Meningitis and Encephalitis: Diagnostic and Management Challenges October 28 th, 2017 Infectious Diseases update 2017 Rodrigo Hasbun, MD MPH FIDSA UT Health Medical School Professor of Medicine Section of Infectious Diseases Objectives Objectives & Disclosures 1) Discuss the management dilemmas in communityacquired 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. 1
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 parameningealfocus or a systemic illness, and with a good clinical outcome 2
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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 immunosuppressed population 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. HasbunR. CurrInf 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 techniques 3. Standardize diagnostic algorithms 5
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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 neuroexam 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 neuroexam and CSF glucose>45, CSF protein <100 and Serum WBC <12K. (Hasbun R, et al. Journal of Infection 2013; 67, 102-110) 8
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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 Next-generation Sequencing Advantages Unbiased Rapid CSF or brain tissue Disadvantages Cost Contamination and latent organisms Availability Samia N. Naccache et al. Clin Infect Dis. 2015;60:919-923 10
Clinical Course Next-generation sequencing Wilson MR et al. NEJM 2014;370:2408-2417 11
Encephalitis HSV 1, VZV, CMV, HHSV-6 WEST NILE VIRUS (JUNE-OCTOBER) ANTIBODY ASSOCIATED (NMDA.VGKC) ACUTE DISSEMINATED ENCEPHALOMYELITIS. Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study Julia Granerod,et al Lancet Infect Dis 2010. 12
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 vestibularcerebellar 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. 13
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 14
Table 3. Neurocognition, fatigue, depression and activities of daily living in WNV retinopathy. 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 Table 4. Bivariate analyses and Logistic Regression Analysis of Factors Associated with WNV Retinopathy. 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 15
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% 16
Adjunctive Valacyclovir for HSE Outcome: Primary: MattisDementia rating scale (MDRS) at 12 months No difference in primary or 2ndary outcomes Gnann JW et al. Clin Infect Dis 2015;61:683-691. 17
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 predilectionfor 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 18
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 19
IDSA Practice Guidelines for the Management of Bacterial Meningitis Clin Infec Dis 2004;39:1267-1284 20
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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. 22
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Bacterial Meningitis: Mortality & Antibiotics Mortality (%) S. pneumoniae N. meningitidis H. influenzae Swartz MN. Bacterial meningitis-a view of the past 90 years. N Engl J Med. 2004 Oct 28;351(18):1826-8 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 2 M. Glimåker et al. Clinical Microbiology and Infection, 2016 3 J.De Gans et al. N Engl J Med, 2002 24
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, 2014 2 A. R. Tunkel et al. IDSA guidelines for Management of Bacterial Meningitis, 2004 3 D. van de Beek et al. ESCMID guideline: Diagnosis and Treatment of Acute Bacterial Meningitis, 2016 25
Netherlands 1 Sweden 2 Denmark 3 USA 4 Study duration Number of patients Overall Steroid use (%) 2006-2014 1995-2014 2003-2010 2011-2014 1391 1746 147 3692 89% 56.6% 73% * 30.36% Steroids ** 78% unk unk unk * steroids given within 1 hour ** steroids given before of with first dose of antibiotics 1 M. Bijlsma et al. The Lancer Infectious Disease, 2016 2 M. Glimåker, Clinical Microbiology and Infection, 2016 3 G Baunbæk-Knudsen, Infectious Diseases 2016 4 Hasbun et al, Clinical Infectious Disease 2017 26
Concerns with use of steroids Can adequate levels of vancomycin in CSF be obtained in those treated with steroids? Yes 1 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 pathway 3,4 1 J.D Ricard et al, Clinical Infectious Disease 2007 2 J.Y Engelen-Lee et al Acta Neuropathologica Communications, 2016 3 M. J. Lucas et al, Intensive Care Med, 2013 4 E.S. Schut et al, Neurology 2009 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. 27
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 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) Initial Imaging Repeat Imaging 12 7 10 5 12 CT and MRI without evidence of infarction MRI- Left frontal cortical vein thrombosis Outcome 5 (normal) CT- No acute abnormalities. Encephalomalacia MRI- multiple acute infarcts in bilateral hemispheres 1 (death) CT- cerebral edema with no evidence of ischemia MRI- multiple acute infarcts in left hemisphere and brain stem 3 (severe disability) CT and MRI without acute abnormalities MRI- acute stroke in caudate and anterior internal capsule 1 (death) MRI without evidence of infarction Left occipital lobe infarct 4 (moderate disability) ID Week 2017 28
Suspect meningitis in patients with recent neurosurgical 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. 29
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) 30
Removal of devices Removal of the infected CSF shunt, external ventricular drain, intrathecalinfusion 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 31
This study included 120 patients with ICH; 40 patients also had HCAMV, whereas 80 patients had ICH with no evidence of HCAMV. 32