When to Consider Neurosurgical Interventions for the Management of Complicated Cryptococcal Meningitis

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Edward R. Cachay, MD, MAS of UC San Diego Owen Clinic presents "When to Consider Neurosurgical Interventions for the Management of Complicated Cryptococcal Meningitis" …

Edward R. Cachay, MD, MAS of UC San Diego Owen Clinic presents "When to Consider Neurosurgical Interventions for the Management of Complicated Cryptococcal Meningitis"

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  • 1. AIDS CLINICAL ROUNDSThe UC San Diego AntiViral Research Center sponsors weeklypresentations by infectious disease clinicians, physicians andresearchers. The goal of these presentations is to provide the mostcurrent research, clinical practices and trends in HIV, HBV, HCV, TBand other infectious diseases of global significance.The slides from the AIDS Clinical Rounds presentation that you areabout to view are intended for the educational purposes of ouraudience. They may not be used for other purposes without thepresenter’s express permission.
  • 2. Neurosurgical considerations in themanagement of complicatedcryptococcal meningitis Edward Cachay M.D., M.A.S Associate Professor of Clinical Medicine Owen clinic -9 November 2012 copyright to Edward Cachay MD, Nov 2012
  • 3. Friday 5:15pm-arrival to the emergency department• 26 yo male presented with 1 mo of headache , hearing loss x 3 weeks and reporting and double vision on the ED.• The patient was unable to communicate 2/2 hearing loss and unable to read 2/2 diplopia.• His mother was at bedside and gave all history• The patient also had complained of generalized weakness with some unsteadiness with walking.• There was no history of fever, chills, vomiting, photophobia .PMH: None including prior STI, no surgeries.NKDAMeds: noneSH: Patient lives in TJ, visiting his family in Chula Vista. Denies tobacco or illicit drugs. Social EtOH.FH: unremarkable copyright to Edward Cachay MD, Nov 2012
  • 4. Physical examVS: BP 147/94 | Pulse 113 | Temp 98.3 °F | Resp 16 | Ht 6 0.25" | 172lb | BMI 23.2 kg/m2 | SpO2 98%• Patient was fully awake in NAD, responded to written instructions and denied headache but expressed concerns with signs about deafness and decreased vision in the right eye.• NAD, WDWN• Dilated pupil more left than right (4mm) slowly reactive. No oral candida, clear ear drums, normal gingiva, OP/NP clear• Neck: mild stiff, supple, No LAD• CV: RRR, no m/g/r• Chest; CTAB• ABD: +bs,s,nt, no palpable spleen• Genitals: No discharge, no hernias• Extrem: No e/c/c• Neuro: AAOx3,pupil more left than right (4mm) slowly reactive, VI palsy bilateral. deafness, mild hyperreflexia, no babinski, meningeal signs +. Fundoscopic exam: Bilateral papilledema. Left side flames and more prominent.• Proximal weakness lower extremities with evidence of incoordination• SKIN: No rash copyright to Edward Cachay MD, Nov 2012
  • 5. Laboratory results available on ER 14.1 135 93 10 39 9.3 TB: 1.1 6.6 191 107 133 38.9 2.8 25 0.58 18 4.2 DB: 0.3 CSF analysis: Rbc: 4; wbc: 3, TP: 41, Glucose: 46 India ink: Positive7:50 pmMedicine resident present case. OP is reported > 55cmH20.45cc drained, still OP > 55cmH20. Ambisome + 5FC initiated. copyright to Edward Cachay MD, Nov 2012
  • 6. Head CT performed on arrival to ER Axial Coronal copyright to Edward Cachay MD, Nov 2012
  • 7. Head CT on arrival to ER. Have you noticed thepapilledema? copyright to Edward Cachay MD, Nov 2012
  • 8. 5:15am Patient tells me he has no double vision butcan’t see with his right eye and left eye vision is blurry.In addition to start antifungal therapy, what would you havedone if you were at the bedside at 5:00am?1. Transfer patient to ICU for frequent neurocheck2. Consult neurosurgery3. Daily CSF opening pressure measurement4. All above5. None of the above copyright to Edward Cachay MD, Nov 2012
