Accepted Manuscript

Isolated Cerebral Aspergillosis in Immunocompetent Patients

Rakan Bokhari, MBBS Saleh Baeesa, MBChB, FRCSC, FAANS Jaudah Al-Maghrabi,
MBBS, FRCPC Tariq Madani, MBBS, FRCPC
PII: S1878-8750(13)01225-4
DOI: 10.1016/j.wneu.2013.09.037
Reference: WNEU 2134
To appear in: World Neurosurgery
Received Date: 21 June 2013
Accepted Date: 18 September 2013
Please cite this article as: Bokhari R, Baeesa S, Al-Maghrabi J, Madani T, Isolated Cerebral
Aspergillosis in Immunocompetent Patients, World Neurosurgery (2013), doi: 10.1016/
j.wneu.2013.09.037.
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Isolated Cerebral Aspergillosis in Immunocompetent Patients

Rakan Bokhari, MBBS
Saleh Baeesa, MBChB, FRCSC, FAANS
Jaudah Al-Maghrabi, MBBS, FRCPC
Tari Madani, MBBS, FRCPC

Affiliations:
!i"ision o# Neurosurger$ %RFB, SSB&, !e'art(ents o# Patholog$ %JAA&, and !e'art(ent o#
Medi)ine %TAM&, Fa)ult$ o# Medi)ine, *ing Abdula+i+ ,ni"ersit$, Jeddah, Saudi Arabia

Running title: -solated Cerebral As'ergillosis
Conflict of interest statement:
The authors de)lare that the arti)le )ontent .as )o('osed in the absen)e o# an$ )o((er)ial or
#inan)ial relationshi's that )ould be )onstrued as a 'otential )on#li)t o# interest.

Correspondence/
Saleh Baeesa, MBChB, FRCSC, FAANS
!i"ision o# Neurosurger$, Fa)ult$ o# Medi)ine
*ing Abdula+i+ ,ni"ersit$
P.0. Bo1 23415
Jeddah 41526
*ingdo( o# Saudi Arabia
7-(ail/ sbaeesa8kau.edu.sa
Fa1/ 96::-4-:;32<;=
Mobile/ 96::555:632<4



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ABSTRACT
Objective:
-solated )erebral as'ergillosis %-CA& has been traditionall$ asso)iated .ith i((uno)o('ro(ised
'atients .ith dis(al out)o(es. Cases o# -CA in the i((uno)o('etent are "er$ rare and 'oorl$
des)ribed. >e des)ribe our e1'erien)e o# #i"e i((uno)o('etent 'atients .ith -CA and
)o('are the( to the literature.
Metods/
Fi"e other.ise health$ i((uno)o('etent 'atients .ith -CA .ere diagnosed in the 'eriod
166:-4311 at *ing Abdula+i+ ,ni"ersit$ ?os'ital, Jeddah, Saudi Arabia. Medi)al re)ords o# the
'atients .ere re"ie.ed .ith standardi+ed data )olle)tion in)luding de(ogra'hi)s, )lini)al
'resentation, radiologi)al #eatures, histo'atholog$ results, treat(ent and out)o(e.
Results/
All the #i"e 'atients had radiologi)al e"iden)e o# )erebral disease@ 'urel$ 'aren)h$(al in #our
and dural-based in one. The 'aranasal sinuses and lungs .ere radiologi)all$ )leared in all
'atients. All under.ent rese)tion .ith anti#ungal thera'$. All 'atients .ere #e(ale .ith a (ean
age o# 4< $ears %range, 1<-<: $ear&. ?eada)he %nA5& and sei+ures %nA;& .ere the 'ri(ar$
'resenting (ani#estations. Fi"e 'atients had brain (agneti) resonan)e i(aging %MR-& and ;
'atients had )o('uted to(ogra'h$ %CT& i(aging 'reo'erati"el$. The diagnosis .as b$
histo'atholog$ %n A 5& orBand #ungal )ultures %n A <& o# the e1)ised (ass.
Surgi)al rese)tion .as )arried out in all 'atients #ollo.ed b$ treat(ent .ith a('hoteri)in B #or
4-; .eeks then oral "ori)ona+ole #or : (onths. 0"erall (ortalit$ .as 43C %nA1&. Follo. u' .as
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(aintained #or an a"erage o# <4 (onths %range 14-51 (onths& .ith inter"al a)uisition o# brain
MR- to do)u(ent eradi)ation.
Conclusion/
-CA in other.ise health$ i((uno)o('etent hosts see(s to ha"e (ore #a"orable 'rognosis
than .hat is re'orted #or i((uno)o('ro(ised hosts.

!e" #ords:
As'ergillosis, Cerebral, Fungal in#e)tion, -((uno)o('etent hosts, Surger$

Abbreviations and Acron"ms:
AT-B/ Di'oso(al A('hoteri)in B
-CA/ -solated )erebral as'ergillosis
-CE/ -tra)ona+ole
CT/ Co('uted to(ogra'h$
MR-/ Magneti) resonan)e i(age
MRS'e)t/ Magneti) resonan)e s'e)tros)o'$
FCE/ Fori)ona+ole

