Journal of Neuro-Ophthalmology, December 2005, Volume 25, Issue 4

Cerebral Perfusion Imaging

There are multiple imaging techniques available to assess cerebral perfusion, including positron emission tomography (PET), xenon computed tomography (XeCT), single photon emission computed tomography (SPECT), perfusion-weighted MRI (PWI), and perfusion computed tomography (PCT). Current interest has focused mainly on their use in the setting of acute brain ischemia. Perfusion imaging may be able to distinguish infarcted from salvageable ischemic tissue as a guide to treatment. Perfusion techniques may also be helpful in cases of chronic ischemia, post-subarachnoid hemorrhage vasospasm, trauma, and contemplated therapeutic carotid artery occlusion.

Cerebral Perfusion Imaging Ellen G. Hoeffner, MD Abstract: There are multiple imaging techniques available review the currently available perfusion imaging techniques to assess cerebral perfusion, including positron emission with an emphasis on PWI and PCT, the techniques most tomography ( PET), xenon computed tomography ( XeCT), often used in current clinical practice ( Table 1). single photon emission computed tomography ( SPECT), perfusion- weighted MRI ( PWI), and perfusion computed tomography ( PCT). Current interest has focused mainly on DYNAMTC PERFUSION CT their use in the setting of acute , ,, ° .. x. . b, r a. i n. isct he, m . ia. Per, f usion D^ ynami. c P_ C,_ T_ stxu d, i. e s are owb tai. n ed, , b y moni. t ori. n g itth e imaging may be able to distinguish rnfarcted from salvage- „ 2 . . ,. t , , , , , , , , , , , . , • . • •, , T. o • first pass of an lodrnated contrast agent through the cerebral able ischemic tissue as a guide to treatment. Perfusion , „_ , . , , „ , • .. /• ^ . , . , , , , ° . . , . . , . vasculature ( 4,6). Changes in tissue attenuation that occur techniques may also be helpful in cases of chronic ischemia, • ,, , • « ^ 7 , • • ,- w, A r, . . ... , , in the brain after the contrast miection are measured ( 1,4,6). post- subarachnoid hemorrhage vasospasm, trauma, and con- _, . Al _,_,„ , A „ Al ^. ' ; , , , , , .. .-, , • Post- processing of the PCT data allows the generation of templated therapeutic carotid artery occlusion. , , , ? • ^ • , • , , color- coded maps of various perfusion parameters, mclud- (/ Neuro- Ophthalmol 2005; 25: 313- 320) ing cerebral blood flow ( CBF), cerebral blood volume ( CBV), mean transit time ( MTT), and the time- to- peak ( TTP), the A time from the start of contrast agent injection to the time variety of imaging techniques have been available to of m a x i m u m e n h a n c e m e n t ( l j 2 j 7 > 8 ) . T h e m a p s g e n e r a t ed assess cerebral perfusion since the 1970s, beginning , , ., , • ., , • ., • e., . . > & & depend on the algorithm used m the processing of the per-with positron emission tomography ( PET) and xenon fi • CT d i ( 4 6\ computed tomography ( XeCT). Over the next two decades, „ . . ,' , • ,• . , ., . T) r, rF , U1 . f ° . . , , ' Recent studies have indicated that PCT may be able single photon emission computed tomography ( SPECT), . ,• .. • , ,, , •, , • , • , tor r cr^ v ^> to distinguish reversible from non- reversible ischemia by perfusion- weighted MRI ( PWI), and perfusion CT ( PCT) • ... .. ,- • . , F . . . . , . „ r • assessing quantitative perfusion parameter values or gener-were introduced into the armamentarium of perfusion .• e u A • e * • * u *• / F atrng maps of penumbra and infarct core using the quanti-lmagmg techniques ( 1). These techniques have been used to . .• , . , • , r, / « m\ TT, i « * u A , ° . /.. . . ,. , tative data and special software ( 9,10). The latter method evaluate a variety of disease states, including acute and ., . ^ OXI , e U1 • , . • • , • ,- , , •, , assumes that as CBF decreases, areas of reversible ischemia chronic ischemia, ischemia from post- subarachnoid hem- •„ , , . • , r* r>\ r u e * N , r , . , will have normal to increased CBV because of autoregu-orrhage ( SAH) vasospasm, head trauma, and m the assess- , . ,-, . .• , e • U1 • e ° „ v . . . , . ., , . latory vasodilatation, whereas areas of irreversible rnfarc-ment of patients requiring therapeutic carotid occlusion ^ ^ haye d e c r e a s e d C B Y Thus> l o w C B V a r e a s m ay ( 1,2). The advent of thrombolytic therapy to treat acute be c o m p a r a b l e t o r e s t r i c t e d d i f f u s i o n a r e a s o n d i f f u s i o n. stroke has intensified the interest in perfusion imaging • , . , • , . • ,, A^ T> T/ I im r> u r • •*• i . . . . . . . . r . weighted images obtained by MRI ( 1,10). Results of initial techniques in an attempt to distinguish already rnfarcted . ,• ^ .