Encéphalites de l’Adulte non immunodéprimé · Encéphalites de l’Adulte non immunodéprimé Bruno Mourvillier Réanimation médicale et Infectieuse GH Bichat Claude Bernard,

Encéphalites de l’Adultenon immunodéprimé

Bruno MourvillierRéanimation médicale et Infectieuse

GH Bichat Claude Bernard, [email protected]

DUCIV2 Février 2016

Encéphalites: points clés1. De quoi parle-t-on?2. Données épidémiologiques récentes3. Algorithme initial4. Traitement initial5. Pathologies auto-immunes: les reconnaître et les

traiter6. Le pronostic

Audrey, 22 ans- 30 octobre 2012: troubles du comportement sans fièvre

- Pas de contexte infectieux dans l’entourage, pas de voyages récents, étudiante en économie

- Examen clinique normal, pas de signes de localisation

- Radio du thorax: normale, ECG normal

- Transfert en psychiatrie après TDM normale

- 3 novembre 2012: 38°C + syndrome méningé: LCR: 10 éléments, prot: 0,12 g/L, sucre: 4,5 mmol/L, ED négatif

- NFS: 8000 GB (70% de PN, pas syndrome monucléosique, Hb: 13g.dL, plaquettes: 220 G/L), PCT: 0,3 ng/L

Q1: Ce cas s’inscrit-il dans le cadre d’une encéphalite?

A. Venkatesan et al. 2013

Encephalites: points clés1. De quoi parle-t-on?2. Données épidémiologiques récentes3. Algorithme initial4. Traitement initial5. Pathologies auto-immunes: les reconnaître et les traiter6. Le pronostic

Q2: le pourcentage de méningo-encéphalites sans étiologie retrouvée est de:

- 10%- 20%- 30%- 50%

Etudes principales

Auteur, pays n %réas Predominants Cause x

Glaser CA et al.2006

1570 58 HSV1, enterovirus, M. pneumoniae

63

Stahl JP et al.2009

253 29 HSV1, VZV, TB 48

Granerod J etal. 2010

203 ?? HSV1, autoimmune 37

Thakur KT et al.2013

103 Tous HSV1, VZV, autoimmune

47

Acute encephalitis in the ICU

CAUSES N = 279INFECTIONS 149(53%)

TB 65 (23%)HSV-1 40 (14%)VZV 14 (5%)Listeria 19 (7%)Other 11 (4%)

IMMUNE-MEDIATED 41 (15%)ADEM 24 (9%)Anti-NMDAR 6 (2%)Other 11 (4%)

UNKNOWN 89 (32%)

BichatMedicalICU1991-2012

RSonneville,EurJNeurol2014

Temporal trends of encephalitis in the ICU

0% 20% 40% 60% 80% 100%

1991-2001

2002-2012

Infections Immune-mediated Undetermined

RSonneville,EurJNeurol2014

20%

Q3: quels examens prescrivez-vous?

CID 2008; 47: 303

63 recommendations



Initial diagnostic algorithm: adults

CSF (20 cc and freeze 5-10cc)

- Gram/cultures

- PCR: HSV/VZV, enterovirus

- Crypto Ag and/or India ink - VDRL

- Oligoclonal bands and IgG index

Serum- Blood cultures

- HIV, syphilis

- Hold serum for antibodies (D1-D10-14)

Imaging- MRI > CT, Chest X-ray and/or CT

- EEG

Other tissues/fluid according to clinical features

(skin biopsy, BAL, throat swab…)


Initial diagnostic algorithm: adultsPCR is the core test

Host factorsImmunocompromised ð opportunistic pathogens (CMV,HHV6/7, Toxo, WNV, fungi…)

Geographical factorsArbovirus+++

Trypanosomiasis

…..

Season and exposure- Tick-borne diseases, Bartonella, Rabies, arbovirus, Naegleria fowleri….