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Introduction:
As'ergillus s'. is a sa'ro'h$ti) (old ubiuitous in the surrounding en"iron(ent.
Although (an$ s'e)ies ha"e been des)ribed, the (aGorit$ o# diseases are )aused b$ A. flavus, A.
fumigatus and A. niger, ea)h re)ogni+ed to ha"e its o.n geogra'hi) distribution and )lini)al
beha"ior. -n our dr$, hot )li(ates o# the Middle 7ast, A.flavus is the 'redo(inant 'athogeni)
s'e)ies %14,<2&.
-n"asi"e As'ergillus in#e)tion usuall$ o))urs in the setting o# )o('ro(ised i((une
s$ste( .ith "er$ #e. )ases re'orted a(ong the i((uno)o('etent hosts %<, :, 13, 11,1;, 15,
1=, 44,4:, <1,<<,<:&. The (aGorit$ o# re'orted )ases either had another e1tra)ranial #o)us %11,
<1, <<& or an i((une s$ste( that .as te('oraril$ )o('ro(ised %6& or )on)urrent illnesses %<&.
-solated )erebral as'ergillosis %-CA&, .ithout sino'ul(onar$ #o)us and in other.ise health$
'atients is e1)eedingl$ rare, .ith onl$ a #e. s)attered )ases re'orted in the literature %5, :,
13,1=,44,4:, <:&. The )lini)al beha"ior o# these re'orted )ases a''ear to be distin)tl$ benign,
.ith all a''ro'riatel$ (anaged 'atients (aking une"ent#ul re)o"eries %:,13, 1=,4:,<:&. This is
in stark )ontrast to the ab$s(al out)o(es o# )erebral as'ergillosis (entioned in the literature
%1:,42,46&.
>e herein re'ort an additional #i"e )ases o# -CA in a''arentl$ i((uno)o('etent
'atients. This re'resents our )enterHs e1'erien)e .ith this rare entit$ o"er the 'ast 15 $ears.
>e ai( to shed light on the )lini)al #eatures, diagnosis, and treat(ent o# this disease .ith
s'e)ial e('hasis on the 'ossible 'rognosti) indi)ators in other.ise health$ 'atients.
Patients and Metods/
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Fro( Januar$ 166: to !e)e(ber 4311, #i"e 'atients .ith isolated %.ithout e1tra)ranial disease,
s'e)i#i)all$ noting sinonasal and 'ul(onar$& )erebral as'ergillosis in other.ise health$ and
i((uno)o('etent 'atients .ere diagnosed and treated at *ing Abdula+i+ ,ni"ersit$ ?os'ital,
Jeddah, Saudi Arabia. The (edi)al re)ords database o# those .ho #ul#illed the in)lusion )riteria
.as retros'e)ti"el$ re"ie.ed. -denti#ied re)ords .ere re"ie.ed .ith standardi+ed data
)olle)tion in)luding 'atient de(ogra'hi)s, )lini)al 'resentation, )o-(orbidities, radiologi)
#eatures, 'atholog$ #indings, diagnosis, treat(ent, )o('li)ations, and out)o(e.
Inclusion/Exclusion Criteria:
The stud$ in)luded all 'atients .ho had/ 1. a )erebral lesion non-)ontiguous .ith the 'aranasal
sinuses@ 4. absen)e o# )lini)al and radiologi)al e"iden)e o# oti), or sinonasal disease@ <.
histo'atholog$ or )ulture o# surgi)all$ e1)ised s'e)i(ens )on#ir(ing )erebral as'ergillosis@ and
;. absen)e o# i((unosu''reesion or an$ s$ste(i) disease. Paranasal sinuses and oti)
in"ol"e(ent .as e"aluated using the sa(e (agneti) resonan)e i(age %MR-& and )o('uted
to(ogra'h$ %CT& studies ordered #or the )erebral lesions as the$ o##er adeuate "isuali+ation
do.n to the (a1illar$ sinuses and (astoid air )ells. Patients .ith an$ sinus or (astoid air )ells
o'a)i#i)ation or (u)osal thi)kening .ere e1)luded. Patients .ere e"aluated #or 'ul(onar$
in"ol"e(ent b$ re"ie.ing their )harts #or res'irator$ s$('to(s and their ad(ission )hest
radiogra'hs. Patients .ere )onsidered i((uno)o('etent as indi)ated b$ absen)e o#
)on)o(itant or 're"ious )hroni) disease su)h as diabetes (ellitus, al)oholis(, leu)o'enia,
hu(an i((unode#i)ien)$ "irus in#e)tion, ad"an)ed li"er or kidne$ disease, (alignan)$, organ
trans'lantation, treat(ent .ith i((unosu''ressi"e or )orti)osteroid (edi)ations, or
intra"enous drug abuse.
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Investigations:
All 'atients on ad(ission had routine blood .orks, in)luding/ )o('lete blood )ount, li"er and
renal #un)tion, #asting blood sugar, and )hest roentgenogra(. 7r$thro)$te sedi(entation rate,
C-rea)ti"e 'rotein le"els .ere ordered in three 'atients. Radiologi)al studies in)luded a1ial and
)oronal CT s)an o# the brain and 'aranasal sinuses and MR- o# the brain .ithout and .ith
intra"enous )ontrast ad(inistration and (agneti) resonan)e s'e)tros)o'$ %MRS'e)t& in all
'atients. All 'atients had 'osto'erati"e MR- brain s)ans .ithin ;2 hours, < (onths a#ter
surger$, and then e"er$ : (onths #or 4 $ears.
Surgical intervention:
All our 'atients under.ent i(age-guided )ranioto($ and (i)rosurgi)al rese)tion in our )enter,
using the ultrasoni) as'irator. -ntrao'erati"e (otor )orte1 (a''ing .as 'er#or(ed in one
'atient .ith rolandi) )orte1 in"ol"e(ent %)ase 4&. This 'atient had 'rior i(age-guided bio's$
and then under.ent )ranioto($ and rese)tion.
Histological and Microbiological Diagnosis:
!iagnosis .as established b$ tissue )ulture and histologi)al and i((unohisto)he(i)al staining
e1a(ination o# the s'e)i(en. The 'roo# o# the diagnosis .as (ade b$ the 'resen)e o#