• . , r. ... .• ., , ,, e ^ . r . b . studies attempting to define quantitative thresholds for areas tissue from ischemic but potentially salvageable tissue ( the e U1 • , , • U1 • e .• • A- . . \ . . „ \- ° i reversible ischemia and irreversible infarction indicate ischemic penumbra) ( 3- 5). Such imaging may allow for ^ ^ s i m i k r tQ f h o s e o b t a i n e d w i f h Q t h e r p e r f o s i o n ^ better selection of patients for thrombolytic therapy with modalities s u c h a s P E T and XeCT ( 11,12) ( Fig. 1). thehopeofrmprovedoutcomesandfewercomphcations. lt „ ^ A- u u *• A * I, , „ ,- , , • However, no studies have been performed assessing the may also allow expansion of the current therapeutic ,-,-. fT> r ™ * •. .. u 1 ^- * u A- ** U . , „ , ^ , , „ . r . , ability of PCT to guide thrombolytic therapy or predict the thAwRiosa2iedsn0fADoiuf9donredGel, oeop d r, wg@ ar prey1r It slC5, um asoU0m se0ifcngmni ociatvEh r3nioer. ane . erfs ds hotRipu tgoMoay eudn otinedroofdse lMin ocagcaficeyolct , hri CtU ivogeI ananVEitnvtoel e lHrrera nseDniv a( tdtlyrG t- i hv P. o e6fSAH, M y/ oA) Nhs eit nocefv(, fnhmu n1 i eN/ gr,) A rs. aU , n rnbT MfHioo, vh rDer, i. a r s, sMl r tiDhtnIya etS r4prHty8aai. osc 1r- tst, a0elmp em9rie tt;, aen wAlEtn Bii.- amo„ ml2llf ail: rmtoloIioet• lsca n rihkciplgyg , a l ee euosCvrm sf ftTae* yb oiu• Tirsvhea s se oauee eib, sdo n mrs0( dina ef1lueoil a s ,3sTs rpspte, ri) eP 1( rroachd,^ ee4iesrna j, srFer) i g sfe. rn, om u u• e b c sc rcrIcie0aon. oo tu fvl nh. ntlria, aejams seusr t * rp cetnan oturrcnuoha ellt, ymtari- sl no r sm aiucnmrp• ciier anaarbswecitlte , on aiu irsuelatitvleynanhanet^ its titdn snai i, o sn nne/ nbg, dwa ( pa slr1 , iia co ct) chnt, eoah.\ i e aote nd ars, rn e zc mtmbo, afs,_ lerarl oa waeolwi mlntni C it tdahilraBd( i u . im1c eFntSh5o i c. t) rtrw.. neo. eh e nodniag, toIril. uh_ fc -- l a- a resultant increase in CBV ( 15). Paired CBF measurements maximally vasodilated and cannot respond further to acet-before and after a vasodilatory stimulus, such as acetazol- azolamide ( 15). CBF values in these regions will not increase amide, can provide information about the presence of appropriately. There may even be a decrease in CBF in the autoregulatory vasodilation and impaired reserve vaso- affected territory after acetazolamide injection as vasodila-dilatory capacity. Acetazolamide normally causes vasodila- tion in other well- perfused brain territories diverts blood tation and an increase in CBF by at least 25% ( 16). But away from fully vasodilated poorly perfused regions ( 17). vascular territories under hemodynamic stress are already Improvement in PCT parameters after stenting or bypass has been demonstrated in case reports ( 13,14), but there are no with this technique, typically a 10 to 30 mm thick section, data on whether PCT can predict which patients are at higher usually at the level of the basal ganglia, which limits risk of stroke or will benefit from revascularization. Studies visualization to portions of the anterior, middle, and poste-of the use of PCT in patients with vasospasm after SAH and rior cerebral artery territories ( 1,2,8). PCT may be contra-those undergoing carotid balloon test occlusion ( BTO) are in indicated in patients with contrast allergies or renal failure; preliminary stages ( 18,19) ( Fig. 2). the high injection rates require the use of a large- bore IV PCT is a rapid technique requiring approximately catheter, which may cause patient discomfort. 1 minute of scanning time and several minutes to obtain post- processed perfusion maps. It can potentially be widely PERFUSION- WEIGHTED MRI available, requiring only a helical CT scanner and appro- The most commonly used MR perfusion technique, priate software ( 1,2). Other CT examinations, such as a is dynamic susceptibility contrast ( DSC) imaging. It is non- contrast CT scan and CT angiography ( CTA), can be similar to PCT in that a contrast agent ( a gadolinium che-obtained in the same setting. However, there are significant late) is injected intravenously that causes changes in the MR concerns regarding the accuracy and reproducibility of the signal as the agent passes through the vasculature. The change quantitative values obtained with this technique ( 1). For in signal intensity is then measured and perfusion maps are example, only a limited area of