Rhomboencephalitis

RhomboencephalitisA Cluster of 5 Cases in Hong Kong : 

RhomboencephalitisA Cluster of 5 Cases in Hong Kong Dr. Lai Kang Yiu Intensive Care Unit Queen Elizabeth Hospital

Rhomboencephalitis: Clinical FeaturesA Cluster of 5 Patients In An Intensive Care Unit In Hong Kong : 

Rhomboencephalitis: Clinical FeaturesA Cluster of 5 Patients In An Intensive Care Unit In Hong Kong From 24/5/2010 to 12/6/2010, our intensive care unit has admitted five patients with rhomboencephalitis with diverse etiologies. One patient died of cardiopulmonary failure. They have similar clinical features and MRI findings on presentation. Typically they have dysconjugate gaze with WEBINO sign due to medial longitudinal fasciculus involvement, double Panda sign on MRI which is previous described in patient with Wilson’s disease and cardiopulmonary complications due to involvement of the respiratory and vasomotor centre. Wilson’s disease is excluded by relevant tests. Two patients with enterovirus infection have hand foot and mouth disease contacted from their children. – one with EV71 and one with EV71 and Coxsackie A16 genetic fragments. Three patients who do not have hand foot and mouth disease has history of travel to China – one suffering from suspected Rickettsia infection, one from suspected Campylobacter jejuni infection and one with unidentified etiologies.

Rhomboencephalitis: ImplicationA Cluster of 5 Patients In An Intensive Care Unit In Hong Kong : 

Rhomboencephalitis: ImplicationA Cluster of 5 Patients In An Intensive Care Unit In Hong Kong The patient who died has a recombinant EV71 and Coxsackie A16 viral fragments. A new mutant of EV71 with Fuyang HEV71 strain and Coxsackie virus A16 (CV-A16) is responsible for the outbreak of EV71 in China in 2008. This strain was associated with enhanced mortality compared with previous EV71 strain. Of the 6,049 cases reported between 1 March and 9 May of 2008, 3023 (50%) were hospitalized, 353 (5.8%) were severe and 22 (0.36%) were fatal. Human EV71 was confirmed as the etiological pathogen of the outbreak. We should be on the alert that this mutant human EV71 strain may have the potential of causing an epidemic of rhomboencephalitis of adult in South East Asia. Since only 1:1000 patient with Campylobacter jejuni infection would develop Guillain-Barré syndrome, we should watch out whether there is an recent outbreak of Campylobacter jejuni gastroenteritis. We should have meticulous check on the food processing industry. Whether there is a new variant of Rickettsia infection in China (with typically isolated elevation in OX2 tire in Weil Felix test) that may present with rhomboencephalitis should be investigated. Our routine primer may not be able to pick up the new variant.

Slide 4: 

Cardiovascular Collapse

Slide 7: 

P1 was admitted on D10 with cardiopulmonary collapse (A16) P2 has dizziness, double vision with transient respiratory Depression (EV71)

Slide 8: 

Wall-Eyed Bilateral Internuclear Ophthalmoplegia

Slide 9: 

Patient 2: No Webino Sign

Slide 10: 

WEBINO Sign (P1)

Slide 11: 

WEBINO Sign (P1)

Slide 12: 

Dysconjugate gaze is generally found among patients with stroke of the brainstem. A small infarction of the rostral pons or caudal midbrain may produce an internuclear opthalmoplegia. A rostral lesion within the midbrain may affect the convergence center thus causing bilateral divergence of the eyes which is known as the WEBINO syndrome (Wall Eyed Bilateral INO) as each eye looks at the opposite "wall". Exotropia Neurological Finding in ICU (P3)

Slide 13: 

WEBINO Sign (P5)

Slide 14: 

Skew Deviation

Slide 15: 

Medial Longitudinal Fasciculus

Slide 16: 

Rostral pons or caudal midbrain involvement Produce an internuclear opthalmoplegia 1 = Oculomotor N nuclei; 2 = Trochlear nerve; 3 = pons; 4= 4th ventricle; 5= abducen nuclei; 6 = vestibular nuclei; 7 = medial longitudinal fasciculus; (P3)

Slide 17: 

MRI Finding with Anatomical Correlation (P3)

Slide 18: 

Medial Longitudinal Fasciculus: Etiology of Skew Deviation (P3)

Slide 19: 

Pons Midbrain Claustrum outside Putamen and pallidum “Face of the panda cub” Double Panda Sign was previous described in patients with Wilson’s Disease

Slide 20: 

The typical 'face of the giant panda' seen in the midbrain on T2-weighted MRI of the brain. Wilson's disease: an update Shyamal K Das and Kunal Ray Nature Clinical Practice Neurology (2006) 2, 482-493 The giant panda sign is due to the preservation of normal signal intensity in the red nuclei and lateral portion of the pars reticulata of the substantia nigra, high signal in the tegmentum, and hypointensity of the superior colliculus. 上視丘 (superior colliculus.) Red nucleus (eye) Substantial nigra (ear) Superior colliculus (chin)

Slide 21: 

T2 weighted MRI of midbrain of Wilson’s disease Normal signal at the red nuclei (eyes) and the lateral aspect of the substantial nigra pars reticulata (ears), high signal at the tegmentum and hypointense supercoliculi. Neuropareidolia: diagnostic clues apropos of visual illusions Arq. Neuro-Psiquiatr. vol.67 no.4 São Paulo dic. 2009 Mesencephalic Panda Sign

Slide 22: 

The “face of the miniature panda” is delineated by the relative hypointensity of the medial longitudinal fasciculi and central tegmental tracts (“eyes of the panda”) in contrast with the hyperintensity of the aqueduct opening into the fourth ventricle (“nose and mouth of the panda”) bounded inferiorly by the superior medullary velum . The superior cerebellar peduncles form the panda’s “cheeks.” T2-weighted axial MRI reveals the “face of the miniature panda” in the pontine tegmentum (arrow) Wilson's disease: an update Shyamal K Das and Kunal Ray Nature Clinical Practice Neurology (2006) 2, 482-493

Slide 23: 

Substantial nigra (ear) Red nucleus (eye) Superior colliculus (chin) ‘Face of the giant panda' seen in the midbrain on MRI of the brain. (P2) Site of medial longitudinal fasciculus

Slide 24: 

“Face of the miniature panda” in the pontine tegmentum (P2) Site of medial longitudinal fasciculus

Slide 25: 

Medial longitudinal fasciculus Clinical and Anatomical Correlation of Exotropia of Patient (P3) Anatomy of Pons

Slide 26: 

Giant Panda Sign (P4)

Slide 27: 

“Face of the miniature panda” (P4) Medial longitudinal Fasciculus involvement

Slide 28: 

“Face of the miniature panda” (P4) Medial longitudinal Fasciculus involvement

Slide 29: 

MRI Brian (14/6/2010) Medial longitudinal fasciculus Giant Panda Sign (P5)

Slide 30: 

Minature Panda Sign (P5) Medial Longitudinal Fasciculus

Slide 33: 

The respiratory rhythm generator with results of brain stem transection. NTS = nucleus tractus solitarius, NAm = nucleus ambigualis, NretroAm= nucleus retroambigualis.

