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The Clinical Epidemiology of • Introduction Encephalitis – Brain Infections Group, Institute of Infection & Global Health, Liverpool ESCMID Encephalitis Course 29-30 October 2014 • Epidemiology Professor Tom Solomon – Basic concepts and Ideas Director, Institute of Infection and Global Health, University of Liverpool – Changing epidemiology of encephalitis

Director, NIHR Health Protection Research Unit in Emerging Infections • Some Examples Chair of Neurology, Walton Centre NHS Foundation Trust – Europe Head, Brain Infections Group – Global @RunningMadProf – Illustrative Cases – Our research, and others

Institute of Infection and Global Health Director: Tom Solomon

Department of Department of Clinical Department of Infection Biology Infection, Microbiology Epidemiology and (Head: Jonathan and Immunology Population Health Wastling) (Head: Nigel Cunliffe) (Head: Matthew Baylis)

Improving the health of humans and animals by tackling key infectious disease in both a UK and global context

Health Protection Research Unit in Emerging & Zoonotic Infections Institute of Infection and Global Health Director: Tom Solomon

Department of Department of Clinical Department of Infection Biology Infection, Microbiology Epidemiology and and Immunology Population Health (Head: Jonathan Vector Biology & Pathogen Wastling) (Head: Nigel Cunliffe) (Head: Matthew Baylis) Climate Detection & Modelling Characterisation Understanding how pathogens cause disease – Lead: Aras Kadioglu

Risk Pioneering diagnostics, treatments and vaccines – Lead: Neil French Assessment of Clinical Emerging & HPRU Surveillance Zoonotic Enhancing food safety and food security – Lead: Diana Williams Threats

Tracking emerging and zoonotic infections – Lead: Eric Fevre Epidemiologica l Approaches Research Themes Research Improving the health of pets, working animals and their owners - Lead: Alan Radford NIHR - £3.9M

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HPRU EBOLA WORK Liverpool Brain Infections Group

Neurological NIHR Biomedical Science Research Centre in Microbial Diseases Division of Neuroscience Tropical Child Health Medicine Infectious Diseases

Vector Biology School of Tropical Division of Paediatrics Medicine Medical Microbiology Zoonotic Wellcome Trust Diseases Tropical Medicine School of Virology Biological Veterinary Science Medicine School of Biomedical National Centre for Science £9.4 M (US$ 15.2M) in Zoonotic Diseases c/o Julian Hiscox Research Income

Brain Infections Group Research Disciplines Translation Research Experimental Medicine Applied / Programmatics Pathogenesis Clinical Research Public Health • Molecular Virology • Clinical Epidemiology • With WHO • Inflammation • Diagnostics • Disease burden • Histopathology • Pathophysiology • Education • Disease models • Case management • Vaccine • Treatment trials implementation Research Areas

HIV Brain Disease

Enterovirus 71, Rabies

Jap Enceph, Dengue, West Nile

Dual CNS Infections Herpes encephalitis

Liverpool Brain Infections Group International Collaborations

• University of Oxford-Wellcome Trust Clinical Research Unit, Centre for Tropical Diseases, Ho Chi Minh City (since 1994) • Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand (since 1994) • Institute of Health and Community Medicine, Universiti Malaysia Sarawak, Malaysia (Since 1997) • University of Texas Medical Branch, Galveston, Texas (since 2001) • Queen Elizabeth Hospital, Blantyre, Malawi (since 2003) • National Institute for Mental Health and Neurological Science (NIMHANS), Bangalore, India (since 2004) • Centres for Disease Control Atlanta, and Colorado, Texas (since 2007) • Kanti Children’s Hospital, Kathmandu, Nepal (since 2009) • Indian Institute for Science, Bangalore (2009) • John Hopkins Baltimore, USA (2009) • Washington University St Louis, USA (2009) • Lerner Research Institute, Cleveland, Ohio (2010)

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Epidemiology?

Epidemiology Clinical epidemiology

• “the science that studies the patterns, • The application of the science of causes, and effects of health and disease epidemiology in a clinical setting. conditions in defined populations. Emphasis is on a medically defined • It is the cornerstone of public health, and population, as opposed to statistically informs policy decisions and evidence- formulated disease trends derived from based practice by identifying risk factors examination of larger population for disease and targets for preventive categories. healthcare.”

Life as a virus Epidemiology

• Who gets disease? • How? Why? When? Where? • Any impact of Disease control? – Vaccination? Other?