the brain can be imaged generated most commonly CBF, CBV, TTP, or MTT PWI is usually performed in conjunction with PWI has had limited use in other clinical settings, diffusion- weighted MRI ( DWI) and assessment of apparent There are some published reports describing its use in diffusion coefficient ( ADC) values. This combination of assessing patients with chronic cerebrovascular disease, techniques can differentiate ischemic from infarcted tissue including with acetazolamide challenge to evaluate cerebro-and predict the death of ischemic tissue if reperfusion does vascular reserve ( 29- 32). The use of PWI in evaluating not occur ( 1,20- 22). In one report, ( 23) these techniques patients with post- SAH vasospasm and during carotid BTO were used to guide intra- arterial thrombolytic therapy. Areas has also been limited ( 33,34). of abnormal diffusion are usually assumed to represent DWI and PWI are relatively time- consuming, re-irreversible infarction. If the PWI abnormality is larger than quiring 15 to 20 minutes of imaging time, even with limited the area of restricted diffusion ( diffusion/ perfusion mis- stroke imaging protocols, and they are generally less avail-match), then the region with normal diffusion, but abnormal able and more expensive than CT ( 1). It is often difficult to perfusion, is called " the ischemic penumbra" ( Fig. 3). If flow adequately screen acutely ill stroke patients for contra-is not restored to the penumbra, the diffusion abnormality indications to MRI and difficult for such patients to coop-will presumably increase in size to include much of the area erate with the relatively protracted examination. Additionally, of perfusion abnormality ( 1,20- 22). More recent studies, monitoring patients in the MR scanning environment can however, have shown a more complicated process. The be problematic. For most clinical uses, relative, not abso-diffusion changes may be partially reversible in patients lute, quantitative perfusion maps can be obtained with MRI undergoing successful recanalization with intra- arterial techniques. However, this method permits imaging of the thrombolysis such that the penumbra includes not only the entire brain, gives information not only on perfusion, but area of diffusion/ perfusion mismatch, but also part of the also on the status of tissue viability via DWI and can assess area of restricted diffusion ( 24- 26). There have also been vacular patency if MRA is added. No ionizing radiation is reports of initially normal diffusion in patients presenting used and there are usually fewer contraindications to gad-within 4 hours of symptom onset who eventually went on to olinium contrast agents than to iodinated contrast, documented infarction. Thus, negative DWI does not ex­clude impending infarction. However, several of these pa- POSITRON EMISSION TOMOGRAPHY tients had abnormal perfusion parameters at the time of PET studies using 15oxygen tracers have often been initial imaging ( 27,28). Also, there is no consensus as to considered the gold standard in the assessment of cerebral which perfusion parameter or combination of parameters perfusion ( 35). Quantitative values can be obtained for CBF, best defines the penumbra, although a decreased CBV CB\ J oxygen extraction fraction ( OEF), and cerebral meta-likely indicates tissue that is destined to infarct ( 1). No bolic rate for oxygen consumption ( CMR02), providing an studies have been performed to assess whether any assessment of energy metabolism as well as cerebral per-perfusion or diffusion parameters indicate risk of hemor- fusion ( 35). PET studies have defined the penumbra as an rhage with thrombolysis. area with severely reduced CBF, increased OEF ( more than Cerebral Perfusion Imaging J Neuro- Ophthalmol, Vol. 25, No. 4, 2005 0.7; normal, 0.4), and relatively preserved CMR02 ( more than 1.4 mL • 100 g_ 1 • min- 1 = 60 | Jimol • 100 g_ 1 • muT1), a pattern called " misery perfusion" ( 35,36). Although the results vary somewhat among authors, the penumbra likely lies between CBF values of approximately 12 mL- 100 g_ 1 • min- 1 and 22 mL • 100 g_ 1 • min- 1. Some studies have indicated that tissue with CBF of as low as 7 mL- 100 g_ 1 - min- 1 may recover. In PET studies, penumbric tissue has been identified up to 48 hours after symptom onset ( 35,36). PET studies using tracers other than 15oxygen, such as llC- flumazenil ( FMZ) or 18fluoromisonidazole, may be helpful in distinguishing irreversibly damaged tissue from potentially salvageable tissue ( 37,38). Although PET studies have shown improved flow in response to thrombolytic therapy, PET has not been used to help select patients for thrombolysis or assess the risk of hemorrhage from such therapy ( 39). PET has proven to be more useful in the assessment of patients with known cerebrovascular disease who have not yet had complete infarction, particularly those with carotid occlusion. Up to 60% of patients with carotid occlu­sion may be asymptomatic because of adequate collateral circulation. PET studies in patients with symptomatic carotid or middle cerebral artery occlusion have shown that an increased OEF is an independent risk factor for stroke ( 15). It is still unknown whether improving this parameter through revascularization procedures would lead to a de­crease in stroke risk ( 15,40). PET has also been used in a wide variety of additional clinical settings, including SAH and carotid BTO. It may be helpful in assessing impaired oxygen metabolism in patients with post- SAH vasospasm ( 41). PET imaging obtained during temporary carotid BTO may be helpful in predicting the adequacy of flow after permanent occlusion ( 42). Although PET is the oldest and best validated per­fusion imaging technique, its use in routine clinical settings is limited. Many hospitals lack PET imaging facilities. Even if these facilities are available, they are rarely avail­able after hours. PET is a complex imaging technique requiring multi- tracer applications and a cyclotron to pro­duce the radiotracers ( 35). There is exposure to significant radiation doses ( 43). Quantitative results require arterial blood gas sampling which is contraindicated in patients receiving thrombolytic therapy ( 35). SINGLE PHOTON EMISSION COMPUTED TOMOGRAPHY SPECT CBF imaging is obtained using 99mTc as the radioisotope attached to hexamethylpropyleneamine ( HMPAO) or ethyl cysteinate dimer ( ECD) ( 1). These tracers cross the blood- brain barrier and localize in the brain tissue in proportion to blood flow at the time of injection. Imaging can be performed up to several hours after injection ( 44). With this semiquantitative technique, activity in an infarcted area is compared with a presumably normal area in the contralateral cerebral hemisphere or to the presumably unaffected cerebellum ( 1). SPECT is a well-established technique with sensitivity of 61%- 74% and a specificity of 88%- 98% to abnormal perfusion in acute stroke ( 45). It is better at detecting cortical infarcts than smaller infarcts involving deep perforating vessels. The threshold of relative CBF between infarcted and viable tissue is between 0.48 and 0.52 in patients not receiving thrombolytic therapy ( 45,46). SPECT studies evaluating perfusion in patients undergoing thrombolytic therapy indi­cate that assessing the degree of perfusion of ischemic tissue may be a more useful guide to treatment than the duration of symptoms. Among patients receiving intra­arterial thrombolysis, relative CBF thresholds for revers­ibility of ischemia and for hemorrhage after such therapy were 0.55 and 0.35, respectively, in one study ( 47). SPECT has been used in conjunction with an acet-azolamide challenge to assess hemodynamic impairment in patients with chronic cerebrovascular disease. This requires performing two examinations separated by one or more days and assumes that CBF does not change significantly between the two tests. Relative ( but not absolute) flow values can be obtained. Ratios of CBF that indicate an in­creased risk of stroke have not been denned ( 1). Likewise, SPECT has been used during carotid BTO, with the radio­tracer being injected while the balloon is inflated. Imaging can be obtained within several hours to document the rel­ative CBF at the time of balloon occlusion. However, no threshold value of lowered CBF indicating inadequate col­lateral circulation has been determined ( 1). There have been limited reports of the use of SPECT in patients with pos­sible post- SAH vasospasm ( 1). SPECT imaging is relatively accessible; most large radiology departments have the appropriate hardware and software ( 1). But it may be difficult to acquire the kit required to make the injected compound on an emergent basis ( 1,45). A low resolution technique compared with MRI and CT, SPECT provides little anatomic detail so that it is necessary to correlate the findings with a higher- resolution imaging modality. Because it is only a semiquantitative technique, it requires comparison to the contralateral " normal" hemisphere ( 1). Relative CBF is the only parameter that can be mea­sured with this technique. XENON COMPUTED TOMOGRAPHY Xenon ( Xe) is an inert gas that is soluble in both water and lipid, x- ray attenuation by Xe is similar to that of iodine, so Xe can be used as a contrast agent in conjunction with CT ( XeCT) ( 1). The gas dissolves rapidly in blood after inhalation and diffuses rapidly into the brain ( 1,48). 