Respiratory Failure : 

Respiratory Failure All the patient except patient 2 required mechanical ventilation. Patient 2 has transient compensated CO2 retention but no intubation or mechanical ventilation required 28/05/10 pH 7.44 PaCO2 5.6 kPa PaO2 17.3 kPa HCO3 28 mmol/L BE 3.3 mmol/L K 4.1 mmol/L (18:40) pH 7.40 PaCO2 6.4 kPa PaO2 12.1 kPa HCO3 29 mmol/L BE 3.5 mmol/L K 3.8 mmol/L (23:31) 29/05/10 pH 7.39 PaCO2 6.4 kPa PaO2 13.8 kPa HCO3 29 mmol/L BE 2.8 mmol/L K 4.0 mmol/L (02:28) pH 7.43 PaCO2 5.5 kPa PaO2 12.9 kPa HCO3 27 mmol/L BE 2.1 mmol/L K 3.9 mmol/L (06:46) pH 7.44 PaCO2 5.4 kPa PaO2 13.9 kPa HCO3 25 mmol/L BE 2.5 mmol/L (12:45) 30/5/10 pH 7.43 PaCO2 5.1 kPa PaO2 13.6 kPa HCO3 25 mmol/L BE 0.3 mmol/L K 3.9 mmol/L (30/05/10) Diplopia and cerebellar sign improved after IVIG therapy.

Slide 35: 

Pneumotaxic center affected Site of vasomotor center This explains why P2 has no vasomotor disturbance but only has diplopia and cerebellar sign with CO2 retention

Slide 36: 

31: Substantial nigra 32: Red nucleus 33:Inferior colliculus 34: Superior colliculus 26: Pons: corticospinal tract 29: Superior cerebellar peduncle 30: Oculomotor nerve 19: Spinal tgrigemial nuclues 20: Lateral cuneate nuclues 21: Inferior olivery nucleus Cerebellar sign Pneumotaxic centre at Medial Parabrachial Nucleus Diplopia due to MLF involvement

Slide 37: 

Parabrachial Pigmented Nucleus: Pneumotaxic center Medial Parabrachial Nucleus Red Nucleus Substantial nigra

Slide 38: 

Carotid body Aortic body Vagus nerve Glossopharyngeal nerve Vasomotor centre Cardioregulatory centre Vagus (parasympathetic) Vasomotor Centre

Slide 39: 

Inhibitory GABAergic input

Slide 40: 

Rostral Ventrolateral Medulla Stimulation  Tachycardia and Hypertension EV 71 Rhombencephalitis Hypertension

P3 Hypertension and Tachycardia : 

P3 Hypertension and Tachycardia Patient 3 has hypertension and tachycardia after ICU admission He was put on MgSO4 infusion on 2/6/2010 - 8/6/2010 to keep Mg level 2-3 mmol/L BP and tachycardia well controlled in the absence of anti-hypertensive medication after MgSO4 infusion Mg SO4 infusion was weaned off after several days when BP become more stable 24 hour urine showed an elevated noradrenaline excretion during hypertensive period Ur. Volume,24h (a) Adrenaline 27(04/06/10) 51(06/06/10) 54(07/06/10) (19 - 113) nmol/d (b) Noradrenaline 283 (04/06/10) 536 (06/06/10) 525 (07/06/10) (63 - 416) nmol/d (c) VMA 7.6 (06/06/10) 7.1 (07/06/10) (N< 41.0) umol/d

Slide 42: 

MgSO4 infusion to keep Mg 2-3 mmol/L MgSO4 infusion to control hypertensive storm from vasomotor centre (P3)

Slide 43: 

Our patient has elevated 24 hour urine for NA Adrenal tumour has been excluded because patient has CT scan of abdomen on 28/5/2010

Slide 44: 

Noradrenaline Peripheral sympathetic vasoconstriction  Constriction of both arterioles and arterial vessel veins and venules. β1-receptors stimulation lead to tachycardia and increased myocardial contractility Sympathetic Stimulation

Slide 45: 

Shock and Cardiovascular Collapse Pathogenesis of Shock in Vasomotor collapse EV 71 Rhombencephalitis

Slide 46: 

Medial Reticular Formation Medial Reticular Formation Vasomotor Centre is at the Medulla Oblongata

Slide 47: 

Medial reticular formation is part of the vasomotor center

Slide 48: 

An example of pulmonary edema secondary to involvement of medial reticular formation in a patient with multiple sclerosis. Cerebral damage can lead to sympathetic stimulation, resulting in systemic and pulmonary hypertension and cardiac dysfunction with secondary neurogenic pulmonary oedema or even vasomotor collapse. The caudal part of the nucleus tractus solitarius, the dorsal motor nucleus of the vagal nerve, and the medial reticular formation are believed to have a role in the pathogenesis of neurogenic acute pulmonary edema A woman with multiple sclerosis and pink saliva Martha T van de Beek, Walter Taal, Rolf F Veldkamp, Dr Charles J Vecht The Lancet Neurology, Volume 2, Issue 4, Pages 254 - 255, April 2003 Pathogenesis of Neurogenic Acute Pulmonary Edema

Slide 49: 

P5

Slide 50: 

P5

Slide 51: 

This patient has cardiovascular collapse probably due to lower brainstem involvement as vasomotor centre is near upper medulla oblongata

Patient 3 (? Unidentified Rickettsia infection) : 

Patient 3 (? Unidentified Rickettsia infection) Weil Felix Test: OX2: 1:80 (2/6/2010) 1:640 (14/06/10) > 1:1280 (28/06/10) OX19: 1:20 (2/6/2010) 1:20 (14/06/10) 1:80 (28/06/10) OXK: <1:20 (2/6/2010) <1:20 (14/06/10) 1:40 (28/06/10) Spotted fever group rickettsia < 1:128 (2/6/10) < 1:128 (18/6/10) Typhus group rickettsia < 1:128 (2/6/10) < 1:128 (18/6/10) Orientia Tsutsugamushi < 1:128 (2/6/10) < 1:128 (18/6/10) Rickettsia Japonica <1:128

Slide 54: 

Japanese spotted fever: report of 31 cases and review of the literature Mahara F Emerg Infect Dis. 1997 Apr-Jun;3(2):105-11. "Candidatus Rickettsia kellyi," India Jean-Marc Rolain,* Elizabeth Mathai,† Hubert Lepidi,* Hosaagrahara R. Somashekar,† Leni G. Mathew,† John A.J. Prakash,† and Didier Raoult Emerg Infect Dis. 2006 Mar;12(3):483-5.

Patient 4 (?Campylobacter Jejuni Infection) : 

Patient 4 (?Campylobacter Jejuni Infection) NCT Mild decrease CMAP of bil median and ulnar nerve, with normal veloocity and F wave LL F waves are all absent Also completely absence sensory response Findings are compatible with Miller-Fisher Variant of GBS Ganglioside GQ1b autoantibodies 57 (N<20) (12/6/2010)

Slide 57: 

Significance of autoimmune reactions against nervous system antigens in neurological diseases Ganglioside GM1 is specifically associated with a pure motor type of GBS (IgG) and with multifocal motor neuropathy (IgM).