as'ergillus gro.th and or the )hara)teristi) h$'hae bran)hing 'attern.
Antifungal thera!:
Anti#ungal thera'$ .as initiated i((ediatel$ a#ter the diagnosis o# isolated )erebral
as'ergillosis .as (ade. T.o 'atients .ere treated .ith intra"enous li'oso(al A('hoteri)in B
%AT-B& gi"en at 5(gBkg slo. in#usion on)e dail$ #or 1; da$s a#ter surgi)al e1)ision, #ollo.ed b$
oral "ori)ona+ole %FCE& #or : (onths in one %)ase 4& and itra)ona+ole %-CE& in the other %)ase <&.
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0ne 'atient .as treated .ith FCE ;33 (g -F loading dose, #ollo.ed b$ 433 (g orall$ t.i)e dail$
#or : (onths %)ase ;&. The re(aining 'atient %)ase 1& .as treated .ith AT-B #or 1; da$s, then
-CE #or 1; da$s, then FCE until her de(ise 4 .eeks later.
"utcome:
Clini)al #ollo. u' .as obtained #ro( the (edi)al re)ords to deter(ine the out)o(e and
)o('li)ations o# the disease in)luding the de"elo'(ent o# an$ 'osto'erati"e neurologi)al
de#i)its or .orsening o# 're-e1isting ones. The #ollo. u' 'eriod ranged #ro( 14 to 51 (onths
.ith a (ean o# <4 (onths.
Results:
Demograhics:
T.ent$-#our 'atients .ith histologi)all$ )on#ir(ed )erebral as'ergillosis .ere identi#ied in the
stud$ 'eriod@ 1: o# these 4; 'atients had e1tra)erebral as'ergillosis, 15 .ith )erebrall$ in"asi"e
#ungal sinusitis, and one .ith in"asi"e 'ul(onar$ as'ergillosis. 0ne 'atient .as e1)luded
be)ause o# de#i)ient in#or(ation in his (edi)al re)ord. T.o i((uno)o('ro(ised 'atients .ith
-CA .ere e1)luded. The re(aining 5 i((uno)o('etent 'atients .ith -CA .ere identi#ied.
The #i"e 'atients .ere #e(ale .ith a (ean age o# 4< $ears %range, 1< - <: $ears&. The )lini)al
)hara)teristi)s and )lini)al 'resentations o# the #i"e 'atients are su((ari+ed in table 1.
#aborator! and $adiological findings:
The 'reo'erati"e blood tests a signi#i)antl$ ele"ated 7SR and CRP in one %)ase 1& o# the three
'atients #or .ho( the$ .ere ordered, other.ise all labs .ere nor(al %table 1&. Chest
radiogra'hs o# all 'atients .ere nor(al. The radiologi)al )hara)teristi)s o# CT and MR- studies
o# the -CA .ere su((ari+ed in table 4. All studies ha"e sho.ed nor(al 'aranasal sinuses and
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(astoid air )ells. The #ungal (ass lesions .ere solitar$ in all and right-sided in ; 'atients. All
#i"e 'atientsI #ungal (asses .ere sub)orti)all$ lo)ated in the )erebru(@ 1 #rontal, 4 'arietal,
and 4 o))i'tote('oral. The a"erage lesionHs si+e .as <.<; )( in (a1i(al dia(eter .ith (arked
surrounding ede(a. The CT brain radiologi)al #eatures in)luded a solitar$ rounded lesion that
.as isodense to gre$ (atter .ith #aint ho(ogenous enhan)e(ent in 4 'atients and
isoBh$'odense lesion .ith (ini(al 'eri'heral enhan)e(ent o# the .all in < 'atients. MR- s)ans
sho.ed the lesions to be isoBh$'ointense in T1-.eighted i(ages %T1>-& in all #i"e 'atients. 0n
T4-.eighted i(ages %T4>-& studies the lesions .ere either )o('letel$ isointense %4 )ases& or
isointense at the )enter .ith h$ointense .all. The 'attern o# enhan)e(ent .as either
ho(ogenous %4 'atients& or 'eri'heral ring enhan)e(ent %< 'atients&. MRS'e)t #indings .ere
not )on)lusi"e@ onl$ one 'atient had lo. )holineBN-A)et$l As'artate %NAA& 'eaks and high
li'idBla)tate 'eaks, .hi)h .ere suggesti"e o# in#la((ator$ 'ro)ess. The re(aining ; 'atients
had high )holineBNAA 'eaks .ith absent li'idBla)tate 'eaks, .hi)h .ere suggesti"e o#
(alignant tu(ors.
The 'reo'erati"e radiologi)al i('ression .as (alignant glio(a in < and l$('ho(a in another.
The lesion in the #i#th 'atient .as belie"ed to be a tuber)ulo(a #or .hi)h the 'atient .as
initiated on antituber)ulous thera'$ in another )enter < .eeks 'rior to her 'resentation to our
)enter.
Histoathological and Microbiological findings:
Mi)ros)o'i) e1a(ination o# the he(ato1$lin-eosin %?J7& stained s'e)i(en re"ealed t$'i)al
granulo(atous rea)tion .ith in#la((ator$ )ells, (ultinu)leate giant )ells, e'ithelioid )ells,
areas o# ne)rosis and )ollagenous )onne)ti"e tissue in ; sa('les %table 1&. The s'e)i(en o# the
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#i#th 'atient %)ase 1& la)ked a granulo(atous rea)tion but sho.ed in#la((ator$ and
(ultinu)leated giant )ells %Figure <A,B&. All had )hara)teristi) broad h$'hae .ith ;5 degree
bran)hing and )onidia seen .ith 'eriodi) a)id-shi## %PAS& and Ko(ori (ethana(ine sil"er
%KSM& stains %Figure < C,!&. Fungal )ultures on Sabouraud agar .ere 'ositi"e in three out o# #i"e
'atients #or As'ergillus #la"us.
Management:
The treat(ent o# our 'atients .ere su((ari+ed in table <.-(age-guided bio's$ .as the initial
'ro)edure #or one 'atient %)ase 4& that a''eared radiologi)all$ to be a high-grade (alignan)$.
-n the re(aining )ases, the tu(or .as dee(ed rese)table and that .as the 'ri(ar$ ai(. 0n)e
the diagnosis .as )on#ir(ed to be #ungal disease, the (anage(ent .as altered in three
