2016/10/07 Presenter: R2 徐子權 Supervisor: CR林靜微 VS王玠能 VS劉清泉 Case Discussion 2016/10/07 Presenter: R2 徐子權 Supervisor: CR林靜微 VS王玠能 VS劉清泉

Patient profile Name:盧xx A 4-month-6-day-old boy Birth date: 2016/05/18 Chart number: 175875xx Admission date: 2016/09/25 17587547

Chief complaint Fever with myoclonic jerks for one day Video

Present illness The 4-month-6-day-old boy, Discharged on 9/17 (bilateral APN, urine culture: E.coli) 9/20 9/23 RTC 9/25 1am 9/25 4am 9/25 10am NCKUH ED: BT:35.7’C HR:148bpm BP:86/54mmHg PE: throat: Injected, soft palate ulcer(+) myoclonus jerk(+) 5 times in 1 hour Decreased appetite. No vomiting, Admission 2 y/o brother HFMD No fever, Urinanalysis: no pyuria Fever 38.1->38.4’C Claforan 180mg IVD Neonatal seizure, bacterial meningitis cannot be ruled out

Past history Birth History: G2P2, C/S, GA:40+2wks, BBW: 3165gm, A/S: 6->8 , DOIC(-), PROM(-) APGAR score: 6->8 , Fetal distress with meconium aspiration syndrome s/p intubation suction NB screen: normal Feeding: 14% RF 800-900 ml per day Vaccination: HBV 2 doses, DTaP,IPV,Hib 1st dose, Prevenar-13 1st dose, Rotarix 1st dose Growth and Development: BW :7.8kg( 50-85 percentile), BL: 70 cm (>95th percentile), HC 42.5 cm (50-85th percentile) No lag head, social smile(+), rolling (+) TOCC: contact hx: His elder brother (2 y/o) being diagnosed of HFMD recently (9/20) Past History: 1. Denied systemic or hereditary history 2. Admitted during 2016/9/13 to 9/17 due to bilateral APN

Pedigree 2 y/o

Physical examination PE Anterior fontanelle: 2fb, soft, no bulging HEENT: conjunctiva: not pale, sclera: anicteric Throat: injected, bilateral soft palate ulcer Neck: supple, no lymphadenopathy Chest: symmetric expansion, bilateral clear breath sounds Heart: regular heart beat, murmur(-) Abdomen: soft, normoactive bowel sound, tenderness (-), muscle guarding (-) Extremities: warm, pitting edema (-) Skin: a small erythematous macule over left palm Vital Signs: T: 36.0°C; P: 140/min; R: 34/min; BP: 91/57mmHg(09/25 10:42) NE consciousness alert pupil size: 2.5mm/2.5mm Light reflex:+/+ Social smile(+), Eye persuit without EOM limitation muscle tone: normal muscle power: full at four limbs DTR:symmetric,2+~3+

Impression 1. Frequent myoclonic jerk, suspect enterovirus infection complicated with CNS involvement

Diagnostic plan CBC/DC, BUN, Cr, AST, ALT, CRP, blood sugar Blood culture Throat swab, anal swab for virus isolation Lumbar puncture for CSF study

Lab data Dex: 116mg/dL

CSF data (9/25 14:27)

Clinical course Resting HR around 180bpm IVIG Resting HR around 180bpm Suspect enteorovirus infection with aseptic meningitis ANS involvement can not be ruled out Transfer to PICU CSF Rocephin

Management Send throat swab for EV71 PCR 通報疾管局for疑似腸病毒重症 IVIG 1gm/kg infusion for 12 hours Add Rocephin and persue CSF culture result Monitor body temperature, heart rate, blood sugar On A-line for BP monitoring Take CXR, check cardiac enzyme, arrange cardiac echo Restrict total daily fluid to 0.7x maintain

X-ray

2016/09/26 15:24:59 Cardaic echo Mild tricuspid regurgitation 1)Situs solitus, levocardia 2)No chamber enlargement 3)Good LV systolic function (LVEF 76.7%) 4)Mild tricuspid regurgitation, PG: 16.3mmHg 5)No PDA, no coarctation

