infarctions caused by embolic mechanisms? *J Neurol Neurosurg Psychiatry*.

carotid artery disease: Review of cerebral perfusion studies. *Stroke*. 2005;36:567-577

pathological examination of post-mortem brains: The problem of white matter high

increased signals of the centrum ovale on magnetic resonance imaging. *Arch*

WW. Brain mr: Pathologic correlation with gross and histopathology. 2.

Hyperintense white-matter foci in the elderly. *AJR Am J Roentgenol*. 1988;151:559- 566

Multimodal MRI of Cerebral Small Vessel Disease 297

[89] Sachdev P, Cathcart S, Shnier R, Wen W, Brodaty H. Reliability and validity of ratings

[90] Gouw AA, van der Flier WM, van Straaten EC, Pantoni L, Bastos-Leite AJ, Inzitari D,

[91] de Groot JC, de Leeuw FE, Oudkerk M, van Gijn J, Hofman A, Jolles J, Breteler MM.

[92] van Straaten EC, Fazekas F, Rostrup E, Scheltens P, Schmidt R, Pantoni L, Inzitari D,

[93] Nebes RD, Meltzer CC, Whyte EM, Scanlon JM, Halligan EM, Saxton JA, Houck PR,

[94] Rovaris M, Iannucci G, Cercignani M, Sormani MP, De Stefano N, Gerevini S, Comi G,

[95] Benedetti B, Charil A, Rovaris M, Judica E, Valsasina P, Sormani MP, Filippi M.

[96] Horsfield MA, Jones DK. Applications of diffusion-weighted and diffusion tensor mri

[97] Mascalchi M, Filippi M, Floris R, Fonda C, Gasparotti R, Villari N. Diffusion-weighted

[98] Beaulieu C. The basis of anisotropic water diffusion in the nervous system - a technical

[99] O'Sullivan M, Summers PE, Jones DK, Jarosz JM, Williams SC, Markus HS. Normal-

[100] Molko N, Pappata S, Mangin JF, Poupon C, Vahedi K, Jobert A, LeBihan D, Bousser

[101] Chabriat H, Pappata S, Poupon C, Clark CA, Vahedi K, Poupon F, Mangin JF, Pachot-

[102] Holtmannspotter M, Peters N, Opherk C, Martin D, Herzog J, Bruckmann H, Samann

to white matter diseases - a review. *NMR Biomed*. 2002;15:570-577

conventional, mt, and dt mri. *Neurology*. 2006;66:535-539

matter hyperintensity progression. *Cerebrovasc Dis*. 2008;25:247-253

measurement. *Psychiatry Res*. 1999;92:103-115

*Ann Neurol*. 2000;47:145-151

study. *Stroke*. 2006;37:836-840

*Neuropsychol Cogn*. 2006;13:326-340

analysis. *Radiology*. 2003;227:731-738

review. *NMR Biomed*. 2002;15:435-455

*Neurology*. 2001;57:2307-2310

*Stroke*. 1999;30:2637-2643

cadasil. *Stroke*. 2001;32:2049-2054

of signal hyperintensities on mri by visual inspection and computerised

Erkinjuntti T, Wahlund LO, Ryberg C, Schmidt R, Fazekas F, Scheltens P, Barkhof F. Reliability and sensitivity of visual scales versus volumetry for evaluating white

Cerebral white matter lesions and cognitive function: The rotterdam scan study.

Waldemar G, Erkinjuntti T, Mantyla R, Wahlund LO, Barkhof F. Impact of white matter hyperintensities scoring method on correlations with clinical data: The ladis

Boada FE, Dekosky ST. The relation of white matter hyperintensities to cognitive performance in the normal old: Education matters. *Neuropsychol Dev Cogn B Aging*

Filippi M. Age-related changes in conventional, magnetization transfer, and diffusion-tensor mr imaging findings: Study with whole-brain tissue histogram

Influence of aging on brain gray and white matter changes assessed by

mr of the brain: Methodology and clinical application. *Radiol Med*. 2005;109:155-197

appearing white matter in ischemic leukoaraiosis: A diffusion tensor mri study.

MG, Chabriat H. Diffusion tensor imaging study of subcortical gray matter in

Clouard M, Jobert A, Le Bihan D, Bousser MG. Clinical severity in cadasil related to ultrastructural damage in white matter: In vivo study with diffusion tensor mri.

P, Gschwendtner A, Dichgans M. Diffusion magnetic resonance histograms as a

[73] Norrving B. Long-term prognosis after lacunar infarction. *Lancet Neurol*. 2003;2:238-245 [74] Longstreth WT, Jr., Arnold AM, Beauchamp NJ, Jr., Manolio TA, Lefkowitz D, Jungreis

[76] Marshall VG, Bradley WG, Jr., Marshall CE, Bhoopat T, Rhodes RH. Deep white matter

[77] Revesz T, Hawkins CP, du Boulay EP, Barnard RO, McDonald WI. Pathological

[78] Fazekas F, Kleinert R, Offenbacher H, Schmidt R, Kleinert G, Payer F, Radner H,

[79] Fernando MS, O'Brien JT, Perry RH, English P, Forster G, McMeekin W, Slade JY,

[82] Matthews PM, Tampieri D, Berkovic SF, Andermann F, Silver K, Chityat D, Arnold DL.

[83] Fazekas F CJ, Alavi A, Hurtig HI, Zimmerman RA. Mr signal abnormalities at 1.5 t in

[84] Schmidt R, Fazekas F, Kapeller P, Schmidt H, Hartung HP. Mri white matter

[85] Scheltens P, Barkhof F, Leys D, Pruvo JP, Nauta JJ, Vermersch P, Steinling M, Valk J. A

[86] Wahlund LO, Barkhof F, Fazekas F, Bronge L, Augustin M, Sjogren M, Wallin A, Ader

[87] Kapeller P, Schmidt R, Enzinger C, Ropele S, Fazekas F. Ct and mri rating of white

[88] Anbeek P, Vincken KL, van Osch MJ, Bisschops RH, van der Grond J. Probabilistic

alzheimer's dementia and normal aging. *AJR Am J Roentgenol*. 1987

magnetic resonance imaging. *J Neurol Sci*. 1993;114:7-12

matter changes. *J Neural Transm Suppl*. 2002:41-45

(mri) in the elderly brain. *Neuropathol Appl Neurobiol*. 2004;30:385-395 [80] Bartynski WS. Posterior reversible encephalopathy syndrome, part 1: Fundamental imaging and clinical features. *AJNR Am J Neuroradiol*. 2008;29:1036-1042 [81] Costello DJ, Eichler AF, Eichler FS. Leukodystrophies: Classification, diagnosis, and

elderly: The cardiovascular health study. *Stroke*. 2005;36:56-61 [75] Hachinski VC, Potter P, Merskey H. Leuko-araiosis. *Arch Neurol*. 1987;44:21-23

hyperintensities. *Neurology*. 1993;43:1683-1689

treatment. *Neurologist*. 2009;15:319-328

*Neurology*. 1991;41:1043-1046

*Neurology*. 1999;53:132-139

1988;167:517-522

1344

C, Hirsch CH, O'Leary DH, Furberg CD. Incidence, manifestations, and predictors of worsening white matter on serial cranial magnetic resonance imaging in the

infarction: Correlation of mr imaging and histopathologic findings. *Radiology*.

findings correlated with magnetic resonance imaging in subcortical arteriosclerotic encephalopathy (binswanger's disease). *J Neurol Neurosurg Psychiatry*. 1989;52:1337-

Lechner H. Pathologic correlates of incidental mri white matter signal

Golkhar A, Matthews FE, Barber R, Kalaria RN, Ince PG. Comparison of the pathology of cerebral white matter with post-mortem magnetic resonance imaging

Magnetic resonance imaging shows specific abnormalities in the melas syndrome.

hyperintensities: Three-year follow-up of the austrian stroke prevention study.

semiquantative rating scale for the assessment of signal hyperintensities on

H, Leys D, Pantoni L, Pasquier F, Erkinjuntti T, Scheltens P. A new rating scale for age-related white matter changes applicable to mri and ct. *Stroke*. 2001;32:1318-1322

segmentation of white matter lesions in mr imaging. *Neuroimage*. 2004;21:1037-1044

Multimodal MRI of Cerebral Small Vessel Disease 299

[118] Kakuda W, Thijs VN, Lansberg MG, Bammer R, Wechsler L, Kemp S, Moseley ME,

[119] Kidwell CS, Saver JL, Villablanca JP, Duckwiler G, Fredieu A, Gough K, Leary MC,

[120] Nighoghossian N, Hermier M, Adeleine P, Blanc-Lasserre K, Derex L, Honnorat J,

[121] Enzinger C, Fazekas F, Matthews PM, Ropele S, Schmidt H, Smith S, Schmidt R. Risk

[122] Karas GB, Scheltens P, Rombouts SA, Visser PJ, van Schijndel RA, Fox NC, Barkhof F.

[123] Zivadinov R, Sepcic J, Nasuelli D, De Masi R, Bragadin LM, Tommasi MA, Zambito-

[124] Kraemer M, Schormann T, Hagemann G, Qi B, Witte OW, Seitz RJ. Delayed shrinkage

[125] Schmidt R, Ropele S, Enzinger C, Petrovic K, Smith S, Schmidt H, Matthews PM,

[126] Preul C, Lohmann G, Hund-Georgiadis M, Guthke T, von Cramon DY. Morphometry

[127] Seshadri S, Wolf PA, Beiser A, Elias MF, Au R, Kase CS, D'Agostino RB, DeCarli C.

[128] Viswanathan A, Godin O, Jouvent E, O'Sullivan M, Gschwendtner A, Peters N,

[129] Fein G, Di Sclafani V, Tanabe J, Cardenas V, Weiner MW, Jagust WJ, Reed BR, Norman

The austrian stroke prevention study. *Ann Neurol*. 2005;58:610-616

A multi-modal analysis in cadasil. *Neurobiol Aging*.31:1629-1636

thrombolysis. *Neurology*. 2005;65:1175-1178

emerging application. *Stroke*. 2002;33:95-98

brain mri study. *Stroke*. 2002;33:735-742

subjects. *Neurology*. 2005;64:1704-1711

disease. *Neuroimage*. 2004;23:708-716

morphometry. *J Neuroimaging*. 2004;14:265-272

offspring study. *Neurology*. 2004;63:1591-1599

2001;70:773-780

2005;252:441-447

1635

Marks MP, Albers GW. Clinical importance of microbleeds in patients receiving iv

Starkman S, Gobin YP, Jahan R, Vespa P, Liebeskind DS, Alger JR, Vinuela F. Magnetic resonance imaging detection of microbleeds before thrombolysis: An

Philippeau F, Dugor JF, Froment JC, Trouillas P. Old microbleeds are a potential risk factor for cerebral bleeding after ischemic stroke: A gradient-echo t2\*-weighted

factors for progression of brain atrophy in aging: Six-year follow-up of normal

Global and local gray matter loss in mild cognitive impairment and alzheimer's

Marsala S, Moretti R, Bratina A, Ukmar M, Pozzi-Mucelli RS, Grop A, Cazzato G, Zorzon M. A longitudinal study of brain atrophy and cognitive disturbances in the early phase of relapsing-remitting multiple sclerosis. *J Neurol Neurosurg Psychiatry*.

of the brain after ischemic stroke: Preliminary observations with voxel-guided

Fazekas F. White matter lesion progression, brain atrophy, and cognitive decline:

demonstrates loss of cortical thickness in cerebral microangiopathy. *J Neurol*.

