ID Encephalitis journal club aug8_OB.pptx

ID Encephalitis journal club aug8_OB.pptx

1. Journal Club Omrao Bawa ID Fellow (PGY-4)

2. 32 yo woman with past h/ meningitis 2 years ago with 2 days fever, HA Brought by family to ER noting she has been “confused” for almost 2 days Saying inaccurate things, not sure where she is, repeating herself and lethargic ER doctor suspects meningitis and starts: ceftriaxone, vancomycin, dexamethasone, acyclovir Orders LP, done 24 hours later After LP, ID consulted LP finally done, shows 0 WBC; protein 50; glucose 56; Gram stain negative ID asks about prior meningitis – she says it was viral and resolved on its own

3. ID Consultant says Biofire is not indicated because there are no cells in CSF, so this patient does not have meningitis Get MRI to look for temporal lobe or other enhancement, this could be HSV-2 Since she had meningitis before, this is likely Mollaret’s Meningitis, and does not require treatment Send Biofire on CSF and if this is negative, may stop antibiotics and acyclovir Send Biofire on CSF and continue acyclovir even if negative Repeat CSF in 2-3 days if HSV-1 is negative as there is a high suspicion for HSV-1 encephalitis

4. Introduction Can normocellular csf be present in a patient with encephalitis from an infectious cause? Early diagnosis of neuroinflammation involves obtaining a CSF sample and assessing it alongside other criteria for encephalitis. This approach helps in underlying cause and guiding appropriate treatment. What happens when your CSF fluid shows absence of pleocytosis? This study investigated clinical features and outcomes in cases of encephalitis where pleocytosis is absent ( ≥ 5 WBCs/mm 3 ) to enhance timely diagnosis and management.

5. Background/Review Encephalitis, continues to result in substantial morbidity and mortality worldwide. diagnosis and management limited partly due to lack of consensus on case definitions, standardized diagnostic approaches i nfection of the brain parenchyma ( temporal lobes and inferior frontal lobe), leading to neurological abnormalities, esp grey matter causing cognitive changes, psychiatric signs, lethargy and seizures. Common Microbiology Enteroviruses Herpes simplex viruses (HSV-1)** Arboviruses HIV (retroviruses) Rabies (rhabdoviruses)

6. Timely and accurate diagnosis with prompt interventions are crucial for managing encephalitis. Often empirical treatment is initiated before diagnosis confirmation and delays or missed diagnosis increases mortality. HSV-1 associated with 70% mortality without treatment (IEC) International Encephalitis Consortium criteria and Graus diagnostic criteria for autoimmune encephalitis. Diagnostic criteria has been developed to identify suspected infections and autoimmune encephalitis without waiting for a definitive diagnostic test result. CSF pleocytosis is in the criteria used to differentiate. Objective: To characterize clinical factors and outcomes with the presence and absence of pleocytosis in an initial CSF test in a new onset of Encephalitis, Does the absence of pleocytosis affect empiric antiviral and immunomodulatory therapy administration? Background and Objective

7. International Encephalitis Consortium Graus criteria

8. Retrospective Study Population: Patients aged 18 or older with ICD-9 discharge codes corresponding to encephalitis in 2 different hospital settings (Texas and Baltimore), from 2005-2023 Data Extraction: Majority of data was obtained during patients initial ER visit of their 1 st hospital admission. Lab tests / Imaging: CBC, platelet count, sodium levels CSF: wbc and diff, glucose, and protein MRI, EEG, Symptoms: Fever, Focal neurological deficits, Seizure-like activity, Headaches, AMS/confusion, Other Development of status epilepticus ICU care requirements Hospitalization outcomes, including Length of stay (LOS) and mortality The delay in empiric treatment initiation measured in time in days from 1 st lumbar puncture to initiation of Acyclovir Methods and data extraction Psychiatric manifestations Memory issues Immunosuppression status (HIV) Recent chemotherapy Transplant (solid organ/bone marrow) Receiving ≥ 20mg prednisone or equivalent for >1 month

9. STATISTICAL ANALYSIS: Univariate statistical analysis was conducted on 597 patients in a combined cohort. The objective was to identify, clinical signs, lab/neurological workup and outcomes associated with normocellular CSF ( ≥ 5 WBCs/mm 3 ) A sub-analysis, with a definite diagnosis of Autoimmune and Infectious encephalitis and were analyzed using a C hi-Squared and Fisher’s exact test Mann-Whitney U test was used to analyze non-parametric continuous variables. Adjusted for confounding variables affecting mortality and length of stay through logistic and linear regression (age, IC, type of encephalitis) Cox regression to investigate time from LP to empiric therapy  

10. Results Out of 597 patients with encephalitis were included in the study, 151 patients did not have pleocytosis (25.3%) 446 patients who had pleocytosis (74.7%) Comparison of All-cause Encephalitis Patients without and with CSF Pleocytosis

11. Comparison of Infectious Encephalitis Patients without and with CSF Pleocytosis

12. Comparison of HSV-1 Encephalitis Patients without and with CSF Pleocytosis

13. Comparison of Clinical Characteristics, Complications, and Prognosis Between Autoimmune Encephalitis Patients without CSF Pleocytosis and Those with CSF Pleocytosis

