ENCEPHALITIS -

CLINICAL PRESENTATION & INITIAL WORKUP

SYLVIANE DEFRES

CONSULTANT INFECTIOUS DISEASES ROYAL LIVERPOOL UNIVERSITY HOSPITAL,

SENIOR CLINICAL LECTURER UNIVERSITY OF LIVERPOOL & LIVERPOOL SCHOOL OF TROPICAL MEDICINE

ESCMID POSTGRADUATE EDUCATION COURSE

3RD ENCEPHALITIS COURSE - GRENOBLE

Plan • Introduction

• Epidemiology brief

• Clinical presentations

• Management

Introduction

• Meningitis– inflammation of meninges– Fever, headache, vomiting,

photophobia, neck stiffness, • Encephalitis

– viral invasion/inflammation of brain parenchyma

– Fever, behavioral change, ‘psychiatric illness’, confusion, coma, focal signs, convulsions

CNS infections - definitions

•Encephalitis• Strictly pathological diagnosis, inflammation brain parenchyma• Surrogate markers used• Causes: viral, small intracellular bacteria, parasites, immune mediated

•Encephalopathy• Syndrome of altered consciousness• Many cases including infections, metabolic, toxic etc

Pathogenesis & clinical presentation depends on the aetiology, different viruses, autoantibodies

• Best estimate of encephalitis incidence of 5.23 cases/100,000/year

• Incidence could be as high as 8.66 cases/100,000/year.

Causes of encephalitis

Infectious AutoimmunePara-/post Infectious Unknown

Causes of encephalitis

Infectious AutoimmunePara-/post Infectious Unknown

viral

fungal

mycobacterial

bacterial

geographic

parasitic

secondary

Cytokine storm

surface

intracellular

sporadic

Causes of acute viral encephalitis

• Togaviridae– Alphaviruses

• Eastern equine• Western equine• Venezuelan equine• chikingunya

• Flaviviridae• St Louis• Murray Valley• West Nile• Japanese• Dengue• Tick borne• Zika

• Bunyaviridae• La Crosse• Rift Valley• Toscana

• Arenaviridae• Arenavirus

• Lymphocytic choriomeningitis• Machupo• Lassa• Junin

• Picornaviridae• Enteroviruses

• Poliovirus• Coxsackie virus• Echovirus• Parechovirus• Hepatitis A

• Reoviridae• Colorado tick fever

• Rhabdoviridae• Lyssavirus• Rabies

• Retroviridae• Lentivirus

• HIV

• Herpesviridae• Herpes viruses

• HSV type 1 & 2• VZV• Herpes B virus

• EBV• CMV

HHV-6• HHV-7

• Adenoviridae• Adenovirus

• More• More• More

• Arenavirus• Lymphocytic

coriomeningitisMchupo• Lassa• Junn

• Paramyxoviridae– Paramyxovirus

• Mumps

– Morbillivirus

• Measles

• Hendra

• Nipah

• Filoviridae• Ebola

• Marburg

Geographical distributions

Non- viral causes

Viral Encephalitis in England: 1989-1998: What did we miss?Emerging Infectious Diseases 2003: 9:234-240)

0

100

200

300

400

500

600

Exotic Herpes

simplex

Varicella

zoster

Measles Mumps Rubella LCMV Adenoviruses Other Unspecified

viral Infection

%

1989–90

1990–91

1991–92

1992–93

1993–94

1994–95

1995–96

1996–97

1997–98

Viral Encephalitis England 1989-1998.

HPA Encephalitis study

HPA Encephalitis study

• Causes of encephalitis in 203 patients

Cause found in 63% of cases

• 86 (42%, 95% CI 35–49) had infectious causes

– 38 (19%) Herpes simplex virus,

– 10 (5%) varicella zoster virus,

– 10 (5%) Mycobacterium tuberculosis;

• 42 (21%) had immune mediated

– 16 antibody-associated

• 75 (37%, C 30–44) unknown

Mailles et al Encephalitis in France 2007 CID

California

1570 pts with Encephalopathy248 infectious aetiology122 non-infectious cause

170/248 viral aetiology – Enterovirus (43/170 25%, median age 12)HSV 1 (40/170 24%, median age 54)VZV (23/170 14%, median age 44)WNV (19/170 11% median age 66)EBV ( 17/170 10% median age 11)Measles (6/170 4% median age 12)HSV 2 (5/170 3% median age 46)