317 J Neuro- Ophthalmol, Vol. 25, No. 4, 2005 Hoeffner Diffusion into the brain is determined by blood flow and solubility of the Xe within different brain compartments ( 48). Patients inhale a mixture of 26%- 32% Xe mixed with 02 over a period of approximately 4.3 minutes. Processing of the data allows generation of CBF maps, from which quantitative data can be extracted ( 1,48). Multiple studies have validated the accuracy of CBF values obtained with XeCT ( 49,50). In acute ischemia, CBF values greater than 20 mL • 100 g_ 1 • mkT1 are associated with sustained viability and reversible neurologic deficit; CBF values less than 10 mL • 100 g_ 1 • mkU1 correlate with eventual infarct volume. CBF between 10 - 20 mL- 100 g_ 1 mkU1 has been associated with neurologic deficits that have been re­versible with aggressive revascularization procedures or with infarction if no revascularization occurred ( 51,52). A CBF of less than 15 mL • 100 g_ 1 min- 1 has been asso­ciated with an increased risk of edema and brain herniation, as well as hemorrhage after thrombolytic therapy ( 53,54). Paired XeCT studies obtained before and after an acetazolamide vasodilatory stimulus have been used to as­sess hemodynamic impairment in patients with chronic ischemia. Decreased vascular response to the acetazolamide indicates pre- existing vasodilatation and loss of normal autoregulatory vascular reserve ( Fig. 4). A decrease in CBF values after acetazolamide administration indicates a high risk of subsequent stroke ( 16,17,55). XeCT has also been used to identify the presence of ischemia ( denned as CBF less than 20 mL • 100 g~ x • min~ v) in patients with post- SAH vasospasm and has been used to document improved CBF after medical or endovascular therapy ( 56- 58). In the setting of carotid BTO, XeCT has been used to help identify patients who clinically pass the BTO but have CBF less than 30 mL • 100 g_ 1 - min- 1, placing them at increased risk of stroke ( 59- 62). Adding acetazolamide may help identify patients who exhaust their cerebrovascular reserve during the BTO ( 62). XeCT is not only a quantitative method of CBF analysis, but this technique is standardized for a given CT system and between different systems ( 1). Being an inert gas, Xe cannot cause allergic reactions, but at the concen­tration used for XeCT, it can cause mild sedation, sensory changes, and nausea ( 63). Despite the widespread avail­ability of standard CT scanners, the relatively low cost of the additional equipment needed to perform XeCT exami­nations, and the extensive medical literature pertaining to its role in evaluating cerebrovascular diseases, this tech­nique has not had extensive use in the United States ( 1,45). Patients with neurologic impairment often cooperate poorly for the examination, during which they must inhale the Xe gas through a face mask or mouthpiece. Patient motion can produce artifacts that hamper interpretation ( 1). CBF is the only parameter that can be measured with XeCT ( 1). Currently there is no commercial supplier of medical grade Xe approved by the Food and Drug Administration; use of the agent is available only under Investigational New Drug authorization ( 1). CONCLUSION Among the many perfusion imaging techniques, PWI and PCT are the two most frequently used in clinical prac­tice. PCT can be performed rapidly and has the potential for wide availability, whereas PWI is a more time- consuming procedure and less readily available, but when used in FIG. 4. Chronic left MCA ischemia as demonstrated by XeCT. ( A) Axial XeCT shows minimally diminished CBF in the left hemisphere ( arrows) compared with the right hemisphere. ( B) After acetazolamide administration, the axial XeCT CBF map shows a normal increase in CBF in all territories except that of the left MCA, where the CBF decreases, compatible with a steal phenomenon from maximally dilated left MCA vasculature. ( C) After a left external carotid to internal carotid artery bypass, the axial XeCT CBF map demonstrates more symmetrical flow between the hemispheres than in ( A). 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