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
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
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…)
A. Venkatesan et al. 2013
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
A. Venkatesan et al. 2013
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?
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
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
Méningo-encéphalite herpétique
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?
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
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
Total with abnormal fi ndings 55
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
Total with abnormal fi ndings 95
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