Can CT Perfusion Guide Patient Selection for Treatment of Delayed Cerebral Ischemia?

doi:10.4236/act.2013.21002

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Advances in Computed Tomography, 2013, 2, 4-12

http://dx.doi.org/10.4236/act.2013.21002 Published Online March 2013 (http://www.scirp.org/journal/act)

Can CT Perfusion Guide Patient Selection for Treatment

of Delayed Cerebral Ischemia?

Pina C. Sanelli1,2*, Rachel Gold1, Nikesh Anumula1, Austin Ferrone1, Carl E. Johnson1,

Joseph P. Comunale1, Apostolos J. Tsiouris1, Howard Riina3, Halinder Mangat4,

Axel Rosengart4, Alan Z. Segal4

1Department of Radiology, Weill Cornell Medical Colleg e, New York, USA

2Department of Public Health, Weill Cornell Medical College, New York, USA

3Department of Neurological Surgery, Weill Cornell Medical College, New York, USA

4Department of Neurology, Weill Cornel l Medical College, New York, USA

Email: *[email protected]

Received November 8, 2012; revised December 20, 2012; accepted January 4, 2013

ABSTRACT

Purpose: To evaluate qualitative and quantitative CT perfusion (CTP) for different treatment options of delayed cere-

bral ischemia (DCI) in aneurysmal SAH. Methods: Retrospective study of consecutive SAH patients enrolled in a pro-

spective IRB-approved clinical trial. Qu alitative analysis of CTP deficits were determined by two b linded neuroradiolo-

gists. Quantitative CTP was performed using standardized protocol with region-of-interest placement sampling the cor-

tex. DCI was assessed by clinical and imaging criteria. Patients were classified into treatment groups: 1) hyperten-

sion-hemodilution-hypervolemia (HHH); 2) intra-arterial (IA) vasodilators and/or angioplasty; 3) no treatment. Mean

quantitative CTP values were compared using ANOVA pairwise comparisons. Receiver operating characteristic (ROC)

curves, standard error (SE) and optimal threshold values were calculated. Results: Ninety-six patients were classified

into three treatment groups; 21% (19/96) HHH, 34% (33/96) IA-therapy and 46% (44/96) no treatment. DCI was diag-

nosed in 42% (40/96); of which 18% (7/40) received HHH, 80% (32/40) IA-therapy, and 2% (1/40) no treatment. CTP

deficits were seen in 50% (48/96); occurring in 63% (12/19) HHH, 94% (31/33) IA-therapy, and 11% (5/44) no treat-

ment. Presence of CTP deficits had 83% sensitivity, 8 9% specificity, 90% positive pred ictive and 81% negativ e predic-

tive values for treat ment. Mean quantitative CTP valu es revealed significant differences in CBF (p < 0.0001) and MTT

(p = 0.0001) amongst the treatment groups. ROC analysis revealed CBF with the highest accuracy of 0.82 (SE 0.04) for

comparing treatment groups. Threshold an alysis calculated CBF of 30 mL/100 gm/min (89% specificity, 7 1% sensitiv-

ity) for determining treatment. Conclusion: These in itial findings of significant differences in CTP deficits for different

treatment groups suggest that CTP may have a potential role in guiding patient selection for treatment of DCI.

Keywords: CT Perfusion; Aneurysmal Subarachnoid Hemorrhage; Delayed Cerebral Ischemia; Treatment

1. Introduction

Delayed cerebral ischemia (DCI) is a serious complica-

tion following aneurysmal SAH, and is the leading cause

of morbidity and mortality in this patient population. Its

pathophysiology is complex and poorly understood lead-

ing to delayed diagnosis. However, proximal vasospasm

is thought to partly contribute to DCI causing reduced

cerebral blood flow (CBF) to the distal vascular territory

[1-3]. DCI manifests as clinical deterioration typically

developing between 4 - 14 days following the initial an-

eurysm rupture with symptoms of focal neurological im-

pairment (such as hemiparesis, hemiplegia, aphasia, etc.),

or a decrease of at least 2 points on the Glasgow Coma

Scale. Early diagnosis and prompt treatment of DCI may

prevent its devastating sequelae of permanent neurologic

deficits, cerebral infarction and death.