• Clinical epidemiology • In addition: – how do they present, clinical features? – Diagnostics important, treatment?

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Virus replication (sex) Reproduction

10 genes 24,000 genes

www.accessexcellence.org

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Happy layer of cells Viruses

Hiders and Jumpers

Unhappy dengue virus infected of cells @RunningMadProf Facebook.com/IGHLiverpool

Herpes simplex virus Brain Infections:

• How does pathogen get into the body? • How does it get into the Central Nervous System?

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Jumping Viruses Respiratory

Routes of spread? • Respiratory • Gastrointestinal • Mucosal • Insect-borne • Injections • Congenital (mother to child) • Sexually transmitted

@RunningMadProf Facebook.com/IGHLiverpool eofdreams.com

Gastrointestinal Mucosal

www.motherandbaby.com.au/ funstuffcafe.com

Insect-borne Sexually Transmitted

www.news.liv.ac.uk

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Tropical Viral Infections Definitions • Six questions to get a handle • Pathogen • What is the Natural host? • Where? – Animals (zoonoses) – On Globe – Bacteria, virus, parasite, causing disease – Humans • What disease syndrome? – Unknown – Haemorrhagic (VHF) • Zoonotic Infections • What is the habitat? – FAR (fever arthralgia rash) – Spread from animals to humans – Urban – CNS – Rural – Other • How is it transmitted • Arbovirus infections – Direct • Is there nosocomial – Arthropod-borne viruses, – Arthropod-borne (insects/ticks) spread? – i.e transmitted by insects or ticks (arthopods) – Both

Zoonoses - Infections that spread from animals to humans account for majority of emerging infections Emerging diseases – why?

www.earthintransition.org/

Emerging diseases – why?

• Increasing & more rapid human travel • Overpopulation • Changing agricultural • ?Global warming • Better diagnostics • Better reporting • Greater awareness

Airline Routes – No. Of airlines flying each route

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Ebola risk: direct and indirect flights

Number of bookings departing Direction Bookings CNK, FNA, MLW or ROB June 2014 Outbound 44,652 Inbound 31,026

Other 3,611

USA at greatest risk of importing Ebola

Neuroanatomy • Meningitis What are the key neuroscience – inflammation of meninges – headache, vomiting, photophobia, neck questions? stiffness, Kernig's signs. CSF pleocytosis • How does the pathogen get into the CNS? • Encephalitis – viral invasion/inflammation of brain • How does the pathogen damage neurones? parenchyma – can we do something to stop it? – behavioral change, ‘psychiatric illness’, confusion, coma, focal signs, convulsions • How much does the host response contribute damage? • Myelitis – can we do something to stop it? – spinal cord (anterior horn cells) – flaccid limb paralysis, absent reflexes

How does the pathogen get into the CNS How does the pathogen get into the CNS? Two paradigms Viraemia and spread across the Tracking up a nerve BBB • Herpes simplex virus • Japanese encephalitis virus • Rabies virus • Enterovirus 71