Stroke risk profile, brain volume, and cognitive function: The framingham

Duering M, Guichard JP, Holtmannspotter M, Dufouil C, Pachai C, Bousser MG, Dichgans M, Chabriat H. Impact of mri markers in subcortical vascular dementia:

D, Schuff N, Kusdra L, Greenfield T, Chui H. Hippocampal and cortical atrophy predict dementia in subcortical ischemic vascular disease. *Neurology*. 2000;55:1626-

surrogate marker and predictor of disease progression in cadasil: A two-year follow-up study. *Stroke*. 2005;36:2559-2565

[103] Molko N, Pappata S, Mangin JF, Poupon F, LeBihan D, Bousser MG, Chabriat H.

[105] Charlton RA, Schiavone F, Barrick TR, Morris RG, Markus HS. Diffusion tensor

follow-up study. *Stroke*. 2005;36:2559-2565

change over time. *Stroke*. 2008;39:1999-2005

*Neuroradiol*. 1996;17:573-578

*Stroke*. 1999;30:1637-1642

2006;1:122-130

2004;251:1183-1189

up study. *Acta Radiol*. 2003;44:199-205

reporting. *Brain*. 2007;130:1988-2003

surrogate marker and predictor of disease progression in cadasil: A two-year

Monitoring disease progression in cadasil with diffusion magnetic resonance imaging: A study with whole brain histogram analysis. *Stroke*. 2002;33:2902-2908 [104] Nitkunan A, Barrick TR, Charlton RA, Clark CA, Markus HS. Multimodal mri in

cerebral small vessel disease: Its relationship with cognition and sensitivity to

imaging detects age related white matter change over a 2 year follow-up which is associated with working memory decline. *J Neurol Neurosurg Psychiatry*.81:13-19 [106] Della Nave R, Foresti S, Pratesi A, Ginestroni A, Inzitari M, Salvadori E, Giannelli M,

Diciotti S, Inzitari D, Mascalchi M. Whole-brain histogram and voxel-based analyses of diffusion tensor imaging in patients with leukoaraiosis: Correlation with motor and cognitive impairment. *AJNR Am J Neuroradiol*. 2007;28:1313-1319 [107] Offenbacher H, Fazekas F, Schmidt R, Koch M, Fazekas G, Kapeller P. Mr of cerebral

abnormalities concomitant with primary intracerebral hematomas. *AJNR Am J*

small experimental intracranial hematomas at 1.5 t and 0.5 t. A 6-7-month follow-

Histopathologic analysis of foci of signal loss on gradient-echo t2\*-weighted mr images in patients with spontaneous intracerebral hemorrhage: Evidence of microangiopathy-related microbleeds. *AJNR Am J Neuroradiol*. 1999;20:637-642 [111] Tanaka A, Ueno Y, Nakayama Y, Takano K, Takebayashi S. Small chronic hemorrhages

and ischemic lesions in association with spontaneous intracerebral hematomas.

Systematic review, subgroup analyses and standards for study design and

hypertensive stroke. Topographical distribution in the supratentorial area. *J Neurol*.

H, Dardel P, Froment JC, Trouillas P. Thrombolysis for ischemic stroke in patients

[108] Greenberg SM, Finklestein SP, Schaefer PW. Petechial hemorrhages accompanying lobar hemorrhage: Detection by gradient-echo mri. *Neurology*. 1996;46:1751-1754 [109] Ripoll MA, Siosteen B, Hartman M, Raininko R. Mr detectability and appearance of

[110] Fazekas F, Kleinert R, Roob G, Kleinert G, Kapeller P, Schmidt R, Hartung HP.

[112] Viswanathan A, Chabriat H. Cerebral microhemorrhage. *Stroke*. 2006;37:550-555

[113] Fiehler J. Cerebral microbleeds: Old leaks and new haemorrhages.  Cerebral microbleeds in patients with

[116] Chalela JA, Kang DW, Warach S. Multiple cerebral microbleeds: Mri marker of a

[117] Derex L, Nighoghossian N, Hermier M, Adeleine P, Philippeau F, Honnorat J, Yilmaz

with old microbleeds on pretreatment mri. *Cerebrovasc Dis*. 2004;17:238-241

diffuse hemorrhage-prone state. *J Neuroimaging*. 2004;14:54-57

**14**

*Pakistan*

**Neuroimaging of Intracranial**

*Stroke Program, The Aga Khan University Hospital*

Maria Khan, Imama Naqvi and Ayeesha Kamran Kamal

Ischemic stroke is now universally accepted as a heterogeneous disease. The need to properly classify stroke subtypes is increasingly driven by the realization that different mechanisms may require different treatments. Also the risk of recurrent vascular events

Intracranial atherosclerotic disease (ICAD) is fast emerging as the predominant mechanism of ischemic stroke in the world and particularly in patients of Asian origin (Kim et al, 2006 and Sacco et al, 1995). Also, ICAD is reported to have the highest risk of recurrent ischemic cerebrovascular events being quoted between 25-30% in two years (Wong et al, 2003 and

It is now well recognized that intracranial atherosclerotic disease predominantly affects patients of Asian, African and Hispanic origin. Since these are the regions of the world which are going to harbor the majority of the world's stroke population, it is expected that

The rates of ICAD reported from Asian countries range between 33-56% depending on what cutoff for stenosis is taken (Huang et al, 1997 and Lee et al, 2003). Caucasians predominantly have extracranial atherosclerosis and rates of intracranial disease vary between 1 and 24%

Data on the prevalence of asymptomatic stenosis are relatively scarce. Warfarin versus Aspirin in Symptomatic Intracranial disease (WASID) trial reported presence of 27% asymptomatic disease in patients who also had symptomatic stenosis (Nahab et al, 2008). Studies of healthy Japanese and Korean populations report asymptomatic disease in 3-3.5% (Park et al, 2006 and Wong et al, 2007). There is a growing need to identify the asymptomatic entity as the process of atherosclerosis can potentially be stalled by timely risk factor management. Several diagnostic modalities are now available and evolving but the focus so far is on the diagnosis of the disease at a stage when it becomes symptomatic. In this chapter we describe the various radiological presentations of stroke secondary to intracranial atherosclerotic disease followed by a description of the tools available for diagnosing the condition. Non invasive modalities are the main focus as the prevalence of the disease increases and the need to identify asymptomatic disease is also increasingly felt.

the disease burden of intracranial atherosclerosis is also going to increase.

**1. Introduction**

Mazighi et al, 2006).

**2. Epidemiology**

differs among various ischemic stroke subtypes.

(e.g., Sacco et al., 1995; Wityk et al., 1996).

**Atherosclerotic Disease**

### **Neuroimaging of Intracranial Atherosclerotic Disease**

Maria Khan, Imama Naqvi and Ayeesha Kamran Kamal *Stroke Program, The Aga Khan University Hospital Pakistan*

#### **1. Introduction**

300 Neuroimaging – Clinical Applications

[130] Jouvent E, Mangin JF, Porcher R, Viswanathan A, O'Sullivan M, Guichard JP, Dichgans

3d mri study of cortical morphology in cadasil. *Brain*. 2008;131:2201-2208 [131] Viswanathan A, Gray F, Bousser MG, Baudrimont M, Chabriat H. Cortical neuronal

[132] Rao DG, Lyons PR. Wallerian degeneration of the pyramidal tract after a thrombotic

[133] Jouvent E, Viswanathan A, Chabriat H. Cerebral atrophy in cerebrovascular disorders.

apoptosis in cadasil. *Stroke*. 2006;37:2690-2695

*J Neuroimaging*.20:213-218

stroke. *J Neurol Neurosurg Psychiatry*. 1998;65:944

M, Bousser MG, Chabriat H. Cortical changes in cerebral small vessel diseases: A

Ischemic stroke is now universally accepted as a heterogeneous disease. The need to properly classify stroke subtypes is increasingly driven by the realization that different mechanisms may require different treatments. Also the risk of recurrent vascular events differs among various ischemic stroke subtypes.

Intracranial atherosclerotic disease (ICAD) is fast emerging as the predominant mechanism of ischemic stroke in the world and particularly in patients of Asian origin (Kim et al, 2006 and Sacco et al, 1995). Also, ICAD is reported to have the highest risk of recurrent ischemic cerebrovascular events being quoted between 25-30% in two years (Wong et al, 2003 and Mazighi et al, 2006).

#### **2. Epidemiology**

It is now well recognized that intracranial atherosclerotic disease predominantly affects patients of Asian, African and Hispanic origin. Since these are the regions of the world which are going to harbor the majority of the world's stroke population, it is expected that the disease burden of intracranial atherosclerosis is also going to increase.

The rates of ICAD reported from Asian countries range between 33-56% depending on what cutoff for stenosis is taken (Huang et al, 1997 and Lee et al, 2003). Caucasians predominantly have extracranial atherosclerosis and rates of intracranial disease vary between 1 and 24% (e.g., Sacco et al., 1995; Wityk et al., 1996).

Data on the prevalence of asymptomatic stenosis are relatively scarce. Warfarin versus Aspirin in Symptomatic Intracranial disease (WASID) trial reported presence of 27% asymptomatic disease in patients who also had symptomatic stenosis (Nahab et al, 2008). Studies of healthy Japanese and Korean populations report asymptomatic disease in 3-3.5% (Park et al, 2006 and Wong et al, 2007). There is a growing need to identify the asymptomatic entity as the process of atherosclerosis can potentially be stalled by timely risk factor management. Several diagnostic modalities are now available and evolving but the focus so far is on the diagnosis of the disease at a stage when it becomes symptomatic.

In this chapter we describe the various radiological presentations of stroke secondary to intracranial atherosclerotic disease followed by a description of the tools available for diagnosing the condition. Non invasive modalities are the main focus as the prevalence of the disease increases and the need to identify asymptomatic disease is also increasingly felt.

Neuroimaging of Intracranial Atherosclerotic Disease 303

Cortically based infarctions in the territory of MCA (anterior territorial infarctions) and PCA (posterior territorial infarctions) have also been described with large vessel atherosclerotic disease. The proposed mechanism is again artery to artery embolism. In case of anterior circulation, as opposed to cardioembolic infarcts, these are usually smaller, and limited to one of the three MCA territories. This can be explained based on the size of cardiac emboli which are larger and likely to give rise to large infarcts. However, with larger emboli occluding proximal MCA or distal internal carotid arteries (ICA), large territorial infarctions may also be seen particularly in the absence of effective collaterals (Rovera et al, 2005). The ischemic cortical lesions may co-exist with smaller cortical or subcortical acute lesions

Fig. 1. Diffusion Weighted Images of Infarct Patterns seen with ICAD. A) Multiple infarcts in Right MCA territory, B) Deep MCA perforator infarct along with patchy cortical infarcts, C) cortical infarct in posterior MCA territory, D) String of pearls pattern in Internal borderzone. (Image Courtesy, Stroke Fellowship Program, Aga Khan University Hospital, Karachi,

**3.2 Cortical territorial infarctions**

resulting from fragmentation of the embolus.