'atients. The one 'atients that under.ent an i(age-guided bio's$ .ere taken ba)k to the
o'erating roo( #or de#initi"e rese)tion %)ase 4&, .hile in another 'atient %)ase <&, the
intrao'erati"e (otor )orte1 (a''ing )aused the surgeon to #orego aggressi"e rese)tion near
the (otor )orte1, lea"ing a 1 )( residual lesion. 0'erati"e a''earan)e in our )ases )onsisted o#
a tough tan-bro.n (ass .ith an al(ost )artilaginous )onsisten)$ and hone$)o(b like
stru)ture. Mi)rosurgi)al e1)ision )ould be sa#el$ a)hie"ed 'ie)e(eal using ultrasoni) as'irator.
0ne notable e1)e'tion .as that o# )ase %1& .hose lesion .as so#ter in )onsisten)$ .ith no
'lane e1isting bet.een nor(al brain and the (ass.
Comlications:
0ne 'atient %)ase 1& had deteriorated 4 .eeks 'osto'erati"el$, .ith the de"elo'(ent o# a high-
grade #e"er, regro.th o# the (ass and resistant brain ede(a des'ite thera'$ .ith AT-B #or 4
.eeks, -CE #or 4 .eeks, and FCE #or the last 4 .eeks o# her li#e a#ter sho.ing no i('ro"e(ent.
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She 'assed a.a$ : .eeks 'osto'erati"el$ .ith the 'arents re#using re'eat surger$. The other ;
'atients had une"ent#ul o'erations. All our 'atients de"elo'ed signi#i)ant h$'okale(ia %*L4.5&
.hile on AT-B@ none had de"elo'ed signi#i)antl$ disturbed kidne$ #un)tion. FCE .as .ell
tolerated .ith onl$ one ad"erse rea)tion, transient "isual obs)uration %)ase 4&. None o# the
'atients reuired )essation o# treat(ent.
Clinical "utcome:
-n our series, #our o# the #i"e 'atients had an unre(arkable 'osto'erati"e )ourse %'atients 4-5&
and re(ained disease-#ree on #ollo. u' MR- s)ans. The re(aining 'atient %'atient 1& initiall$
i('ro"ed in the #irst 4 .eeks 'osto'erati"el$ but her )ondition deteriorated and she 'assed
a.a$ : .eeks 'ost o'erati"el$, .ith #urther inter"ention re#used.
$iscussion:
-n"asi"e in#e)tion b$ As'ergillus s'. is usuall$ a )onseuen)e o# the hostIs de'ressed i((une
#un)tion. Dess )o((onl$, this in#e)tion (a$ o))ur in the a''arentl$ i((uno)o('etent
subGe)ts %<1,1;&. Most o# these )ases are sino'ul(onar$, .hi)h is e1'e)ted )onsidering the
(oldIs )oloni+ation 'atterns %4,<1,<5&.
-n"ol"e(ent o# the brain b$ in"asi"e #ungal disease is a "er$ (orbid entit$ .ith dis(al )lini)al
out)o(es, the o"erall (ortalit$ being in the range o# 63-133C %1:,42,46&. Re'orts o# )erebrall$
in"asi"e as'ergillus in#e)tions in a''arentl$ health$ i((uno)o('etent subGe)ts are also not
reassuring, e"en .ith surgi)al inter"ention and adGun)ti"e thera'$ %<1, 44, 41, 6&. ?o.e"er, a
)loser look at the 're"iousl$ re'orted )ases re"eals the 'resen)e o# #a)tors that (a$ ha"e
)ontributed to the obser"ed 'oor out)o(es. These #a)tors in)lude i((unosu''ression
te('orar$ or other.ise as a result o#/ steroid or )$toto1i) drug use, ad"an)ed li"er disease,
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diabetes (ellitus, )hroni) al)oholis(, end stage renal disease and (etastati) (alignan)$ %4<&.
Another #eature )o((on to (ost o# these )ases is the 'resen)e o# another disease or #o)us o#
in#e)tion that (a$ be a )on#ounding sour)e o# (orbidit$ and (ortalit$ %11,<1,<<&.
There is a dearth o# literature on in"asi"e As'ergillus disease 'resenting as isolated brain
lesions in a''arentl$ i((uno)o('etent, other.ise health$ hosts %<, 5,:, 13, 15,1=,44, 4:,<:&.
The la)k o# in#or(ation about CNS as'ergillosis in this 'arti)ular subset o# 'atients (akes
in#or(ed )ounseling on 'rognosis in this sele)t 'o'ulation "er$ di##i)ult.
Another )hallenge 'osed b$ the absen)e o# i((unosu''ression or another #o)us o# in#e)tion
%t$'i)all$ sinonasal or 'ul(onar$& is the di##i)ult$ o# sus'e)ting #ungal disease, as these are the
usual )lini)al 'ointers to suggest #ungal disease, 'arti)ularl$ .hen there is dire)t e1tension #ro(
the sinuses.
The absen)e o# e1tra)ranial in"ol"e(ent also narro.s the o'tions #or obtaining tissue sa('les
#or histo'atholog$ and )ulture. Atte('ts, there#ore, ha"e been (ainl$ )on)entrated on
identi#$ing 'athogno(i) radiologi) signs %2,4;,45,<4& and diagnosti) serologi) (arkers %1,12& to
a"oid the unne)essar$ (orbidit$ o# a brain bio's$. This goal un#ortunatel$ re(ains elusi"e.
The ad"ent o# e##e)ti"e anti#ungal treat(ent and the in"ol"e(ent o# (ulti'le dis)i'lines ha"e
resulted in a do)u(ented i('ro"e(ent in sur"i"al. Ne"ertheless, the 'rognosis #or this disease
re(ains gri(. A re)ent large )ohort o# i((uno)o('ro(ised on)olog$ 'atients sho.ed sur"i"al
rates o# <1C at a (edian o# <63 da$s #ollo. u' .ith o'ti(al thera'$ %42&. An aggressi"e surgi)al
a''roa)h in non-i((uno)o('ro(ised 'atients .ith "arious #ungal diseases in"ading the CNS
hel'ed redu)e the (ortalit$ to <6C in an older series %;3&. A (ore re)ent series o#
i((uno)o('etent 'atients .ith )erebrall$ in"asi"e sinus disease had a (ortalit$ rate o# ::C