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Viral causes of encephalitis CNS infections Para/Post infectious causes Groups Viruses Bacteria Acute disseminated encephalomyelitis Herpes viruses (family Herpesviridae) Viral illnesses with febrile convulsions Herpes simplex virus type 1 Small bacteria (mostly intracellular) Shigella Herpes simplex virus type 2 Mycoplasma Viral infections associated with swollen fontanelle Varicella zoster virus type 1 Chlamydia Guillain-Barré syndrome Epstein-Barr virus Rickettsia (including scrub typhus, rocky mountain spotted fever) Cytomegalovirus Erlichiosis Non infectious diseases Human herpes virus 6 & 7 Coxiella (Q fever) Vascular Enteroviruses (Family Picornaviridae) Bartonella (Cat Scratch fever) Vasculitis Enterovirus 70 Tropherema whipplei (Whipple's disease) Systemic lupus erythematosis Enterovirus 71 Brucellosis Behcet's disease Typhoid fever Sub-arachnoid & sub-dural haemorrhage Poliovirus Ischaemic cerebrovascular accidents Coxsackieviruses, Echoviruses, Parechovirus Spirochetes Paramyxoviruses (family Paramyxoviridae) Syphilis Neoplastic Measles virus Lyme Neuroborreliosis Primary brain tumour Mumps virus Leptospirosis Metastases Borrelia recurrentis (Relapsing fever) Paraneoplastic limbic encephalitis Others (rarer causes) Influenza viruses, Adenovirus, Parvovirus B19, Lymphocytic choreomeningitis virus, Rubella virus, Other bacteria Metabolic encephalopathy Zoonotic viruses Subacute bacterial endocarditis Hepatic encephalopathy Listeria Renal encephalopathy Rabies, other lyssaviruses Nocardia Hypoglycaemia Nipah virus Actinomycosis Reye's syndrome Arboviruses (most are also zoonotic) Parameningeal infection Toxic encephalopathy (alcohol, drugs) Flaviviruses (family Flaviviridae) Abscess Hashimoto's disease West Nile virus Japanese encephalitis virus Parasites Other Malaria Drug reactions Tick-borne encephalitis Trypanosomiasis Epilepsy Dengue Amoebic encephalitis - Naegleria fowleri Hysteria Alphaviruses (Family Togaviridae) Cysticercosis Voltage gated K channel limbic encephalitis Western, Eastern and Venezuelan Equine encephalitis virus Echinococcus Chikungunya Trichinosis Bunyaviruses Amoebiasis Lacrosse virus Fungi Coltiviruses Cryptococcus Colorado tick fever Candidiasis Non-Viral causes of encephalitis Vesiculoviruses Coccidiomycosis Histoplasmosis Chandipura virus North American blastomycosis and encephalopathy

Epidemiology Epidemiology of encephalitis • Some pathogens constant across globe, – e.g. HSV • Others varies with geography – Esp Arthropod-borne & Zoonotic • HIV and other immunocompromise has changed epidemiology – CMV, EBV, Toxoplasma more important • Vaccination has changed epidemiology in some places – Polio, Measles, Mumps, Japanese encephalitis

Encephalitis Incidence Arboviruses – growing in importance

• West Nile virus in USA and Europe • Tick-borne encephalitis virus in Europe • Dengue and Chikungunya spreading

• Impact of • 12,000 articles screened
87 papers reviewed
– climate change? 25 examined incidence of encephalitis – Changing agricultural practice – People movement – etc Jmor et al 2008

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Incidence of Acute Encephalitis Syndrome (AES) • Case definitions and diagnostic criteria, aetiologies, study types and reliability varied

• Incidence varies with geography, and age • Western industrialised settings, incidences of AES – 10.5–13.8 per 100,000 for children A man that was sleepy – 2.2 per 100,000 for adults • All age groups, incidences of AES – 6.34 per 100,000 tropical settings – 7.4 per 100,000 Western setting.

Jmor et al 2008 t

Mr KR, Hx, Exam

• 52 male, 1 week Hx of What would you do next? • Fever, frontal headache, malaise, lethargic, Sleeping ++ 15 hrs/day • Occ blurring of vision • CT • Poor coordination • Start antibiotics • Hiccoughs 24hrs • No photophobia, No neck stiffness • LP • Mild dry cough, watery diarrhoea, itching after hot bath • 2/12 earlier Scuba Diving in Egypt • Observe • PMHx Hep A 1996 • Malaria film

• O/E • Pyrexial 38.5, NIL else • CXR normal • Na 127 Thoughts & next steps? t t

Similar to this Differential, Progress

• Day 1 DD ?SBE, • Day 3 infective, tropical, • Temp Up, Periph WCC ?underlying malignancy up • Day 5 • Day 2, SHO • Still headache, temp 40, • DD ?Atypical pneumonia voice sl slurred, v sleepy – (chest clear, sats 99%) (haloperidol) • BCs, malaria film, Rx • CT head clarithromycin • Haloperidol for hiccoughs

t Report: Could be infective in nature; t

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• Day 5, 19.00pm LP done • Day 6, 10.30am, results The basics – WCC 220 (lymphocytes), – RCC<4, Protein 1.75, Gluc 2.5 • Encephalopathy – definition • Orientated in T, S & P – Syndrome of Altered consciousness • Await AFB, d/w neurosurgery – Many cases included infections, metabolic, etc • Encephalitis – definition • D7 Repeat bloods – Strictly pathological diagnosis, inflammation brain parenchyma • D8, insuff CSF for TB/AFB – Surrogate markers used – Causes Neurologist called: Imp Meningitis / Encephalitis • Viral, small intracellular bacteria, parasites immune mediated Rx IV Aciclovir, await MRI brain CSF positive by PCR for HSV type 1

