when to consider neurosurgical interventions for the management of complicated cryptococcal...

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AIDS CLINICAL ROUNDS

Neurosurgical considerations in the management of complicated cryptococcal 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

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.

NKDA

Meds: none

SH: Patient lives in TJ, visiting his family in Chula Vista. Denies tobacco or illicit drugs. Social EtOH.

FH: unremarkable


Physical exam VS: 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


Laboratory results available on ER

6.6 14.1

191

38.9

135

2.8

93

25

10

0.58

107 39

18 4.2

9.3 TB: 1.1

Rbc: 4; wbc: 3, TP: 41, Glucose: 46

7:50 pm Medicine resident present case. OP is reported > 55cmH20. 45cc drained, still OP > 55cmH20. Ambisome + 5FC initiated.

India ink: Positive

CSF analysis:

DB: 0.3 133


Head CT performed on arrival to ER

Axial Coronal


Head CT on arrival to ER. Have you noticed the papilledema?


5:15am Patient tells me he has no double vision but can’t see with his right eye and left eye vision is blurry.

In addition to start antifungal therapy, what would you have done if you were at the bedside at 5:00am?

1. Transfer patient to ICU for frequent neurocheck

2. Consult neurosurgery

3. Daily CSF opening pressure measurement

4. All above

5. None of the above


7:35 am: The neurosurgery team documented

“Pt current symptoms are focal in nature and does not appear to have altered sensorium, denies significant HA at present time. Does not appear to have symptomatic intracranial hypertension currently.”

a. decadron 10 mg x 1 then 4q6

b. MRI brain and c-spine with and w/o contrast

c. recommend continuing daily high volume LP's

d. Agree with transferring to ICU


Do you agree with using high dose steroids in this clinical situation?

a. Yes

b. No


The data of using steroids in HIV-related cryptococcal meningitis

Steroids (n=41)

Not steroids (n=191)

P

2w successful clinical response 41% 86% 0.001

Negative csf fungal cultures at 2 weeks

41% 62% 0.001

Graybille R at al. CID, 2000, 30:47-54

Dexamethasome or Metilprednisolone (n=41)

Other steroids (n=200)

P

Mortality within 2 weeks 20% 3% 0.0001


Steroids have no benefit and may create more problems:


The burden of disease was better known when patient is in the ICU

Blood culture: 1 of 4 bottles positive for cryptococcus

csf cultures: grew Cryptococcus spp. within 2 days even in routine media

Rbc: 4; wbc: 3, TP: 41, Glucose: 46

csf CRAG: 1: 8,182

India ink: Positive CSF analysis:


CD4: 36 and HIV VL= 1’215,713

Potential mechanism (s) behind the patient symptoms. Which one do you think is the most important at this point?

1. Elevated CSF pressure

2. Cryptococcomas

3. Vascular infarcts/vasculitis

4. Nerve infiltration with Cryptococcus.

5. Meningeal irritation


Brain MRI Hospital Day #2


Brain MRI Hospital Day #2: Figure Depicts normal VII nerve different nuclei and tracts


Left auditory canal illustrating normal VII and Vestibulo-coclear nerve


Progression of Intracranial hypertension

Back to Medicine Owen


Fundoscopic exam Hospital day #10


Ocular exam Hospital day #11


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.


CSF flow


Figure below depicts normal dynamic circulation of Cerebrospinal fluid


Downloaded from http://en.wikipedia.org/wiki/Cerebrospinal_fluid


Loyse AIDS 2010, 24:405-410

Aracnoid granulation anatomy


Loyse AIDS 2010, 24:405-410

It was not until recently that we had histophatological prove of mechanism associated to elevated ICP in HIV related cryptococcal meningitis


Loyse AIDS 2010, 24:405-410

Multiple organism filling aracnoid granulations


Loyse AIDS 2010, 24:405-410

A plumbing system with increasing resistance


o

o

The mesh get clotted


Eschematic representation of cryptooccal yeast; (5mm) diameter

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


Baseline CSF opening pressure does not correlate with mortality when frequent lumbar punctures are done


Bicani et al, AIDS. 2009;23:701–6

Scatter plot of baseline cryptococcal CSF Colony forming units count vs baseline opening pressure


Bicani et al, AIDS. 2009;23:701–6

Definition of complicated cryptococcal meningitis

• 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


Clinical features at baseline in patients with cryptococcal meningitis-Owen clinic


Uncomplicated

cryptococcal meningitis

n = 68

Complicated

cryptococcal meningitis

n = 14 P value

Meningeal signs 12 (14.6) 8 (11.8) 4 (28.6)