Specific signs and symptomsEx: respiratory symptomsðMycoplasma pneumoniae


N°11: “ MRI is the most sensitive neuroimaging test to evaluate patients with encephalitis” (A-I).

q MRI is more sensitive and specific (vs. CT)

q Diffusion-weighted/FLAIR imaging is superior to conventional MRI for the detection of early signal abnormalities (HSV1, enterovirus, West-Nile)

q Some characteristic neuroimaging patterns have been observed in patients with encephalitis caused by specific agents (HSV, flavivirus, enterovirus)

q ADEM & other immune-mediated encephalitis +++

Tunkel CID 2008

Brain MRI patterns

Normal MRI

Grey matterlesions

White matter lesions

Bilateral TL« Limbic »

INFECTIOUS

IMMUNE-MEDIATED

Causes of acute encephalitis with characteristic radiologic features

Cause Typical MRI patternHSV-1 Inflammatory lesions in temporal lobes,

insula, operculum

VZV Multiple infarctionsIrregularities of arteries

CMV Ventriculitis

Tuberculosis Basilar meningitisHydrocephalusInfarctionTuberculomas

ADEM Bilateral white matter T2-hyperintense lesions

Immune-mediated Normal MRIMesial temporal lobe involvement

Clin Infect Dis 2013;56:825–32

T/BG :41 Other :317 pPediatric (< 18 y)Respiratory virus 18 (44) 67 (12) 0.003West Nile virus 4(10) 3 (1) 0.004

Enterovirus 2 (5) 71 (22) 0.007Adults

Creutzfeld Jacob 6 (35) 17 (5) 0.0004MT 3 (18) 18 (6) 0.08

HSV1 0 49 (16) 0.09

Tunkel Clin Inf Dis 2008

2013

PLEDs

HSV1 encephalitis

Audrey: ondes lentes diffuses « compatibles avec encéphalite »

Q4: quel traitement initial?


Tunkel CID 2008

• La 1ère des encéphalites infectieuses graves en fréquence

• Incidence : 0.2-0.4 cas / 100000

• Pas de « terrain favorisant » le + souvent...

• Répartition bimodale :

< 20 ans

50-70 ans

• Pas de variation saisonnière, sex ratio = 1

• Physiopathologie : Réactivation virus HSV-1 (90%)

M Sabah, BMJ 2012

Méningo-encéphalite herpétique



Autres hypothèses :

•Réactivation dans parenchyme cérébral ?

•Voie olfactive ?

•Primo-infection HSV-1 ?

Réactivation virus HSV-1 (90%) ds gg trigéminé puis transport axonal vers parenchyme (lobe frontaux et temporaux)

184 patients with PCR-proven HSV-1 encephalitis

• Signes neurologiques frustres

• Formes cliniques sans fièvre (10-15%)

• LCR : absence de pléiocytose (10-15%)

• TDM initial normal : 33% des patients avt J7

• PCR HSV négative au début des symptômes

M Sabah, BMJ 2012

I Than, Neurology 2012

• Acyclovir IV : 10 mg/kg/8h IVL (fonction rénale normale)

• Durée ACV : 14 à 21 jours CAR– Existence de rechutes à l’arrêt à J10– Persistence de PCR + au delà de 10 jours chez certains

patients

• PCR de contrôle à l’arrêt du traitement (+++ si évolution clinique imparfaite sur le plan neurologique)

• Pas de bénéfice au traitement d’entretien par valacyclovir en entretien

EncéphaliteHSV-1

AVenkatesan,ClinInfDis2013GnannJWJr,ClinInfDis2015

Adverse outcome at 6-month: 84 adults

Clin Infect Dis 2002

Variables OR CI95% pSAPS2>27 3.7 1.3-10.6 0.014

Admission– ACVRx>2days

3.1 1.1-9.1 0.037

SMALL VESSELMULTIFOCAL

VASCULOPATHY

LARGE VESSELGRANULOMATOUS

ARTERITISMCA ANEURYSM AND SAH

DGilden,LancetNeurol2009

Audrey, 22 ans- 3 novembre 2012: 38°C + syndrome méningé: LCR: 10 éléments, prot: 0,12 g/L, sucre: 4,5 mmol/L, ED et cultures négatives; PCR HSV-, VZV-, CMV-, entérovirus-, BAAR négatifs, VIH -

- 8 novembre : IRM normale

- Transfert en USC à BCB avec GCS: 11, 38°C, mâchonnement

- PL2: 102 GB/mL (90 lymphocytes), prot: 0,80 g/L, sucre: 3,8 mmol/L

- EEG: Tracés d’encéphalite diffuse

Q5: peut-il s’agir d’une encéphalite auto-immune?

