Meningitis and Encephalitis: Diagnostic and … broad differential diagnosis (>100 causes) ......

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Meningitis and Encephalitis: Diagnostic

and Management Challenges

October 28th, 2017

Infectious Diseases update 2017

Rodrigo Hasbun, MD MPH FIDSA

UT Health Medical School

Professor of Medicine

Section of Infectious Diseases

Objectives & Disclosures

� Objectives

� 1) Discuss the management dilemmas in community-

acquired meningitis syndromes.

� 2) Describe the current utilization of cranial imaging and

adjunctive dexamethasone in the US.

� 3) Explore novel technologies and clinical models that

could aid physicians in their management of CNS

infections.

� Disclosures: Biomeriaux, Biofire Diagnostics.

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� 37 Hospitals in 20 countries from 2012-2014

� 1504 out of 2583 (58%) of all CNS infections had

unknown etiologies

Aseptic Meningitis

(Wallgren 1925)

� Acute community-acquired syndrome

� with cerebrospinal fluid (CSF) pleocytosis

� in the absence of a positive Gram stain and

culture, without a parameningeal focus or a

systemic illness,

� and with a good clinical outcome

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Meningitis with a negative Gram stain is

seen in 94% of patients with CAM.

➤➤➤➤Physician Uncertainty

�A broad differential diagnosis (>100 causes)

�An increasing immunosuppressedpopulation

�Relative lack of experience of physicians with bacterial meningitis

�Lack of recent prospective clinical studies documenting the actual proportion of treatable etiologies

�The majority have unidentified etiologies

.

Hasbun R. Curr Inf Dis Rep 2000, 2:345-351

Solutions

1. To derive and validate a clinical models that identifies a subgroup of patients with meningitis and a negative Gram stain who are at low risk of having an adverse clinical outcome and for an urgent treatable cause.

2. Explore novel molecular diagnostic techniques3. Standardize diagnostic algorithms

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Risk Scores in adults with meningitis with

negative Gram stain

� Low risk (<1%) for an adverse clinical outcome in 567

adults if age <60, normal neuro exam and CSF glucose

>45. (Khoury et al. Mayo Clin Proc. 2012 Dec;87(12):1181-8)

� Zero risk (0%) for an urgent treatable etiology in 960

adults if immunocompetent, normal neuro exam and

CSF glucose>45, CSF protein <100 and Serum WBC

<12K. (Hasbun R, et al. Journal of Infection 2013; 67, 102-110)

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Pros and Cons of Film Array

Pros

• Rapid, easy to do, excellent diagnostic accuracy, small sample size (0.2ul), checks for urgent etiologies and etiologies that can help discharge the patient.

• Only multiplex Meningitis Encephalitis panel

Cons

• Does not check for West Nile virus, TB, travel related pathogens (Zika, Toscana, Chickengunyan)

• False positive with S. pneumoniae

� Advantages

� Unbiased

� Rapid

� CSF or brain tissue

� Disadvantages

� Cost

� Contamination and

latent organisms

� Availability

Next-generation

Sequencing

Samia N. Naccache et al. Clin Infect Dis. 2015;60:919-923

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Clinical CourseNext-generation

sequencing

Wilson MR et al. NEJM 2014;370:2408-2417

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Encephalitis

� HSV1, VZV, CMV, HHSV-6

� WEST NILE VIRUS (JUNE-OCTOBER)

� ANTIBODY ASSOCIATED (NMDA.VGKC)

� ACUTE DISSEMINATED ENCEPHALOMYELITIS.

Causes of encephalitis and differences in their clinicalpresentations in England: a multicentre, population-basedprospective study Julia Granerod,et al Lancet Infect Dis 2010.

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Date of admission WNV (June to October) 1 wk later

� 86% of encephalitis cases, 25% of meningitis, and 20% fever cases had

abnormal neurological exams after acute infection

� Anomalies: abnormal motor strength, vibratory sensory loss, tandem gait and

balance abnormalities, hearing loss, and postural or intention/action tremors

� 63% of encephalitis cases had impaired tandem gait, suggesting vestibular-

cerebellar and/or dorsal column dysfunction

� At the time of the second assessment 7 years later, 57% of WNF, 33% of

WNM, and 36% of WNE had developed new neurological complications.

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Out of 111 patients, 27 (24%) had evidence for West Nile virus associated retinopathy

(WNVR); this observation was higher (49%) in those patients who initially presented with

encephalitis.