Slide 58: 

Anti-GQ1b and GD1b Antibodies ☼☼ Ganglioside GD1b present in dorsal root ganglia, cerebellar granular layer or spinocerebellar Ia fibers. . Anti GD1b Ab are specifically associated with sensory disturbances including paresthesia or dysesthesia and cerebellar ataxic neuropathy Kusunoki, S, Shimizu, J, Chiba, A, et al.: Experimental sensory neuropathy induced by sensitization with ganglioside GD1b. Ann Neurol 39: 424-431, 1996 Ophthalmoplegia Chiba, A, Kusunoki, S, Obata, H, et al.: Serum anti-GQ1b IgG antibody is associated with ophthalmoplegia in Miller Fisher syndrome and Guillain-Barré syndrome: Clinical and immunohistochemical studies. Neurology 43: 1911-1917, 1993.

Slide 59: 

Anti-GQ1b IgG antibody syndrome: clinical and immunological range[Odaka: J Neurol Neurosurg Psychiatry, Volume 70(1).January 1, 2001.50-55]

Slide 60: 

Nosological relations between Miller Fisher syndrome, acute ophthalmoparesis, Bickerstaff's brain stem encephalitis, and Guillain-Barré syndrome [Odaka: J Neurol Neurosurg Psychiatry, Volume 70(1).January 1, 2001.50-55]

Slide 61: 

? Most early finding

Slide 63: 

Medulla Oblongata Involvement (P4)

Slide 64: 

Medulla Oblongata Involvement (P4)

Slide 65: 

Medulla Oblongata Involvement (P4)

Slide 66: 

Around 1:1000 will developed GBS. In a Swedish cohort of 29,567 individuals with laboratory-confirmed C. jejuni infection. The authors noted that of 6,293 persons below age 20 years, no cases of GBS were found. Among 20,856 adults aged 20–59 years, the rate of GBS was 14 per 100,000, while in the set of 2,417 people over age 59 years, the rate was 248 per 100,000 Between 30-50% of all GBS cases are linked to C. jejuni infection, usually appearing 1-3 weeks after bacterial infection with F:M ratio 3.5:1 (c.f 1.5:1)

Slide 67: 

Thank you for your attention

Slide 68: 

EV71 radiculomyelitis tends to be unilateral and to specifically involve both the anterior horn cells of the cord and the ventral roots. MR imaging allows early detection of spinal cord and root lesions.

Slide 69: 

HFM disease usually begins with a fever, poor appetite, malaise (feeling vaguely unwell), and often with a sore throat.

Slide 70: 

Hand Foot and Mouth Disease Acute Haemorrhagic Conjuncitivitis Herpangina

The Evolution of EV71 toOur First PatientThe ICU Nurse Who Died : 

The Evolution of EV71 toOur First PatientThe ICU Nurse Who Died Dr. Lai Kang Yiu Intensive Care Unit Queen Elizabeth Hospital

Slide 72: 

Single +ve strand RNA virus with high mutation rate due to low-fidelity replication and frequent recombination Human Enterovirus

Slide 73: 

Human Enterovirus

Slide 74: 

Genetic evolution of enterovirus 71: epidemiological and pathological implications. Bible JM. Pantelidis P. Chan PK. Tong CY. Reviews in Medical Virology. 17(6):371-9, 2007 Nov-Dec. 10 year cycle We are heading for the 4th cycle

Slide 75: 

Epidemiology of enterovirus 71 in the Netherlands, 1963 to 2008. van der Sanden S. Koopmans M. Uslu G. van der Avoort H. Dutch Working Group for Clinical Virology. Journal of Clinical Microbiology. 47(9):2826-33, 2009 Sep.

Slide 76: 

Analysis of recombination and natural selection in human enterovirus 71. Chen X. Zhang Q. Li J. Cao W. Zhang JX. Zhang L. Zhang W. Shao ZJ. Yan Y. Virology. 398(2):251-61, 2010 Mar 15. Appearance of intratypic recombination of enterovirus 71 in Taiwan from 2002 to 2005. Huang SC. Hsu YW. Wang HC. Huang SW. Kiang D. Tsai HP. Wang SM. Liu CC. Lin KH. Su IJ. Wang JR. Virus Research. 131(2):250-9, 2008 Feb. Appearance of mosaic enterovirus 71 in the 2008 outbreak of China. Ding NZ. Wang XM. Sun SW. Song Q. Li SN. He CQ. Virus Research. 145(1):157-61, 2009 Oct. EV71 proteins are extensively influenced by stabilizing selection. Recombination events were found to be distributed nonrandomly with the highest frequency at the 3D (viral polymerase) region. Due to the absence of proofreading activity, the misinsertion rate by the 3D polymerase is high, and mutations accumulate during replication. intratypic recombination recombination play an important role in the formation of genetic diversity in enterovirus. Intratypic and intertypic recombination of EV71 nonstructural genes during natural infection and circulation lead to production of new EV71 variants. Co-infection is common in China. Recombination frequently occurs among EV71 circulating in China, and might bring a novel biologic characteristic, such as immune escape or improved virulence.

In the past, many outbreaks of EV71were not associated with hand foot and mouth disease or herpangina until the outbreak in Japan 1973 and 1978. : 

In the past, many outbreaks of EV71were not associated with hand foot and mouth disease or herpangina until the outbreak in Japan 1973 and 1978. Schmidt NJ, Lennett EH, Ho HH. An apparently new enterovirus isolated from patients with disease of the central nervous system. J Infect Dis. 1974;129:304 –309. Chumakov M, Voroshilova M, Shindarov L, et al. Enterovirus 71 isolated from cases of epidemic poliomyelitis-like disease in Bulgaria. Arch Virol. 1979;60:329 –340. Deibel R, Gross LL, Collins DN. Isolation of a new enterovirus. Proc Soc Exp Biol Med. 1975;148:203–207. Blomberg J, Lycke E, Ahlfors K, et al. New enerovirus type associated with epidemic of aseptic meningitis and/or hand, foot, and mouth disease. Lancet. 1974;2:l12. Shindarov LM, Chumakov MP, Voroshilova MK, et al. Epidemiological, clinical, and pathomorphological characteristics of epidemic poliomyelitislike disease caused by enterovirus 71. J Hyg Epidemiol Microbiol Immunol.1979;23:284 –295. Nagy G, Takatsy S, Kukan E, et al. Virological diagnosis of enterovirus type 71 infections: experiences gained during an epidemic of acute CNS diseases in Hungary in 1978. Arch Virol. 1982;71:217–227. Coxsackie A16 is characterized by its dermatotropic clinical features and EV71 is characterized by its neurotropic clinical features.