14. It was noted that >1/4 th of there patients who had “acute encephalitis” lacked CSF pleocytosis 19% infectious causes, 39% autoimmune (26% were unknown origin) 25% of patients with HSV-1 encephalitis had normocellular CSF Patients with no pleocytosis were equally likely to have infectious or autoimmune encephalitis and were less likely to receive empiric treatment (Acyclovir) The presence of pleocytosis was linked to a higher likelihood of neurological dysfunction at presentation but did not corollate with increased hospital stay or mortality Fewer patients presenting without pleocytosis received empiric Acyclovir compared with those with pleocytosis suggesting that physicians rely on LP results to guide treatment decisions. The study also did not find a correlation between pleocytosis and earlier administration of empiric acyclovir in infectious encephalitis or immunotherapy in autoimmune encephalitis (unlike some prior studies) Summary of Important Findings

15. Results No pleocytosis was more likely to have CCI >=2 (55 vs 42%), p=-.01 With pleocytosis there was more fever and HA New seizure, psychiatric and memory deficits more common with no pleocytosis ; and more likely to have FOUR score No pleocytosis , similar proportion autoimmune (25%) and infectious (31%) MRI abnormality or epileptiform not associated with pleocytosis Only 47% of no pleocytosis got acyclovir 47 (19%) of patients with infectious encephalitis had no pleocytosis HSV-1 76/190 (40%) +; 18/76 had no pleocytosis (24%) HSV-1 with pleocytosis – more HA and fever, more MRI abnormalities w/o pleocytosis – more severe neurological impairment, GCS <8 29% of patients

16. Conclusions This Retrospective study of 600 adults (2005-2023) showed no pleocytosis among 19% of patients with an infectious cause. Almost ¼ of patients with HSV-1 encephalitis (HSE) had normocellular CSF. Explanation: Encephalitis is inflammation of brain parenchyma whereas meningitis inflammation of the meninges. So if you have pure encephalitis w/o meningoencephalitis, you may have normocellular CSF. Seen in other encephalitides (West Nile Virus, Rabies, Tickborne cencephalitis , HSE). Implications: Multiplex molecular assays for meningoencephalitis in some health centers may be restricted to patients with CSF pleocytosis. In this study ¼ of patients with HSE, a disease with 70% mortality, would have missed this opportunity for diagnosis.

17. Discussion Why did I chose this study? Is this study well done? Strengths? Limitations? Learn from study? Learn statistically? Generalizable? Applicable to our setting? Ho will you apply to your clinical practice?

18. Strengths Practical question with practical results Large Sample Size, ie enough HSV-1 cases (72)

19. Limitations Timeframe retrospectively enrolled 2005-2023 , 2006-2016 (Baltimore) (Guidelines from 2013 and 2016); prospectively 2016-2022 – is this cohort different, better studied Observational – so important variables overlooked – confounding; - other factors not measured may be playing role; missing data; publication bias; data collection and entry, data quality assurance – not planned ahead, so may be compromised, some data inevitably missing (relying on ER dr note for ex for details of neurological history); Very few confounding factors noted in the regression analysis Initial presentation consistent with meningitis rather than encephalitis – how was this done Time from LP to initiation of treatment (? Rather than time from admission as per ref 23)

20. Take Home Points 25% of patients with encephalitis, equally infectious or autoimmune, have no pleocytosis – not associated with immune status 25% of HSV-1 encephalitis have no pleocytosis and these patients are less likely to get acyclovir This is dangerous for a disease with 70% mortality  Pleocytosis or lack of cannot be used to differentiate infectious from autoimmune encephalitis (as risk score suggests) We should not use pleocytosis to qualify for Biofire (molecular multiplex)

21. ID Consultant says Biofire is indicated even if there are no cells in CSF, so this patient does not have meningitis Get MRI to look for temporal lobe or other enhancement, this could be HSV-1 This is not likely Mollaret’s Meningitis , because she does not have any cells in CSF or evidence of inflammation of the meninges Send Biofire on CSF and if this is negative, may stop antibiotics and but continue acyclovir Send Biofire on CSF and continue acyclovir even if negative, and send HSV-1 Repeat CSF in 2-3 days if HSV-1 is negative as she has a high suspicion for HSV-1 encephalitis

22. References Ellul, M., & Solomon, T. (2018). Acute encephalitis – diagnosis and management. Clinical Medicine , 18 (2), 155–159. https://doi.org/10.7861/clinmedicine.18-2-155 Venkatesan, A., Tunkel , A. R., Bloch, K. C., Lauring , A. S., Sejvar , J., Bitnun , A., Stahl, J., Mailles , A., Drebot , M., Rupprecht , C. E., Yoder, J., Cope, J. R., Wilson, M. R., Whitley, R. J., Sullivan, J., Granerod , J., Jones, C., Eastwood, K., Ward, K. N., . . . Cherry, J. (2013). Case Definitions, diagnostic Algorithms, and Priorities in Encephalitis: Consensus Statement of the International Encephalitis Consortium. Clinical Infectious Diseases , 57 (8), 1114–1128. https://doi.org/10.1093/cid/cit458 Habis , R., Kolchinski , A., Heck, A. N., Bean, P., Probasco , J. C., Hasbun , R., & Venkatesan, A. (2024). Absence of cerebrospinal fluid pleocytosis in encephalitis.  Clinical Infectious Diseases . https://doi.org/10.1093/cid/ciae391 -Common causes of meningitis and encephalitis in children.  | Download Table (researchgate.net) (PDF) meningitis and encephalitis in infants and children. (n.d.). https://www.researchgate.net/publication/221773925_Meningitis_and_encephalitis_in_infants_and_children