There are several treatment options for DCI typically

used in clinical practice. Medical management with hy-

pervolemic, hemodilution and hypertensive (HHH) ther-

apy is commonly used as the initial treatment. HHH is a

systemic therapy used to improve global cerebral perfu-

sion by increasing both blood pressure and flow to the

brain. For patients that do not adequately respond to

HHH therapy, more selective invasive intra-arterial (IA)

therapy is performed to immediately dilate an artery in

spasm using vasodilatory medications and/or angioplasty

in order to improve the blood flow to a specific region of

the brain. However, in some patients continuous close

observation in the neuro-intensive care unit (N-ICU) set-

ting is sufficient depending on the patient’s clinical con-

*Corresponding a uthor.

P. C. SANELLI ET AL. 5

dition and considering the risks associated with both

HHH and IA-therapy. The main complications that may

occur with HHH are cerebral edema, aneurysm re-bleed-

ing, pulmonary edema, and potential cardiac injury re-

lated to the aggressive use of pressor type medications

[4]. Several important risks associated with IA-therapy

include vascular injury (such as dissection and vessel

rupture), cerebral infarction and death related to the arte-

rial catheterization techniques and balloon angioplasty.

Therefore, more accurate assessment of patients who

require treatment of DCI is critical to improve patient

selection in order to provide maximal treatment benefit

and to minimize exposing patients to unnecessary serious

risks.

Several methods are used for the diagnosis of DCI re-

lated to vasospasm, including clinical examination, neu-

rologic monitoring devices, transcranial Doppler ultra-

sound (TCD), CTA, and DSA. Many institutions have

also employed CT perfusion (CTP) to evaluate the

hemodynamic status of the brain at the capillary level.

CTP is a dynamic imaging study using cine scanning to

capture the first pass of contrast through the brain to as-

sess cerebral perfusion. The acquired dataset is post-pro-

cessed using a deconvolution algorithm to construct the

perfusion maps of CBF, cerebral blood volume (CBV)

and mean transit time (MTT). The principle of CTP is

that these perfusion parameters can be derived from the

mathematical algorithm that describes the relationship

between the arterial input, capillary flow and venous

drainage. The arterial and venous time attenuation curves

are obtained from the acquired dataset, representing the

time series data of contrast through the brain. Two as-

sumptions are made with CTP including that blood and

contrast have the same hemodynamic properties and

there is a linear relationship between contrast concentra-

tion in the brain with the measured Hounsfield units.

There are several advantages of CTP compared with

other perfusion imaging techniques, including its non-

invasiveness, short acquisition time, widespread avail-

ability, and limited patient contraindications lending to

its usefulness in this critically ill patient population. In

the literature, several studies have reported the ability of

CTP to detect impairment of cerebral perfusion thought

to occur in the development of DCI and vasospasm

[1-3,5]. However, not all perfusion deficits correlate with

symptoms of DCI or arterial narrowing on imaging stud-

ies, indicating that not all perfusion deficits require

treatment. In particular, the issue of which perfusion

deficits require treatment with HHH and/or IA-therapy

has not been fully explored. Thereby, further under-

standing of these CTP deficits is needed in order to im-

prove patient selection for treatment of DCI. Quan titative

differences in CTP deficits may assist in identifying pa-

tients earlier who require treatment, particularly in pa-

tients with limited clinical assessments, uncertain clinical

findings, and discrepant clinical and imaging data, that

may lead to delayed diagnosis and treatment.

The purpose of this study is to evaluate qualitative and

quantitative CTP for different treatment options of DCI

in aneurysmal SAH. Our hypothesis is that there are sta-

tistically significant differences in the CTP parameters in

patients who are selected for different treatment regi-

mens.