Enterovirus 71 : 

Enterovirus 71 First isolated in 1969 in stool from an infant suffering from encephalitis in California Bulgaria in 1975 (44/705 death due to bulbar encephalitis) 77.3％ aseptic meningitis 21.1％ acute flaccid paralysis No evidence of hand foot and mouth disease Hungary in 1978 (826 patients with 47 deaths) 87.7％ aseptic meningitis 4 had hand foot and mouth disease Japan 1973 and 1978 A large-scale epidemic of hand, foot and mouth disease associated with enterovirus 71 infection in Japan in 1978. Tagaya I, Takayama R, Hagiwara A Jpn J Med Sci Biol. 1981 Jun;34(3):191-6.

Japan 1973 and 1978 ~ 36,000 CasesBrain stem encephalitis and paralysis : 

Japan 1973 and 1978 ~ 36,000 CasesBrain stem encephalitis and paralysis Tagaya and K. Tachibana, Epidemic of hand, foot and mouth disease in Japan, 1972–1973: difference in epidemiologic and virologic features from the previous one, Japanese Journal of Medical Science and Biology 28 (August (4)) (1975), pp. 231–234. A. Hagiwara, I. Tagaya and T. Yoneyama, Epidemic of hand, foot and mouth disease associated with enterovirus 71 infection, Intervirology 9 (1) (1978), pp. 60–63. Outbreaks of hand, foot, and mouth disease by enterovirus 71. High incidence of complication disorders of central nervous system. Y Ishimaru, S Nakano, K Yamaoka, and S Takami Arch Dis Child. 1980 August; 55(8): 583–588. A large-scale epidemic of hand, foot and mouth disease associated with enterovirus 71 infection in Japan in 1978. Tagaya I. Takayama R. Hagiwara A. Japanese Journal of Medical Science & Biology. 34(3):191-6, 1981 Jun. 96% of these the CNS disorder appeared between days 2 and 4 after the onset of HFMD. Unlike the large vesicular rash of Coxsackie 16, the rash of EV71 infection, is frequently papular and/or petechial, often with areas of diffuse erythema on the trunk and limbs

Slide 80: 

Oral ulcers distributed not on soft palate only as in typical hand-foot mouth disease

Slide 81: 

Vesicles on hand and foot were smaller (pin-point) than typical HFM disease

Slide 82: 

Vesicles on hand and foot were smaller (pin-point) than typical HFM disease

Slide 83: 

Sometimes the skin lesion consisted of petechiae-like clusters

Slide 84: 

~ 6000 reported cases with 29 death Rapidly progressive cardiorespiratory failure during an outbreak of hand, foot, and mouth disease caused primarily by enterovirus 71 (EV71 B3 genotype) L.G. Chan, U.D. Parashar, M.S. Lye, F.G. Ong, S.R. Zaki and J.P. Alexander et al., Deaths of children during an outbreak of hand, foot, and mouth disease in sarawak, Malaysia: clinical and pathological characteristics of the disease, Clinical Infections and Disorders 31 (September (3)) (2000), pp. 678–683. 1977 Sarawak Malaysia29 death < 6yr

Slide 85: 

PM: Normal myocardium with no evidence of inflammation or myocyte necrosis or degeneration. CNS tissue showed congestion, edema, and perivascular and meningeal lymphocytic infiltration. Brain-stem tissue, showed extensive neuronal degeneration and necrosis associated with an inflammatory reaction resembling microabscesses and positive staining for anti-EV71 monoclonal antibody. L.G. Chan, U.D. Parashar, M.S. Lye, F.G. Ong, S.R. Zaki and J.P. Alexander et al., Deaths of children during an outbreak of hand, foot, and mouth disease in sarawak, Malaysia: clinical and pathological characteristics of the disease, Clinical Infections and Disorders 31 (September (3)) (2000), pp. 678–683.

1988 Taiwan Outbreak EV 71(C2 genotype) : 

1988 Taiwan Outbreak EV 71(C2 genotype) In 1998, an epidemic of EV71 infection affected 90 000 children in Taiwan. Among the 405 children hospitalized with acute neurologic disease, 78 died. In this outbreak, there was clinical, neuroradiologic, and pathologic evidence that the chief neurologic complication was rhombencephalitis or brainstem lesions. Most of the fatal cases initially involved minor neurologic symptoms, but the children rapidly died of acute onset of pulmonary edema (PE) and/or hemorrhage (PH) with rapid progression of cardiopulmonary failure within hours after admission. (1)Wang SM, Liu CC, Tseng HW, et al. Clinical spectrum of enterovirus 71 infection in children in southern Taiwan, with an emphasis on neurological complications. Clin Infect Dis. 1999;29:184–190 (2) Huang CC, Liu CC, Chang YC, Chen CY, Wang ST, Yeh TF. Neurologic complications in children with enterovirus 71 infection. N Engl J Med. 1999;341:936–942 (3) Ho M, Chen ER, Hsu KH, et al. The enterovirus type 71 epidemic of Taiwan, 1998. N Engl J Med. 1999;341:929–935 (4) Chang LY, Lin TY, Hsu KH, et al. Clinical features and risk factors of pulmonary edema after enterovirus 71-related hand, foot, and mouth diseases. Lancet. 1999;354:1682–1686 (5) Lum LC, Wong KT, Lam SK, et al. Fatal enterovirus 71 encephalomyelitis. J Pediatr. 1998;133:795–798 (6) Liu CC, Tseng HW, Wang SM, Wang JR, Su IJ. An outbreak of enterovirus 71 in Taiwan, 1998: epidemiologic and clinical manifestations. J Clin Virol. 2000;17:23–30

Slide 87: 

129,106 cases of hand-foot-and-mouth disease or herpanginain 2 waves of the epidemic in 1998 (< 10 % of the estimated total) 405 patients (0.31%) with severe disease (most were ≤five years old) 78 patients (0.06%) died 91 % were ≤five years old, highest in the age group 7 to 12 mths 83 % (65) had pulmonary edema or pulmonary hemorrhage. Enterovirus71 isolated 48.7% outpatients with uncomplicated hand-foot-and-mouth disease or herpangina 75 % of hospitalized patients who survived 92 % of patients who died

Virus Isolates in the Taiwan 1998 Outbreak : 

Virus Isolates in the Taiwan 1998 Outbreak Enterovirus71 Coxsackie virus A16 and Other enteroviruses: Coxsackie virus B1, B2, B3, and B5; Echovirus 6, 7, 11, 22, and 27; and Poliovirus (Sabin-vaccine strain) were circulating in the community Enterovirus71 was more prevalent among severely ill, hospitalized patients

Slide 89: 

Viruses Isolated in Severe Infections: 96 patients 75% HFMD, 11% Herpangina 81%

Lethal cases : 

Lethal cases 78 patients died 83 percent (65) died of pulmonary edema or hemorrhage -most frequent lethal complication Most were ≤3years old Died within one to two days after admission Viral cultures available for 68/ 78 31 had negative cultures 37 had positive cultures 92 percent were enterovirus71 97 percent (32/33) who died of pulmonary edema or hemorrhage were infected with enterovirus71 (only one with coxsackievirus B5)