A B

C D

Pakistan)

Additionally, with a greater number of patients now being offered endovascular treatment, there is a need to have cost-effective, minimally invasive and reliable methods to follow these patients up.

#### **3. Infarct patterns**

Literature now exists on infarct patterns associated with intracranial large artery atherosclerosis. The underlying mechanisms leading to ischemia in the diseased arterial territory include artery-to-artery embolism, thrombosis leading to complete occlusion or to local branch occlusion and hemodynamic compromise (Wong et al, 2002). A combination of these factors may also co-exist in some patients. Depending on the mechanism of ischemia, the infarct pattern may differ.

#### **3.1 Border-zone Infarctions**

Border-zone infarctions have been described with intracranial atherosclerotic disease for decades. Recently the concept of border-zones has been revisited and two types of borderzone infarctions have been described (Yong et al, 2006). Internal border-zone infarctions involve the area between the territory of anterior, middle and posterior cerebral arteries and the territory supplied by the lenticulostriate, anterior choroidal and Heubner arteries. The term cortical border-zone is used for areas located between the cortical supply of the anterior and middle cerebral arteries (anterior cortical border-zone) and between middle and posterior cerebral arteries (posterior cortical border-zone). It is proposed that the two types of infarctions may have different underlying pathophysiology.

#### **3.1.1 Cortical border-zone infarctions**

For the cortical border-zone infarctions, artery-to-artery embolism has been proposed as causative since the 1980's. Several studies (Torvik et al, 1982, Pollanen et al, 1990, Masuda et al, 1994, Belden et al, 1999) describe border-zone or watershed infarctions resulting from atheromatous large vessel intracranial disease. With Transcranial Doppler monitoring this mechanism has been further validated. Using this modality, impaired clearance of emboli has been documented with middle cerebral artery (MCA) stenosis and patients with this condition were found to have multiple small cerebral infarcts especially in the border-zone territories of MCA with anterior and posterior cerebral arteries (Wong et al, 2002).

#### **3.1.2 Internal border-zone infarctions**

For internal border-zone infarctions, hemodynamic compromise is believed to be the proximate cause. Infarct patterns described include single lacunes in internal border-zone or a string of pearls or scattered pearl appearance on diffusion weighted imaging (DWI) (Turtzo et al, 2009). The underlying mechanism is believed to be a gradual reduction in the perfusion pressure in the stenosed artery. This leads to development of collateral blood supply from branches of extracranial carotid artery. With progression of disease, these collaterals are unable to maintain the hemodynamics and maximal hypoperfusion occurs in the terminal zones of the distribution of MCA and its perforators. These are the internal border-zone areas and the association of these infarcts with increased oxygen extraction fraction has been documented suggesting hemodynamic compromise as the likely mechanism (Yamauchi et al, 2009).

#### **3.2 Cortical territorial infarctions**

302 Neuroimaging – Clinical Applications

Additionally, with a greater number of patients now being offered endovascular treatment, there is a need to have cost-effective, minimally invasive and reliable methods to follow

Literature now exists on infarct patterns associated with intracranial large artery atherosclerosis. The underlying mechanisms leading to ischemia in the diseased arterial territory include artery-to-artery embolism, thrombosis leading to complete occlusion or to local branch occlusion and hemodynamic compromise (Wong et al, 2002). A combination of these factors may also co-exist in some patients. Depending on the mechanism of ischemia,

Border-zone infarctions have been described with intracranial atherosclerotic disease for decades. Recently the concept of border-zones has been revisited and two types of borderzone infarctions have been described (Yong et al, 2006). Internal border-zone infarctions involve the area between the territory of anterior, middle and posterior cerebral arteries and the territory supplied by the lenticulostriate, anterior choroidal and Heubner arteries. The term cortical border-zone is used for areas located between the cortical supply of the anterior and middle cerebral arteries (anterior cortical border-zone) and between middle and posterior cerebral arteries (posterior cortical border-zone). It is proposed that the two

For the cortical border-zone infarctions, artery-to-artery embolism has been proposed as causative since the 1980's. Several studies (Torvik et al, 1982, Pollanen et al, 1990, Masuda et al, 1994, Belden et al, 1999) describe border-zone or watershed infarctions resulting from atheromatous large vessel intracranial disease. With Transcranial Doppler monitoring this mechanism has been further validated. Using this modality, impaired clearance of emboli has been documented with middle cerebral artery (MCA) stenosis and patients with this condition were found to have multiple small cerebral infarcts especially in the border-zone

For internal border-zone infarctions, hemodynamic compromise is believed to be the proximate cause. Infarct patterns described include single lacunes in internal border-zone or a string of pearls or scattered pearl appearance on diffusion weighted imaging (DWI) (Turtzo et al, 2009). The underlying mechanism is believed to be a gradual reduction in the perfusion pressure in the stenosed artery. This leads to development of collateral blood supply from branches of extracranial carotid artery. With progression of disease, these collaterals are unable to maintain the hemodynamics and maximal hypoperfusion occurs in the terminal zones of the distribution of MCA and its perforators. These are the internal border-zone areas and the association of these infarcts with increased oxygen extraction fraction has been documented suggesting hemodynamic compromise as the likely

territories of MCA with anterior and posterior cerebral arteries (Wong et al, 2002).

types of infarctions may have different underlying pathophysiology.

these patients up.

**3. Infarct patterns**

the infarct pattern may differ.

**3.1 Border-zone Infarctions**

**3.1.1 Cortical border-zone infarctions**

**3.1.2 Internal border-zone infarctions**

mechanism (Yamauchi et al, 2009).

Cortically based infarctions in the territory of MCA (anterior territorial infarctions) and PCA (posterior territorial infarctions) have also been described with large vessel atherosclerotic disease. The proposed mechanism is again artery to artery embolism. In case of anterior circulation, as opposed to cardioembolic infarcts, these are usually smaller, and limited to one of the three MCA territories. This can be explained based on the size of cardiac emboli which are larger and likely to give rise to large infarcts. However, with larger emboli occluding proximal MCA or distal internal carotid arteries (ICA), large territorial infarctions may also be seen particularly in the absence of effective collaterals (Rovera et al, 2005). The ischemic cortical lesions may co-exist with smaller cortical or subcortical acute lesions resulting from fragmentation of the embolus.

Fig. 1. Diffusion Weighted Images of Infarct Patterns seen with ICAD. A) Multiple infarcts in Right MCA territory, B) Deep MCA perforator infarct along with patchy cortical infarcts, C) cortical infarct in posterior MCA territory, D) String of pearls pattern in Internal borderzone. (Image Courtesy, Stroke Fellowship Program, Aga Khan University Hospital, Karachi, Pakistan)

Neuroimaging of Intracranial Atherosclerotic Disease 305

DSA has several advantages over other modalities used for assessing intracranial stenosis. It provides excellent visualization of the anatomy of the vessel, the severity and length of stenosis and the presence of collateral circulation. However, the major disadvantage lies in the high skill required to perform the study. Another disadvantage is the morbidity associated with the procedure including stroke, arterial dissections, puncture site infection, thrombosis of punctured artery leading to limb ischemia and formation of pseudoaneurysms. In addition to this it carries the risk of nephrotoxicity associated with iodinated

Fig. 2. DSA images showing disease in Right vertebral artery. A) Tight stenosis in Right vertebral artery, B) Post stenting restoration of flow.(Image Courtesy: Dr. Tanveer-ul-Haq**,**  Associate Professor ,Section Head, Vascular and Interventional Radiology, Radiology

When conducted for diagnostic purposes, risk associated with the procedure has gone down over the past years. The most recent estimate quotes the risk of stroke at 0.03% and of arterial dissections at 0.14%. The non-neurologic complications related to the arterial puncture were also not commonly seen (Fifi et al, 2009). In a dedicated unit for cerebral angiographies, the risk of neurologic complications can approach zero (Thiex et al, 2010). Interestingly, the risk of neurological adverse events was higher in patients with known intracranial atherosclerotic disease who underwent cerebral angiography in the WASID trial. 2% of these patients experienced neurological symptoms although all were transient

Given the disadvantages of DSA and the increased morbidity and potential mortality associated with it, non-invasive modalities are increasingly being utilized for assessment of

Phase contrast MRA utilizes the velocity differences and hence the phase shifts in moving spins to provide image contrast in flowing vessels. The phase of magnetization from the

Department, Aga Khan University Hospital , Karachi, Pakistan)

A B

and 6.1% had non-neurologic complications (Cloft et al, 2011).

**4.2.1 Phase contrast (PC) and Time of Flight (TOF) MRA**

intracranial atherosclerotic disease.

**4.2 Magnetic Resonance Angiography (MRA)**

contrast used in the procedure.

In the posterior circulation, large artery atherosclerosis involving the vertebrobasilar arteries leads to infarctions in the territories of posterior inferior cerebellar artery (PICA), superior cerebellar artery (SCA) and PCA. Small territorial and nonterritorial cerebellar infarcts are also described with vertebrobasilar disease (Amarenco et al, 1994).

#### **3.3 Lacunar infarctions**

Lacunar infarctions in the centrum semiovale have also been described with intracranial atherosclerotic disease. When large (>1.5 cm) and present in the internal border-zone, these are thought to result from hemodynamic compromise. When small (<1.5 cm) they may arise secondary to artery to artery embolism. In this case, they may be accompanied by other small acute infarcts in the same large artery territory (Bogousslavsky and Regli, 1992). Posterior circulation lacunes have also been described with large vessel disease, particularly when they occur in isolation.

#### **3.4 Perforator artery infarctions**

With atherosclerotic involvement of MCA, local branch occlusion has also been described leading to deep perforator artery infarctions. Pial infarctions, those occurring in the vascular territories supplied by the superior and inferior branches of MCA have also been described with MCA disease (Lee et al, 2005). Thrombotic occlusion in the former and distal embolization in the latter is thought to be the underlying mechanism.

#### **3.5 Multiple acute brain infarctions**

Multiple acute brain infarctions, particularly in the same arterial territory have also been described (Roh et al, 2000 and Kang et al, 2003). The mechanism is believed to be distal embolizations from large vessel unstable plaque. Such infarcts are typically located in a single anterior or posterior arterial territory, but anatomic variations may explain other patterns such as involvement of anterior and posterior circulations simultaneously in case of a fetal-PCA or posterior communicating artery patency, or involvement of bilateral ACA territories in case of a single ACA supplying both hemispheres.

#### **4. Imaging of vessels**

The diagnosis of intracranial atherosclerotic disease rests on either direct visualization of the vessels or determination of their flow characteristics. Several non-invasive modalities like magnetic resonance angiography (MRA), computerized tomographic angiography (CTA) and transcranial doppler (TCD) are now available for screening and diagnostic purposes. However, the gold standard for diagnosis is still catheter based conventional angiography.

#### **4.1 Catheter based conventional and Digital Subtraction Angiography (DSA)**

DSA has been the reference standard for evaluation of intracranial stenosis and occlusion for decades. The technique involves injection of a radio-opaque dye via an intra-arterial catheter. Usually the femoral or radial arteries are used. Cerebral angiography is performed after catheterizing the cerebral arteries. The term digital subtraction angiography is used when a computer based software subtracts two images that are obtained before and after administration of contrast media. Modern DSA also incorporates three-dimensional reconstructed images which provide even better details.