t t

Learning Points from this case HSV encephalitis annual incidence • Most studies 2-4 per million, annually • Presentation can be subtle, fluctuant – 1-2 per 250,000, annually • Clues – Each DGH (300,000) 2-3 cases per year – Lethargy Drowsiness, Sleeping 15hrs/day, • USA (Johnstone 1998) Severe Headache, Hiccoughs, SIADH – 2000 annually (population 291 million) • Beware “atypical pneumonia” – 6.9 per million annually • Chase and act on LP result • UK Hospital Statistics (Davison et al EID 2003) – 120-175 cases annually (1989-98) (population 60 million) – 2-3 per million

r

Incidence – Any Viral Encephalitis HSV encephalitis

• Most studies: 5-10 per 100,000 – Expect 3000-6000 annually in UK • Most is HSV type 1 • Average DGH (300,000) – Oral transmission – 15-30 cases per year – 1-2 viral encephalitis per month • About 10% HSV type 2 • UK Hospital Episode Statistics – Genital transmission – 6400 cases of suspected encephalitis in 10 years – 1.5 per 100,000 (under-reporting) – (more often causes meningitis) – 3800 unspecified – 1400 HSV – Causes encephalitis in immunocompromised – 300 VZV adults, and neonates – 64 “exotic” – (measles mumps, rubella, adenovirus, LCMV) – In children
consider for sexual abuse

Beghi 1984 Davison et al EID 2003

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What are the clinical features of Why encephalitis is missed encephalitis? • Wrongly attributing a patient’s fever and confusion • Classically – “urinary tract infection” – “chest infection” – Flu-like prodrome, rapidly followed by severe • Failure to recognise a febrile illness, headache, nausea, vomiting, altered – “afebrile on admission” consciousness, seizures, focal signs, • Ignoring a relative says patient behaviour, “not quite right” – “Glasgow coma score =15” meningism • Wrongly attributing clouding of consciousness • Subtle presentations – “drugs or alcohol” • Failure to properly investigate a patient with a fever and – Low grade fever, behavioural changes, seizure speech and language disturbances • Failure to do a lumbar puncture, even though there are – Especially in immunocompromised no contraindications

New UK guidelines on encephalitis

Management Alogrithm

Understanding and Improving Management Alogrithm the Outcome in Encephalitis

National Institutes for Health Service Research (NIHR) Programme Grant

@RunningMadProf for a copy

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Hospitalisations in England

ENCEPH-UK programme by diagnosis: 1989-1998

Exotic Measles, mumps, 1% UK-ChiMES (UK Childhood Intervention rubella HSV Adult cohort studies Meningitis & Encephalitis randomised cluster cohort Study trial 2% 22%

ENCEPH-UK ENCEPH-UK Retrospective cohort Prospective cohort Meningitis study study study VZV

Clinical 5% Quality of Life Development Aetiology & predictors & End-user Neuropsychological & Health of Randomised Disease clinical experience outcomes economics cluster trial mechanisms Adenoviruses outcomes Unknown * * * 60% 2% Other 8% Common to both meningitis and encephalitis studies * From Davison et al. Emerg Infect Dis. 2003
T

HPA Encephalitis study c/o Julia Granerod, Natasha Crowcroft Encephalitis in the UK Royal Preston Hospital

Hope Hospital Manchester Royal Infirmary Royal Manchester Children’s Hospital Birch Hill Hospital, Rochdale Fairfield General Hospital, Bury North Manchester General Hospital Rochdale Infirmary, Rochdale The Royal Oldham Hospital, Oldham

Alder Hey Children’s Hospital Walton Centre for Neurology & Neurosurgery Royal Liverpool University Hospital Barts & the London University Hospital Aintree Great Ormond Street Guy’s and St. Thomas’ King’s College Hospital National Hospital for Neurology & Neurosurgery Royal Free Hospital North Devon District Hospital, Barnstaple St. George’s Hospital University College Hospital Chelsea & Westminster Hammersmith Hospital St. Mary’s Hospital

Royal Devon and Exeter Hospital Torbay District General Hospital Derriford Hospital

Encephalitis Mimics Causes of encephalitis [No. (%. 95%CI)]