Q5: peut-il s’agir d’une encéphalite auto-immune?


FLAIR T1gadolinium

n=153 patients with acute steroïd-refractory CNS inflammatory demyelinating diseases

Clinical Infectious Diseases 2012;54(7):899–904

“Anti-NMDAR encephalitis was identified 4 times as frequently as HSV-1, WNV, or VZV”

* < 30 yrs

*

• AC anti-récepteur NMDA dans le LCR : fortement positifs

• Diagnostic définitif :

Encéphalite auto-immune à anticorps anti-récepteur NMDA(anti-NMDAR encephalitis)

RESULTATS

100 patients

Dalmau Lancet Neurol 2008

Articles

www.thelancet.com/neurology Vol 7 December 2008 1093

access to all the data in the study and had fi nal responsibility for the decision to submit for publication.

ResultsTable 1 summarises the clinical information. 86 patients who could be assessed had headache, low-grade fever, or a non-specifi c viral-like illness within 2 weeks before hospital admission. 77 patients presented with prominent psychiatric symptoms, including anxiety, agitation, bizarre behaviour, delusional or paranoid thoughts, and visual or auditory hallucinations. 23 presented with short-term memory loss or seizures alone or associated with psychiatric manifestations.

During the fi rst 3 weeks of symptom presentation, 76 patients had seizures. 88 patients developed decreased consciousness, progressing to a catatonic-like state, with periods of akinesis alternating with agitation, and diminished or paradoxical responses to stimuli (eg, no response to pain but resisting eye opening). Some patients mumbled unintelligible words or had echolalia. Eye contact or visual tracking was absent or inconsistent. During this clinical stage, large proportions of patients developed dyskinesias, autonomic instability, and central hypoventilation (median time of ventilatory support,

8 weeks; range 2–40 weeks). Orofacial dyskinesias were the most common; these included grimacing, masticatory-like movements, and forceful jaw opening and closing, resulting in lip and tongue injuries or broken teeth. 37 patients had cardiac dysrhythmias, including tachycardia or bradycardia, with prolonged pauses in seven patients; four needed pacemakers. 52 patients had dyskinesias,

Patients

Women and girls 91

Median age, range (years) 23, 5–76

Prodromal symptoms (information available for 84 patients) 72

Symptom presentation

Psychiatric (fi rst seen by psychiatrist) 77

Neuropsychiatric (fi rst seen by neurologists) 23

Seizures

Any type 76

Generalised tonic-clonic 45

Partial complex 10

Other* 30

Dyskinesias and movement disorders

Any type 86

Orofacial 55

Choreoathetoid and complex movements with extremities, abdomen or pelvis

47

Abnormal postures (dystonic, extension), muscle rigidity, or increased tone

47

Other† 25

Autonomic instability‡ 69

Central hypoventilation 66

Data are numbers unless otherwise stated. *Eight secondary generalised seizures, six refractory status epilepticus, seven focal motor, seven not classifi ed, two epilepsia partialis continua. †Nine myoclonus, eight abnormal ocular movements (eye deviation, nystagmus or ocular dipping), fi ve tremor, three ballismus. ‡37 cardiac dysrhythmia (16 tachycardia, seven bradycardia, 14 both); 36 dysthermia (27 hyperthermia, three hypothermia, six both); 21 blood pressure instability (12 hypertension, three hypotension, six both); 20 hyperhydrosis; 18 sialorrhoea; six hyperpnoea; four adynamic ileus.

Table 1: Characteristics and clinical features

Patients

EEG (information for 92 patients)

Total with abnormal fi ndings 92

Slow activity* 71

Epileptic activity 21

Brain MRI


Medial temporal lobes 22

Cerebral cortex 17

Cerebellum 6

Brainstem 6

Basal ganglia 5

Contrast enhancement in cortex, meninges, basal ganglia 14

Other† 8

CSF


Lymphocytic pleocytosis‡ 91

Increased protein concentration§ 32

Oligoclonal bands positive (information for 39 patients) 26

Tumour (information for 98 patients)