In the posterior circulation, large artery atherosclerosis involving the vertebrobasilar arteries leads to infarctions in the territories of posterior inferior cerebellar artery (PICA), superior cerebellar artery (SCA) and PCA. Small territorial and nonterritorial cerebellar infarcts are

Lacunar infarctions in the centrum semiovale have also been described with intracranial atherosclerotic disease. When large (>1.5 cm) and present in the internal border-zone, these are thought to result from hemodynamic compromise. When small (<1.5 cm) they may arise secondary to artery to artery embolism. In this case, they may be accompanied by other small acute infarcts in the same large artery territory (Bogousslavsky and Regli, 1992). Posterior circulation lacunes have also been described with large vessel disease, particularly

With atherosclerotic involvement of MCA, local branch occlusion has also been described leading to deep perforator artery infarctions. Pial infarctions, those occurring in the vascular territories supplied by the superior and inferior branches of MCA have also been described with MCA disease (Lee et al, 2005). Thrombotic occlusion in the former and distal

Multiple acute brain infarctions, particularly in the same arterial territory have also been described (Roh et al, 2000 and Kang et al, 2003). The mechanism is believed to be distal embolizations from large vessel unstable plaque. Such infarcts are typically located in a single anterior or posterior arterial territory, but anatomic variations may explain other patterns such as involvement of anterior and posterior circulations simultaneously in case of a fetal-PCA or posterior communicating artery patency, or involvement of bilateral ACA

The diagnosis of intracranial atherosclerotic disease rests on either direct visualization of the vessels or determination of their flow characteristics. Several non-invasive modalities like magnetic resonance angiography (MRA), computerized tomographic angiography (CTA) and transcranial doppler (TCD) are now available for screening and diagnostic purposes. However, the gold standard for diagnosis is still catheter based conventional angiography.

DSA has been the reference standard for evaluation of intracranial stenosis and occlusion for decades. The technique involves injection of a radio-opaque dye via an intra-arterial catheter. Usually the femoral or radial arteries are used. Cerebral angiography is performed after catheterizing the cerebral arteries. The term digital subtraction angiography is used when a computer based software subtracts two images that are obtained before and after administration of contrast media. Modern DSA also incorporates three-dimensional

**4.1 Catheter based conventional and Digital Subtraction Angiography (DSA)**

also described with vertebrobasilar disease (Amarenco et al, 1994).

embolization in the latter is thought to be the underlying mechanism.

territories in case of a single ACA supplying both hemispheres.

reconstructed images which provide even better details.

**3.3 Lacunar infarctions**

when they occur in isolation.

**3.4 Perforator artery infarctions**

**3.5 Multiple acute brain infarctions**

**4. Imaging of vessels**

DSA has several advantages over other modalities used for assessing intracranial stenosis. It provides excellent visualization of the anatomy of the vessel, the severity and length of stenosis and the presence of collateral circulation. However, the major disadvantage lies in the high skill required to perform the study. Another disadvantage is the morbidity associated with the procedure including stroke, arterial dissections, puncture site infection, thrombosis of punctured artery leading to limb ischemia and formation of pseudoaneurysms. In addition to this it carries the risk of nephrotoxicity associated with iodinated contrast used in the procedure.

Fig. 2. DSA images showing disease in Right vertebral artery. A) Tight stenosis in Right vertebral artery, B) Post stenting restoration of flow.(Image Courtesy: Dr. Tanveer-ul-Haq**,**  Associate Professor ,Section Head, Vascular and Interventional Radiology, Radiology Department, Aga Khan University Hospital , Karachi, Pakistan)

When conducted for diagnostic purposes, risk associated with the procedure has gone down over the past years. The most recent estimate quotes the risk of stroke at 0.03% and of arterial dissections at 0.14%. The non-neurologic complications related to the arterial puncture were also not commonly seen (Fifi et al, 2009). In a dedicated unit for cerebral angiographies, the risk of neurologic complications can approach zero (Thiex et al, 2010). Interestingly, the risk of neurological adverse events was higher in patients with known intracranial atherosclerotic disease who underwent cerebral angiography in the WASID trial. 2% of these patients experienced neurological symptoms although all were transient and 6.1% had non-neurologic complications (Cloft et al, 2011).

Given the disadvantages of DSA and the increased morbidity and potential mortality associated with it, non-invasive modalities are increasingly being utilized for assessment of intracranial atherosclerotic disease.

#### **4.2 Magnetic Resonance Angiography (MRA)**

#### **4.2.1 Phase contrast (PC) and Time of Flight (TOF) MRA**

Phase contrast MRA utilizes the velocity differences and hence the phase shifts in moving spins to provide image contrast in flowing vessels. The phase of magnetization from the

Neuroimaging of Intracranial Atherosclerotic Disease 307

agent to shorten the T1 of the blood so that in the first pass of the contrast agent, the arteries show up in striking contrast to the surrounding stationary tissues and veins. The CE MRA provides better anatomic delineation of vascular structures and can better assess areas of changing flow direction. This is because the technique depends on the intrinsic T1 signal of blood, rather than the flow characteristics and is minimally affected by dephasing seen with

A certain degree of expertise is needed to time the image acquisition to minimize venous contamination. If the image is taken too early, arteries will not contrast enhance and if it is taken too late, the image will be contaminated by contrast uptake in the veins and surrounding tissues. For external carotids it is a widely used technique, but for assessment

Quantitative MRA (QMRA) is a newer technique that utilizes TOF and Phase contrast MRI to determine the vessel anatomy and measure blood flow. This allows for hemodynamic assessment of areas supplied by stenotic vessels. The technique has been shown to be particularly useful in prognosticating future risk of stroke in symptomatic vertebrobasilar disease. Those found to have a low distal flow on QMRA had a 71% stroke free survival at 2 years as opposed to a 100% stroke free survival for those with a normal flow (Amin-Hanjani

QMRA has also found utility in assessment of flow before and after stent placement (Brisman, 2008). More importantly for in-stent restenosis it is now an evolving non-invasive technique. In these patients, CTA and MRA are not of use due to the artifacts produced by the stent and DSA continues to be the mainstay for assessment of stent thrombosis. Recently QMRA has shown promise as a screening tool for in-stent stenosis with 100% sensitivity and negative predictive value and 92% specificity (Prabhakaran et al, 2009). QMRA can also be used to determine regional blood flow and indicate the adequacy of collateral flow and overall cerebral hemodynamics in patients of intracranial atherosclerotic disease (Zhao et al, 2007).

Another emerging technique is HR-MRI which allows for imaging of the atherosclerotic plaque. It creates sufficiently thin slices through the vessel wall to allow for determination of plaque size, composition and biological activity (Yuan et al, 2006). This modality can also

Determination of plaque composition in terms of lipids, fibrous tissue and calcium and plaque activity in terms of inflammation can help determine whether a plaque is vulnerable or stable. HR MRI can also detect intraplaque hemorrhage which is another marker of plaque instability and can help predict risk of future vascular events (Turan et al, 2009 and Altaf et al, 2007). Furthermore, imaging the plaque directly can help determine presence of non-stenotic lesions which are generally missed with conventional MRA. Particularly in the evaluation of basilar artery, it was found that HR MRI detected atherosclerotic disease as a cause of pontine infarction in 42% of cases where TOF MRA and CE MRA had failed to show any basilar disease (Klein et al, 2010). Recently the technique has also found utility in

In future, HR MRI can potentially provide targets for intervention at an early stage of intracranial atherosclerotic disease, detect non stenotic athterosclerotic lesions, and predict

help discriminate from other non-atherosclerotic etiologies of vessel narrowing.

guiding endovascular intervention of basilar artery (Jiang et al, 2011).

future risk of vascular events based on plaque morphology and characteristics.

complex flow.

et al, 2005).

of intracranial vasculature it is still underutilized.

**4.2.3 Quantitative MRA (QMRA)**

**4.2.4 High Resolution MRI (HR-MRI)**

moving spins is taken as non-zero and that from the stationary spins is zero. Time of Flight MRA depends on the flow and movement of protons in blood through the imaging plane. It derives contrast between flowing blood and stationary tissues by manipulating the magnitude of magnetization. From the moving spins the magnitude is large and from static spins it is small. Both techniques can be used using two or three-dimensional acquisition although 3-D images have a long acquisition time.

The main advantage of the modality lies in its non-invasive nature. There is no radiation exposure and no iodinated contrast exposure. It requires very little user interaction for acquisition and processing of images. When compared to the gold standard DSA, TOF-MRA has sensitivity in the range of 70% for intracranial stenosis and 81% for occlusion and a negative predictive value of 98% for stenosis and 99% for occlusion (Bash et al, 2005). Another study identified 87% negative predictive value for detecting a greater than 50% stenosis (Feldmann et al, 2007). These results may be slightly improved by use of Maximum Intensity Projections (MIP).

There are however, several limitations when using PC and TOF MRA for intracranial stenosis evaluation. Firstly since it depends on changes in blood flow, it is prone to motion artifacts and to changes in the direction of the flow. The spatial resolution is also inferior to DSA and CTA. Another major drawback is its inability to distinguish between high grade stenosis and occlusion. Stenotic lesions are sites where complex, slow or in-phase flow characteristics are seen (Furst et al, 1995). Because of this there are proton spin dephasing artifacts and flow signal intensity loss is seen at severely narrowed sites. In addition, TOF technique requires longer imaging time.

Fig. 3. TOF-MRA images of intracranial stenosis. A) Stenosis seen in bilateral PCAs, B) Severe atherosclerotic disease in supraclinoid ICA, bilateral MCA and ACA. (Image Courtesy, Stroke Fellowship Program, Aga Khan University Hospital, Karachi, Pakistan)

#### **4.2.2 Contrast Enhanced (CE) MRA**

Some of the disadvantages of TOF and PC MRA can be overcome with the use of gadolinium dye. CE-MRA utilizes the time of flight technique along with use of contrast

moving spins is taken as non-zero and that from the stationary spins is zero. Time of Flight MRA depends on the flow and movement of protons in blood through the imaging plane. It derives contrast between flowing blood and stationary tissues by manipulating the magnitude of magnetization. From the moving spins the magnitude is large and from static spins it is small. Both techniques can be used using two or three-dimensional acquisition

The main advantage of the modality lies in its non-invasive nature. There is no radiation exposure and no iodinated contrast exposure. It requires very little user interaction for acquisition and processing of images. When compared to the gold standard DSA, TOF-MRA has sensitivity in the range of 70% for intracranial stenosis and 81% for occlusion and a negative predictive value of 98% for stenosis and 99% for occlusion (Bash et al, 2005). Another study identified 87% negative predictive value for detecting a greater than 50% stenosis (Feldmann et al, 2007). These results may be slightly improved by use of Maximum

There are however, several limitations when using PC and TOF MRA for intracranial stenosis evaluation. Firstly since it depends on changes in blood flow, it is prone to motion artifacts and to changes in the direction of the flow. The spatial resolution is also inferior to DSA and CTA. Another major drawback is its inability to distinguish between high grade stenosis and occlusion. Stenotic lesions are sites where complex, slow or in-phase flow characteristics are seen (Furst et al, 1995). Because of this there are proton spin dephasing artifacts and flow signal intensity loss is seen at severely narrowed sites. In addition, TOF

Fig. 3. TOF-MRA images of intracranial stenosis. A) Stenosis seen in bilateral PCAs, B) Severe atherosclerotic disease in supraclinoid ICA, bilateral MCA and ACA. (Image Courtesy, Stroke Fellowship Program, Aga Khan University Hospital, Karachi, Pakistan)

Some of the disadvantages of TOF and PC MRA can be overcome with the use of gadolinium dye. CE-MRA utilizes the time of flight technique along with use of contrast

although 3-D images have a long acquisition time.

