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Cerebrospinal fluid metabolites as biomarkers to distinguish between viral and autoimmune encephalitis

Cerebrospinal fluid metabolites as biomarkers to distinguish between viral and autoimmune encephalitis

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Cerebrospinal fluid metabolites as biomarkers to distinguish between viral and autoimmune encephalitis

  1. 1. Amani Al-Mekhlafi PhD student Magdeburg, 27.09.2019 Cerebrospinal fluid metabolites as biomarkers to distinguish between viral and autoimmune encephalitis MHH: Martin Stangel, Kurt-Wolfram Sühs (Dept. of Neurology), Volkhard Kaever (Emeritus, Research Core Unit Metabolomics) TWINCORE: Maike Kuhn, Frank Pessler HZI: Frank Klawonn
  2. 2. AGENDA • Introduction • Aims • Study Cohort • Results • Next step
  3. 3. Page 3 | Viral vs. autoimmune CNS disorders . Viral meningitis/encephalitisAutoimmune neuroinflammation CMV HSV Enteroviruses Anti-NMDA-r encephalitis Multiple Sclerosis
  4. 4. Clinical challenge: similar presentation – different treatments Name der PräsentationSeite 4 | Altered mental status, focal neurological deficits, seizures Mild neuroinflammation Mild-to-moderate disruption of blood-CSF-barrier Non-specific changes on imaging (MRI) Antivirals (if available for pathogen) Immunosuppression Plasmapheresis B cell depletion Viral Autoimmune Pathogen detection (PCR, etc.) Autoantibody detection
  5. 5. CSF Analysis Seite 5 | Deisenhammer et al. Routine cerebrospinal fluid (CSF) analysis ,2011
  6. 6. Aims • To identify candidate biomarkers that can accurately differentiate between viral and autoimmune encephalitis and could potentially be developed into a rapid (bedside) diagnostic • Comparison with standard diagnostic parameters (CSF leukocytes, etc.) Name der PräsentationSeite 6 |
  7. 7. Study Cohort Six patient groups Name der PräsentationSeite 7 | Total n= 79
  8. 8. Biomaterial: cerebrospinal fluid (CSF) Name der PräsentationSeite 8 | 1-2 h Storage Sample collection Centrifugation Clinical diagnostics Cells Supernatant
  9. 9. Targeted metabolomic profiling Biocrates AbsoluteIDQ® p180 Kit Name der PräsentationSeite 9 | • Mass spectrometry-based assay for biological tissues and fluids, including CSF • 96-well format www.biocrates.com, www.sciex.com API4000 Triple-Quadrupol-MS (RCU Metabolomics, MHH) Maike Kuhn
  10. 10. Detectable metabolites Name der PräsentationSeite 10 | Jones et al., Progress in Lipid Research 2010, Commons.wikimedia.org, vinmetrica.com, eichler.mgh.harvard.edu Total n= 188
  11. 11. Name der PräsentationSeite 11 |
  12. 12. Results Name der PräsentationSeite 12 |
  13. 13. HAUCA Curve Indicates how much the correlation between the biomarker and the disease exceed the pure random effect. Name der PräsentationSeite 13 | 108 15 13
  14. 14. Standard parameter analysis MS NMDA Ent. men HSV Z.men_enc Chi-square P vlaue Kruskal-Wallis test P value Demographic Age (Year) Mean(sd) 38(11.6) 38(20.5) 41(19.4) 58(16.4) 53(21) 0.04 Median(range) 33(23-58) 30(19-69) 33(22-76) 56(29-76) 55(13-80) Gender male 53% 13% 60% 78% 60% 0.14 female 47% 87% 40% 22% 40% Blood Parameter Leukocytes count 1000/µl Mean(sd) 7.9(3.7) 6.3(2.7) 7.5(3.0) 8.5(4) 7.8(3.3) 0.84 Median(range) 6.5(2.8-18.2) 6.4(2.1-9.7) 7.3(4-14) 10.1(1.8-12.8) 6.9(3.8-13.6) C-reactive Protien mg/l Mean(sd) 3.2(5.4) 13.01(12.9) 9.3(12.3) 22.1(37.3) 13.6(32.3) 0.14 Median(range) 1(1-23) 11.2(1-37) 4(1-39) 3(1-102) 2 (1-128) CSF Parameter Leukocytes count 1/µl Mean(sd) 10.6(11.6) 