2. Materials and Methods

2.1. Study Design

A retrospective study of 104 consecutive aneurysmal

SAH patients enrolled in a prospective clinical trial fro m

December 2004 to December 2008 was performed. This

study was approved by the institutional review board

(IRB) and a health insurance portability and accountabil-

ity act (HIPAA) waiver was obtained. Inclusion criteria

were adult patients (18 years and older) with documented

aneurysmal SAH at admission based on the initial non-

contrast head CT, cerebrospinal fluid analysis, CTA and/

or DSA. Exclusion criteria were CTP exams performed

after treatment of DCI or after cerebral infarction oc-

curred. All subjects in the study underwent surg ical clip-

ping and/or endovascular coiling for aneurysm repair and

were monitored in the N-ICU, as per usual standard-of-

care. Chart review was performed for the clinical and de-

mographic characteristics of the study population, in-

cluding age, gender, aneurysm location and treatment,

and Hunt Hess grades on presentation. Treatment man-

agement decisions were based on all clinical and imaging

data available, with the exception of CTP. Patients were

categorized into three treatment groups as 1) medical

HHH only; 2) IA-therapy; and 3) no treatment (close

observation). Patients classified in the IA-therapy group

did not adequately respond to HHH as the initial treat-

ment.

The diagnosis of DCI was determined for each treat-

ment group to assess appropriate classification of patients.

DCI was determined in this cohort by incorporating the

most relevant clinical and imaging outcome measures, as

recommended by the recent consensus expert opinion [6].

Furthermore, Reichman et al. developed and evaluated a

reference standard incorporating these outcomes meas-

ures to assess aneurysmal SAH patients applicable to

clinical practice [7]. This reference standard consists of

angiographic criteria for vasospasm based on the arterial

luminal narrowing on DSA compared with the normal

parent vessel and comparison with DSA performed on

initial presentation. In this study, DSA interpretations

were performed by two observers, one of two intervene-

tional neuroradiologists at our institution who performed

the exam (with either 10 or 25 years experience) and a

neuroradiologist blinded to all patient information (22

P. C. SANELLI ET AL.

years’ experience). For disagreements, a third neurora-

diologist (10 years’ experience) independently reviewed

the exam in a blinded fashion. In patients who did not

have DSA performed, the following clinical and/or im-

aging criteria were used: a) clinical criteria—a permanent

neurologic deficit on clinical examination, distinct from

the deficit at baseline produced by the SAH event or sur-

gical intervention, which was not attributable to other

causes; b) imaging criteria-cerebral infarction on fol-

low-up CT and/or MR imaging that occurred after day 4.

This criterion has been used to effectively exclude pri-

mary brain damage from SAH and/or surgical intervene-

tion [8].

Clinical outcome measures were also determined for

each treatment group to further assess appropriate classi-

fication of patients. At discharge from the N-ICU, pa-

tients were evaluated for a permanent neurologic deficit

on physical examination and cerebral infarction on fol-

low-up CT and/or MR imaging. Discharge status was

also documented as home, rehabilitation care facility

(acute rehabilitation or long-term skilled nursing), and

death.

2.2. CTP Scanning Protocol, Post-Processing and

Data Collection

CTP was performed during the typical time-period for

DCI, between days 6 - 8 in asymptomatic patients and on

the same day clinical deterioration occurred in sympto-

matic patients. There is a standard scanning protocol for

CTP at our institution using GE Lightspeed or Pro—16

scanners (General Electric Medical Systems, Milwaukee,

WI) with cine 4i scanning mode and 45 second acquisi-

tion at 1 rotation per second using 80 kVp and 190 mA.

A scanning volume of 2.0 cm was used consisting of 4

slices at 5.0 mm thickness with its inferior extent se-

lected at the level of the basal ganglia, above the orbits,

to minimize radiation exposure to the lenses. Approxi-

mately 45 mL of nonionic iodinated contrast was admin-

istered intravenously at 5 mL/s using a power injector

with a 5-second delay.