Intensity Projections (MIP).

technique requires longer imaging time.

**4.2.2 Contrast Enhanced (CE) MRA**

agent to shorten the T1 of the blood so that in the first pass of the contrast agent, the arteries show up in striking contrast to the surrounding stationary tissues and veins. The CE MRA provides better anatomic delineation of vascular structures and can better assess areas of changing flow direction. This is because the technique depends on the intrinsic T1 signal of blood, rather than the flow characteristics and is minimally affected by dephasing seen with complex flow.

A certain degree of expertise is needed to time the image acquisition to minimize venous contamination. If the image is taken too early, arteries will not contrast enhance and if it is taken too late, the image will be contaminated by contrast uptake in the veins and surrounding tissues. For external carotids it is a widely used technique, but for assessment of intracranial vasculature it is still underutilized.

#### **4.2.3 Quantitative MRA (QMRA)**

Quantitative MRA (QMRA) is a newer technique that utilizes TOF and Phase contrast MRI to determine the vessel anatomy and measure blood flow. This allows for hemodynamic assessment of areas supplied by stenotic vessels. The technique has been shown to be particularly useful in prognosticating future risk of stroke in symptomatic vertebrobasilar disease. Those found to have a low distal flow on QMRA had a 71% stroke free survival at 2 years as opposed to a 100% stroke free survival for those with a normal flow (Amin-Hanjani et al, 2005).

QMRA has also found utility in assessment of flow before and after stent placement (Brisman, 2008). More importantly for in-stent restenosis it is now an evolving non-invasive technique. In these patients, CTA and MRA are not of use due to the artifacts produced by the stent and DSA continues to be the mainstay for assessment of stent thrombosis. Recently QMRA has shown promise as a screening tool for in-stent stenosis with 100% sensitivity and negative predictive value and 92% specificity (Prabhakaran et al, 2009). QMRA can also be used to determine regional blood flow and indicate the adequacy of collateral flow and overall cerebral hemodynamics in patients of intracranial atherosclerotic disease (Zhao et al, 2007).

#### **4.2.4 High Resolution MRI (HR-MRI)**

Another emerging technique is HR-MRI which allows for imaging of the atherosclerotic plaque. It creates sufficiently thin slices through the vessel wall to allow for determination of plaque size, composition and biological activity (Yuan et al, 2006). This modality can also help discriminate from other non-atherosclerotic etiologies of vessel narrowing.

Determination of plaque composition in terms of lipids, fibrous tissue and calcium and plaque activity in terms of inflammation can help determine whether a plaque is vulnerable or stable. HR MRI can also detect intraplaque hemorrhage which is another marker of plaque instability and can help predict risk of future vascular events (Turan et al, 2009 and Altaf et al, 2007). Furthermore, imaging the plaque directly can help determine presence of non-stenotic lesions which are generally missed with conventional MRA. Particularly in the evaluation of basilar artery, it was found that HR MRI detected atherosclerotic disease as a cause of pontine infarction in 42% of cases where TOF MRA and CE MRA had failed to show any basilar disease (Klein et al, 2010). Recently the technique has also found utility in guiding endovascular intervention of basilar artery (Jiang et al, 2011).

In future, HR MRI can potentially provide targets for intervention at an early stage of intracranial atherosclerotic disease, detect non stenotic athterosclerotic lesions, and predict future risk of vascular events based on plaque morphology and characteristics.

Neuroimaging of Intracranial Atherosclerotic Disease 309

The major advantage of CTA lies in its non-invasive nature compared to DSA and better image quality compared to MRA. It takes less time for acquisition of images; it is not affected by motion artifacts and is independent of hemodynamic effects seen with MRA. There is also a high inter-reader reliability in quantitation of stenotic lesions (Bash et al, 2005). Another major advantage over MRA lies in the ability of CTA to accurately depict areas of low flow distal to severely stenotic vessels (Skutta et al, 1999 and Bash et al, 2005). It was previously thought that petrous and cavernous ICA are regions elusive to CTA due to bony or calcium artifacts (Skutta et al, 1999 and Hirai et al 2002). However, newer studies do not report this problem likely because of better post processing and acquisition techniques

Limitations of CTA include radiation exposure and risk of nephrotoxicity with the use of intravenous contrast agent. Another limitation to the technique is skill required for optimal contrast gradient-timing to avoid venous contamination and for post processing of the images to avoid contamination with surrounding structures. For accurate visualization of vessels to avoid over or underestimation of stenosis, there is a need for optimally adjusting window and level settings (Bash et al, 2005). CTA may be inferior to MRA in certain respects

Transcranial Doppler (TCD) is a useful, non invasive, real time and portable mechanism of investigating 50 to 99% stenosis of the intracranial arteries. Ultrasound is a travelling wave of energy that has a frequency of more than 20,000 Hz which is above the audible range for humans. The Doppler effect, first described by Christian Andreas Doppler, is the change or shift in the frequency or wavelength of a wave due to relative movement between the sound scatterer and the receiver. In TCD, the Doppler effect can be used to determine the speed and direction of flow in blood vessels. Many red blood cells move at varying speeds through an insonated vessel and the TCD sample volume is relatively large. The signal received from any sample volume within a vessel is a mixture of the different Doppler frequency shifts

Low frequency ultrasound can penetrate the skull; the temporal bone is the thinnest portion of the skull and allows successful insonation. An inadequate temporal window is a major cause of insufficient evaluation of cerebral vessels during TCD. The prevalence of this finding is 14.5% and is increased in non white females greater than 60 years of age. (Ratanakorn, 1998). The temporal window allows the ICA, MCA, ACA to be sampled, the occipital allows the posterior circulation to be reviewed, and the ophthalmic allows the

Spectral waveforms are identified by their direction, depth of insonation, velocity characteristics, and spectral measurements are then performed to report the following parameters for the cerebral circulation: Mean Flow Velocity (MFV) and the Pulsatility

MFV correlates well with vessel patency and degree of arterial stenosis. The PI is an indirect measure of peripheral resistance. Post stenotic vessels with blunted waveforms have low

where PSV= Peak Systolic Velocity and EDV= End Diastolic Velocity

MFV=PSV +2 EDV)/3 (1)

PI= (PSV-EDV) /MFV (2)

as it provides no information on flow characteristics across a stenotic lesion.

(Bash et al, 2005).

**4.4 Transcranial Doppler (TCD)**

forming a spectrum that is displayed visually.

collateral information to be gathered.

Index (PI).

#### **4.3 Computerized Tomography Angiography (CTA)**

Computed tomography (CT) angiography is a relatively new non-invasive procedure that allows for accurate visualization of vascular structures and differentiates them from adjacent bone and soft tissues. Helical or Spiral CTA is acquired with the X-ray tube continuously rotating in a 360 degree turn while the table transports the patient slowly through the scanner. The slice thickness and the scan time for each helical series determine the extent of anatomic coverage. Axial images are stacked to form a volume of image data that can be processed in various formats like maximum intensity projection, multiplanar reformation and shaded surface display. This allows for 3 dimensional reconstruction of vessels similar to DSA.

An iodinated contrast is injected through a peripheral vein and both arterial and venous phases can be easily obtained. Unlike MRA, CTA is not dependent on flow characteristics of the blood. Instead it relies on relative penetrance of the contrast agent within the blood vessel. New scanners allow smaller slice thickness and hence greater resolution. Additionally, three-dimensional reformatting allows for excellent appreciation of anatomic relationships between bones, soft tissues, and the vascular system. Spiral or helical CTA is now used commonly for the evaluation of intracranial stenosis and provides excellent anatomic visualization.

The sensitivity of CTA for detection of intracranial occlusion is almost 100% compared to DSA (Nguyen-Huynh et al, 2008 and Bash et al, 2005). For detection of stenotic lesions greater than 50%, the sensitivity is 97.1% and specificity is 99.5%. With this high sensitivity and specificity it is an excellent tool for screening people with intracranial stenosis. Helical CTA has also been shown to be superior to DSA in detecting vessel patency in posterior circulation where low flow states can produce an impression of occlusion on DSA (Bash et al, 2005).

Fig. 4. CTA image demonstrating stenotic lesions in right vertebral, right M2 segment and left M1 segment of MCA. (Image Courtesy: Dr. Tanveer-ul-Haq**,** Associate Professor ,Section Head, Vascular and Interventional Radiology, Radiology Department, Aga Khan University Hospital , Karachi, Pakistan.)

Computed tomography (CT) angiography is a relatively new non-invasive procedure that allows for accurate visualization of vascular structures and differentiates them from adjacent bone and soft tissues. Helical or Spiral CTA is acquired with the X-ray tube continuously rotating in a 360 degree turn while the table transports the patient slowly through the scanner. The slice thickness and the scan time for each helical series determine the extent of anatomic coverage. Axial images are stacked to form a volume of image data that can be processed in various formats like maximum intensity projection, multiplanar reformation and shaded surface display. This allows for 3 dimensional reconstruction of

An iodinated contrast is injected through a peripheral vein and both arterial and venous phases can be easily obtained. Unlike MRA, CTA is not dependent on flow characteristics of the blood. Instead it relies on relative penetrance of the contrast agent within the blood vessel. New scanners allow smaller slice thickness and hence greater resolution. Additionally, three-dimensional reformatting allows for excellent appreciation of anatomic relationships between bones, soft tissues, and the vascular system. Spiral or helical CTA is now used commonly for the evaluation of intracranial stenosis and provides excellent

The sensitivity of CTA for detection of intracranial occlusion is almost 100% compared to DSA (Nguyen-Huynh et al, 2008 and Bash et al, 2005). For detection of stenotic lesions greater than 50%, the sensitivity is 97.1% and specificity is 99.5%. With this high sensitivity and specificity it is an excellent tool for screening people with intracranial stenosis. Helical CTA has also been shown to be superior to DSA in detecting vessel patency in posterior circulation where low flow states can produce an impression of occlusion on DSA (Bash et

Fig. 4. CTA image demonstrating stenotic lesions in right vertebral, right M2 segment and left M1 segment of MCA. (Image Courtesy: Dr. Tanveer-ul-Haq**,** Associate Professor ,Section Head, Vascular and Interventional Radiology, Radiology Department, Aga Khan University

**4.3 Computerized Tomography Angiography (CTA)**

vessels similar to DSA.

anatomic visualization.

Hospital , Karachi, Pakistan.)

al, 2005).

The major advantage of CTA lies in its non-invasive nature compared to DSA and better image quality compared to MRA. It takes less time for acquisition of images; it is not affected by motion artifacts and is independent of hemodynamic effects seen with MRA. There is also a high inter-reader reliability in quantitation of stenotic lesions (Bash et al, 2005). Another major advantage over MRA lies in the ability of CTA to accurately depict areas of low flow distal to severely stenotic vessels (Skutta et al, 1999 and Bash et al, 2005). It was previously thought that petrous and cavernous ICA are regions elusive to CTA due to bony or calcium artifacts (Skutta et al, 1999 and Hirai et al 2002). However, newer studies do not report this problem likely because of better post processing and acquisition techniques (Bash et al, 2005).