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des'ite (ulti(odal thera'$ and being other.ise health$ %<1&. No re"ie. has e"aluated
out)o(es o# health$ i((uno)o('etent 'atients .ith no )o-(orbidities or e1tra)ranial disease
.ho ha"e undergone o'ti(al and ti(el$ treat(ent. The )ounseling o# these 'atients on
'rognosis i# a''ro'riate thera'$ is ad(inistered there#ore re(ains under in#or(ed.
A re"ie. o# literature %Table ;& sho.s that onl$ #i"e )ases )on#or(ed to our )riteria and
re)ei"ed ti(el$ adeuate treat(ent, .ith all sho.ing e1)ellent res'onse to treat(ent,
e1)lusi"el$ (edi)al in one %13&, (ulti(odal in another three %:,1=,4:& and, rather sur'risingl$,
e1)lusi"el$ surgi)al in the re(aining )ase %<:&. An -ndian series o# 2 'atients %5&, although the
largest in the literature, .as not suitable #or in)lusion in our anal$sis sin)e it in)luded 'atients
.ho .ere de)lared #ree o# sinonasal disease b$ sinus 1-ra$s, a 'oorl$ sensiti"e in"estigation #or
sinusitis %;&. Their #ollo. u' .as short and reliant on s$('to(s to dete)t re)urren)e. !es'ite
that, the #ailure rate in that series .as 53C, .ith 4 'atients d$ing and another t.o .ith
re)urren)e o# s$('to(s in a relati"el$ short #ollo. u' 'eriod o# :-14 (onths. The #ailure rate
in that series (ight ha"e been higher had the #ollo. u' 'eriod been e1tended or had an MR-
been a)uired during that 'eriod.
Three other )ases o# -CA in i((uno)o('etent 'atients .ere #ound in the literature %<,15,44&.
T.o ended .ith #atal out)o(es/ due to )on)urrent disse(inated a(oebiasis in one %<&, and
non-)o('lian)e .ith FCE in the other a#ter an initial #a"orable res'onse %44&. 0ne additional
)ase .as e1)luded due to la)k o# (ention o# the 'osto'erati"e )ourse and 'resen)e o# lung
in#iltrates that .ere not in"estigated %15&. These three )ases are there unsuitable to dra.
)on)lusions #ro(, be)ause out)o(e assess(ent is la)king, or a##e)ted b$ e1trinsi) #a)tors
unrelated to disease or thera'$.
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>e atte('ted to address the de#i)ien)$ o# out)o(e assess(ent o# this entit$ in the literature
b$ des)ribing our e1'erien)e in addition to suggesting 'redi)tors o# a good 'rognosis .ith
thera'$, other than i((uno)o('eten)e, and )o('aring the( to si(ilar )ases in the literature.
The 'redi)tors .e re)ogni+ed .ere 'atient-related, radiologi), histo'athologi) and treat(ent-
related.
%atient Characteristics:
0ur 'atients had no sinonasal, oti), or 'ul(onar$ in"ol"e(ent@ #a)tors that (a$ )o('li)ate the
surgi)al (anage(ent or a)t as inde'endent sour)es o# (orbidit$. The$ .ere also not kno.n to
be diabeti) or i((unosu''ressed b$ (edi)ation, (alnutrition or s$ste(i) disease. Fi"e si(ilar
)ases ha"e been des)ribed in the literature as s'oradi) )ase re'orts .ith good out)o(es %table
;&. Another i('ortant 'redi)tor o# 'osto'erati"e out)o(e in our series is #un)tional status on
'resentation, .ith all #our .ho 'resented in a good state (aking a #ull re)o"er$ and returning
to their nor(al li"es, this .as also )onsistent in #our o# the other #i"e )ases in the literature all
o# .ho( sur"i"ed.
$adiologic %rognostic Indicators:
The enhan)e(ent 'attern a#ter )ontrast inGe)tion is )onsidered a #un)tion o# the 'atientIs
i((une res'onse %<6&. 0ur series is )onsistent .ith this, suggesting a"id )ontrast u'take as a
(arker o# good 'rognosis %133C sur"i"al&. Both )ases .ith )ore enhan)e(ent sur"i"ed %133C
sur"i"al&, .hile one o# the three )ases .ith ring enhan)ing lesions did not %::.= C sur"i"al&. The
(ortalit$ )ase in our series .as the onl$ one .ith a .eakl$ enhan)ing .all. Fro( the #i"e )ases
in the literature/ three .ere .ith a"id )ore u'take o# )ontrast, %13,1=,4:&. The t.o other )ases
.ere ring enhan)ing %:& and heterogeneousl$ enhan)ing %<:&.
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The utilit$ o# MRS'e)t in diagnosis is de'endent on )o('aring the )holine le"els in the other
he(is'here, an absolute ele"ation )onsistent .ith glio(as and a si(ilar le"el )onsistent .ith
as'ergillo(as %4;&. MRS'e)t (ight be "aluable in do)u(enting re)o"er$ and 'rognosis, .ith
in)reasing NAA le"els )orrelating .ith a resol"ing in#e)tion %<=&. 0ur MRS'e)t #indings .ere
si(ilar to that (entioned in the literature .ith )holine s'ikes in all )ases e1)e't one %table 4&.
No )o('arison .as (ade .ith that o# the )ontralateral side and no )orrelation #ound .ith
out)o(e. Ado'ting a rese)ti"e strateg$ 're"ented serial )o('arison o# MRS'e)t o"er ti(e.
Effect of Surgical Extent on "utcome:
A re)ent s$ste(ati) re"ie. o# the subGe)t re"ealed that the e1tent o# surger$ did not )orrelate
.ith )lini)al out)o(e, thus adding to the )ontro"ers$ surrounding .hat )onstitutes o'ti(al
(anage(ent o# this disease in the neurosurgi)al )o((unit$ %<2&. Neurosurgi)al inter"ention,
'er se, though, has been asso)iated .ith i('ro"ed out)o(es and sur"i"al %4=, 46&. Surger$