Post-processing of the acquired images into cerebral

blood flow (CBF), cerebral blood volume (CBV) and

mean transit time (MTT) maps were performed on a GE

Advantage Workstation using CTP software version 3.0

(General Electric Medical Systems). This software em-

ploys a deconvolution method, which is considered most

accurate for low contrast injection rates [9]. The post-

processing technique was standardized for all patients

according to recommended guidelines [10] with the arte-

rial input function as the A2 segment of the anterior

cerebral artery (ACA) [11] and venous function as the

superior sagittal sinus.

The perfusion maps were qualitatively evaluated by

two neuroradiol ogi st s (10 a nd 7 years e xperience) blin ded

to clinical and imaging data to determine the presence of

perfusion deficits, defined as areas of reduced CBF and/

or prolonged MTT. Focal perfusion abnormalities due to

the primary hemorrhagic event and su rgical intervention,

as identified on the acquired images from the CTP data-

set, were not included as perfusion deficits related to DCI.

After reviewing the images independently, consensus ju-

dgment was determined.

Quantitative analysis was conducted using a standard-

ized method with contiguous regions-of-interest (ROI)

placement, measuring 157 mm2, sampling the cerebral

cortex. Each CTP slice had up to 24 ROIs distributed in

the following territories: approximately 6 ROIs in ACA,

12 ROIs in middle cerebral artery (MCA) and 6 ROIs in

posterior cerebral artery (PCA). CTP studies were ana-

lyzed blinded to all clinical a nd imaging data to li mit test

review bi a s.

2.3. Statistical Analysis

Only CTP exams performed at the diagnostic stage, prior

to treatment for DCI and prior to cerebral infarction,

were included in the analysis in order to minimize con-

founding bias as both treatment and infarction affect the

cerebral perfusion maps. The incidence of qualitative

CTP deficits in each treatment group was calculated.

CTP test characteristics (sensitivity, specificity, positive

and negative predictive values) were determined using 2

× 2 table analysis with 95% confidence intervals (CI).

Quantitative CTP data was analyzed by calculating the

mean CBF, CBV and MTT and its standard deviation

(SD) for the three treatment groups. For patients with

focal perfusion deficits, ROIs within the affected region

were isolated and arithmetic means were calculated. In

patients without focal deficits, all ROIs for all 4 slice

locations were included in the arith metic means. In order

to minimize the contribution of vascular pixels from

large vessels, CBF values >100 mL/100 gm/min were

excluded from the statistical analysis and not used in

calculating the me an CBF, CBV and MTT , as this method

has been published in the evaluation of ischemia [12].

The ROIs in the perfusion abnormalities due to the pri-

mary hemorrhagic event and/or surgical intervention,

were not included in the statistical analysis. Normality of

the distribution of continuous variables was assessed by

plotting histograms and the Shapiro Wilks test. Com-

parison between the treatment groups was performed

using ANOVA pairwise comparisons. Statistical signifi-

cance was accepted at p < 0.05. Receiver operator char-

acteristic (ROC) curves were generated for each CTP pa-

rameter and the area-under-the-curve (AUC) calculated

to quantify the overall accuracy. Maximum-likelihood

ROC models and standard error (SE) were fitted assum-

ing a binormal distribution for the underlying latent

variable. The threshold values for CBF, MTT and CBV

P. C. SANELLI ET AL.

were assessed using the northwest corner method, repre-

senting the point va lue on the ROC curve with the great-

est discrimination ability between treatment groups. The

statistical analysis was performed by a biostatistician

using Stata version 10 and R version 2.7.2 software.

3. Results

3.1. Study Population Characteristics

A total of 96 aneurysmal SAH patients were included in

the statistical analysis from the 104 patients enrolled in

the prospective clinical trial. Eight patients were ex-

cluded for the following reasons: CTP exams were not

performed prior to treatment for DCI (n = 4), CTP ac-

quired data was not retrievable from the archives for

post-processing in this study (n = 3), and post-processing

could not be performed due to severe motion degradation

(n = 1). The median age (range) was 49 years old (28 -

80 years) with a 73% (70/96) female predominance.