  • 9. 7:35 am: The neurosurgery team documented“Pt current symptoms are focal in nature and does notappear to have altered sensorium, denies significant HA atpresent time. Does not appear to have symptomaticintracranial hypertension currently.”a. decadron 10 mg x 1 then 4q6b. MRI brain and c-spine with and w/o contrastc. recommend continuing daily high volume LPsd. Agree with transferring to ICU copyright to Edward Cachay MD, Nov 2012
  • 10. Do you agree with using high dose steroids inthis clinical situation?a. Yesb. No copyright to Edward Cachay MD, Nov 2012
  • 11. The data of using steroids in HIV-relatedcryptococcal meningitis Steroids Not steroids P (n=41) (n=191) 2w successful clinical response 41% 86% 0.001 Negative csf fungal cultures at 2 41% 62% 0.001 weeks Dexamethasome or Other steroids P Metilprednisolone (n=41) (n=200)Mortality within 2 weeks 20% 3% 0.0001 Graybille R at al. CID, 2000, 30:47-54 copyright to Edward Cachay MD, Nov 2012
  • 12. Steroids have no benefit and may create moreproblems: copyright to Edward Cachay MD, Nov 2012
  • 13. The burden of disease was better known when patientis in the ICU CSF analysis: Rbc: 4; wbc: 3, TP: 41, Glucose: 46 India ink: Positive csf CRAG: 1: 8,182 csf cultures: grew Cryptococcus spp. within 2 days even in routine media Blood culture: 1 of 4 bottles positive for cryptococcus CD4: 36 and HIV VL= 1’215,713 copyright to Edward Cachay MD, Nov 2012
  • 14. Potential mechanism (s) behind the patient symptoms.Which one do you think is the most important at thispoint?1. Elevated CSF pressure2. Cryptococcomas3. Vascular infarcts/vasculitis4. Nerve infiltration with Cryptococcus.5. Meningeal irritation copyright to Edward Cachay MD, Nov 2012
  • 15. Brain MRI Hospital Day #2 copyright to Edward Cachay MD, Nov 2012
  • 16. Brain MRI Hospital Day #2: Figure Depicts normal VIInerve different nuclei and tracts copyright to Edward Cachay MD, Nov 2012
  • 17. Left auditory canal illustrating normal VII and Vestibulo-coclear nerve copyright to Edward Cachay MD, Nov 2012
  • 18. Progression of Intracranial hypertension Back to Medicine Owen copyright to Edward Cachay MD, Nov 2012
  • 19. Fundoscopic exam Hospital day #10 copyright to Edward Cachay MD, Nov 2012
  • 20. Ocular exam Hospital day #11 copyright to Edward Cachay MD, Nov 2012
  • 21. Clinical course:• The patient underwent a V-P shunt placement on Hospital day #12• At the time V-P shunt placement last csf positive cultures was from day 3. csf obtained on day 5 and 6 were no growth and still do until today• Steroids were fully stopped hospital day #14• Patient completed a total of 19 days of Ambisome + 5FC (14d from most recent documented negative csf culture). Therapy was limited due to AKI (creatinine up to 2.1)• Patient was discharged on hospital day #21• CSF culture obtained from ventricles during V-P placement grew after 10 days of collection after patient was discharged home. copyright to Edward Cachay MD, Nov 2012
  • 22. CSF flow copyright to Edward Cachay MD, Nov 2012
  • 23. Figure below depicts normal dynamic circulationof Cerebrospinal fluid Downloaded from http://en.wikipedia.org/wiki/Cerebrospinal_fluid copyright to Edward Cachay MD, Nov 2012
  • 24. Loyse AIDS 2010, 24:405-410copyright to Edward Cachay MD, Nov 2012
  • 25. Aracnoid granulation anatomy Loyse AIDS 2010, 24:405-410 copyright to Edward Cachay MD, Nov 2012
  • 26. It was not until recently that we had histophatologicalprove of mechanism associated to elevated ICP in HIVrelated cryptococcal meningitis Loyse AIDS 2010, 24:405-410 copyright to Edward Cachay MD, Nov 2012