ENCEPH-UK programme of studies

* Common to both meningitis and encephalitis studies

ENCEPH-UK programme

Adult cohort studies

ENCEPH-UK Retrospective cohort study

ENCEPH-UK Prospective cohort study

Clinical predictors &

clinical outcomes

Quality of Life & Health

economics

End-user experience

Neuropsychological outcomes

Development of

Randomisedcluster trial

Aetiology & Disease

mechanisms

UK-ChiMES (UK Childhood Meningitis &

Encephalitis cohort Study

Meningitis study

Intervention randomised cluster trial

** *

Core Outcomes(encephalitis)

60 hospital sites

29 adults sitesDec 2012 to Dec 2015

31 paediatric sites Jan 2012 to March 2016

ENCEPH UK cohort

65 [28%]

30 [13%]

10 [4%],

61 [26%],

67 [29%],

Encephalitis Final diagnoses

HSV

other viruses

otherorganisms

45% encephalitis infectious 26% autoimmune causes29% remain unknown

233

HSV encephalitis

Infected before adulthood

Mucous membranes Retrograde axonal transport Trigeminal ganglion

Periodic reactivation with antegrade axonal transport

Further retrograde axonal transport OR

Reactivation of latent virus present in the CNS

End user experience - HSV

• Account of diagnosis & treatment from perspective of those affected by condition

• Narratives provide detailed stories

• Diverse data obtained

• analysis focuses around common themes

• 30 narrative interviews patients with HSV encephalitis & carers

End user experience – case vignettes

• ‘Greg’ and ‘Nicola’ • ‘Ben’ and ‘Janet’

• Ben ‘strange symptoms’ out walking, started tripping

• Janet found him slumped > to GP assuming stroke

• Paramedics queried diagnosis & suspected norovirus

• Early hours of morning, Ben felt ‘in cloud cuckoo land’ & ‘didn’t know how to get taxi home’

• Subsequent days Ben was ‘out of it’ and ‘spent much of his time asleep’

• Janet called GP unhappy with lack of improvement: assured would visit next day

• Found Ben collapsed on floor>>ambulance

• Greg felt ‘unwell & wobbly’ on feet

• Nicola took him > GP who > local urgent care unit

• Assessed for stroke, normal CT scan and sent home to wait for ‘urgent’ MRI

• Next day Greg was drowsy, Nicola took him to urgent care again insisting they do something: “he’s not right… I’m not taking him home until you find out what is going on”

The medical history – the detailed story!

• Symptoms – clues, patterns• Duration of symptoms

• Past medical history

• Social history• Including travel

Clinical presentation encephalitis

• Cardinal features• Fever

• Alteration in level of consciousness

• Seizures

• Other symptoms• Headache

• Cognition

• Hallucinations

• Behaviour/personality

• Focal neurology• Age• Immunocompromise• Animals/ vectors/ travel

• Cardinal features

– May not always be present

– Not if brainstem

• Neurotropisms of different viruses

• Extremes of age

Clinical presentation encephalitis

Symptoms

Fever Headache Fatigue

Seizures Decreased consciousness Paralysis

Irritability

Abnormal movements

Clinical presentation - history

• Presenting symptoms• Change in behaviour/ personality/ cognition

• New onset or change in seizures

• Febrile or history of febrile or flu like illness

• Rash

• Headache

• Neck stiffness +/- photophobia

• Abnormal movements

• Hallucinations

• Focal neurological symptoms –dependent on location!

• Seizures• Focal motor

• Non convulsive/ subtle motor

• Refractory to routine Mx

Rhomboencephalitis

• Cranial nerve palsies• Ocular movements

• Facial weakness

• Palate

• Autonomic

• Early respiratory

Pathogens

• Viral• Enteroviruses/ flaviviruses/

alphaviruses

• Bacterial• Listeria/ brucella/ bartonella

• Mycobacterial

• TB (basal meningitis)

• Spirochaetes• Borrelia

• Non infective• Lymphoma/ sarcoid

Vasculitis

• Stroke like presentation• Hemiparesis

• Cortical sensory loss

• Homonymous hemianopia

• Dysphasia

• Timing• At time of presentation or

• During treatment

Pathogens• Viral

• VZV

• Bacterial• Nocardia

• Treponemal• Syphilis

• Mycobacterial• TB

• Angioinvasive fungi• Aspergillus

• Other fungi• Cryptococcus

The story - duration

TBE

More clinical history• Past medical history

• Previous episodes of encephalitis

• Known malignancy

• Known HIV positive

• Previous measles

• Drug History• Include vaccination history

Measles!