o##ers the theoreti) ad"antage o# de)reasing #ungal load, allo.ing better anti#ungal
'enetration, relie"ing (ass e##e)t and de)reasing the lo)al neuroto1i) and in#la((ator$ e##e)t
e1erted b$ the #ungal in#e)tion %<;&. The degree o# rese)tion is still a (atter o# )ontinuing
debate in the (anage(ent o# )erebral as'ergillosis. So(e re)o((end a )onser"ati"e surgi)al
a''roa)h %<1&, .hile others ad"o)ate aggressi"e and radi)al rese)tions as a (eans o# )ure %41&.
0ur series lends su''ort to 'ro'onents o# the latter a''roa)h o# aggressi"e rese)tions as long
as elouent areas are not "iolated. Da)k o# skull base in"ol"e(ent allo.ed us to e"ade the
(orbidit$ o# )erebros'inal #luid %CSF& leaks #ollo.ing its re)onstru)tion. Although t.o o# the
#i"e )ases in the literature re)ei"ed no debulking surger$, i('ro"ing solel$ on FCE %13&.
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An i('ortant issue to anti)i'ate .ith the surgi)al (anage(ent o# this disease is an o))asionall$
obser"ed sudden deterioration 'osto'erati"el$ %<3&. This is )hara)teri+ed b$ 'osto'erati"e
h$'erther(ia and (alignant brain ede(a and has a "er$ 'oor 'rognosis. >e belie"e one o# our
'atients %)ase 1& had su))u(bed to this. So(e ha"e 'ro'osed that 'reo'erati"e anti#ungals
(a$ be 're"enti"e, but this is $et to be 'ro"en %<3, <1&. -t is also .orth (entioning that unlike
(an$ o# the )ases re'orted, .e did not en)ounter a single )ase .ith 'osto'erati"e is)he(i)
de#i)it, des'ite it being rather )o((on in the literature %43&.
Histoathologic &eatures Correlating 'ith %rognosis:
T.o (ain rele"ant #eatures asso)iated .ith good out)o(es are the robustness o# the
in#la((ator$ res'onse and the absen)e o# angioin"asi"eness. These )hara)teristi)s .ere noted
in all our sur"i"al )ases, .ith the (ortalit$ )ase dis'la$ing a la)k o# .ell #or(ed granulo(atous
rea)tion but no e"iden)e o# angioin"asi"eness. Angioin"asi"eness is a (aGor sour)e o# (orbidit$
in these in#e)tions and their absen)e resulted in a #ortunate absen)e o# is)he(i) and
he(orrhagi) )o('li)ations a##e)ting our out)o(es %43&.
(he choice of Antifungal drugs:
The o"erall i('ro"e(ent in sur"i"al o# )erebral as'ergillus in#e)tions is largel$ attributed to the
dis)o"er$ o# e##e)ti"e no"el anti#ungal thera'euti)s. FCE has been 'ro"en (ore e##e)ti"e than
AT-B .ith #e.er side e##e)ts .hile a)hie"ing better CSF 'enetration %1<, 42&. The )o(bination
o# these t.o (edi)ations, ho.e"er, has been #ound to be s$nergisti) and is )urrentl$ the
re)o((ended regi(en %=&. The 'reo'erati"e initiation o# thera'$ has also been asso)iated .ith
better out)o(es %<1&.
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-n our series, )o(bination anti#ungal thera'$ o# FCE and AT-B has been ad(inistered to #our o#
our sur"i"al )ases in a ti(el$ (anner, .hile in the (ortalit$ )ase .e used -CE instead, an
in#erior )hoi)e %46&. FCE .as ad(inistered as sal"age #our .eeks later due to its una"ailabilit$
at the ti(e. A(ong the #i"e )ases in the literature %.e e1)luded one due to non-)o('lian)e
.ith FCE .ith #atal out)o(es %44&, it .as initial sole thera'$ in one )ases .ith su))ess %13&, and
'ro"ed also su))ess#ul in another 'osto'erati"el$ as sal"age thera'$ %:&. The e1)e'tions either
relied on a('hoteri)in in )onGun)tion .ith surger$ %1=,4:& or re#used thera'$ %<:&@ all sur"i"ed.
This res'onse rate )o('ares #a"orabl$ to series o# i((uno)o('ro(ised 'atients re)ei"ing FCE
(entioned else.here in the literature %4=& and to those .ith i((uno)o('etent 'atients
re)ei"ing non-FCE regi(ens %<1&.
Conclusions/
-CA is a rare entit$ .hose out)o(e is not .ell des)ribed in the literature. Although
'reo'erati"e identi#i)ation re(ains elusi"e, the )o(bination o# radiologi) and s'e)tros)o'i)
#eatures in addition to serolog$ #or the dete)tion o# As'ergillus antigens (a$ be o# hel'.
Radiologi) )hara)teristi)s %na(el$ e1tent o# )ontrast u'take& .ere )orrelated .ith sur"i"al in
our series, in addition to histologi) #eatures %la)k o# angioin"asi"eness and a robust
granulo(atous res'onse&. 0ur series lends )reden)e to ad"o)ates o# an adeuate %not
ne)essaril$ )o('lete& redu)tion in the #ungal load b$ surgi)al rese)tion .hen .aiting #or the
e##e)t o# anti#ungals is not an o'tion. The sur"i"al rate o# 23C in our series and 63C .hen
a))ounting #or the additional #i"e )ases in the literature is better than that (entioned in the
literature #or )erebral as'ergillosis in general, and should 'ro"ide reassuran)e to 'h$si)ian and
'atient alike .hen en)ountering su)h )ases in 'ra)ti)e. >e attribute this high sur"i"al rate to
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i((uno)o('eten)e, absen)e o# additional #o)i o# disease, unusual la)k o# )erebro"as)ular
)o('li)ations and a"ailabilit$ o# e##e)ti"e anti#ungal treat(ent. -t re(ains to be seen .hether
ne.er anti#ungals .ill #urther i('ro"e disease out)o(es.