Ninety-two percent (88/96) of the aneurysms were lo-

cated in the anterior circulation. The treatment for aneu-

rysm repair in this study population was 54% (52/96)

surgical clipping and 46% (44/96) endovascular coiling

procedures. The clinical Hunt Hess grades on presenta-

tion were 48% (46/96) high grades 3, 4 and 5 and 52%

(50/96) l o w g r a des 1 and 2.

The study population was defined into three treatment

groups; 20% (19/96) of patients received HHH only,

34% (33/96) underwent IA-therapy and 46% (44/96) re-

ceived no treatment (close observation).

3.2. Qualitative CTP Analysis

The median day CTP was performed was day 7 after

aneurysm rupture. Qualitative CTP deficits were seen in

50% (48/96) of the study population, occurring in 95%

(38/40) of patients with DCI and 18% (10/56) without

DCI. These CTP deficits were seen in 94% (31/33) of

patients who underwent IA-therapy, 63% (12/19) who

received HHH, and 11% (5/44) who did not receive

treatment. The test characteristics (95% CI) for qualita-

tive CTP deficits were 83% (70% - 91%) sensitivity,

89% (76% - 95%) specificity, 90% (7 8% - 95%) positive

predictive value, and 81% (68% - 90%) negative predic-

tive value for determining patients requiring treatment.

3.3. Quantitative CTP Analysis

The mean quantitative values and standard deviation for

CBF, CBV and MTT for each treatment group are shown

in Table 1. There are statistically significant differences

in the CBF and MTT values amongst the three treatment

groups. Specifically, pairwise comparisons showed a sta-

tistically significant difference between the no treat-

ment and IA-therapy groups for the CBF (p < 0.0001),

CBV (p = 0.0343) an d MTT (p < 0.000 1) . Fur ther more, a

statistically significant difference was also seen between

the HHH and IA-therapy groups only for CBF (p =

0.0406).

ROC curve analysis comparing the treatment and no

treatment groups revealed that CBF and MTT had the

highest overall accuracy of 0.82 (SE 0.04) and 0.81 (SE

0.05), respectively (Figure 1(a)). A similar trend is seen

in the analysis comparing the HHH and IA-therapy

groups with the highest overall accuracy for CBF of 0.72

(SE 0.07) an d MTT of 0.69 ( SE 0 .08) (Figure 1(b)).

Threshold analysis was performed using the northwest

corner method to determine the CTP value with the grea-

test discrimination ability between the treatment groups

(Table 2).

3.4. Clinical Outcomes

DCI was diagnosed in 42% (40/96) of patients according

to the clinical and imaging criteria used in this study. In

the IA-therapy group, 97% (32/33) of patients were clas-

sified as DCI compared to 37% (7/19) in the HHH and

2% (1/44) in the no treatment groups. Since DCI was

determined retrospectively using defined criteria for the

purpose of this study, all treatment decisions were based

on the clinical and imaging data available at the time of

decision-making, with the exception of CTP.

Patient outcomes were evaluated using clinical and

imaging criteria at the time of discharge from the N-ICU

(Table 3). The IA-therapy group had the highest occur-

rence of permanent neurologic deficits and cerebral in-

farction, followed by the HHH and no treatment groups.

The discharge status was also evaluated as a surrogate

outcome measure (Table 4). A similar trend was also

observed in the IA-therapy group having the worst out-

comes with the highest mortality rate during hospitaliza-

tion and the highest occurrence of patients requiring

Table 1. Mean quantitative CTP values and standard deviation for each treatment group.

Mean (SD) No treatment HHH IA p-value

CBF (mL/100 gm/min) 40.6 (11.1) 33.2 (15.4) 24.4 (11.9) <0.0001

CBV (mL/100 gm) 2.01 (0.51) 1.99 (0.68) 1.71 (0.66) 0.0825

MTT (sec) 4.7 (1.7) 6.6 (4.3) 7.4 (2.7) 0.0001

P. C. SANELLI ET AL.

(a)

(b)

Figure 1. Receiver operator characteristic (ROC) curves of CBF, CBV and MTT for comparison of treatment groups.

Table 2. Threshold analysi s for treatment options; (a) Treat-

ment vs. no treatment; (b) HHH vs. IA-therapy.