Immunocompetent Immunocompromised Total patients*(n=172) paents†(n=31) Herpes simplex virus 37 (22%, 16–28) 1 (3%, 0·1–17) 38 Acute disseminated 23 (14%, 9–19) .. 23 encephalomyelitis Antibody-associated 15 (9%, 5–14) 1 (3%, 0·1–17) 16 encephalitis Mycobacterium tuberculosis 9 (5%, 2–10) 1 (3%, 0·1–17) 10 Varicella zoster virus 4 (2%, 0·6–6) 6 (19%, 7–37) 10 Streptococci 4 (2%, 0·6–6) .. 4 Enterovirus 3 (2%, 0·4–5) .. 3 Dual finding .. 3 (10%, 2–26) 3 Toxoplasma gondii .. 2 (6%, 1–21) 2 Epstein-Barr virus .. 1 (3%, 0·1–17) 1 Human herpesvirus-6 .. 1 (3%, 0·1–17) 1 HIV .. 1 (3%, 0·1–17) 1 JC virus .. 1 (3%, 0·1–17) 1 Listeria monocytogenes .. 1 (3%, 0·1–17) 1 Pneumococcus .. 1 (3%, 0·1–17) 1 Other‡ 13 (8%, 4–13) .. 13 Unknown 64 (37%, 30–45) 11 (35%, 19–55) 75 Granerod et al, Lancet ID 2010 Granerod et al, Lancet ID 2010

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What are the clinical features of Clinical features [No. (%), 95%CI)] of encephalitis in HPA study

encephalitis? All encephalitis* HSV (n=203) (n=38)

Fever 147 (72, 66–78) 29 (76, 60–89) Headache 122 (60, 53–67) 16 (42, 26–59) Seizures 105 (52, 45–59) 24 (63, 46–78) Lethargy 111 (55, 48–62) 16 (42, 26–59) Irritability 75 (37, 30–44) 11 (29, 15–46) Personality/behavioural change 131 (64, 57–71) 24 (63, 46–78) Stiff neck 46 (23, 17–29) 5 (13, 4–28) Focal neurology 73 (36, 29–43) 16 (42, 26–59) Coma (GCS

Neurologic Complications of the Reactivation of Varicella encephalitis Varicella–Zoster Virus

• Rare • Vasculitis involved in pathology • No evidence but treatment usually with aciclovir & steroids • Varicella may also cause other neurological presentations including para/post infectious cerebellitis, myelitis, stroke

Gilden et al NEJM 2000

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History

• Linh is fourth of 4 children • Linh , 4-year-old in Southern Vietnam • Vaccinated against measles and polio. • Four-day illness. • 2 days High fever, runny nose, cough, and sore • No previous major illnesses throat. • No family history of note. • No vomiting or diarrhoea. • Lived with her parents, siblings and • Day 3 mother bought a mixture of unknown grandparents in a poor area on the edge of Ho drugs at a local store - did not lower the fever. Chi Minh city. • Day 4 Confused, her eyes rolled up, and she had intermittent twitching and spasms in her • Father was a cyclo-driver. face.

Differential diagnosis Examination

• Tmperature was 39°C, pulse 132, respiratory rate 40, blood pressure 110/80. • No rash or lymphadenopathy; • heart sounds were normal, • Bilateral coarse crackles in the chest • Abdominal examination was normal. • Neuro Exam - Signs? • Unconscious • - an abnormal flexion response to pain, • - no eye movements, • - no verbal response to pain. • Continuous twitching - left side of face. • No neck stiffness. • Limbs were flaccid with absent deep tendon reflexes in the legs

Qn 2 List the investigations you Differential diagnosis would do?

• Arboviral encephalomyelitis • Bacterial Meningitis/Abscess • Japanese encephalitis, • TBM other • Cerebral Malaria • Other viral encephalitis • Tetanus • Herpes Simplex Virus 1, • Drugs/Toxins Herpes Zoster Virus, • Secondary Bacterial Enteroviruses Pneumonia • Polio, Rabies • Acute Disseminated encephalomyelitis • Post infectious – measles • Post vaccine

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• CNS (central nervous system) Infections in Asia – What are the causes? – Can we improve diagnosis? – Can we improve outcome?