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Culture su'ernatants o# 'atient-deri"ed As'ergillus isolates ha"e to1i) and l$ti) a)ti"it$
to.ards neurons and glial )ells. F7MS -((un Med Mi)robiol 46/<3<-<1<, 4333.
<5. Ste"ens !A, *an FD, Judson MA, Morrison FA, !u((er S, !enning !>, Bennett J7,
>alsh TJ, Patterson TF, Panke$ KA: Pra)ti)e guidelines #or diseases )aused b$
As'ergillus. Clin -n#e)t !is <3/ :6:-=36, 4333.
<:. Thakar S, Chi)kabasa"iah OT, ?egde AS/ S'ontaneous resolution o# in"asi"e )erebral
as'ergillosis #ollo.ing 'artial rese)tion in a (edi)all$ untreated in#ant. J Neurosurg
Pediatr 13 %1&/ =1-=;, 4314.
<=. Turgut M, 0+sunar O, 0n)Q S, Ak$Q+ 0, 7rtuRrul MB, Tekin C, KQltekin B, Sakar$a S:
-n"asi"e #ungal granulo(a o# the brain )aused b$ As'ergillus #u(igatus/ a )ase re'ort
and re"ie. o# the literature. Surg Neurol :6 %4&/ 1:6-1=;, 4332.
<2. >ebb BJ, Fikra( ?R/ Chroni) in"asi"e sinus as'ergillosis in i((uno)o('etent hosts/ a
geogra'hi) )o('arison. M$)o'athologia 1=3 %:&/ ;3<-;13, 4313.
<6. Oa(ada *, Eoarski K?, Roth(an M-, Eagardo MT, Nishi(ura T, Sun CC/ An intra)ranial
as'ergillo(a .ith lo. signal on T4-.eighted i(ages )orres'onding to iron
a))u(ulation. Neuroradiolog$ ;< %=&/ 556-:1, 4331.
;3. Ooung RF, Kade K, Krinnell F/ Surgi)al treat(ent #or #ungal in#e)tions in the )entral
ner"ous s$ste(. J Neurosurg :</<=1-<=2, 1625.
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%igure &egends
%igure ':
Preo'erati"e i(aging s)ans o# 'atient 1 de(onstrating a right 'arietal isodense lesion .ith
surrounding ede(a on 'lain CT s)an (A) .ith enhan)ed ho(ogenousl$ (B). The lesion .as
isointense in T1>- (C) and h'ointense in T4>- s)an ($) .hi)h enhan)ed ho(ogeneousl$ and
has indistin)t borders (*+%+,). MRS'e)t de(onstrated high )holineBlo. NAA 'eaks (-).
%igure .:
Preo'erati"e i(aging s)ans o# 'atient < de(onstrating a right 'arietal lesion .ith isodense .all
and h$'odense )enter in 'lain CT s)an (A) that has 'eri'heral enhan)e(ent (B). The lesion .as
isoBh$'odense on T1>- (C) and h$'ointense in T4>- s)ans ($) .hi)h enhan)ed 'eri'herall$
(*+%+,). MRS'e)t de(onstrated lo. )holineBNAA and high li'idBla)tate 'eaks (-).
%igure /:
A: Photo(i)rogra'h at lo. 'o.er se)tion re"eals )hroni) granulo(atous in#la((ations .ith
nu(erous (ultinu)leated giant )ells .ith e1tensi"e areas o# ne)rosis a''ear in the )enter.
%?J7 stain, S133&. B: At higher 'o.er se)tion, (ultinu)leated giant )ells .ith e('t$ s'a)es
re'resent the #ungal organis(s are de(onstrated. %?J7 stain, S;33&. C: Photo(i)rogra'h
de(onstrating se'tated #ungal h$'hae .ith so(e bran)hed at right angles. %KMS stain&. $:
So(e #ungal h$'hae are de(onstrated .ithin the (ultinu)leated giant )ells. %PAS stain&.

