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

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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

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: Positive

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


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 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


Steroids have no benefit and may create more
problems:


The burden of disease was better known when patient
is 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


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 Complicated
cryptococcal meningitis cryptococcal meningitis P value
n = 68 n = 14
Meningeal signs 12 (14.6) 8 (11.8) 4 (28.6)

Initial altered mental status(
15 (22.1) 6 (42.9) 0.18
scale ≤13)
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) 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) 0.79
CSF India ink positive 57 (85) 14 (100) 0.20
CSF culture positive 64 (97) 14 (100) 1.0
Blood culture positive for
35 (75) 8 (80) 1.0
Cryptococcus species

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 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


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 Block shunt, 3 times Died from uncontrolled infection
craneotomy
4 Subtemporal descompression no Good with rapid recovery of vision
5 External descompression, VP shunt Block shunt, 3 times Good
1w later

6 External ventricular drainaga, VP no Good
shunt 1 we later

7 VP shunt Block shunt, once Good
shunt 1 we later

9 VP shunt Block shunt, once Severe dsiability (blind and partially deaf)
shunt 1 we later

11 VP shunt No Good

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

Shunts can be placed in context of active infection

copyright to Edward Cachay MD, Nov 2012 Park et al Clin Infect Dise.1999 Mar;28(3):629-33

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 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 alive

Copyright Edward Cachay M.D. Cachay et al-Owen clinic unpublished data
November 2011


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, 12 Diffuse cerebral edema
blindness
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

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

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