escmid postgraduate education course 3 encephalitis …€¦ · •best estimate of encephalitis...
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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
• 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!!
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