Neurosyphilis as an Emerging Feature in the HIV Setting. Christina M. Marra, MD University of Washington Seattle, WA, USA

Transcription

1 Neurosyphilis as an Emerging Feature in the HIV Setting Christina M. Marra, MD University of Washington Seattle, WA, USA

2 Syphilis in the Developing World Region Sub-Saharan 3,530,000 3,828,000 Africa S and SE Asia 5,790,000 4,038,000 Latin Am and 1,260,000 2,928,000 Caribbean TOTAL 12,220,000 11,760,000

3 US P/S Syphilis # Cases

4 Natural History of Syphilis Infection Neuroinvasion 2-6 weeks Primary Chancre, regional adenopathy Early Neurosyphilis Secondary Rash, generalized adenopathy 1-3 months 1-3 months Lifetime latency > 70% Latent months - decades Tertiary Gumma Cardiovascular Late Neurosyphilis

5 Neuroinvasion +CSF PCR, RT- PCR, RIT Clearance 70% Transient Meningitis Persistent Meningitis 30% Spontaneous Resolution Symptomatic Neurosyphilis 20%

6 Neurosyphilis Diagnosis CSF-VDRL specific, not sensitive False negatives 30-70% Elevated CSF WBCs Can be hard to distinguish from HIV CSF-FTA-ABS sensitive but not specific

7 Non-CNS Syphilis Treatment Early syphilis Benzathine penicillin G 2.4 MU IM X 1 Late syphilis Benzathine penicillin G 2.4 MU IM weekly X 3 BPG does not achieve measurable penicillin levels in CSF Does this matter?

8 Abnormal CSF 6 Months After Penicillin Stage N % CSFs Abnormal Seronegative Primary Seropositive Primary Secondary Altschuler et al, Am J Syphil 1949;33

9 Neurosyphilis in HIV+ After Benzathine Penicillin Musher (JID 1991;163;1201-6) Identified 42 cases of neurosyphilis in HIVinfected individuals Asx neurosyphilis 5 Acute meningitis 24 Meningovascular 11 General paresis 1

10 Neurosyphilis in HIV+ After Benzathine Penicillin Musher (JID 1991;163;1201-6) Of the 42 cases of neurosyphilis 16 previously treated with benzathine penicillin 5 (31%) developed neurosyphilis within 6 months of early syphilis treatment Increased risk of neurorelapse

11 BPG vs Enhanced Tx for Early Syphilis Rolfs RT et al (NEJM 1997;337: ) 440 HIV- and 101 HIV+ with early syphilis Randomized to BPG vs BPG plus 2 g amoxicillin and 500 mg probenecid tid X 10 d (enhanced tx) 102 HIV- and 47 HIV+ had LP at entry

12 BPG vs Enhanced Tx for Early Syphilis Rolfs RT et al (NEJM 1997;337: ) Treatment failure not more common in those with T. pallidum in pre-tx CSF Treatment failure not influenced by treatment assignment No clinical neurosyphilis over 1 year of follow-up Concluded that CSF evaluation in early syphilis not useful

13 BPG vs Enhanced Tx for Early Syphilis Rolfs RT et al (NEJM 1997;337: ) Insufficient power to determine influence of detection of T. pallidum in CSF on treatment response in HIV+ subjects 80% power to detect a 50% difference in treatment response

14 Conservative Approach Cannot predict who will clear CSF abnormalities and who will not Literature describes neurorelapse in HIV+ patients with early syphilis LP for all HIV+ patients with syphilis, regardless of stage Treat for neurosyphilis if CSF WBC elevated or CSF-VDRL reactive

15 UK Guidelines Early or late syphilis in HIV+ Procaine penicillin 2 MU IM daily plus probenecid 500 mg po qid, both for 17 days Same as for neurosyphilis

16 UW Neurosyphilis Study Study Goals Determine risk factors for neurosyphilis Identify better diagnostic tests Determine predictors of neurosyphilis treatment response

17 WBC > 20 or +CSF-VDRL in 268 HIV+ Stage Early Late Adj OR 95% CI P-value 1.1 ref RPR > 1: <0.001 CD4 < Syphilis Tx 0-14 d 15 d-1yr > 1 yr ref

18 Yield of LP Using Serum RPR vs CDC Criteria in HIV+ Syphilis RPR 1:32 or greater Late Stage % who undergo LP % +CSF-VDRLs identified

19 Simple CSF Tests for Neurosyphilis RPR easier than VDRL, used on blood in developing world Not optimized for CSF FTA requires fluorescent microscope Commercial rapid treponemal tests detect antibodies to recombinant T. pallidum antigens Simple High sensitivity and specificity on blood Performance on CSF?

20 Performance of Simple Tests in HIV+ Syphilis CSF-VDRL+ (n=10) CSF-VDRL- (n=27) CSF RPR+ 7 0 CSF-SDI+ 7 2 FTA-ABS+ 10 8

21 Diagnostic Performance Sensitivity Specificity CSF-RPR 70% 100% CSF-SDI 70% 93% CSF-VDRL NA NA NS = CSF-VDRL+

22 Neurosyphilis Treatment Aqueous crystalline penicillin G, 3-4 MU IV q 4 or as a continuous infusion of 24 MU/d for days Procaine penicillin, 2.4 MU IM q d plus probenecid 500 mg PO qid, both for days Second line Ceftriaxone 2 g IV/d for days

23 Assessing NS Treatment Response Not like other kinds of bacterial meningitis Can t assess culture becomes negative Normalization of CSF WBC, CSF-VDRL Normalization of serum RPR

24 Normalization in HIV+ P-Value for Each Measure CSF WBC CSF- VDRL Serum RPR Baseline NS NS <0.005 value CD4 <200 NS RNA > NS ARV tx NS