Slide 91: 

Number of Cases of Hand-Foot-and-Mouth Disease and Herpangina Reported in Taiwan as a Whole and in Each of Its Four Regions by Sentinel Physicians from the Week of March 29, 1998, through the Week of December 27, 1998. The total number of cases was 129,106

Enterovirus 71 : 

Enterovirus 71 Hong Kong 1985: 5 children with acute flaccid monoplegia; 3 had hand foot and mouth disease, 1 has oral lesion and 1 has diffuse erythema in limbs. 1999: 8 death Malaysia in 1997 (at least 31 deaths) Taiwan in 1980, 1986, 1998 1980: 20 children poliomyelitis-like flaccid paresis associated with hand-foot-and-mouth disease or herpangina 1986 in Kaohsiung 1998 large outbreak (78 deaths) Singapore 2007: April 15–21: 688 cases reported 2008 Late March –mid April: 2,600 cases reported, no serious cases Enterovirus 71 in Taiwan Chang LY. Pediatrics & Neonatology. 49(4):103-12, 2008 Aug. Monoplegia caused by Enterovirus 71: an outbreak in Hong Kong. Samuda GM, Chang WK, Yeung CY, Tang PS. Pediatr Infect Dis J. 1987 Feb;6(2):206-8.

China 1999-2010 : 

China 1999-2010 Shenzhen 1999-2004: EV71 (C4) and CA16 co-circulation In patients with HFMD, EV71 (12.93%) and CA16 (27.89%). The etiological viral pathogens were not identified in approximately 60% of HFMD cases. The cause of low rate of viral isolation is unclear 2002: Shanghai CA16: EV71 = 6.4:1 2/9 belong to a new lineage (C4) within genogroup C One patient with EV71-associated HFMD had a complication of encephalitis with convulsion, shock, coma and dyspnea. 2007: Beijing Cox A16 and 2 strains of EV71 of C4 subtype

Hand Foot & Mouth Disease in China : 

Hand Foot & Mouth Disease in China http://www.moh.gov.cn/publicfiles/business/htmlfiles/mohbgt/s3582/200902/39079.htm http://www.moh.gov.cn/publicfiles///business/cmsresources/mohbgt/cmsrsdocument/doc7307.doc http://www.phac-aspc.gc.ca/tmp-pmv/2010/hfm-mpb07082010-eng.php

Slide 95: 

Major Outbreak of EV71 in China in 2008 EV71 spreading from Zhejiang 浙江 to Anhui 安徽 then to rest of China Phylogenetic analysis of all EV71 strains isolated from the mainland Chinese samples established C4 as the predominant genotype. 488,955 cases were reported among children in China with 126 deaths. F. Yang, L. Ren, Z. Xiong, J. Li, Y. Xiao and R. Zhao et al., Enterovirus 71 outbreak in the People's Republic of China in 2008, Journal of clinical Microbiology 47 (July (7)) (2009), pp. 2351–2352. http://www.moh.gov.cn/publicfiles/business/htmlfiles/mohbgt/s3582/200902/39079.htm

Etiologies for Increasing Incidence of EV71 in China since 2008 : 

Etiologies for Increasing Incidence of EV71 in China since 2008 Ever-increasing travel and migration spreads the disease further by moving infected people between population centers. In May 2008, China added HFMD to its category C of notifiable diseases, meaning that all diagnosed cases must be reported. The recent apparent ncrease in EV71 infection might be due to higher reporting rates rather than an increase in disease prevalence. The genetic changes in the circulating EV71 strain. Before 2004, the predominant strain was called C4b; since then, a different strain, C4a, has been most common. C4a also caused the epidemic in 2008

Slide 97: 

Zhang et al. Virology Journal 2010, 7:94 http://www.virologyj.com/content/7/1/94

Slide 98: 

An emerging recombinant human enterovirus 71 responsible for the 2008 outbreak of Hand Foot and Mouth Disease in Fuyang city of ChinaYan Zhang Virol J. 2010; 7: 94. Published online 2010 May 12. doi: 10.1186/1743-422X-7-94.PMCID: PMC2885340

Slide 99: 

An emerging recombinant human enterovirus 71 responsible for the 2008 outbreak of Hand Foot and Mouth Disease in Fuyang city of ChinaYan Zhang Virol J. 2010; 7: 94. Published online 2010 May 12. doi: 10.1186/1743-422X-7-94.PMCID: PMC2885340

Slide 100: 

China - Alarming Outbreak of "Mutated" Virulent form of Hand, Foot, and Mouth Disease in Guangxi 2010 From January to April 11 2010, Guangxi reported a total of 17,345 cases of hand, foot and mouth disease (mainly caused by EV71 virus disease) resulting in 27 deaths. The disease quickly spread from Quanzhou county (全州縣) in Guilin (桂林) to Liuzhou(柳州) and to the rest of Guangxi Zhuang Autonomous Region. Many children were admitted in shock state with pulmonary edema and pulmonary hemorrhage. Patient 1 in Hong Kong

EV 71 Radiculomyelitis : 

EV 71 Radiculomyelitis Dr. Lai Kang Yiu Intensive Care Unit Queen Elizabeth Hospital

Slide 102: 

Unilateral AFP and transient urinary retention in 18-month-old girl with lumbosacral radiculomyelitis. A, Contrast-enhanced axial T1-weighted image (752/15/1) at L1 level shows strong enhancement of the left ventral root (arrowhead) and mild enhancement of the left anterior horn cells (arrow) of the sacral cord. B, Left anterior horn lesion (arrow) is inconspicuous on gradient-echo T2-weighted image. Acute flaccid paralysis (Radiculomyelitis)

Slide 103: 

Radiculomyelitis causing bilateral AFP and urinary retention. A, Unenhanced axial T1-weighted image (752/15) shows hypointense lesions (arrowheads) in the anterior horn cells of spinal cord bilaterally at T11 level. B, Contrast-enhanced T1-weighted image at the same level as in A shows predominant enhancement of the ventral roots (arrowheads). The anterior horn cell lesions do not enhance. C, Contrast-enhanced T1-weighted image at the conus level clearly shows the predominant ventral root enhancement. The slightly hyperintense dot at the left dorsal root region (arrowhead) is probably due to enhancement of the radicular vein. D, The anterior horn cell lesions are hyperintense and more conspicuous on gradient-echo T2-weighted image (808/15/20) as compared with T1-weighted image (A). E, Sagittal fast spin-echo T2-weighted image (2300/103/2) shows the extent of the anterior horn cell lesions (arrowheads) from midthoracic to conus levels.

Slide 104: 

Persistent weakness of right lower limb 2 months after EV71 infection in a 16- month-old infant. A, Axial fast spin-echo T2-weighted image (4000/80/3) at lumbosacral cord 2 months after acute paralysis shows a hyperintense lesion in the right anterior horn region (arrow). B, Sagittal fast spin-echo T2-weighted image shows a long-segment hyperintense lesion (arrowheads) extending from the lower thoracic to the lumbosacral levels.