(a)

Threshold Specificity/Sensitivity

CBF 30 %71%/89

MTT 5.1 %71%/75

CBV 1.7 %52%/75

(b)

Threshold Specificity/Sensitivity

CBF 26 %79%/74

MTT 6.4 %61%/74

CBV 1.5 %52%/84

Table 3. Clinical outcomes determined by clinical and im-

aging criteria.

Total

(n = 96)

treatment

(n = 44)

HHH

(n = 19) IA

(n = 33)

Functional

deficit/disability 28% (27/96) 11% (5/44) 26% (5/19) 52% (17/33)

Cerebral

infarction 14% (13/96) 0% 11% (2/19) 33% (11/33)

rehabilitative care following discharg e.

4. Discussion

DCI related to vasospasm is a complex entity involving

Table 4. Discharge status for treatment gr oups.

Discharge

status Total

(n = 96)

treatment

(n = 44)

HHH

(n = 19) IA (n = 33)

Home 52% (50/96)68% (30/44) 53% (10/19)30% (10/33)

Rehabilitative

care 43 % (41/96)32% (14/44) 42% (8/19)58% (19/33)

Acute

rehabilitation 33% (32/96)23% (10/44) 26% (5/19)52% (17/33)

Long-term

skilled 10% (9/96)9% (4/44) 16% (3/19)6% (2/33)

Death 5% (5/96)0% 5% (1/19) 12% (4/33)

delayed narrowing of the intracranial arteries that may

lead to clinical deterioration, cerebral infarction and

death. Current treatment options include medical man-

agement with HHH as the initial treatment to increase

systemic blood pressure and flow in order to globally

increase cerebral perfusion. Typically, if patients do not

adequately respond to HHH then more invasive tech-

niques, such as intra-arterial therapy with vasodilatory

medications and/or angioplasty, are used to improve re-

gional blood flow by selectively dilating individual cere-

bral arteries. Finally, close observation in the N-ICU may

also be sufficient in some patients given the life-threaten-

ing complications associated with both HHH and IA-

therapy. Therefore, more accurate patient selection for

treatment of DCI is critical in order to provide maximal

treatment benefit while minimizing exposure of patients

to serious risks.

P. C. SANELLI ET AL. 9

In current practice, patient selection for treatment of

limited due to few studies

if there are qualitative

CI is based on clinical signs and symptoms coupled

with imaging information of arterial narrowing for vaso-

spasm. In recent years, CTP has also been used as a

complimentary diagnostic tool for evaluation of DCI

related to vasospasm. Specifically, qualitative CTP defi-

cits have a high sensitivity and specificity [1-3,5,13-15]

for vasospasm reported in 97% of patients with vaso-

spasm compared to 24% without vasospasm [5]. Fur-

thermore, Aralasmak et al. correlated CTP deficits and

the degree of vessel narrowing with CTP deficits occur-

ring in 83% of patients with severe vasospasm compared

to 26% with mild-moderate and 15% without vasospasm

[2]. Dankbaar et al. also demonstrated that the flow terri-

tory of the vessel with the most severe vasospasm corre-

sponded with the least perfused region on CTP [16].

More recently, investigations have focused on using quan-

titative CTP and determining a threshold value. Several

studies have reported CBF and MTT with the highest

diagnostic accuracy for DCI [3,5,16]. A CBF threshold

of 35 mL/100 gm/min (90% sensitivity, 68% specificity)

and MTT threshold of 5.5 sec (73% sensitivity, 79%

specificity) have been reported [5]. Similarly, Dankbaar

et al. described an MTT threshold of 5.9 sec for DCI [16].

Wintermark et al. also described the utility of CTP in the

diagnosis and management of vasospasm suggesting that

a CBF threshold of 39 .3 mL/100 gm/min repr esented the

most accurate (94.8%) indicator for endovascular therapy

[3]. These results support the possibility that CTP-based

criteria may be able to assist in differentiating patients

according to the severity of DCI in attempts to guide pa-

tient selection for treatment.