Japanese encephalitis virus (JEV) INDIA PIC •Flavivirus, Flaviviridae • West Nile virus • Dengue

4 genotypes of JEV recognised Envelope (E) protein important in viral entry into cells

Rey et al, Nature 1994

Japanese encephalitis (JE)

• Thirty-two areas • 70,000 cases/year endemic for JE in 24 • 10-30% mortality Asian and Western Summer Pacific countries epidemics sorted into 10 incidence groups • Approx 67 900 JE cases typically occur annually – 1.8 per 100 000 – 5.4 per 100 000 in • Vaccines Endemic, children – Expensive year round – Not available to most • No antiviral treatment

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Natural History of JEV Fatal disease Japanese encephalitis: CNS infection Epidemiology Asymptomatic / • SE Asia, India, Western Febrile illness • Cycle Pacific, China – Birds->pigs->humans – Summer epidemics in • Vector temperate North – Endemic/sporadic in – Culex tropical South tritaeniorhynchus • Expanding • Mosquito vectors – Culex • Rural/Peri-urban • 40-60,000 cases/year tritaeniorhynchus and others • Virus ubiquitous • children>adults in Asia • Apparent to inapparent • Non immune adults infection: • 1 in 300 infections susceptible – 1 in 25 (service personnel), symptomatic – 1 in 300-1000 (children)

Diagnostic arbovirology Diagnosis

Solomon et al BMJ 2003

Detection of NS1 antigen

JE: Clinical features • Fever, headache, • Outcome coma • Convulsions* – 20% fatal, Clinical – ?subtle motor Sz – 40% sequalae • Raised ICP* – 30% recovery • Polio-like flaccid • Complications * paralysis • ‘Parkinsonism’ – pneumonia Features – malnutrition – mask-like facies – cogwheel rigidity – contractures – tremor – bedsores

* Management

Clinical features represent the anatomical location (Parkinsonism, flaccid paralysis); seizures and raised intracranial pressure may be treatable

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Control of Japanese encephalitis Disease Control

Solomon et al BMJ 2003

Vaccines against JE

Solomon, T Control of Japanese encephalitis – within our grasp? NEJM 2006

• Bulletin WHO 2008

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Road Blocks to Vaccine Implementation

Disease Burden Surveillance Death Recognition Disability Diagnosis Health economics

Demand Vaccination

c/o Dr Pem Namgyal, WHO

The LiverpoolA simOutcome Score - aLOS simple assessment tool for assessing outcome in JapaneseTeam encephalitis assessment

19 million children immunized in India in 2006 Japanese Encephalitis Control Partners

Bill & Melinda CDIBP, China Gates Foundation

National and State Ministries of Health of 25 countries International Pediatric Association

c/o PATH, Seattle c/o Asheena Khalakdina,

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Japanese encephalitis Control Programme: 2005-2013

• Vaccination in in 11 new countries Japanese encephalitis is • More than 200 million vaccinated spreading - why?

• Estimated 854,000 cases and 214,000 deaths avoided • Associated saving US$ 1.024 billion across Asia

@RunningMadProf Facebook.com/IGHLiverpool

Climate Change and Japanese Japanese encephalitis cases – 2004 encephalitis

@RunningMadProf Facebook.com/IGHLiverpool c/o Dr Cyril Caminade

Japanese encephalitis cases – 2005 Japanese encephalitis cases – 2006

c/o Dr Cyril Caminade c/o Dr Cyril Caminade

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Japanese encephalitis cases – 2007

c/o Dr Cyril Caminade

Maximum Parsimony Phylogeny of the Flaviviruses Cell Fusing Agent Apoi

95 Rio Bravo 100 Powassan Langat Louping Ill Tick Borne Encephalitis Yellow Fever Dengue - 4 97 100 Dengue - 2 Dengue - 3 100 Dengue - 1 St Louis encephalitis 100 West Nile Kunjin 100 Murray Valley Encephalitis 500 changes 100 Japanese Encephalitis Solomon, J Neurovirol, 2003

Welcome to Texas

West Nile virus arrives in USA

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• Age-Specific Incidence and Seroprevalence of Japanese Encephalitis in Endemic Areas of Asia and West Nile encephalitis in Nonendemic Areas of Europe.

E 1,3

D 3 C 1,2,3 2,3 F 3 3 2 2 1 1 JEV serogroup 4 JEV serogroup 4 1,2 ancestor 5 ancestor 5 B MVE MVE

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Spread of recent JEV JKT6468 Envelope protein – predicted 3D structure modeled on TBEV [Rey et al, Nature 1995 top view genotypes? using Swissmodel (www.expasy.org/swissmod/)]

E327

Dom III

E38 Dom II Dom I

E399 stem- anchor

Transmission of Japanese encephalitis virus through mosquito vectors

Daniel Impoinvil • Does vector competence differ for different genotypes? • How might climate change affect this? • Can this inform modeling of disease spread?