Acute Pulmonary Edemawith RhombencephalitisComplicating EV 71 : 

Acute Pulmonary Edemawith RhombencephalitisComplicating EV 71 Dr. Lai Kang Yiu Intensive Care Unit Queen Elizabeth Hospital

10 such patients from a series of 150 patients with bulbar poliomyelitis developed pulmonary edema The pulmonary edema was described as sudden in its onset, resisted all forms of treatment, and resulted in death. All had involvement of the dorsal nuclei of the vagus and the vasomotor (medial reticular) nuclei in the medulla oblongata. : 

10 such patients from a series of 150 patients with bulbar poliomyelitis developed pulmonary edema The pulmonary edema was described as sudden in its onset, resisted all forms of treatment, and resulted in death. All had involvement of the dorsal nuclei of the vagus and the vasomotor (medial reticular) nuclei in the medulla oblongata. Poliomyelitis: a study of pulmonary edema. Baker A.B. Neurology 1957;7:743-51.

Slide 107: 

Extracorporeal life support for treatment of children with enterovirus 71 infection-related cardiopulmonary failure Jan SL. Lin SJ. Fu YC. Chi CS. Wang CC. Wei HJ. Chang Y. Hwang B. Chen PY. Huang FL. Lin MC. Intensive Care Medicine. 36(3):520-7, 2010 Mar.

Slide 109: 

Mechanism of fulminant pulmonary edema caused by enterovirus 71 Kao SJ, Yang FL, Hsu YH, Chen HI Clin Infect Dis. 2004 Jun 15;38(12):1784-8. Epub 2004 May 19. Sympathetic activity, AP, and HR increased with respiratory stress. Thereafter, parasympathetic activity increased with decreases in AP and HR. The lungs showed edema with inducible nitric oxide synthase (iNOS) expression. Destruction of the medial, ventral, and caudal medulla may lead to sympathetic overactivation, causing blood to shift to the lungs. The pathogenesis of PE may also involve iNOS and nitric oxide.

Slide 110: 

Extracorporeal life support for treatment of children with enterovirus 71 infection-related cardiopulmonary failure Jan SL. Lin SJ. Fu YC. Chi CS. Wang CC. Wei HJ. Chang Y. Hwang B. Chen PY. Huang FL. Lin MC. Intensive Care Medicine. 36(3):520-7, 2010 Mar. 0.1% 11-19% Stage 1 : Hand, foot and mouth disease/ herpangina Stage 2: CNS involvement Stage 3: Cardiopulmonary failure (a) Coexisting with hypertension (b) Co-existing with hypotension Stage 4: Convalescence Without mechanical support, 71–83% of patients die within 12–24 h after the onset of CPF, and those who survive may have severe neurological sequelae. Acute CPF usually is transient and quickly reversible if an optimal treatment that can maintain hemodynamic stability and restore heart function to improve end-organ perfusion is initiated.

Slide 111: 

PM: Normal myocardium with no evidence of inflammation or myocyte necrosis or degeneration. CNS tissue showed congestion, edema, and perivascular and meningeal lymphocytic infiltration. Brain-stem tissue, showed extensive neuronal degeneration and necrosis associated with an inflammatory reaction resembling microabscesses and positive staining for anti-EV71 monoclonal antibody. L.G. Chan, U.D. Parashar, M.S. Lye, F.G. Ong, S.R. Zaki and J.P. Alexander et al., Deaths of children during an outbreak of hand, foot, and mouth disease in sarawak, Malaysia: clinical and pathological characteristics of the disease, Clinical Infections and Disorders 31 (September (3)) (2000), pp. 678–683.

Slide 113: 

A, Chest radiographs of patient 2 were initially normal. B, Increased alveolar density without obvious cardiomegaly after PE.

Slide 114: 

Heart is grossly hypertrophic and there is no inflammatory change on microscopy

Slide 115: 

EV71 associated Rhomboencephalitis with upper cervical myelitis

Fatal Case of Enterovirus 71 Infection, France, 2007Sophie Vallet, Marie-Christine Legrand-Quillien, Thomas Dailland, Gaëtan Podeur, Stéphanie Gouriou, Isabelle Schuffenecker, Christopher Payan, and Pascale MarcorellesEmerging Infectious Diseases • www.cdc.gov/eid • Vol. 15, No. 11, November 2009 : 

Fatal Case of Enterovirus 71 Infection, France, 2007Sophie Vallet, Marie-Christine Legrand-Quillien, Thomas Dailland, Gaëtan Podeur, Stéphanie Gouriou, Isabelle Schuffenecker, Christopher Payan, and Pascale MarcorellesEmerging Infectious Diseases • www.cdc.gov/eid • Vol. 15, No. 11, November 2009 Acute pulmonary edema in EV71 infections was rarelyreported before the 1998 outbreak in Taiwan . Since then, this disease, which is often fatal, has been more frequently described, with known prognostic factors, includingclinical and biologic features such as central nervoussystem involvement, leukocytosis, decreased blood pressure,and hyperglycemia. The reported fatal infection ran a biphasic course, with death occurring within a few hours of the onset of respiratory distress. This devastating syndrome is believed to result from the extensive damage of bulbar vasomotor and respiratory centers. In the study by Kao et al.all 21 patients who had acute pulmonary edema associated with these signs died within 4 hours of the development of acute respiratory distress syndrome

Slide 117: 

A) Horizontal section of the medulla at the level of the inferior olivari nuclei, showing multiple infl ammatory areas (clear areas); original magnifi cation ×4. B) Severe edematous area with infl ammatory cells, macrophages, edema, and perivascular cuffi ng (arrow); original magnifi cation x200, hematoxylin-eosin stain. Fatal Case of Enterovirus 71 Infection, France, 2007Sophie Vallet, Marie-Christine Legrand-Quillien, Thomas Dailland, Gaëtan Podeur, Stéphanie Gouriou, Isabelle Schuffenecker, Christopher Payan, and Pascale MarcorellesEmerging Infectious Diseases • www.cdc.gov/eid • Vol. 15, No. 11, November 2009

Muscle was a major replication site for EV71. : 

Muscle was a major replication site for EV71. EV71 then spread to CNS from peripheral nerve by retrograde axonal transport (fast axonal transport) that can be blocked by colchicine. The transmission route of EV71 in mice 姚奕全中華民國93年2004

Slide 119: 

Perivascular cuffing (see arrow) by polymorphs and mononuclear cells, and oedema in the Virchow-Robin space First fatal case of enterovirus 71 infection in Hong Kong Hong Kong Medical Journal DKKNg HKMJ Vol 7 No 2 June 2001

Slide 120: 

Neuronal degeneration and necrosis with mixed inflammatory infiltrate and neuronophagia. L.G. Chan, U.D. Parashar, M.S. Lye, F.G. Ong, S.R. Zaki and J.P. Alexander et al., Deaths of children during an outbreak of hand, foot, and mouth disease in sarawak, Malaysia: clinical and pathological characteristics of the disease, Clinical Infections and Disorders 31 (September (3)) (2000), pp. 678–683.