49.6(61.04) 129.1(235.3) 187.5(233.4) 199.8(400.2) 0.002 Median(range) 7.7(.7-48) 22.4(1.7-172) 9.2(.7-619) 90.7(16-723) 38(1.7-1536) Qalb Mean(sd) 6.3(1.8) 17.2(15.01) 9.5(5) 26.8(13.5) 14.9(9.9) 1.78e-05 Median(range) 6.2(2.5-9.6) 8.7(6.2-41.1) 8.9(2.7-21.7) 31.8(6.8-44.4) 11.4(4.5-41.1) Blood-CSF-barrier disruption no disruption(1) 53% 75% 20% 11% 20% 0.0005 Light(2) 47% 25% 70% 11% 40% Moderate(3) 0% 0% 10% 11% 27% Sever(4) 0% 0% 0% 67% 13% Protein_concentration g/l Mean(sd) .48(0.11) .45(0.2) .57(.21) 1.3(.62) 0.82(.49) 0.0005 Median(range) .49(0.31-0.66) .42(0.2-0.9) .52(.24-.98) 1.2(.52-2.3) 0.65(0.31-2.05) Lactate mmol/L Mean(sd) 1.8(0.42) 2.1(0.4) 2.1(.62) 2.5(.54) 2.8(1.1) 0.003 Median(range) 1.6(1.3-2.4) 2.2(1.4-2.6) 1.9(1.6-3.6) 2.3(1.8-3.4) 2.6(1.5-5.5) Q_IgG Mean(sd) 6.3(3.7) 8.2(5.2) 5.2(3.3) 23.4(16.7) 9.1(5.2) 0.004 Median(range) 4.8(1.6-13.2) 7.95(1.6-14.9) 5(1.3-13.6) 19.6(4.5-58.4) 8.5(3.2-21.1) IgG_Index Mean(sd) 1.03(.64) 1.1(0.71) .53(.05) .82(.24) 0.63(.17) 0.0002 Median(range) 0.79 (.55-.2.9) 0.71(0.5-2.4) .53(.47-.63) .76(.5-1.3) 0.57(0.5-1.2) Name der PräsentationSeite 14 | Qalb MS NMDA Ent.men HSV Z.men_enc Kruskal-Wallis test Mean 6.3 17.2 9.5 26.8 14.9 1.78e-5 Median 6.2 8.7 8.9 31.8 11.4
  15. 15. First look at biomarker potential – a shimmer of hope Name der PräsentationSeite 15 | Autoimmune Viral Metabolites Lipids Amino acids Standard parameters
  16. 16. Changes in CSF lipids contribute the most to differences Name der PräsentationSeite 16 | Metabolites Standard parameters
  17. 17. CSF metabolites are more accurate biomarkers than standard diagnostic CSF parameters for the distinction between viral and autoimmune neuroinflammation Name der PräsentationSeite 17 | Standard CSF Parameter AUC Metabolites AUC Selection frequency Q-albumin 0.86*** C5 0.93*** 1 Leukocyte count 0.74** PC.aa.C30.0 0.92*** 1 Protein concentration 0.78*** PC.ae.C32.2 0.92*** 1 IgG-index 0.76*** C4 0.92*** 1 Lactate 0.74** SM.C16.0 0.91*** 1 BCB dysfunction 0.79*** PC.aa.C38.0 0.90*** 1 AUC0.5 1.0 Receiver operating characteristic (ROC) curve analysis perfect biomarkerworthless
  18. 18. Highest CSF concentrations of C5 and C4 in herpes virus infection Name der PräsentationSeite 18 | C5 & C4 C5 C4
  19. 19. Name der PräsentationSeite 19 | Comparison Q-albumin C5 C4 HSV vs. autoimmune 0.94*** 0.98*** 0.99*** VZV vs. autoimmune 0.89*** 0.95*** 0.92*** Enterovirus vs. autoimmune 0.76*** 0.92*** 0.92*** C5 and C4 are the most accurate biomarkers for CNS infection by all three viral pathogens
  20. 20. Sensitivity, specificity and predictive values Sensitivity Specificity PPV NPV C5 0.879 0.845 0.807 0.904 C4 0.752 0.785 0.720 0.812 Q-albumine 0.483 0.637 0.502 0.619 Name der PräsentationSeite 20 |
  21. 21. Virus-induced mitochondrial dysfunction? Name der PräsentationSeite 21 | Beta-oxidation ATP
  22. 22. Summary • Acylcarnitines C5 and C4 are highly accurate CSF biomarkers to distinguish between viral and autoimmune neuroinflammation Name der PräsentationSeite 22 |
  23. 23. Next Steps • Validation in larger cohorts needed • ?Virus-induced dysregulation of mitochondrial function ? Name der PräsentationSeite 23 |
  24. 24. Acknowledgement Name der PräsentationSeite 24 | Core Unit Metabolomics Volkhard Kaever Annette Garbe Clinic for Neurology Martin Stangel Kurt-Wolfram Sühs & colleagues MHH - Junge Akademie Maike Kuhn Frank Pessler Frank Klawonn
  25. 25. Magdeburg, 27.09.2019 Thank you for your attention

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