Throat swab( 9/25 sent, 9/26 report)

CSF data (9/25 14:27) (9/26 18:51)

Cardiac echo(9/26 21:01) Impression: Relative decreased aortic VTI noted

Management 2nd dose IVIG 1gm infusion Start Milrinone (Primacor) 0.25mcg/kg/min to lower afterload Close monitoring clinical condition

Clinical course echo echo ->4C MBD IVIG IVIG CSF Throat EV-71(+) Primacor ->4C MBD IVIG IVIG CSF CSF Throat EV-71(+) Rocephin 9/27 morning fever 38’C, myoclonic jerk *2-> no more fever and myoclonic jerk thereafter Dex (mg/dL) 116 105 95 98 97

Check CSF virus isolation result

Final diagnosis Enteorovirus 71 infection, with aseptic meningitis and autonomic nervous system dysfunction post immunoglobulin (2 dose) and Milrinone (aseptic meningitis, myoclonic jerk, tachypnea, decreased aortic velocity time integral)

Discussion Enterovirus infection

Enterovirus transmission 人類是腸病毒唯一的傳染來源。 潛伏期為2到10天，平均約3到5天。 主要經由腸胃道（糞-口、水或食物污染）或呼吸道（飛沫、咳嗽或打噴嚏）傳染，亦可經由接觸病人皮膚水泡的液體而受到感染。 在發病前數天，喉嚨部位與糞便就可發現病毒，此時即有傳染力，通常以發病後一週內傳染力最強；而患者可持續經由腸道釋出病毒，時間長達8到12週之久。

Epidemiology 腸病毒適合在濕、熱的環境下生存與傳播，臺灣地處亞熱帶，全年都有感染個案發生。 腸病毒疫情每年約自3月下旬開始上升，於5月底至6月中達到高峰後，即緩慢降低，而後於9月份開學後再度出現一波流行。 以年齡層分析，患者以5歲以下幼童居多，約佔所有重症病例90%；在死亡病例方面，以5歲以下幼童最多。 重症致死率約在3.8%至25.7%之間。引起腸病毒感染併發重症之型別以腸病毒71型為主，克沙奇病毒居次。

Enterovirus-associated severe case number between 1998 and 2012 in Taiwan

腸病毒感染併發重症之前驅病徴 嗜睡、意識改變、活力不佳、手腳無力，神經併發症多在發疹二至四天後出現。 肌躍型抽搐（類似受到驚嚇的突發性全身肌肉收縮動作）。 持續嘔吐。 持續發燒、活動力降低、煩躁不安、意識變化、昏迷、頸部僵硬、肢體麻痺、抽搐、呼吸急促、全身無力、心跳加快或心律不整等。 高危險群病患，其特徵包括：年齡小於三歲、家中的第二個病例、高燒超過攝氏39 度、燒超過 3天、肌躍型抽搐 (myoclonic jerk) 其他抽搐、頭痛、嘔吐、嗜睡、肢體無力、高血糖 (>150mg/dl)、白血球過高（>17500/mm 3）

腸病毒71型感染有80%為手足口病，有些病例的手腳皮疹十分細小且不明顯，故應仔細觀察。 腸病毒71型感染併發重症主要有腦幹腦炎、心臟衰竭、肺水腫與肺出血等表現，這些嚴重病症均於發病後7天內出現，平均為發病後3天左右。

Indication for IVIG therapy 出現手足口病或疱疹性咽峽炎臨床症狀，或雖無以上症狀，但與其他確定病例有流行病學上相關的腸病毒感染個案，並且符合下列條件之一: 1.急性腦炎，尤其是供伴隨局部特異性腦幹神經症狀：失調（ataxia）、對側偏癱（cross hemiplegia）、特定顱神經損害（specific cranial Ns lesion）。 2. 急性腦脊髓炎：如急性肢體麻痺(Acute flaccid paralysis) 3, 自主神經機能失調（autonomic nervous system dysregulation）：如肌躍型抽搐合併無明顯誘發因素之心率過速（心跳每分鐘超過140次）或高血壓。 4. 敗血症候群（Sepsis syndrome）。