Slide 121: 

Enterovirus 71 viral antigens, as seen in a single neuron

Slide 122: 

(A) T2-weighted sagittal section through the posterior fossa in Patient 1, 4 days after onset of pulmonary edema (PE). Note the hyperintense signal abnormality in the posterior pons and medulla, which extends into the region of the anterior horns of the cervical spine, typical of the MRI changes in the acute phase of the disease. (B) T1-weighted sagittal section through the posterior fossa in Patient 5, 28 days after disease onset. Note the hypointense signal abnormality consistent with encephalomalacia in the posterior pons and medulla, concordant with persistent central respiratory failure and severe bulbar palsy. (C) T2-weighted axial section at the level of C3 in the cervical spine in Patient 4, 56 days after disease onset. Note the persistent hyperintense signal abnormality in the regions of the anterior horns bilaterally, consistent with persistent injury of anterior horn cells of the phrenic nerves and concordant with the observation of unstimulatable phrenic nerves. Survival after pulmonary edema due to enterovirus 71 encephalitis M. A. Nolan, M. E. Craig, M. M. Lahra, W. D. Rawlinson, P. C. Prager, G. D Neurology 2003;60;1651-1656

Slide 123: 

Cardiopulmonary manifestations of fulminant enterovirus 71 infection Wu JM, Wang JN, Tsai YC, Liu CC, Huang CC, Chen YJ, Yeh TF. Pediatrics. 2002 Feb;109(2):E26-. Fulminant EV71 infection may lead to severe neurologic complications and acute PE. Magnetic resonance imaging revealed that all 5 infants had brainstem lesions. The acute PE and cardiopulmonary decompensation in EV71 infection are not directly caused by viral myocarditis. The mechanism of PE may be related to increased pulmonary vascular permeability caused by brainstem lesions and/or systemic inflammatory response instead of increased pulmonary capillary hydrostatic pressure. Cardiopulmonary function usually returns to nearly normal within days, but the neurologic sequelae are severe and usually permanent. All patients had tachycardia and hyperthermia. Transient systolic hypertension was noted in 1 patient, and 1 presented with hypotension. Pulmonary artery pressure in all 5 infants was normal or mildly elevated (26-31 mm Hg), and central venous pressure ranged from 10 to 22 mm Hg. Pulmonary artery occlusion pressures were normal or slightly elevated (13-16 mm Hg). Systemic and pulmonary vascular resistances were transiently increased in only 1 patient. The stroke volume index decreased to 15.3 to 35.7 mL/M2 (normal: 30-60 mL/M2), but because of the elevated heart rate, the cardiac index did not decrease.

Slide 124: 

Extracorporeal life support for treatment of children with enterovirus 71 infection-related cardiopulmonary failure Jan SL. Lin SJ. Fu YC. Chi CS. Wang CC. Wei HJ. Chang Y. Hwang B. Chen PY. Huang FL. Lin MC. Intensive Care Medicine. 36(3):520-7, 2010 Mar.

Slide 125: 

Extracorporeal life support for treatment of children with enterovirus 71 infection-related cardiopulmonary failure. Jan SL. Lin SJ. Fu YC. Chi CS. Wang CC. Wei HJ. Chang Y. Hwang B. Chen PY. Huang FL. Lin MC. Intensive Care Medicine. 36(3):520-7, 2010 Mar. The myocardial recovery time was 71 ± 28 (median, 69) h, and the ECLS duration was 93 ± 33 (median, 93) h. Six surviving patients had a good neurological outcome at hospital discharge. All surviving patients had some neurological sequelae but showed improvement at follow-up The present cohort had better neurological outcomes (46 vs. 0%, P = 0.005) and a higher survival rate (77 vs. 30%, P = 0.024) than the past cohort.

Slide 126: 

Acute encephalitis caused by intrafamilial transmission of enterovirus 71 in adult. Hamaguchi T. Fujisawa H. Sakai K. Okino S. Kurosaki N. Nishimura Y. Shimizu H. Yamada M. Emerging Infectious Diseases. 14(5):828-30, 2008 May.

Slide 127: 

Thank you for your attention

Treatment of EV71 Rhomboencephalitis : 

Treatment of EV71 Rhomboencephalitis Dr. Lai Kang Yiu Intensive Care Unit Queen Elizabeth Hospital

Slide 129: 

Enterovirus 71 in Taiwan. Chang LY. Pediatrics & Neonatology. 49(4):103-12, 2008 Aug.

Slide 131: 

Diseases caused by enterovirus 71 infection. Lee TC. Guo HR. Su HJ. Yang YC. Chang HL. Chen KT. Pediatric Infectious Disease Journal. 28(10):904-10, 2009 Oct. Rupintrivir is a promising candidate for treating severe cases of Enterovirus-71 infection. Zhang XN. Song ZG. Jiang T. Shi BS. Hu YW. Yuan ZH. World Journal of Gastroenterology. 16(2):201-9, 2010 Jan 14. Enterovirus 71: epidemiology, pathogenesis and management. Wang SM. Liu CC. Expert Review of Antiinfective Therapy. 7(6):735-42, 2009 Aug. Wang SM, Lei HY, Huang MC, et al. Modulation of cytokine production by intravenous immunoglobulin in patients with enterovirus 71-associated brainstem encephalitis. J Clin Virol 2006;37:47−52. Therapeutic efficacy of milrinone in the management of enterovirus 71-induced pulmonary edema. Wang SM. Lei HY. Huang MC. Wu JM. Chen CT. Wang JN. Wang JR. Liu CC. Pediatric Pulmonology. 39(3):219-23, 2005 Mar. Glucose-6-phosphate dehydrogenase deficiency enhances enterovirus 71 infection Hung-Yao Ho1, , Mei-Ling Cheng, , Shiue-Fen Weng1, Lo Chang, Tsun-Tsun Yeh1, Shin-Ru Shih1,and Daniel Tsun-Yee Chiu1,J Gen Virol 89 (2008), 2080-2089

Slide 132: 

A. The picornavirus binds to a receptor on the cell surface (A). RNA with VPg at the 5' end is translated into one primary translation product (B) which is then cleaved (C). The positive strand genomic RNA also associates with an RNA polymerase that is bound to the cytoplasmic surface of vesicles, probably from the endoplasmic reticulum, and is copied to negative stand RNA. VPg is also at the 5' end of the negative strand (the poly U end) (D). The negative strand is copied to genomic positive strand RNA (E) which associates with the procapsid to form a 150S virus (G) that is released on cell lysis

Slide 133: 

Schematic of the enterovirus genome, the polyprotein products and their major functions. A diagrammatic representation of the enterovirus genome is shown. The 11 mature polypeptides are shown, together with the three main cleavage intermediates. The main biological functions are included for each polypeptide. UTR, untranslated region; IRES, internal ribosome entry site; VPg, viral protein genome-linked. http://www.jbiomedsci.com/content/16/1/103

Slide 134: 

Role of 3D Protease

Slide 135: 

Role of 3D Protease

Slide 136: 