  • 27. Multiple organism filling aracnoid granulations Loyse AIDS 2010, 24:405-410 copyright to Edward Cachay MD, Nov 2012
  • 28. A plumbing system with increasing resistance o o copyright to Edward Cachay MD, Nov 2012
  • 29. The mesh get clotted Eschematic representation of cryptooccal yeast; (5mm) diameter copyright to Edward Cachay MD, Nov 2012
  • 30. Outcome of treatment according to baseline CSF opening pressure for 221 patients with AIDS and cryptococcal meningitis. Graybill J R et al. Clin Infect Dis. 2000;30:47-54 copyright to Edward Cachay MD, Nov 2012
  • 31. Baseline CSF opening pressure does not correlate with mortality when frequent lumbar punctures are done Bicani et al, AIDS. 2009;23:701–6 copyright to Edward Cachay MD, Nov 2012
  • 32. Scatter plot of baseline cryptococcal CSF Colonyforming units count vs baseline opening pressure Bicani et al, AIDS. 2009;23:701–6 copyright to Edward Cachay MD, Nov 2012
  • 33. Definition of complicated cryptococcalmeningitis• Death is not the only relevant outcome of this opportunistic infection .• Our group has worked in incorporating definitions of complicated cryptococcal meningitis: I. death but also incorporates II. two elements of long term morbidity: (1) persistently (≥ 14 days) abnormal neurologic exam either by altered mental status or focal neurologic findings, (2) surgical intervention to control intractable intracranial hypertension. Cachay et al. AIDS Research and Therapy, 2010, 7: 29 copyright to Edward Cachay MD, Nov 2012
  • 34. Clinical features at baseline in patients with cryptococcalmeningitis-Owen clinic Uncomplicated Complicated cryptococcal meningitis cryptococcal meningitis P value n = 68 n = 14Meningeal signs 12 (14.6) 8 (11.8) 4 (28.6)Initial altered mental status( 15 (22.1) 6 (42.9) 0.18scale ≤13)Focal neurological findings 3 (4.4) 7 (50) 0.0001Seizures 3 (4.4) 2 (14.3) 0.20CSF opening pressure ( cmH20) 26.9 (5–57) 43.4 (15–61) 0.0001CSF wbc (/ml) 49.9 ( 0–500) 26.3 (0–210) 0.36 glucose(mg/dl) 40.7 ( 2–103) 45.8 (11–122) 0.34 protein (mg/dl) 77.9 (27–278) 73.9 ( 25–178) 0.79CSF India ink positive 57 (85) 14 (100) 0.20CSF culture positive 64 (97) 14 (100) 1.0Blood culture positive for 35 (75) 8 (80) 1.0Cryptococcus species Cachay et al. AIDS Research and Therapy, 2010, 7: 29 copyright to Edward Cachay MD, Nov 2012
  • 35. Recently reviewed IDSA guidelines: copyright to Edward Cachay MD, Nov 2012
  • 36. Practical points without clear guides:- Even in clinical trials controlling ICP aggressively median number of LPs were 8 within first 2 weeks- After how long should be considering placing a definitive neurosurgical shunt?- Are all patients the same? What if they have concurrent focal complications such as in our case? copyright to Edward Cachay MD, Nov 2012
  • 37. Why is this important?• In our institution over the last 22 years approximately 1 of 7 ARV naïve HIV patients presenting with a new diagnosis of cryptococcal meningitis had a complicated course.• Approximately 1 of 2 patients presenting with complicated cryptococcal meningitis required a neurosurgical shunt procedure. Cachay et al. AIDS Research and Therapy, 2010, 7: 29 copyright to Edward Cachay MD, Nov 2012
  • 38. Risk associated to V-P shunt placement+ Immediate:-- Mechanical complications: Vascular Structural-- Infection: Primary: Seeding Cryptococcus into the peritoneum Secondary: Superimposed bacterial infection+ Delayed:-- Shunt extrusion-- Infection copyright to Edward Cachay MD, Nov 2012
  • 39. Clin Infect Dis. 2003 Sep 1;37:673-8copyright to Edward Cachay MD, Nov 2012