Neurologic syndromes - Aseptic meningitis -Acute flaccid paralysis - Rhombencephalitis grading Grade I: Myoclonus with tremor, ataxia or both Grade II: Myoclonus with cranial-nerve involvement Grade III: Rapid cardiopulmonary failure CHAO-CHING HUANG, CHING-CHUAN LIU NEJM 1999

Phase based therapy of critical EV-71 infection (Stage 1); hand, foot and mouth disease (HFMD)/herpangina (Stage 2); central nervous system (CNS) involvement (Stage 3); cardiopulmonary failure 3A:Hypertension、pulmonary edema、ANS dysregulation 3B:hypotension— cardiopulmonary collapse (Stage 4): convalescence Chang Gung Children’s Hospital Outcome of enterovirus 71 infections with or without stage-based management: 1998 to 2002 LUAN-YIN CHANG, SHAO-HSUAN HSIA, et al. THE PEDIATRIC INFECTIOUS DISEASE JOURNAL Vol. 23, No. 4, April 2004

Phase based therapy of critical EV-71 infection CNS involvement, Stage 2, myoclonic jerk, limb weakness, cranial nerve palsy, seizure and consciousness disturbance. For increased intracranial pressure: fluid restriction and osmotic diuretics IVIG is given in all cases beyond stage 2 because of potential antiviral effect. IVIG did not, however, affect the incidence of sequelae or prevent progress to cardiopulmonary failure. viral invasion of the CNS combined with the resulting immune response. Outcome of enterovirus 71 infections with or without stage-based management: 1998 to 2002 LUAN-YIN CHANG, SHAO-HSUAN HSIA, et al. THE PEDIATRIC INFECTIOUS DISEASE JOURNAL Vol. 23, No. 4, April 2004

Mechanism of neurogenic pulmonary edema mechanism of EV71-related pulmonary edema not to be directly caused by viral myocarditis but possibly related to increased pulmonary vascular permeability caused by brainstem lesions and/or systemic inflammatory response patients with cardiopulmonary failure were found to have significantly elevated pro-inflammatory cytokines, white blood cell counts and glucose values. The best predictor for this condition was the concentration of serum IL-6 Wu JM, Wang JN, Tsai YC, et al. Cardiopulmonary manifestations of fulminant enterovirus 71 infection. Pediatrics 2002; 109:e26.

Modulation of cytokine production by IVIG in patients with enterovirus 71-associated brainstem encephalitis Plasma cytokine concentrations (IL-1ɞ, IL-6, IL-8, IFN-ɣ, TNF-ɑ, IL-2, IL-4, IL-5, IL-10, and IL-13) were monitored on admission and within 12–24 h after administration of IVIG in a cohort of children (n = 22) with virologically confirmed EV71 infection, from March 2000 through April 2004. SM Wang, HY Lei et al. Journal of Clinical Virology 37 (2006) 47–52

Modulation of cytokine production by intravenous immunoglobulin in patients with enterovirus 71-associated brainstem encephalitis SM Wang, HY Lei et al. Journal of Clinical Virology 37 (2006) 47–52

Modulation of cytokine production by IVIG in patients with enterovirus 71-associated brainstem encephalitis All of the patients with ANS dysregulation and 50% of those with pulmonary edema survived. The high mortality in patients with pulmonary edema, in spite of IVIG therapy, meant that when patient deteriorated from ANS dysregulation to pulmonary edema it was too late for patients to commence IVIG. Patients with ANS dsyregulation is the critical timing to received IVIG infusion Modulation of cytokine production by intravenous immunoglobulin in patients with enterovirus 71-associated brainstem encephalitis SM Wang, HY Lei et al. Journal of Clinical Virology 37 (2006) 47–52

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