Initial altered mental status(

scale ≤13) 15 (22.1) 6 (42.9) 0.18

Focal neurological findings 3 (4.4) 7 (50) 0.0001

Seizures 3 (4.4) 2 (14.3) 0.20

CSF opening pressure ( cmH20) 26.9 (5–57) 43.4 (15–61) 0.0001

CSF

wbc (/ml)

glucose(mg/dl)

protein (mg/dl)

49.9 ( 0–500)

40.7 ( 2–103)

77.9 (27–278)

26.3 (0–210)

45.8 (11–122)

73.9 ( 25–178)

0.36

0.34

0.79

CSF India ink positive 57 (85) 14 (100) 0.20

CSF culture positive 64 (97) 14 (100) 1.0

Blood culture positive for

Cryptococcus species 35 (75) 8 (80) 1.0

Cachay et al. AIDS Research and Therapy, 2010, 7: 29

Recently reviewed IDSA guidelines:


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?


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.



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


Clin Infect Dis. 2003 Sep 1;37:673-8


Patients with acute decompensating and rapid interventions had better outcomes

Age/gender Symptoms CSF OP baseline

CSF OP highest

Time to VP shunt

Outcome

19/M AMS, L VI palsy 60 >60 10d Recovery

71/M AMS and decrease VA

33 36 4d Recovery

25/F AMS, decrease VA

14 60 15d Recovery

57/F Decrease VA and hearing loss

40 60 24d Deafness persisted

Clin Infect Dis. 2003 Sep 1;37:673-8


HOW SOON CAN NEUROSURGICAL SHUNTS BE PLACED ?


Earlier evidence from 1980s Procedure Complications Outcome

1 VP shunt no Good

2 VP shunt no Good

3 VP shunt 6 weeks after craneotomy

Block shunt, 3 times Died from uncontrolled infection

4 Subtemporal descompression no Good with rapid recovery of vision

5 External descompression, VP shunt 1w later

Block shunt, 3 times Good

6 External ventricular drainaga, VP shunt 1 we later

no Good

7 VP shunt Block shunt, once Good


no Good

9 VP shunt Block shunt, once Severe dsiability (blind and partially deaf)


no Good

11 VP shunt No Good

Chan et al, Neurosurgery, 1989, 25:44-8 copyright to Edward Cachay MD, Nov 2012

Park et al Clin Infect Dise.1999 Mar;28(3):629-33

Shunts can be placed in context of active infection


We know that patients with a baseline focal neurological exam have the highest risk for developing complicated forms of cryptococcal meningitis

Shall we more aggressive in these individuals?


Risk factors for developing complicated cryptococcal meningitis 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

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.


Our experience at UCSD –Owen clinic


Characteristics of patients with cryptococcal meningitis that required neurosurgical shunting at the Owen clinic in last 22 years

Age

(years)

CD4 CSF OP

(cmH20)

Meningeal

signs

Focal

findings

+

India

ink

+ blood

Cx

csf

CRAG

AMS CT focal

finding

Outcome

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 alive

Copyright Edward Cachay M.D. November 2011

Cachay et al-Owen clinic unpublished data


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.


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


and what happen with our patient?


25 days after shunting


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


Our clinical observations suggest that patients may benefit 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 LPs

2. 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.


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.


Acknowledgements I


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 )


In HIV Negative patients: it is not uncommon to have severe

Sex/age (yr) Presenting Neurological exam GCS Head CT

1 F/22 HA, diplopia Papilledema, 6th palsy 15 Hydrocephalus

2 M/15 HA, fever Meningismus 15 Hydrocephalus

3 F/54 HA, decrease visual Decrease vision, hypopituitarism 12 Intrasellar Cyst

4 M/32 HA, fever, blindness Meningismus, papilledema, blindness

12 Diffuse cerebral edema

5 M/24 HA, fever Ataxia, Papilledema, 6th palsy 12 Posterior fossa cyst

6 M/31 Fever, drowsiness Meningismus, papilledema 12 Hydrocephalus

7 F/60 Acute confusion Meningismus 10 Hydrocephalus

8 M/33 Coma, fever Meningismus 7 Hydrocephalus

9 F/36 Coma, fever Meningismus, papilledema 3 Hydrocephalus

10 M/28 Coma, fever Meningismus, 3 Hydrocephalus

11 M/9 Coma, fever Meningismus, 3 Hydrocephalus

Chan et al, Neurosurgery, 1989, 25:44-8 copyright to Edward Cachay MD, Nov 2012

when to consider neurosurgical interventions for the management of complicated cryptococcal...

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