Individuals with WNVR had more frequent involvement of the macula and peripheral

involvement compared to those patients without WNVR (p<0.05).

Fig 1. Severe retinopathy seen in four patients with history of West Nile virus infection.

Hasbun R, Garcia MN, Kellaway J, Baker L, Salazar L, et al. (2016) West Nile Virus Retinopathy and Associations with Long Term

Neurological and Neurocognitive Sequelae. PLOS ONE 11(3): e0148898. https://doi.org/10.1371/journal.pone.0148898

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0148898

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Table 3. Neurocognition, fatigue, depression and activities of daily living in WNV retinopathy.




Table 4. Bivariate analyses and Logistic Regression Analysis of Factors Associated with WNV

Retinopathy.




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Herpes encephalitis

� Most common causes of

endemic encephalitis in the

US

� Treatable causes of

encephalitis

� Untreated: Mortality

>70%

� Acyclovir treatment:

Mortality 14-19%,

Sequelae in ~50%

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Adjunctive Valacyclovir for HSE

� Outcome:

� Primary: Mattis Dementia rating

scale (MDRS) at 12 months

� No difference in primary or 2ndary

outcomes

Gnann JW et al. Clin Infect Dis 2015;61:683-691.

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The frequency of autoimmune N-methyl-D-aspartate receptor encephalitis

surpasses that of individual viral etiologies in young individuals enrolled in

the California Encephalitis Project.

Gable MS, Sheriff H, Dalmau J, Tilley DH, Glaser CA.Clin Infect Dis. 2012 Apr;54(7):899-904.

� 65% of anti-NMDAR encephalitis occurred in patients

aged <18 years.

� This disorder demonstrated a predilection for females,

seizures, language dysfunction, psychosis, and EEG

abnormalities more frequent in patients with anti-

NMDAR encephalitis and autonomic instability

(P<0.05) c/w viral etiologies.

Anti-NMDAR Encephalitis Following HSE

and with VZV

� 2007-Anti-NMDAR

encephalitis first described

� 2013-report of anti-

NMDAR encephalitis

following HSE

� 2016- two cases described

with concomitant VZV

Armangue T, et al Ann Neurol. 2014 Feb;75(2):317-23

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Suspected Meningitis: Role of cranial imaging

CT of the Head before LP in Adults with Suspected Meningitis

Hasbun, Abrahams, Jekel, Quagliarello N Engl J Med 2001; 345:1727-1733

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IDSA Practice Guidelinesfor the Managementof BacterialMeningitisClin Infec Dis 2004;39:1267-1284

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The WHO reports that as of June 2015, over 220 million persons aged 1 to 29 years have

received meningococcal A conjugate vaccine in 15 countries of the African belt.

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Bacterial Meningitis: Mortality

& Antibiotics

Swartz MN. Bacterial meningitis-a view of the past 90 years. N Engl J Med. 2004 Oct 28;351(18):1826-8

Mo

rtali

ty (

%)

S. pneumoniae

N. meningitidis

H. influenzae

Adjunctive dexamethasone� Steroids are the only adjunctive therapy shown to decrease

mortality and hearing loss in high income countries.1,2

� In a European multicenter study, overall mortality decreased from 15% to 7%.3

� In patients with pneumococcal meningitis, mortality decreased from 34% to 14%.3

2M. Glimåker et al. Clinical Microbiology and Infection, 2016

3J.De Gans et al. N Engl J Med, 2002

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� Adjunctive dexamethasone, given 10-20 minutes prior or concomitantly with antibiotics, was endorsed by IDSA in 2004.1,2

� The Swedish and the UK guidelines also recommend adjunctive steroids in their national guidelines.2,3

� The European Society of Infectious Disease recommends that adjunctive dexamethasone can be given up to 4 hours after receiving antibiotics (based on expert opinion)3

1 R. Lopez Castelblanco et al. The Lancet Infectious Disease, 20142A. R. Tunkel et al. IDSA guidelines for Management of Bacterial Meningitis, 20043 D. van de Beek et al. ESCMID guideline: Diagnosis and Treatment of Acute Bacterial Meningitis, 2016

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Netherlands1 Sweden2 Denmark3 USA4

Studyduration

2006-2014 1995-2014 2003-2010 2011-2014

Number of patients

1391 1746 147 3692

Overall Steroid use

(%)

