensated stage () Close observation of clinical evolution auxiliary by laboratory tests and serial monitoring of echocardiogram can help physicians stage critical EV 71 infection correctly. ( 臨狀 71) Adequate intervention management (ECLS) can effectively decrease mortality and neurological sequelae. ( 降神 ) ~ The End ~

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