  • 40. Patients with acute decompensating and rapidinterventions had better outcomes Age/gender Symptoms CSF OP CSF OP Time to VP Outcome baseline highest shunt 19/M AMS, L VI palsy 60 >60 10d Recovery 71/M AMS and 33 36 4d Recovery decrease VA 25/F AMS, decrease 14 60 15d Recovery VA 57/F Decrease VA and 40 60 24d Deafness hearing loss persisted Clin Infect Dis. 2003 Sep 1;37:673-8 copyright to Edward Cachay MD, Nov 2012
  • 41. HOW SOON CAN NEUROSURGICAL SHUNTSBE PLACED ? copyright to Edward Cachay MD, Nov 2012
  • 42. Earlier evidence from 1980s Procedure Complications Outcome1 VP shunt no Good2 VP shunt no Good3 VP shunt 6 weeks after Block shunt, 3 times Died from uncontrolled infection craneotomy4 Subtemporal descompression no Good with rapid recovery of vision5 External descompression, VP shunt Block shunt, 3 times Good 1w later6 External ventricular drainaga, VP no Good shunt 1 we later7 VP shunt Block shunt, once Good8 External ventricular drainaga, VP no Good shunt 1 we later9 VP shunt Block shunt, once Severe dsiability (blind and partially deaf)10 External ventricular drainaga, VP no Good shunt 1 we later11 VP shunt No Good copyright to Edward Cachay MD, Nov 2012 et al, Neurosurgery, 1989, 25:44-8 Chan
  • 43. Shunts can be placed in context of active infectioncopyright to Edward Cachay MD, Nov 2012 Park et al Clin Infect Dise.1999 Mar;28(3):629-33
  • 44. We know that patients with a baseline focalneurological exam have the highest risk fordeveloping complicated forms of cryptococcalmeningitis Shall we more aggressive in these individuals? copyright to Edward Cachay MD, Nov 2012
  • 45. Risk factors for developing complicated cryptococcalmeningitis within 2 weeks of admission-Owen clinic Risk Factor Unadjusted OR (95% CI) p Adjusted OR (95% CI) p Baseline focal neurologic findings 21.7(3.7-149.3) .00001 17.2(2.6-114.9) .003 Initial CSF opening pressure ≥30 cmH20 4.3(1.1-19) .01 1.9(0.36-10.7) .44 Baseline log2 csf CRAG 1.5(1.1-2.2) .02 Initial abnormal head CT 17.7(1.2-944) .002 32.6(1.1-927.8) .04 Model N = 80, ROC area 0.92, Hosmer-Lemeshow c2 p < 0.00001 Cachay et al. AIDS Research and Therapy, 2010, 7: 29 copyright to Edward Cachay MD, Nov 2012
  • 46. Limitations in HIV patients+ The risk of shunt infection in the context of severe immunosuppression, and peritoneal Cryptococcus seeding from direct transport of infected fluid has historically discouragedsurgeons from implanting CSF shunts in patients with HIV and cryptococcal meningitis.+ To date, only 9 cases of ventriculoperitoneal (VP) shunt placement in HIV- infected patients with elevated ICP and cryptococcal meningitis without hydrocephalus have been reported in the English literature. However 4 cases of L-P shunts placements in patients with ocular complications were reported with documentation of reversibility of symptoms when shunts were placed promptly. copyright to Edward Cachay MD, Nov 2012
  • 47. Our experience at UCSD –Owen clinic copyright to Edward Cachay MD, Nov 2012
  • 48. Characteristics of patients with cryptococcal meningitis that required neurosurgical shunting at the Owen clinic in last 22 years Age CD4 CSF OP Meningeal Focal + + blood csf AMS CT focal Outcome (years) (cmH20) signs findings India Cx CRAG finding ink 1 28 126 37 1 Yes yes yes 32768 0 0 alive 2 25 9 51 1 yes yes yes 8192 1 1 alive 3 35 50 13 0 0 yes yes 32768 0 0 alive 4 35 22 30 0 0 yes yes 32768 0 0 alive 5 48 76 45 1 0 yes yes 32768 0 0 alive 6 27 9 20 0 yes yes yes 256 1 0 alive 7 33 20 27 0 0 yes yes 65536 0 0 alive 8 43 17 > 55 0 yes Yes Yes 32768 0 0 alive 9 45 5 > 55 1 yes yes yes 4096 0 0 alive 10 47 2 >55 0 No yes unkn unkn 0 0 aliveCopyright Edward Cachay M.D. Cachay et al-Owen clinic unpublished dataNovember 2011 copyright to Edward Cachay MD, Nov 2012