Vaccination history!

Past medical history

Past medical history

Measles • Primary measles encephalitis

– Concurrent with measles infection

– 1-3/1000 cases of measles

• Acute post measles encephalitis– Immune mediated, 2-30 days after

– 1/1000

• Measles inclusion body encephalitis– Immunodeficient, persistent virus

– Within 1 year of infection

– 75% mortality

• Subacute sclerosing panencephalitis– 1/25,000 (<1yrs 1/5500)

– Symptoms 6-15 years after infection

Chickenpox/ VZV

• Encephalitis• Concurrent with rash

• Aseptic meningitis

• Cerebellitis• 6-11 days after rash eruption (typically

1 week)

• Vasculitis• Large vessel arteritis, 7 weeks after

zoster)

Clinical presentation – the history continued• Past medical history

• Previous episodes of encephalitis

• Known malignancy

• Known HIV positive

• Previous measles

• Drug History• Include vaccination history

• Social history

– Smoking

– Alcohol

– Drug use

– Sexual history

• Travel History!

Travel history

Travel history

‘TRAVEL’

• T – time of onset

• R – room and board

• A – activities

• V – vaccination and pre travel preparation

• E – exposure

• L – location

Or the 5 (6) ‘W’s

• Where?

• Why? And with whom?

• When?

• What?

• ‘W’accination’s?

Exactly where!

Business, holiday, VFR

Exact dates!

Specific exposures

Vaccinations, malaria prophylaxis, bite prevention, & compliance

Where & exposures

Malaria!World Malaria report 2017

Exposure risks

Sandfly - toscana

Aedes sp– WNV, EEV, zika

Ticks – TBE, Borrelia

Bat - rabies

Cat scratch -bartonella

Kayaking -leptospirosis

Hillwalking - TBE

Unpasteruizedcheese - listeria

Unpasteurized milk - Brucella

Dog bite - rabies

When

Seasons/ events• Meningitis : end of dry season in central Africa/ Hajj

• Dengue: end of rainy season in India

• Falciparum malaria: end of rainy season SSA/ tropics

Incubation periods

• Short <10 days

• Medium 10-21 days

• Long >21 days

Duration in destination/ exposure

• Year round infections• Adenovirus, enteroviruses EBV HSV 1&2 VZV• Bartonella, syphilis

• Winter– Influenza parainfluenza, rotavirus

• Spring summer– Arbovirus – Erhlichia– Rickettsia

Seasons specific to certain countries

Vaccine preventable?

Infection Mortality Morbidity Vaccine preventable

HSV 10-20% ~45-50% no

VZV encephalitis (elderly) 20% 40% Yes

Measles 10-15% in primary 75% in inclusion body100% in SSPE

Further 25% Yes as MMR

Mumps 0.01% 25% Yes as MMR

Rubella 0-50%* 10-20% Yes as MMR

Tick borne encephalitis 0.5-2% European formUp to 35% far Eastern

10%~30%

Yes

Rabies (Lysavirus) 100% Yes

Japanese encephalitis ~25% ~45% Yes

West nile 10-20% 40-50% No

Examination

• Pyrexia • Not always present

• General examn; incl skin! Rashes.• Looking for alternative diagnoses too!

• But non CNS signs may be present in encephalitis too

• CNS• Meningism – may be present

• Kernig’s/ brudzinki’s very limited utility

• Confusion (collateral important/ MMSE and AMT insenstive

• Reduced conscisouness but GCS is insenstive

• Focal signs

• Papilloedema

• Seizures (partial/ GTC)

Rashes

Fundoscopy

Abnormal movements

Abnormal movements

Autoimmune

UK guidelines

Investigations

Investigations – cerebrospinal fluid

Lymphocytes& polymorphonuclear cells

Lymphocytes only

Gram positive cocco bacilli

Appearance Lymphocytes Polymorphs Protein Glucose ratio

Normal values "Gin clear" <5 mm3* nil 0.2-0.4 g/L ~60%

Bacterial meningitis Turbid/purulent ** *** <50%

Viral meningis Clear/turbid (20-300) nil N/ >50%

Fungal meningitis Clear/turbid (20-200) nil N/ N/

Tuberculous meningitis Turbid/viscous (100-500) nil/ <50%

*although up to 50 mm3 are frequently observed in HIV without opportunistic infection **may become lymphocyte predominant after antibiotics***can be several thousand cells/mm3

Two tiered investigations

Two tiered investigations

Sensitivity 96% and the specificity 99% when CSF is studied between 48 h and 10 days from the onset of symptoms