• Leverhulme Foundation (£750,000) – Matthew Bayliss (Vet School, PI) – Mike Lehane (School of Tropical Medicine)

Dengue Neurological Manifestations of Dengue

• Mosquito-borne flavivirus Solomon et al. Lancet 2000 • 5% of suspected CNS infections Dengue Fever / DHF – – 6 (4.2%) of 378 CNS patients vs. 4 (1.4%) of 286 controls [OR 3.1 (1.7-5.8 • 100 million cases per year p=0.039)]

• Pathophysiology – Encephalopathy as part of severe DHF – Dengue viruses cross blood brain barrier -> ‘encephalitis’

Similar incidence reported in Thailand, India (Chokephaibulkit, K, Paed ID 2002)

Model of flavivirus neurotropism

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Aedes albopictus in Europe 2008 and predicted impact of climate change

• CHIKV in plasma samples of 8 (14%) of 58 children with suspected central nervous system infection in Bellary, India. • CHIKV was also detected in the cerebrospinal fluid of 3 children

Lewthwaite et al, EID 2009

DIAGNOSTICS OF CNS INFECTIONS

Rabies is under-recognised and under-reported Viral Central Nervous System Infections in Children from a Malaria-Endemic Area of Malawi: a Prospective Cohort Study

• 513 children with suspected CNS infection – Excluded bacterial – 94 (18%) died. • 163 (32%) had P. falciparum parasitaemia, of whom 34 died; • 133 (26%) had at least one virus detected in the central nervous system (CNS) by polymerase chain reaction (PCR), with 43 deaths. • Twelve different viruses were detected, – adenovirus most common (42 patients). • 45 (9%) children had both parasitaemia and viral infection; – 27 (35%) of 78 diagnosed clinically with cerebral malaria.

Rabies encephalitis is common in Malawi and can be misdiagnosed as

Cerebral Malaria - Emerging Infectious Diseases 2007, 13: 136-9 Mallewa et al. Lancet Global Health 2013

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Another Case

Ooi et al, Lancet Neurology 2010

Human Enterovirus 71 (HEV71)

• Family Picornaviridae, Genus Enterovirus – Genogroups A, B(1-4), C(1-4) – Human Enterovirus Species A

• Isolated in 1969 California – stool of a child with viral encephalitis – Faeco-oral spread • 1970s-80s Sporadic cases / modest outbreaks (all continents) – 1975 Bulgaria – 1978 Hungary

• Clinically – Hand foot and mouth disease (HFMD) – Neurological disease (aseptic meningitis, encephalitis, paralysis) – Pulmonary oedema

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Brainstem encephalitis in EV71 EV71 outbreaks across Asia

T2 weighted MRI, mid saggital – 1997 • Sarawak – 1998 • Peninsular Malaysia, Singapore; Japan, • Taiwan (Est 1.5 million cases - Huang, NEJM,1999) • Perth – 2000 • Sarawak, Singapore, Korea, Japan, Taiwan, Sydney – 2001 • Taiwan, Sydney

Ooi MH, et al.Clin ID 2003 HFMD admissions, Sibu Hospital, Sarawak

• Emergence of new subgenotypes during outbreaks Genogroup analysis for the HEV-71 patients

• 68 Genogroup B4 • 68 Genogroup C1 • 41 Genogroup B5 (newly emerged)

• Genogroups of HEV-71 differ in their virulence

Ooi MH, et al. Human enterovirus 71 disease in Sarawak, Malaysia: a prospective clinical, virological, and molecular epidemiological study. Clin Infect Dis. 2007 Mar 1;44(5):646-56.

Funding

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@RunningMadProf Liverpool Neurological Infectious Diseases Course Liverpool Medical Institution • -YouTube Channel: Tom Solomon – “Sex Drugs & Emerging Viruses” – Does Liverpool Have the World’s Biggest Brain?

Feedback from previous courses: “Would unreservedly recommend to others” “An excellent 2 days!! The best course for a long time” Convenors: Prof Tom Solomon, Enitan Carrol, Rachel Kneen & Dr Nick Beeching www.liv.ac.uk/neuroidcourse email [email protected] @RunningMadProf Facebook.com/RunningMadProf

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