Limitations of CTA include radiation exposure and risk of nephrotoxicity with the use of intravenous contrast agent. Another limitation to the technique is skill required for optimal contrast gradient-timing to avoid venous contamination and for post processing of the images to avoid contamination with surrounding structures. For accurate visualization of vessels to avoid over or underestimation of stenosis, there is a need for optimally adjusting window and level settings (Bash et al, 2005). CTA may be inferior to MRA in certain respects as it provides no information on flow characteristics across a stenotic lesion.

#### **4.4 Transcranial Doppler (TCD)**

Transcranial Doppler (TCD) is a useful, non invasive, real time and portable mechanism of investigating 50 to 99% stenosis of the intracranial arteries. Ultrasound is a travelling wave of energy that has a frequency of more than 20,000 Hz which is above the audible range for humans. The Doppler effect, first described by Christian Andreas Doppler, is the change or shift in the frequency or wavelength of a wave due to relative movement between the sound scatterer and the receiver. In TCD, the Doppler effect can be used to determine the speed and direction of flow in blood vessels. Many red blood cells move at varying speeds through an insonated vessel and the TCD sample volume is relatively large. The signal received from any sample volume within a vessel is a mixture of the different Doppler frequency shifts forming a spectrum that is displayed visually.

Low frequency ultrasound can penetrate the skull; the temporal bone is the thinnest portion of the skull and allows successful insonation. An inadequate temporal window is a major cause of insufficient evaluation of cerebral vessels during TCD. The prevalence of this finding is 14.5% and is increased in non white females greater than 60 years of age. (Ratanakorn, 1998). The temporal window allows the ICA, MCA, ACA to be sampled, the occipital allows the posterior circulation to be reviewed, and the ophthalmic allows the collateral information to be gathered.

Spectral waveforms are identified by their direction, depth of insonation, velocity characteristics, and spectral measurements are then performed to report the following parameters for the cerebral circulation: Mean Flow Velocity (MFV) and the Pulsatility Index (PI).

$$\text{MFV=PSV+2 EDV}/\text{\(3\)}\tag{1}$$

$$\text{PI} = \text{(PSV-EDV)} / \text{MFV} \tag{2}$$

where PSV= Peak Systolic Velocity and EDV= End Diastolic Velocity MFV correlates well with vessel patency and degree of arterial stenosis. The PI is an indirect measure of peripheral resistance. Post stenotic vessels with blunted waveforms have low

Neuroimaging of Intracranial Atherosclerotic Disease 311

CO2 inhalation or apnea. Impaired vasomotor reactivity with CO2 has been tested with TCD and shown to correlate with stroke risk in patients with carotid stenosis (Visser et al, 2000).

Direct visualization of the vessels using the above techniques gives a reliable estimate of the anatomic degree of stenosis. Since intracranial atherosclerotic disease is a slowly progressive condition, it leads to chronic hypoperfusion and development of collaterals. The development of collaterals does not guarantee their persistence and they are also prone to hemodynamic fluctuations and occlusion secondary to artery to artery embolization in cases where they originate from cortical vessels. These collaterals can also be visualized using the vessel imaging techniques already described. Whether these collaterals are adequate to maintain perfusion in the territory of stenotic vessel needs evaluation with other modalities

Blood flow through the capillaries is referred to as perfusion and this is responsible for delivering oxygen to the brain tissue.  Regional cerebral blood flow is proportional to the regional cerebral metabolism. Initial compensatory mechanism to deal with a decrease in perfusion is vasodilatation. Once maximum vasodialtion has occurred, oxygen extraction fraction increases to maintain the metabolic needs of the cerebral tissue. Regional cerebrovascular reserve (rCVR) is another parameter that can be measured to gauge the

Several techniques are now available to measure perfusion through the brain. These include positron emission tomography (PET), single-photon emission CT (SPECT), xenon-enhanced CT, perfusion CT and MRI, and TCD. Addition of acetazolamide challenge to various

PET imaging measures cerebral oxygen extraction fraction (OEF) and has been the gold standard so far for identifying hemodynamic failure (Derdeyn et al, 2002). It allows for measurement of CBF, CBV and Mean Transit Time (MTT). It is currently being used to select patients with poor hemodynamic reserve, secondary to ICAD, eligible for external to internal carotid bypass. The benefit of this procedure can then also be gauged by imaging, translating as improved oxygen perfusion in previously occluded areas. Small retrospective studies have shown the outcome of external to internal bypass to be favorable (Nagata et al, 1991 and Mendelowitsch et al, 2004). PET is restricted in its utility because of its high cost

SPECT can be similarly utilized to measure rCVR and when used with acetazolamide challenge it provides additional information regarding hemodynamic status of the brain (Ozgur et al, 2001). This again has been utilized to judge the dependency on external carotid-internal carotid (EC-IC) and leptomeningeal collaterals. Use of acetazolamide challenge allows for assessment of vasomotor reactivity (VMR) as well which when impaired predicts future stroke. Although SPECT is more widely available compared to PET, its disadvantage lies in longer imaging time and inferior spatial resolution (Eskey and

Two major trials are currently ongoing to recruit patients with poor hemodynamic reserve secondary to atherosclerotic disease and to evaluate the effectiveness of the bypass procedure. These include the Carotid Occlusion Surgery Study in US (COSS) (Grubb et al, 2003) which is using PET and the Japanese EC-IC bypass Trial (JET) (Mizumura et al, 2004) which is utilizing SPECT for hemodynamic monitoring. They have so far validated the

imaging modalities to recruit candidates for the procedure.

imaging modalities increases their sensitivity for picking up decreased rCVR.

**4.5 Hemodynamic monitoring**

of which TCD has already been discussed.

vasodilatory capacity of the arterioles.

and limited availability.

Sanelli, 2005).

resistance and chronic hypertensives have high PI. In addition TCD can provide information on the presence or absence of microembolic signals and the progression and regression of stenosis.

The advantages of TCD are that the vessels are insonated non- invasively, at the bedside and repeatedly without any harm to the patients. The limitations of TCD include a lack of windows, operator dependency, and the fact that lesser degrees of stenosis are not picked up and that direct evaluation is limited to the basal intracranial vessels.

TCD is a useful adjunct to the diagnosis of ICAD in the following ways

1. Non invasive diagnosis of 50 – 70% stenosis and response to therapy

Velocity thresholds that predict a significant MCA stenosis have been reported. As a rule in a vessel with straight walls a 50% diameter reduction doubles the velocity and a 70 % stenosis can quadruple the velocity at the exit of the stenosis compared with a prestenotic segment or to the contralateral side.

The criteria that are used include MFV, Peak systolic velocity (PSV) and stenotic to prestenotic ratios. The velocity criteria for determining the degree of stenosis in the different vessels are reported from the SONIA study that in addition, reported the Positive and Negative predictive values (PPV and NPV). When using non invasive imaging it is important to correlate the status of the extracranial carotid artery. Collateral flow and decreased volume flow from the proximal carotid stenosis without adequate collateral flow results in false positive and false negative interpretations respectively. To further help avoid false positives a prestenotic to post stenotic MCA velocity ration of 1 :>2 should be used in addition to the MFV threshold.

The relative portability of TCD has led to wide scale applications in population screenings to detect asymptomatic disease and to follow the regression of stenosis and response to therapy in large scale interventional studies. It has therefore been used as a biologic surrogate marker much like carotid Intima media Thickness (IMT). However, it is not clear at this point whether the regressive changes in TCD can predict clinically important amelioration of outcomes.

#### 2. Characterization of Microembolic Signals (MES)

When following standardized assessment, the detection of microembolic signals in stenotic arteries in real time can predict the appearance of stroke (Garami and Alexandrov, 2008). Microembolic signals are common in patients with large artery disease and are an independent marker of future stroke risk of intracranial stenosis. In the CLAIR study (Wong et al, 2010) the administration of two antiplatelet agents reduced the appearance of MES in patients with Intracranial stenosis who were given aspirin and clopidogrel within 7 days of their stroke. Whether this reduction in microembolic activity results in reduction of the occurrence of stroke remains to be tested in large scale clinical trials.

#### 3. Adequacy of Collaterals and Vasomotor Reactivity

Collaterals have a significant effect on stroke outcomes, and with very severe stenoses they are shown to have a protective effect as opposed to lesser degrees of stenoses in which case the presence of collaterals signifies a greater instability (Liebeskind et al, 2010). TCD can help in evaluation of collaterals at the circle of Willis. Leptomeningeal and other secondary collaterals cannot be evaluated with this technique. Contrast addition to the imaging can help improve its sensitivity. Tests of vasomotor reactivity are also used to assess the adequacy of collaterals. A vasodilatory challenge can be given such as acetazolamide, or CO2 inhalation or apnea. Impaired vasomotor reactivity with CO2 has been tested with TCD and shown to correlate with stroke risk in patients with carotid stenosis (Visser et al, 2000).

#### **4.5 Hemodynamic monitoring**

310 Neuroimaging – Clinical Applications

resistance and chronic hypertensives have high PI. In addition TCD can provide information on the presence or absence of microembolic signals and the progression and regression of

The advantages of TCD are that the vessels are insonated non- invasively, at the bedside and repeatedly without any harm to the patients. The limitations of TCD include a lack of windows, operator dependency, and the fact that lesser degrees of stenosis are not picked

Velocity thresholds that predict a significant MCA stenosis have been reported. As a rule in a vessel with straight walls a 50% diameter reduction doubles the velocity and a 70 % stenosis can quadruple the velocity at the exit of the stenosis compared with a prestenotic

The criteria that are used include MFV, Peak systolic velocity (PSV) and stenotic to prestenotic ratios. The velocity criteria for determining the degree of stenosis in the different vessels are reported from the SONIA study that in addition, reported the Positive and Negative predictive values (PPV and NPV). When using non invasive imaging it is important to correlate the status of the extracranial carotid artery. Collateral flow and decreased volume flow from the proximal carotid stenosis without adequate collateral flow results in false positive and false negative interpretations respectively. To further help avoid false positives a prestenotic to post stenotic MCA velocity ration of 1 :>2 should be used in

The relative portability of TCD has led to wide scale applications in population screenings to detect asymptomatic disease and to follow the regression of stenosis and response to therapy in large scale interventional studies. It has therefore been used as a biologic surrogate marker much like carotid Intima media Thickness (IMT). However, it is not clear at this point whether the regressive changes in TCD can predict clinically important

When following standardized assessment, the detection of microembolic signals in stenotic arteries in real time can predict the appearance of stroke (Garami and Alexandrov, 2008). Microembolic signals are common in patients with large artery disease and are an independent marker of future stroke risk of intracranial stenosis. In the CLAIR study (Wong et al, 2010) the administration of two antiplatelet agents reduced the appearance of MES in patients with Intracranial stenosis who were given aspirin and clopidogrel within 7 days of their stroke. Whether this reduction in microembolic activity results in reduction of the

Collaterals have a significant effect on stroke outcomes, and with very severe stenoses they are shown to have a protective effect as opposed to lesser degrees of stenoses in which case the presence of collaterals signifies a greater instability (Liebeskind et al, 2010). TCD can help in evaluation of collaterals at the circle of Willis. Leptomeningeal and other secondary collaterals cannot be evaluated with this technique. Contrast addition to the imaging can help improve its sensitivity. Tests of vasomotor reactivity are also used to assess the adequacy of collaterals. A vasodilatory challenge can be given such as acetazolamide, or

up and that direct evaluation is limited to the basal intracranial vessels. TCD is a useful adjunct to the diagnosis of ICAD in the following ways 1. Non invasive diagnosis of 50 – 70% stenosis and response to therapy

stenosis.

segment or to the contralateral side.

addition to the MFV threshold.

amelioration of outcomes.