Lakeman &Whitley, 1995 Tebas et al.,1998

An LP within 4 hr is still likely to be positive

Michael BD EMJ 2010

Remember to do an HIV test

• HIV seroconversion meningoencephalitis

• Late infection• Cytomegalovirus

• Epstein Barr virus

• Human herpes virus 6

• JC – progressive multifocal leukoencephalopathy

• Fungi; cryptococcal

Range of HIV sensitivity – screening to diagnosis

Day 1 36 hours later

All encephalitis (203) HSV (38) HSV (65 ENCEPHUK)

CT 51/170 (30%, 23-37) 18/32 (56%, 38-74) 24/58 (42%)

MRI 102/169 (60%, 53–68) 25/28 (89%, 71–98) 48/50 (96%)

CT scan be normal; especially early on

60% bilateral

Neuroimaging

HSV • CT sensitivity 80%

• CT specificity 100%

• MRI sensitivity 81%

• MRI specificity 100%

ADEM• CT sensitivity 0%

• CT specificity 99%

• MRI sensitivity 20%

• MRI specificity 99%

Investigations – MRI scans – clues?

JEV

Bilateral thalami & basal ganglia Rhomboencephalitis

listeriaHSV

Bilateral temporal lobes

Investigations – MRI scans – clues?

JC virus

Progressive Multifocal Leukoencephalopathy (PML)

Cerebellitis

VZVCMV

Ventriculitis

Is EEG useful?

• Typically shows generalised slowing

• May show focal seizures• May show PLEDs (periodic

lateralising epileptiform discharges)

Study in ITU setting (mortality 19.7%)All consecutive acute encephalitis patients 1 or more EEGs103 patients admitted; 76 had EEGs median within 1 day

Normal EEG predicted survival independently from possible confounders

Consensus statement international consortium –case definition

Conclusions

• Many causes of encephalitis! – Overlap of encephalopathy and encephalitis

• Most common sporadic cause = Herpes simplex virus type 1

• Importance of history taking

• Especially social and travel history including vaccinations

• Evidence of encephalitis ie inflammation definitive on brain biopsy– Surrogates of

• Cerebrospinal fluid analysis; confirm inflammation try to identify organism

• Inflammation on brain imaging

• Other tests to identify cause incl. blood tests (PCR & serology tests), EEG, other biopsies

FundersNIHRMRF

University of LiverpoolProf Tom Solomon Ms Hayley Jelleyman Ms Chloe Smith Mr Greg Gibson Mr James McKenna Mr Richard Crew Dr Ruth Backman Dr Jessie Cooper Ms Anna Bridges

Oxford Vaccine groupProf Andrew PollardManish SadaranganiNatalie MartinLouise WillisEmma HarperRebecca BeckleyKelly Fitzgerald Annabel CoxonSimon NadelPaul Heath

University of ManchesterDr Laura Parkes

Kings College LondonProf Michael KopelmanDr Lara HarrisDr Julia Griem

Public Health EnglandDr David BrownDr Julia Granerod

Patients & RelativesPIs/ Nurses /R&D depts

University of ExeterDr Antonieta Medina-Lara

Dr Mike GriffithsDr Rachel KneenDr Ben MichaelMs Claire MatataMs Alison GummeryDr Chris CheyneDr Marta Van de HoekDr Ciara KearnsDr Jessie Cooper

Walton Neuroscience centreDr Kumar DasDr Maneesh BhojakDr Simon Keller

Encephalitis SocietyDr Ava Easton

Rest of steering committee!!

sdefres@Liverpool.ac.uk

Thank you

Some cases

Case 1

• 54M taxi driver• A&E; “general slowness” for 1 week

– 7/7 prior headache & slept for 24hrs– Then c/o of fever, lethargy & anorexia– Became unsteady on feet & talking

“silly”– Day 4 GP diagnosed labyrinthitis– headaches & unsteady, cont slurred

speech

• PMH: Type 2 DM & HTN

• FH: Father ischaemic stroke 68yrs & CABG post MI & Mother angina

• Social history: Smokes 10-15/ day; alcohol rarely

• T 37.6oC, GCS 15/15, HR 58 bpm, BP 132/75 mmHg

• CVS/ RS/GI all normal• Neuro

– slow but normal gait– Slurred speech– Generalised bradykinesia– Cranial nerves normal– Tone, power & reflexes normal all 4

limbs– Coordination deficient upper limbs– 8/10 mental test score

• FBC Ues glucose normal• CRP 28mg/l

CT headArea of hypoattenuation in right frontal & temporal lobes reported as in keeping with acute ischaemia cerebral infarction