All 58

Women

Mature teratoma of the ovary 35

Inmature teratoma of the ovary 14

Radiologically demonstrated teratoma 4

Other¶ 3

Men

Immature teratoma of the testis 1

Small-cell lung cancer 1

Treatment

Tumour resection 51

Immunotherapy 92

Corticosteroids 76

Intravenous immunoglobulin 62

Plasma exchange 34

Rituximab 10

Cyclophosphamide 9

Azathioprine 1

Other|| 10

Only supportive care 2

*EEG delta or theta activity, generalized or in frontotemporal regions. †Other areas of abnormal signal in MRI FLAIR/T2: four corpus callosum, two hypothalamus, one periventricular, one multifocal white-matter change. ‡Median 32 cells/μL, range 5–480 cells/μL. §Median 67 mg/dL, range 49–213 mg/dL. ¶One sex-cord stromal tumour, one neuroendocrine tumour, one teratoma of the mediastinum. ||Seven chemotherapy, three electroconvulsive therapy.

Table 2: Ancillary tests and treatment

Findings of 100 pts with encephalitis and NR1-NR2 antibodies

MRI Normal in 45% of patients

Dalmau Lancet Neurol 2008

Lancet Neurology 2011

Femme jeune+/- associé à tumeur(Tératome ovarien > 50% +++)

IRM PELVIENNE

Lancet Neurology 2011

Titulaer, Lancet Neurol 2013

Lancet Neurol 2013

Lancet Neurol 2013

Encephalites: points clés1. De quoi parle-t-on?2. Données épidémiologiques récentes3. Algorithme initial4. Traitement initial5. Pathologies auto-immunes: les reconnaître et les

traiter6. Le pronostic

Mailles, CID 2012

Encephalitis in ICU patients:outcome

n Mortality Poor outcome*

Sonneville R et al. ESICM 2013

279 47 (17%)(3-month)

24 (10%)

Thakur KT et al. Neurology 2013

103 19 (18%)In-hospital

47 (56%)

* mRS: 3-5

Encephalitis in ICU patients: factors associated with mortality (1)

Thakur KT et al. Neurology 2013

Encephalitis in ICU patients: factors associated with mortality (2)Variables Adj OR 95%CI p

Poor functional status 6.34 1.98-21.75 0.002

Body temperature°C 0.72 0.53-0.97 0.03

Glasgow Coma score < 8 7.09 3.06-17.03 < 0.001

Time between hospital admission and ICU, d

1.04 1.01-1.07 0.008

Aspiration pneumonia 4.02 1.47-11.03 < 0.001

CSF protein, g/L 1.57 1.17-2.11 < 0.001

Sonneville R et al. ESICM 2013

Virus émergents

Virus Zones géographiques

West Nile Monde

Toscana Italie, Espagne, Portugal, France

Encéphalite Japonaise Asie

Entérovirus 71 Asie, Australie

Rage Asie, Afrique, US

Chikungunya Réunion, Inde, Indonésie

Nipah et Hendra Australie, Asie

Lyssavirus Australie, Europe

Figure 1. Approximate Global Distribution of Medically Important Members of the Japanese Encephalitis Serogroup of Flaviviruses.This group consists of St. Louis encephalitis, Japanese encephalitis, Murray Valley encephalitis, and West Nile viruses (including Kunjin virus,which is a subtype of West Nile virus found in Australia).

GE Thwaites, Lancet 2002

TB if score < 4

Conclusions

1. Le diagnostic étiologique des méningo-encéphalites reste un défi

2. Les recommandations et algoritmes récents peuvent nous aider

3. L’IRM est un élément central du diagnostic4. Les encéphalites auto-immunes sont mieux

reconnues et il faut y penser, surtout chez les sujets jeunes

• ENCEPHALITE AIGUË CONFIRMEEsi mise en évidence:

• d’un pathogène pourvoyeur d’encéphalite (histologie, microbiologie, sérologie)

• d’un “contexte dysimmunitaire” associé à encéphalite(examens immunologiques sang, LCR)

• Encéphalite probable sinon ….

A.Venkatesan,ClinInfectDis2013

Encéphalite aiguë

NM Vora, Neurology 2013

é

éSTABLE

263 500 patients

Burden of encephalitis-associatedhospitalisations in the United States,1998-2010

Documents

Encéphalites de l’Adulte non immunodéprimé · Encéphalites de l’Adulte non immunodéprimé Bruno Mourvillier Réanimation médicale et Infectieuse GH Bichat Claude Bernard,