2. Characterization of Microembolic Signals (MES)

3. Adequacy of Collaterals and Vasomotor Reactivity

occurrence of stroke remains to be tested in large scale clinical trials.

Direct visualization of the vessels using the above techniques gives a reliable estimate of the anatomic degree of stenosis. Since intracranial atherosclerotic disease is a slowly progressive condition, it leads to chronic hypoperfusion and development of collaterals. The development of collaterals does not guarantee their persistence and they are also prone to hemodynamic fluctuations and occlusion secondary to artery to artery embolization in cases where they originate from cortical vessels. These collaterals can also be visualized using the vessel imaging techniques already described. Whether these collaterals are adequate to maintain perfusion in the territory of stenotic vessel needs evaluation with other modalities of which TCD has already been discussed.

Blood flow through the capillaries is referred to as perfusion and this is responsible for delivering oxygen to the brain tissue.  Regional cerebral blood flow is proportional to the regional cerebral metabolism. Initial compensatory mechanism to deal with a decrease in perfusion is vasodilatation. Once maximum vasodialtion has occurred, oxygen extraction fraction increases to maintain the metabolic needs of the cerebral tissue. Regional cerebrovascular reserve (rCVR) is another parameter that can be measured to gauge the vasodilatory capacity of the arterioles.

Several techniques are now available to measure perfusion through the brain. These include positron emission tomography (PET), single-photon emission CT (SPECT), xenon-enhanced CT, perfusion CT and MRI, and TCD. Addition of acetazolamide challenge to various imaging modalities increases their sensitivity for picking up decreased rCVR.

PET imaging measures cerebral oxygen extraction fraction (OEF) and has been the gold standard so far for identifying hemodynamic failure (Derdeyn et al, 2002). It allows for measurement of CBF, CBV and Mean Transit Time (MTT). It is currently being used to select patients with poor hemodynamic reserve, secondary to ICAD, eligible for external to internal carotid bypass. The benefit of this procedure can then also be gauged by imaging, translating as improved oxygen perfusion in previously occluded areas. Small retrospective studies have shown the outcome of external to internal bypass to be favorable (Nagata et al, 1991 and Mendelowitsch et al, 2004). PET is restricted in its utility because of its high cost and limited availability.

SPECT can be similarly utilized to measure rCVR and when used with acetazolamide challenge it provides additional information regarding hemodynamic status of the brain (Ozgur et al, 2001). This again has been utilized to judge the dependency on external carotid-internal carotid (EC-IC) and leptomeningeal collaterals. Use of acetazolamide challenge allows for assessment of vasomotor reactivity (VMR) as well which when impaired predicts future stroke. Although SPECT is more widely available compared to PET, its disadvantage lies in longer imaging time and inferior spatial resolution (Eskey and Sanelli, 2005).

Two major trials are currently ongoing to recruit patients with poor hemodynamic reserve secondary to atherosclerotic disease and to evaluate the effectiveness of the bypass procedure. These include the Carotid Occlusion Surgery Study in US (COSS) (Grubb et al, 2003) which is using PET and the Japanese EC-IC bypass Trial (JET) (Mizumura et al, 2004) which is utilizing SPECT for hemodynamic monitoring. They have so far validated the imaging modalities to recruit candidates for the procedure.

Neuroimaging of Intracranial Atherosclerotic Disease 313

Karachi Intracranial Stenosis Study (KISS) funded by the Higher Education Commission Government of Pakistan**.** The International Cerebrovascular Translational Clinical Research and Training Program (ICT\_CRT) at the Aga Khan University is supported by funds from the Award Number D43TW008660 from the Fogarty International Center and the National Institute of Neurologic Disorders and Stroke. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Fogarty International

Altaf, N., Beech, A., Goode, S.D., Gladman, J.R., Moody, A.R., Auer, D.P., & MacSweeney,

Amarenco, P., Levy, C., Cohen, A., Touboul, P.J., Roullet, E., & Bousser, M.G. (1994) Causes

Amin-Hanjani, S., Du, X., Zhao, M., Walsh, K., Malisch, T.W., & Charbel, F.T. (2005) Use of

Bash, S., Villablanca, J.P., Jahan, R., Duckwiler, G., Tillis, M., Kidwell, C., Saver, J., & Sayre, J.

Belden, J.R., Caplan, L.R., Pessin, M.S., & Kwan, E. (1999) Mechanisms and clinical features of posterior border-zone infarcts. *Neurology, 53*, 1312-1318. ISSN 0028-3878 Bogousslavsky, J., & Regli, F. (1992) Centrum ovale infarcts: subcortical infarction in the

Brisman, J.L. (2008) Wingspan stenting of symptomatic extracranial vertebral artery stenosis

Cloft, H.J., Lynn, M.J., Feldmann, E., & Chimowitz, M. Risk of Cerebral Angiography in

Derdeyn, C.P., Videen, T.O., Yundt, K.D., Fritsch, S.M., Carpenter, D.A., Grubb, R.L., &

Eskey, C.J., & Sanelli, P.C. (2005) Perfusion imaging of cerebrovascular reserve.

Felberg, R.A., Christou, I., Demchuk, A.M., Malkoff, M., & Alexandrov, A.V. (2002)

Feldmann, E., Wilterdink, J.L., Kosinski, A., Lynn, M., Chimowitz, M.I., Sarafin, J., Smith,

flow velocity thresholds. *J Neuroimaging, 12*, 9-14. ISSN 1051-2284

consecutive patients. *Stroke, 25*, 105-112. ISSN 0039-2499

*Neuroradiol, 26*, 1012-1021. ISSN 0195-6108

vertebrobasilar disease. *Stroke, 36*, 1140-1145. ISSN 0039-2499

report of two cases. *Neurosurg Focus, 24*, E14. ISSN 1092-0684

*Neuroimaging Clin N Am, 15*, 367-381, xi. ISSN 1052-5149

S.T. (2007) Carotid intraplaque hemorrhage detected by magnetic resonance imaging predicts embolization during carotid endarterectomy. *J Vasc Surg, 46*, 31-

and mechanisms of territorial and nonterritorial cerebellar infarcts in 115

quantitative magnetic resonance angiography to stratify stroke risk in symptomatic

(2005) Intracranial vascular stenosis and occlusive disease: evaluation with CT angiography, MR angiography, and digital subtraction angiography. *AJNR Am J*

superficial territory of the middle cerebral artery. *Neurology, 42*, 1992-1998. ISSN

and perioperative evaluation using quantitative magnetic resonance angiography:

Patients with Symptomatic Intracranial Atherosclerotic Stenosis. *Cerebrovasc Dis, 31*,

Powers, W.J. (2002) Variability of cerebral blood volume and oxygen extraction: stages of cerebral haemodynamic impairment revisited. *Brain, 125*, 595-607. ISSN

Screening for intracranial stenosis with transcranial Doppler: the accuracy of mean

H.H., Nichols, F., Rogg, J., Cloft, H.J., Wechsler, L., Saver, J., Levine, S.R., Tegeler, C., Adams, R., & Sloan, M. (2007) The Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis (SONIA) trial. *Neurology, 68*, 2099-2106. ISSN 0028-3878

Center or the National Institutes of Health.

36. ISSN 0741-5214

0028-3878

0006-8950

588-591. ISSN 1015-9770

**7. References**

Perfusion studies using CT and MRI can also reliably estimate CVR in patients with intracranial stenosis. Perfusion CT provides quantitative values for CBF, CBV and MTT and has recently been shown to have a significant correlation with SPECT parameters. MTT was the most predictive of a decreased CVR in this study even without use of acetazolamide challenge(Kim et al, 2009).

Xenon-enhanced computed tomography (XeCT) has been in use for the past two decades to measure cerebral blood flow and is frequently utilized by revascularization experts to calculate the cerebrovascular reserve capacity (Wintermark et al, 2001). Its major advantage lies in its superior spatial resolution, accuracy, and reproducibility. Xenon gas is inhaled and its concentration is measured in the brain by CT scanner. There is a potential for adverse reaction to the gas besides radiation exposure and motion artifacts can also affect image quality (Wintermark et al, 2005).

To conclude several techniques are available for assessment of cerebral hemodynamics. Each carries its own advantages and disadvantages. PET due to its expense and limited availability is restricted in its utilization, but SPECT and Perfusion CT are reasonable alternatives.

#### **5. Conclusion**

Intracranial atherosclerosis is the progressive atherosclerotic stenosis of the arteries at the base of the brain. This condition is responsible for 10 – 50% of ischemic strokes worldwide. It is more common in Asians, Hispanics, Blacks and South East Asians and thus in absolute numbers is probably the most common cause of stroke in the world. Radiologically, it presents with border-zone ischemia, either in the internal border-zone area or the distal cortical area, with discrete cortical infarction or a lacunar perforator infarction with involvement of the parent vessel. The intracranial stenosis and its associated collaterals can be best quantified by catheter angiography, however this is invasive and not entirely without risk. Non invasively, MRA, CTA and TCD all offer valuable and complementary information. MRA can assess flow and stenosis, however it may overestimate preocclusive stenosis. CTA may be useful in these settings where actual anatomic accuracy is needed to differentiate preocclusive stenosis from complete occlusion since it is not flow dependent. TCD provides real time hemodynamic information to delineate the mechanism of stroke in the individual patient – whether it is a flow related hemodynamic stroke, whether or not regression has occurred or that the patient has microemboli from platelet aggregation. Additionally TCD has good negative predictive value in reporting 50 – 90% stenosis. It is postulated that stenosis of less than 50% may also be responsible for stroke through embolizations from unstable plaque. However, very little is known about this entity except that High resolution MRI can visualize these plaques in vivo. For those with high grade progressive stenosis, the prognosis clearly depends on the extent of collateralization. This can be investigated with PET, SPECT and perfusion CT to best select patients for EC\_IC Bypass procedures which are currently investigational.

#### **6. Acknowledgments**

Dr Maria Khan is a neurovascular fellow whose training is currently funded by Award Number D43TW008660 from the Fogarty International Center and the National Institutes of Neurologic Disorders and Stroke. Dr Ayeesha Kamal is the Principal Investigator for the Karachi Intracranial Stenosis Study (KISS) funded by the Higher Education Commission Government of Pakistan**.** The International Cerebrovascular Translational Clinical Research and Training Program (ICT\_CRT) at the Aga Khan University is supported by funds from the Award Number D43TW008660 from the Fogarty International Center and the National Institute of Neurologic Disorders and Stroke. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Fogarty International Center or the National Institutes of Health.