A review of the literature is

rformed in evaluating imaging based criteria for pa-

tient selection for treatment of DCI. In recent years, it is

becoming more apparent that image-based criteria may

have a role in patient selection for treatment of acute

stroke. Turk et al. reported similar rates of good func-

tional outcome and low rates of intracranial hemorrhage

when endovascular treatment was performed based on

CTP rather than time-guided selection [17,18]. This po-

tential for image-based criteria may also have a role in

aneurysmal SAH, particularly in patients with limited

clinical examination, uncertain clinical findings, or dis-

crepant clinical and imaging data. In the prospective ma-

nagement of patients, which perfusion deficits require

treatment with HHH and/or IA-therapy still remains un-

certain because not all perfusion deficits correspond to

symptoms of DCI or arterial narrowing on imaging stud-

ies indicating that not all perfusion deficits require treat-

ment (Figure 2). Thereby, further quantitative analysis of

CTP deficits is needed to differentiate treatment groups

in order to guide patient selection.

Our study focused on determining

(a)

(b)

(c)

Figure 2. 57-year-old status coil embolization of a right

infarction on follow-up CT imaging.

post

posterior communicating artery aneurysm. CT perfusion

was performed on day 7 for the purposes of the study pro-

tocol and shows a focal perfusion deficit with elevated MTT

(a) and reduced CBF (b) in the right MCAterritory in the

parietal region. Quantitative evaluation of the perfusion

deficit reveals a CBF of 37 mL/100 gm/min. The patient was

asymptomatic and noncontrast CT (c) reveals no corre-

sponding abnormality in this region. The patient did not

receive treatment and was discharged home with resump-

tion of normal daily activities. There was no evidence of a

permanent neurologic deficit on clinical exam or cerebral

P. C. SANELLI ET AL.

and/or quantitative differences in CTP deficits for dif-

ferent treatment groups of DCI. The presence of a CTP

deficit has a 90% positive predictive value for treatment.

CTP deficits occurred in 94% (31/33) of the IA-therapy

and 63% (12/19) of HHH groups compared to 11% (5/44)

of the no treatment group. Further quantitative analysis

revealed that CBF was the only perfusion parameter that

showed a statistically significant difference in the pair-

wise comparisons of all three treatment groups. In addi-

tion, ROC curve analyses supported that CBF has the

highest accuracy for determining the treatment group

(Figure 1). Using this data, threshold analysis can be

performed to help guide patien t selection by determining

the CBF value on the ROC curve with the greatest dis-

crimination ability between treatment groups. In this

study, a CBF threshold of 30 mL/100 gm/min can be

used as a guideline for a patient that should be carefully

considered for treatment of DCI. Furthermore, a CBF

threshold of 26 mL/100 gm/min can be used as a rough

guide for possibly considering patients who may also

require more invasive techniques with IA-therapy. Given

the proximity of these two threshold values, caution is

emphasized when using absolu te quantitative CTP values

for the diagnosis and management of patients in clinical

practice. The use of quantitative threshold values is lim-

ited in clinical practice due to differences in scanner

equipment, techniques and post-processing methods em-

ployed. Importantly, standardization and validation of

CTP methodology and post-processing techniques are

necessary for its widespread implementation in SAH pa-

tients.

In this study, CTP deficits in the IA-therapy group had

the most severely reduced CBF and prolonged MTT

(Figure 3). The IA-therapy group had 97% of patients

diagnosed with DCI, whereas the no treatment group had

only 2% of patients with DCI. As expected, the IA- the-

rapy group also had the worst outcomes with the highest

mortality rate (12%) and greatest percentage of patients

with functional disability (52%) and cerebral infarction

(33%). Whereas patients who had no treatment with

close observation, the mean CBF and MTT values were

within normal ranges. Improved outcomes were seen in

the no treatment group with the highest rate of patients

discharged home (68%), lowest incidence of functional

disability (11%) and no cerebral infarction on follow-up

CT/MR imaging. These findings support that there was

appropriate classification of aneurysmal SAH patients in

the different treatment groups.