EV71 3C protease and its effect on rupintrivir binding 3C protease is a chymotrypsin-like protease of piconaviruses responsible for processing the poly-proteins translated from RNA genomes into functional enzymes and structural proteins essential for viral replication

Rupintrivir is a Novel Inhibitor of Human Rhinovirus 3C Protease : 

Rupintrivir is a promising candidate for treating severe cases of Enterovirus-71 infection. Zhang XN. Song ZG. Jiang T. Shi BS. Hu YW. Yuan ZH. World Journal of Gastroenterology. 16(2):201-9, 2010 Jan 14. Rupintrivir is a Novel Inhibitor of Human Rhinovirus 3C Protease Rupintrivir had favorable binding affinity with 3C protease of China 2008 EV71 virus isolated in Shanghai

Glucose-6-phosphate dehydrogenase deficiency enhances enterovirus 71 infection : 

Glucose-6-phosphate dehydrogenase deficiency enhances enterovirus 71 infection Cellular redox status affects infectivity as well as the outcome of enterovirus 71 (EV71) infection. Treatment with N-acetylcysteine offered resistance to EV71 propagation and a cytoprotective effect on the infected cells. Glucose-6-phosphate dehydrogenase deficiency enhances enterovirus 71 infection. Ho HY. Cheng ML. Weng SF. Chang L. Yeh TT. Shih SR. Chiu DT.

Slide 139: 

The 3C Protein of Enterovirus 71 Inhibits RIG-I Mediated IRF3 Activation and Type I Interferon Responses Xiaobo Lei, Xinlei Liu, Yijie Ma, Zhenmin Sun, Yaowu Yang, Qi Jin*, Bin He*, and Jianwei Wang J. Virol. doi:10.1128/JVI.02491-09 Infection with enterovirus 71 or expression of its 2A protease induces apoptotic cell death. Kuo RL, Kung SH, Hsu YY, Liu WT. J Gen Virol. 2002 Jun;83(Pt 6):1367-76. The 3C protease activity of enterovirus 71 induces human neural cell apoptosis. Li ML, Hsu TA, Chen TC, Chang SC, Lee JC, Chen CC, Stollar V, Shih SR. Virology. 2002 Feb 15;293(2):386-95. Blocked by NAC

Slide 140: 

Water extract of Glycyrrhiza uralensis inhibited enterovirus 71 in a human foreskin fibroblast cell line. Kuo KK. Chang JS. Wang KC. Chiang LC. American Journal of Chinese Medicine. 37(2):383-94, 2009. Sialylated glycans as receptor and inhibitor of enterovirus 71 infection to DLD-1 intestinal cells. Yang B. Chuang H. Yang KD. Virology Journal. 6:141, 2009. Antiviral effect of epigallocatechin gallate on enterovirus 71. Ho HY. Cheng ML. Weng SF. Leu YL. Chiu DT. Journal of Agricultural & Food Chemistry. 57(14):6140-7, 2009 Jul 22. Enterovirus 71 maternal antibodies in infants, Taiwan. Luo ST. Chiang PS. Chao AS. Liou GY. Lin R. Lin TY. Lee MS. Emerging Infectious Diseases. 15(4):581-4, 2009 Apr. Sheng-Ma-Ge-Gen-Tang inhibited Enterovirus 71 infection in human foreskin fibroblast cell line. Chang JS. Wang KC. Chiang LC. Journal of Ethnopharmacology. 119(1):104-8, 2008 Sep 2.

Slide 141: 

Sialylated glycans as receptor and inhibitor of enterovirus 71 infection to DLD-1 intestinal cells. Yang B. Chuang H. Yang KD. Virology Journal. 6:141, 2009.

Slide 142: 

Thank you for your attention

Vaccination for EV71Risk of Rhomboencephalitis : 

Vaccination for EV71Risk of Rhomboencephalitis Dr. Lai Kang Yiu Intensive Care Unit Queen Elizabeth Hospital

Slide 144: 

Non-enveloped, spherical, about 30 nm in diameter, composed of a protein shell surrounding the naked RNA genome. The capsid consists of a densely-packed icosahedral arrangement of 60 protomers, each consisting of 4 polypeptides, VP1, VP2, VP3 and VP4. VP4 is located on the internal side of the capsid. VP1 protein, responsible for adsorption and the uncoating process of the virus can bind three human proteins, i.e. ornithine decarboxylase (ODC1), gene trap ankyrin repeat (GTAR), and KIAA0697 expressed in brain tissue, and their interactions may interfere the proteins’ function in brain leading to neurological complications such as acute flaccid paralysis and encephalitis. EV71: an emerging infectious disease vaccine target in the Far East?. Xu J. Qian Y. Wang S. Serrano JM. Li W. Huang Z. Lu S. Vaccine. 28(20):3516-21, 2010 Apr 30. ? Ag for vaccination

EV71 induced IgG could enter BBB and cross-reacted with brain tissue in EV71 infected neonatal mice, and then the peptides of EV71 that could induce cross-reactivity with brain tissue were identified, which should be avoided in future vaccine designing. : 

EV71 induced IgG could enter BBB and cross-reacted with brain tissue in EV71 infected neonatal mice, and then the peptides of EV71 that could induce cross-reactivity with brain tissue were identified, which should be avoided in future vaccine designing. All of the tested EV71 infected patients’ sera were presence of IgG to cross-react with health human brain tissues Identification of EV71 fragments inducing cross-reactivity to human brain tissue Peptides of P230-323, P646-755, P857-1012 and P1329-1440 could induce strong IgG cross-reactivity to human brain tissue. The significant of cross reactivity was not relevant to the specific IgG titer induced by individual peptides, which indicated the cross reactivity was a specific IgG behavior rather than an antibody dose dependent artifact. EV71 infection increased BBB permeability and IgG transport and enhance both the naïve IgG and EV71 induced IgG entry. The cross-reactivity of the enterovirus 71 to human brain tissue and identification of the cross-reactivity related fragments. Jia CS. Liu JN. Li WB. Ma CM. Lin SZ. Hao Y. Gao XZ. Liu XL. Xu YF. Zhang LF. Qin C. Virology Journal. 7:47, 2010.

Slide 146: 

The cross-reactivity of the enterovirus 71 to human brain tissue and identification of the cross-reactivity related fragments. Jia CS. Liu JN. Li WB. Ma CM. Lin SZ. Hao Y. Gao XZ. Liu XL. Xu YF. Zhang LF. Qin C. Virology Journal. 7:47, 2010.

Taiwan-made enterovirus vaccine could be ready by early 20112010/07/01 : 

Taiwan-made enterovirus vaccine could be ready by early 20112010/07/01 Speaking at a seminar organized by the Centers for Disease Control, Su Ih-jen, deputy head intendent of National Cheng Kung University Hospital, who also headed an EV71 vaccine research team under the National Health Research Institute (NHRI) , said their EV71 (B4) vaccine is expected to be available on a commercial basis in 2011 if the new vaccine passes the human trials which would begin in September 2010.

Slide 148: 

Thank you for your attention