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Tables
Table ':
Clini)al 'ara(eters o# #i"e 'atients .ith -CA.
Table .:

Radiologi) 'atterns o# -solated Cerebral As'ergillosis in our #i"e )ases.

Table /:
Treat(ent and out)o(e o# -CA in our stud$.
Table 0:
Su((ar$ o# re'orted )ases in the literature o# -CA in in i((uno)o('etent 'atients.



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Table 1:
Clinical parameters of five patients with Isolated Cerebral Aspergillosis.

Case Age/sex Symptoms
Neurological
Signs
WBC ESR CRP istopat!ology
"ungal
Culture
1 13/F
Headache
and
declining
school
performance
(6 months
!ei"#res
and
drowsiness
(3 da$s
left
hemiparesis
and
papilledema
%.& '( (3
)on*
gran#lomato#s
with
Aspergill#s
h$phae
Aspergill#s
flav#s
# 16/F
Headache (+
months
,is#al
dist#rbance
(3 wee-s
left
hemiparesis.
hemianopsia.
and
papilledema
+.%
)ot
done
)ot
done
/ran#lomato#s
with
Aspergill#s
h$phae
Aspergill#s
species
$ ('/F
Headache (+
months
!ei"#res (3
wee-s
left
hemiparesis
and
hemianopsia
10.1 1& 1.6
/ran#lomato#s
with
Aspergill#s
h$phae
Aspergill#s
flav#s
% (6/F
Headache (%
months
!ei"#res ((
wee-s
2ight
hemianopsia
10.'
)ot
done
)ot
done
/ran#lomato#s
with
Aspergill#s
H$phae
)o growth
& 36/F
Headache
and
vomiting ((
months
!ei"#res ((
wee-s
left
hemiparesis
and
hemianopsia
6.+ + 6.&
/ran#lomato#s
with
Aspergill#s
H$phae
)o growth
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Table 2:

Radiologic patterns of Isolated Cerebral Aspergillosis in our five cases.

Patient CT scan MRI-T1WI MRI-T2WI Mri-T1=Gad MRSpect
Case 1
Iso/hypodense
with minimal
peripheral
enhancement
of the wall
Iso /
hypointense
Double ring
sign
(hypointense
core to grey
matter then
edema
hyper then
hypointense
wall)
hin irregular
rim
enhancement
Choline/!AA
pea"
Case2
Isodense to
grey matter
with mild
homogenous
enhancement
#eterogenous
isointense
patches of
hypointensity
#ypointense
rim. Core is
isointense to
grey matter

Central
enhancement$
wall not
enhancing.
Choline/!AA
pea"
Case 3
Isodense with
mild
homogenous
enhancement
Iso/hypointense
!odular wall
with double
ring sign
Core shows
homogenous
upta"e$ wall
patchy
enhancement
%ow
Choline/!AA
#igh
%ipids/lactate
Case 4
Iso/hypodense
with minimal
peripheral
enhancement
of the wall
Iso/hypointense
Double ring
sign
hic" regular
rim
enhancement
Choline/!AA
pea"
Case 5
Iso/hypodense
with minimal
peripheral
enhancement
of the wall
Iso /
hypointense
#ypointense
wall and
hyperintense
core
hin irregular
rim
enhancement
Choline/!AA
pea"

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Table 3:
Summary of the management of Isolated Cerebral Aspegillosis in our study.

Case
Prior
treatment
Surgery
Antifungal
agents
Adverse
reactions
Functional
status
Follow
up
Outcome
1 None
Gross
total
resection
AT- B for 2
!s"
folloed
by IC# for 2
!s"
folloed
by $C# for
2 !s
%total of &
!s'
(enal
impairment
)eath at &
ee!s
NA
)eath at &
ee!s
None
Image
guided
biopsy
then
Gross
total
resection
AT- B for 2
!s"
folloed
by $C# for
* months
(enal
impairment
$isual
disturbance
Normal
+,
months
Complete
reco-ery
3 None
Small
residual
on motor
strip
AT- B for
2!s"
folloed
by $C# for
* months
(enal
impairment
Normal
.,
months
Complete
reco-ery
! None
Gross
total
resection
AT- B for
2!s"
folloed
by $C# for
* months
(enal
impairment
Normal
2.
months
Complete
reco-ery
"
Anti-
tuberculous
therapy for
, month
Gross
total
resection
$C# for *
months
None Normal
,2
months
Complete
reco-ery

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Table 4:
Summary of reported cases in the literature of Isolated Cerebral Aspergillosis in
immunocompetent patients.
Author
(Reference)
Number
of ICA
cases
/total
cases
Reason for exclusion to
be ICA
Intervention Outcome
De lastours
(10)
1 / 2
ne case !I" #$e and
the other alcoholic
%iopsy plus "C&
for ' (ee)s
Complete reco$ery
run (*) 0 / 1
Concurrent hepatic
amebiasis
+one (post
mortem)
,eath from
amebiasis
Chen (') 1 / 1 +one
%iopsy plus A-.%
and "C&
Complete reco$ery
Curone (/) 0 / 1
!igh dose steroids
inta)e
Abscess drainage
plus A-.%
,eath from
resistance
Nara!an (22) 0 / 1 +one %iopsy plus A-.%
,ied from a
relapse due to
non.compliance to
"C&
"ouati (10) 1 / *
ne patient (as !I"
and one ,iabetic
Surgery plus A-.%
Complete reco$ery
(no mention of
follo( up
duration)
Challa (1) 0 / 2
Sinus disease and
recurrence not
appropriately screened
Surgery plus A-.%
2 deaths and 2
relapsed (ithin 12
months.
+o postoperati$e
imaging
#almon (2') 1 / 1 +one Surgery plus A-.% Complete reco$ery
$ul%arni (11) 0 / 1
3n)no(n lung
infiltrations
%iopsy then
surgery (hen no
regression
4eco$ery (but
follo( up 20 days)
Tha%ar (*') 1 / 1 +one
4esection and
drainage of
multiple masses
+o recurrence but
cerebral
hemispheric
atrophy

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