  • 49. Clinical observations• Every patient who had ≥ 5 large volume LP within first 14 days and still had elevated ICP required ultimately a shunt intervention• Patients who had acute AMS descompensation (i.e posturing, decortication) required shunt despite initial trials of ventriculostomy or lumbar drain placements.• Promptness of intervention appear to matter for patients with visual impairment. copyright to Edward Cachay MD, Nov 2012
  • 50. Outcomes:• Most patients who required a CSF surgical shunt placement had the intervention done during their third week of hospitalization (median: day 21, range: day 5 to 30)• No immediate or late surgical infections were recorded• All except one (shunt placed in 2012) patients remained alive after a median of 5 years of follow-up copyright to Edward Cachay MD, Nov 2012
  • 51. and what happen with ourpatient? copyright to Edward Cachay MD, Nov 2012
  • 52. 25 days after shunting copyright to Edward Cachay MD, Nov 2012
  • 53. 25 days after shunting copyright to Edward Cachay MD, Nov 2012
  • 54. 25 days after shunting copyright to Edward Cachay MD, Nov 2012
  • 55. The current status• The indications for shunting in HIV-related cryptococcal meningitis are not well understood or universally agreed upon.• Most groups suggest early shunt placement for hydrocephalus to avoid irreversible neurological complications• There are lack of practical clinical rules for consideration of neurosurgical shunt placement and initiate –often long- conversations with neurosurgery team copyright to Edward Cachay MD, Nov 2012
  • 56. Our clinical observations suggest that patients maybenefit from neurosurgical placement if:1. Patients have persistent csf OP >35cmH20 and no AMS:+ After 7 days on treatment with minimum 6 large volume LPs+ After 11 days of therapy and minimum 5 large volume LPs2. Patients with sensory-neural focal findings (blindness and deafness) and negative with MRI evidence of nerve infiltration to increase changes of irreversible damage.3. Patients with acute deterioration of mental status will benefit from urgent shunting when other alternative causes are immediately rule out. copyright to Edward Cachay MD, Nov 2012
  • 57. Conclusions• A subset of patients with complicated meningitis will benefit from neurosurgical shunting to prevent irreversible neurological damage.• Shunt insertions are not associated with spread of infection, do not prevent mycological cure, and infrequently require late revisions.• Future collaborative efforts are needed to define prospectively the proposed indications for shunt placement. copyright to Edward Cachay MD, Nov 2012
  • 58. Acknowledgements I copyright to Edward Cachay MD, Nov 2012
  • 59. Acknowledgements II• Justin Brown (Neurosurgery)• Scott Pannel (Radiology)• Jeffrey Lee (Opthalmology)• Amy Sitapati, Theo katsivas and Joe caperna• Nina Haste (Retro)• Wollelaw Agmas (Owen research ) copyright to Edward Cachay MD, Nov 2012
  • 60. In HIV Negative patients: it is not uncommon to have severe Sex/age (yr) Presenting Neurological exam GCS Head CT1 F/22 HA, diplopia Papilledema, 6th palsy 15 Hydrocephalus2 M/15 HA, fever Meningismus 15 Hydrocephalus3 F/54 HA, decrease visual Decrease vision, hypopituitarism 12 Intrasellar Cyst4 M/32 HA, fever, blindness Meningismus, papilledema, 12 Diffuse cerebral edema blindness5 M/24 HA, fever Ataxia, Papilledema, 6th palsy 12 Posterior fossa cyst6 M/31 Fever, drowsiness Meningismus, papilledema 12 Hydrocephalus7 F/60 Acute confusion Meningismus 10 Hydrocephalus8 M/33 Coma, fever Meningismus 7 Hydrocephalus9 F/36 Coma, fever Meningismus, papilledema 3 Hydrocephalus10 M/28 Coma, fever Meningismus, 3 Hydrocephalus11 M/9 Coma, fever Meningismus, 3 Hydrocephalus copyright to Edward Cachay MD, Nov 2012 et al, Neurosurgery, 1989, 25:44-8 Chan