89% 56.6% 73%* 30.36%

Steroids ** 78% unk unk unk

1M. Bijlsma et al. The Lancer Infectious Disease, 2016

**steroids given before of with first dose of antibiotics

2M. Glimåker, Clinical Microbiology and Infection, 2016

4Hasbun et al, Clinical Infectious Disease 2017

3G Baunbæk-Knudsen, Infectious Diseases 2016

*steroids given within 1 hour

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Concerns with use of steroids� Can adequate levels of vancomycin in CSF be obtained in those

treated with steroids? Yes1

� Increased hippocampal apoptosis in rats. On autopsy, no difference was seen in patients who had received dexamethasone and those who did not.2

� Delayed cerebral thrombosis (DCT)

� One study found a 1% incidence of DCT.3

� Possible mechanisms include increased C5a and C5b-9 levels in CSF and increased tissue factor/factor VII pathway3,4

1 J.D Ricard et al, Clinical Infectious Disease 2007

3 M. J. Lucas et al, Intensive Care Med, 20134E.S. Schut et al, Neurology 2009

2 J.Y Engelen-Lee et al Acta Neuropathologica Communications, 2016

Results

� 48 out of 120 (40%) patients were given steroids within 4 hours of antibiotic administration.

� 17 out of 120 (14.1%) received steroids 10-20 minutes prior or at the same time as antibiotics as per the IDSA 2004 guidelines.

� The median duration of steroids was 4 days.

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Delayed Cerebral Thrombosis (DCT)

� DCT was seen in 5/120 (4.1%) of our patients

� S pneumoniae (3), MRSA (1), Listeria (1).

� 5/5 (100%) of patients with DCT and 43/115 (37.4%) of patients without DCT received steroids within 4 hours of antibiotics. p= 0.01.

� 4/5 patients had an adverse clinical outcome with 2 deaths.

ID Week 2017

ID Week 2017

Patient 1 Patient 2 Patient 3 Patient 4 Patient 5

Sex Female Male Male Female Male

Age 49 63 26 69 31

Organism Streptococcus

pneumoniae

Streptococcus

pneumoniae

Streptococcus

pneumoniae

MRSA Listeria

monocytogenes

Steroids Dexamethasone Dexamethasone/Methylprednisolone

Dexamethasone Dexamethasone Dexamethasone

Timing of thrombosis (days)

12 7 10 5 12

Initial Imaging CT and MRI without evidence of infarction

CT- No acute abnormalities.Encephalomalacia

CT- cerebral edema with no evidence of ischemia

CT and MRI without acuteabnormalities

MRI without evidence ofinfarction

Repeat Imaging MRI- Left frontal cortical vein thrombosis

MRI- multiple acute infarcts in bilateral hemispheres

MRI- multiple acute infarcts in left hemisphere and brain stem

MRI- acute stroke in caudate and anterior internal capsule

Left occipital lobe infarct

Outcome 5 (normal)

1 (death)

3 (severe disability)

1 (death)

4 (moderatedisability)

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Suspect meningitis in patients with recent neuro-

surgical procedures with new fever, headache,

altered mental status, meningismus, seizures

CSF Profile may be unreliable (e.g., chemical

meningitis)

CSF lactate and procalcitonin level may help

Empiric therapy should be vancomycin and

antipseudomonal cephalosporin/meropenem

Intrathecal therapy should be used for patients

not responding to IV therapy

Removal of devices are very important.

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Open Forum

ID 2016

Limitations of using the CSF

lactate levels

� the high proportion of antibiotic exposure before the

CSF analysis rendering cultures negative (>50%)

� the wide range of values in patients with proven health

care-associated meningitis (1– 22.8 mmol/L)

� ∼50 % of patients get a CSF lactate drawn in clinical

practice (Srihawan et al OFID 2016)

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Removal of devices

� Removal of the infected CSF shunt, external ventricular

drain, intrathecal infusion pump, or deep brain stimulator

with re-implantation of the device once repeat negative

CSF cultures is key.

� In CSF shunt infections, lack of removal of the shunt is

associated with a successful outcome only in 35 % of

patients with high mortality, immediate shunt removal and

reinsertion in 65–75 %, and shunt removal with a delayed

reimplementation in more than 85 % of patients. (J Hosp

Infect. 2016;93(4):323–8)

OFID 2016

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This study included 120 patients with ICH; 40 patients also had HCAMV,

whereas 80 patients had ICH with no evidence of HCAMV.

Meningitis and Encephalitis: Diagnostic and … broad differential diagnosis (>100 causes) ......

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