We acknowledge several limitations in this study; in-

cluding the retrospective study design limiting the out-

comes data collection, specifically for clinical informa-

tion. In addition, CTP provides limited brain coverage

for evaluation of perfusion deficits. However, emerging

CT scanner technology will continue to improve and

(a)

(b)

(c)

Figure 3. 35 year-old status post surgical clipping of a right

posterior communicating a aneurysm and developed rtery

new left-sided upper extremity hemiparesis and pronator

drift on day 6. Noncontrast CT (a) demonstrates no new

hemorrhage or hydrocephalus to explain the patient’s sym-

ptoms. However, there is early hypodensity involving the

right basal ganglia. CT perfusion performed the same day

shows a large perfusion deficit in the right MCA territory

in the frontal and parietal regions and focal perfusion defi-

cit in the left ACA territory with elevated MTT (b) and

reduced CBF (c). Quantitative evaluation reveals a CBF of

18 mL/100 gm/ min in the right MCA and CBF of 17 mL/

100 gm/min in the left ACA perfusion deficits. The patient

received HHH therapy and also underw ent IA-therapy wi th

verapamil and angioplasty of the right MCA and left ACA.

Patient developed cerebral infarction in the right anterior

temporal lobe and basal ganglia.

P. C. SANELLI ET AL. 11

provide broader coverage for which this data may be

applicable. Another limitation is that the region of CTP

imaging was not coordinated with the location of the

arterial narrowing on DSA or region referable to symp-

toms. Therefore, it is conceivable that this region may

not have been imaged on the CTP or possibly averaged

with a larger region of normal perfusion, resulting in in-

creased false negatives and lower accuracy in our study.

This method was not used in order to reduce work-up

and observer bias by not having knowledge of the clini-

cal exam and DSA results prior to CTP scanning and in-

terpretation.

5. Conclusion

There is a clinical need to more accurately select aneu-

nts for treatment of DCI in order to

This publication was made possible by Grant Num

ational Institute of

[1] J. W. Dankbaar, N. K. de Rooij, B. K. Velthius, C. J.

Frijns, G. J. Rchaaf, “Diagnosing

Delayed Cerebrent CT Modalit

rysmal SAH patie

provide maximal treatment benefit while minimizing

patient exposure to serious complications. Critically ill

and comatose patients with limited clinical examinations,

uncertain clinical findings, and discrepant clinical and

imaging data remain challenging to assess for treatment.

CTP provides additional information regarding hemody-

namic disturbance in the brain. Qualitative CTP deficits

have a 90% positive predictive value for determining

patients who require treatment. Since it remains uncer-

tain which perfusion deficits require HHH and/or IA-

therapy, further evaluation with quantitative analysis is

needed to differentiate treatment groups. In this study,

CBF showed statistically significant differences for the

different treatment groups. CBF also had the highest ac-

curacy and discrimination ability on the ROC curve for

determining treatment groups using threshold analysis.

These preliminary findings support continued work in

this field with larger prospective clinical trials as CTP

may have a role in guiding patient selection for treatment

of DCI by its quantitative evaluation of perfusion defi-

cits.

6. Acknowledgements

ber

Neu- 5K23NS058387-02 from the N

rological Disorders and Stroke (NINDS), a component of

the National Institutes of Health (NIH). Its contents are

solely the responsibility of the authors and do not neces-

sarily represent the official view of NINDS or NIH.

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bbreviations

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doppler ultrasound

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nit

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PubMed.

CTP: computed tom

SAH: subarachnoid

DCI: delayed cerebral ischemia

CBF: cerebral blood flow

CBV: cerebral blood volume

MTT: mean transit time

HHH: hypertension hemodilut

IA: intra-arterial

DSA: digital subtraction angiography

TCD: transcranial

CTA: computed tomography angiography

MCA: middle cerebral arte

PCA: posterior cerebral ar tery

N-ICU: ne ur o- i nt e nsi ve care u

ROI: region of interest

ROC: receiver operator characteris

AUC: area under curve

ANOVA: analysis of variance

SE: standard error

SD: standard deviation

CI: confidence inter