Case 1

• Mon am review

• Pyrexial over weekend

• LP performed• opening pressure normal

• WCC 514 x106/l (99% lymphocytes)

• Protein 2.90 g/l

• Glucose 3.1 (serum 6.6 mmol/l)

• MRI performed

• Aciclovir/ amox and gent started day 3• Day 6 less hesitant speech, HSV PCR positive• Aciclovir 14 days IV• Despite treatment, patient remained off work and continues to

have word-finding difficulties & cognitive slowing

Case 2• 54yr F

• Normally fit

• Presented 3 week history nausea, dry mouth night sweats, headache dizziness and metallic taste

• Family report short memory impaired

• PMH nil of note

• Travel: return from south East Asia, no malaria prophylaxis or vaccinations

• Normal routine bloods, CXR

• In AMU tonic clonic seizure, post ictal expressive dysphasia

• LP– WCC 188 (100% Lymphs)

– RCC 366

– Protein 0.66

– glucose 2.7

• Rx aciclovir, doxycycline, ceftriaxone

• Tests – HSV VZV entero parecho all neg

– HIV /syphilis neg

– Culture neg

Case 2

• Day 5 aggressive behaviour & labile mood

• Unresponsive episodes despite antiepileptic med & cont acyclovir

• Rhythmical athetoid movements right arm

• Increasingly confused, MOCA 20/30

• MRI nad

• Symptom onset 16 days after leaving Hong Kong, neurology began on day of admission

• Repeat LP WCC 136 (100%L) prot 0.34

• CRAG neg TB neg cytology nil

• Flavivirus serology neg

Arrived Hong kong 29/12/16

Visited Shensen Ho Chi Minh City Pho Quoc and Mui N (mostly urban)

Departed 15/1/17

Case 2

• Increasing frequency of unresponsive episodes & rhythmical movements

• EEG ‘delta brush’ rhythmical delta activity 1-3 Hz with superimposed activity ‘riding’ on the delta waves

• CT PET

– Left adnexal cyst

– Gynae review unlikely teratoma but will resect given clinical severity of case

• Methylprednisolone

– Within 24 hours dramatic recovery

• Histology: mature cystic teratoma, NMDA receptor antibodies POSITIVE

Case 3• 30 yr Butcher

• 4/7 bifrontal headache, onset after work

• Vomiting fever night sweats

• 2 yrs prior hospitalised ‘viral illness’ spots mouth throat and genital area

• Examn unremarkable except– T 38.6oC

– 2 cm epitrochlear Lymph node

– Area inflamm right 5th digit

• Routine bloods nad

• CRP <5

• Presumptive diagnosis of cat scratch disease

• Plan

– excision biopsy

– Azithromycin

– Bartonella serology

– EBV/CMV/HIV/ Toxo, brucella

Case 3

• EEG nad

• Over 48hours

– More encephalopathic

– More ataxic

– Autonomic features; urinary retention, sleep disturbance

– Speech & swallow declined

• CSF

– HSV 1&2 VZV entero all neg

– No growth

Treatment

• Aciclovir

• Amoxicillin

• Doxycycline & rifampcicin (azith stopped)

• IVIG

Bartonella Ab titres: Evidence of recent Bartonella infection

B.henselae IgM <20, IgG 256B.quintana IgM <20, IgG 256

Bartonella henselae was detected by PCR and speciation confirmed by DNA sequencing (on lymph node biopsy).

Case 3

• Day 5

– Agitated overnight

– Found staggering in corridor

– Profound gait & limb ataxia

– Left facial weakness

– Left sensorineural hearing loss

– Left 6th nerve palsy

• LP

– OP 32cm H20

– WCC 194 (100% L)

– Protein 0.77

– Glucose 3.6/6.3

MRI: subtle area of

hyperintensity at

medullopontine level

Take home messages

• Think of encephalitis! – Not always febrile

– Not always decreased consciousness

– May be subtle cognitive or behavioural

• HSV type 1 commonest form in UK

• Don’t forget travel history

• Urgent investigations– CT head may be normal…. Or even reported as a stroke!

– CSF HSV PCR may be negative early on; if features consistent repeat LP 48 hours

– MRI scan

• High dose IV aciclovir & repeat LP at 14 days

• Dex Enceph!

• Follow-up and support; Encephalitis society