#### **7. References**

312 Neuroimaging – Clinical Applications

Perfusion studies using CT and MRI can also reliably estimate CVR in patients with intracranial stenosis. Perfusion CT provides quantitative values for CBF, CBV and MTT and has recently been shown to have a significant correlation with SPECT parameters. MTT was the most predictive of a decreased CVR in this study even without use of acetazolamide

Xenon-enhanced computed tomography (XeCT) has been in use for the past two decades to measure cerebral blood flow and is frequently utilized by revascularization experts to calculate the cerebrovascular reserve capacity (Wintermark et al, 2001). Its major advantage lies in its superior spatial resolution, accuracy, and reproducibility. Xenon gas is inhaled and its concentration is measured in the brain by CT scanner. There is a potential for adverse reaction to the gas besides radiation exposure and motion artifacts can also affect image

To conclude several techniques are available for assessment of cerebral hemodynamics. Each carries its own advantages and disadvantages. PET due to its expense and limited availability is restricted in its utilization, but SPECT and Perfusion CT are reasonable

Intracranial atherosclerosis is the progressive atherosclerotic stenosis of the arteries at the base of the brain. This condition is responsible for 10 – 50% of ischemic strokes worldwide. It is more common in Asians, Hispanics, Blacks and South East Asians and thus in absolute numbers is probably the most common cause of stroke in the world. Radiologically, it presents with border-zone ischemia, either in the internal border-zone area or the distal cortical area, with discrete cortical infarction or a lacunar perforator infarction with involvement of the parent vessel. The intracranial stenosis and its associated collaterals can be best quantified by catheter angiography, however this is invasive and not entirely without risk. Non invasively, MRA, CTA and TCD all offer valuable and complementary information. MRA can assess flow and stenosis, however it may overestimate preocclusive stenosis. CTA may be useful in these settings where actual anatomic accuracy is needed to differentiate preocclusive stenosis from complete occlusion since it is not flow dependent. TCD provides real time hemodynamic information to delineate the mechanism of stroke in the individual patient – whether it is a flow related hemodynamic stroke, whether or not regression has occurred or that the patient has microemboli from platelet aggregation. Additionally TCD has good negative predictive value in reporting 50 – 90% stenosis. It is postulated that stenosis of less than 50% may also be responsible for stroke through embolizations from unstable plaque. However, very little is known about this entity except that High resolution MRI can visualize these plaques in vivo. For those with high grade progressive stenosis, the prognosis clearly depends on the extent of collateralization. This can be investigated with PET, SPECT and perfusion CT to best select patients for EC\_IC

Dr Maria Khan is a neurovascular fellow whose training is currently funded by Award Number D43TW008660 from the Fogarty International Center and the National Institutes of Neurologic Disorders and Stroke. Dr Ayeesha Kamal is the Principal Investigator for the

challenge(Kim et al, 2009).

quality (Wintermark et al, 2005).

Bypass procedures which are currently investigational.

**6. Acknowledgments**

alternatives.

**5. Conclusion**

Neuroimaging of Intracranial Atherosclerotic Disease 315

Mizumura, S., Nakagawara, J., Takahashi, M., Kumita, S., Cho, K., Nakajo, H., Toba, M., &

Nagata, S., Fujii, K., Matsushima, T., Fukui, M., Sadoshima, S., Kuwabara, Y., & Abe, H.

Nahab, F., Cotsonis, G., Lynn, M., Feldmann, E., Chaturvedi, S., Hemphill, J.C., Zweifler, R.,

Nguyen-Huynh, M.N., Wintermark, M., English, J., Lam, J., Vittinghoff, E., Smith, W.S., &

Ozgur, H.T., Kent Walsh, T., Masaryk, A., Seeger, J.F., Williams, W., Krupinski, E., Melgar,

Pollanen, M.S., & Deck, J.H. (1990) The mechanism of embolic watershed infarction:

Prabhakaran, S., Warrior, L., Wells, K.R., Jhaveri, M.D., Chen, M., & Lopes, D.K. (2009) The

Ratanakorn, D., Kremkau, F.W., Myers, L.G., Meads, D.B., & Tegeler, C.H. (1998) Mirror-

Roh, J.K., Kang, D.W., Lee, S.H., Yoon, B.W., & Chang, K.H. (2000) Significance of acute

Rorick, M.B., Nichols, F.T., & Adams, R.J. (1994) Transcranial Doppler correlation with angiography in detection of intracranial stenosis. *Stroke, 25*, 1931-1934. ISSN 0039-2499 Rovira, A., Grive, E., & Alvarez-Sabin, J. (2005) Distribution territories and causative mechanisms of ischemic stroke. *Eur Radiol, 15*, 416-426. ISSN 0938-7994 Sacco, R.L., Kargman, D.E., Gu, Q., & Zamanillo, M.C. (1995) Race-ethnicity and

Skutta, B., Furst, G., Eilers, J., Ferbert, A., & Kuhn, F.P. (1999) Intracranial stenoocclusive

Thiex, R., Norbash, A.M., & Frerichs, K.U. The safety of dedicated-team catheter-based

experimental studies. *Can J Neurol Sci, 17*, 395-398. ISSN 0317-1671

intracranial in-stent stenosis. *Stroke, 40*, 991-993. ISSN 0039-2499

Manhattan Stroke Study. *Stroke, 26*, 14-20. ISSN 0039-2499

*Am J Neuroradiol, 31*, 230-234. ISSN 0195-6108

angiography. *AJNR Am J Neuroradiol, 20*, 791-799. ISSN 0195-6108

atherosclerotic disease? *Stroke, 39*, 1184-1188. ISSN 0039-2499

display. *Ann Nucl Med, 18*, 13-21. ISSN 0914-7187

95-101. ISSN 0001-6268

ISSN 0039-2499

*Res, 13*, 209-216. ISSN 0161-6412

*Neurol, 2*, 29-33.ISSN 1738-6586

177. ISSN 1051-2284

0039-2499

atherosclerotic occlusion of the internal carotid artery. *Acta Neurochir (Wien), 146*,

Kumazaki, T. (2004) Three-dimensional display in staging hemodynamic brain ischemia for JET study: objective evaluation using SEE analysis and 3D-SSP

(1991) Evaluation of EC-IC bypass for patients with atherosclerotic occlusive cerebrovascular disease: clinical and positron emission tomographic studies. *Neurol*

Johnston, K., Bonovich, D., Kasner, S., & Chimowitz, M. (2008) Prevalence and prognosis of coexistent asymptomatic intracranial stenosis. *Stroke, 39*, 1039-1041.

Johnston, S.C. (2008) How accurate is CT angiography in evaluating intracranial

M., & Labadie, E. (2001) Correlation of cerebrovascular reserve as measured by acetazolamide-challenged SPECT with angiographic flow patterns and intra- or extracranial arterial stenosis. *AJNR Am J Neuroradiol, 22*, 928-936. ISSN 0195-6108 Park, K.Y., Chung, C.S., Lee, K.H., Kim, G.M., Kim, Y.B., & Oh, K. (2006) Prevalence and risk

factors of intracranial atherosclerosis in an asymptomatic korean population. *J Clin*

utility of quantitative magnetic resonance angiography in the assessment of

image artifact can affect transcranial Doppler interpretation. *J Neuroimaging, 8*, 175-

multiple brain infarction on diffusion-weighted imaging. *Stroke, 31*, 688-694. ISSN

determinants of intracranial atherosclerotic cerebral infarction. The Northern

disease: double-detector helical CT angiography versus digital subtraction

diagnostic cerebral angiography in the era of advanced noninvasive imaging. *AJNR*

Fifi, J.T., Meyers, P.M., Lavine, S.D., Cox, V., Silverberg, L., Mangla, S., & Pile-Spellman, J.

Furst, G., Hofer, M., Sitzer, M., Kahn, T., Muller, E., & Modder, U. (1995) Factors influencing

Garami, Z., & Alexandrov, A.V. (2009) Neurosonology. *Neurol Clin, 27*, 89-108, viii. ISSN

Grubb, R.L.Jr., Powers, W.J., Derdeyn, C.P., Adams, H.P.Jr., & Clarke, W.R. (2003) The Carotid Occlusion Surgery Study. *Neurosurg Focus, 14*, e9. ISSN 1092-0684 Hirai, T., Korogi, Y., Ono, K., Nagano, M., Maruoka, K., Uemura, S., & Takahashi, M. (2002)

subtraction angiography. *AJNR Am J Neuroradiol, 23*, 93-101. ISSN 0195-6108 Huang, Y.N., Gao, S., Li, S.W., Huang, Y., Li, J.F., Wong, K.S., & Kay, R. (1997) Vascular

Kang, D.W., Latour, L.L., Chalela, J.A., Dambrosia, J., & Warach, S. (2003) Early ischemic

Kim, E., Sohn, C.H., Na, D.G., Kim, J.E., Chang, K.H., Kim, J.H., & Jeon, S.J. (2009) Perfusion

Kim, J.T., Yoo, S.H., Kwon, J.H., Kwon, S.U., & Kim, J.S. (2006) Subtyping of ischemic stroke

Klein, I.F., Lavallee, P.C., Mazighi, M., Schouman-Claeys, E., Labreuche, J., & Amarenco, P.

Lee, S.J., Cho, S.J., Moon, H.S., Shon, Y.M., Lee, K.H., Kim, D.I., Lee, B.B., Byun, H.S., Han,

Liebeskind, D.S., Cotsonis, G.A., Saver, J.L., Lynn, M.J., Turan, T.N., Cloft, H.J., &

Masuda, J., Yutani, C., Ogata, J., Kuriyama, Y., & Yamaguchi, T. (1994) Atheromatous

Mazighi, M., Tanasescu, R., Ducrocq, X., Vicaut, E., Bracard, S., Houdart, E., & Woimant, F.

Mendelowitsch, A., Taussky, P., Rem, J.A., & Gratzl, O. (2004) Clinical outcome of standard

tomography. *J Comput Assist Tomogr, 33*, 546-551. ISSN 0363-8715

weighted imaging study. *Stroke, 36*, 2583-2588. ISSN 0039-2499

in Korean patients. *Arch Neurol, 60*, 1561-1564. ISSN 0003-9942

the GESICA study. *Neurology, 66*, 1187-1191. ISSN 0028-3878

atherosclerosis. *Ann Neurol*. ISSN 0364-5134

*44*, 1231-1237. ISSN 0028-3878

medical center. *J Vasc Interv Radiol, 20*, 442-447. ISSN 1051-0443

*Tomogr, 19*, 692-699. ISSN 0363-8715

*Neurol, 2*, 225-230. ISSN 1738-6586

0733-8619

ISSN 0028-3878

ISSN 0364-5134

(2009) Complications of modern diagnostic cerebral angiography in an academic

flow-induced signal loss in MR angiography: an in vitro study. *J Comput Assist*

Prospective evaluation of suspected stenoocclusive disease of the intracranial artery: combined MR angiography and CT angiography compared with digital

lesions in Chinese patients with transient ischemic attacks. *Neurology, 48*, 524-525.

lesion recurrence within a week after acute ischemic stroke. *Ann Neurol, 54*, 66-74.

computed tomography evaluation of cerebral hemodynamic impairment in patients with unilateral chronic steno-occlusive disease: a comparison with the acetazolamide challenge 99mTc-hexamethylpropyleneamine oxime single-photon emission computed

based on vascular imaging: analysis of 1,167 acute, consecutive patients. *J Clin*

Basilar artery atherosclerotic plaques in paramedian and lacunar pontine infarctions: a high-resolution MRI study. *Stroke, 41*, 1405-1409. ISSN 0039-2499 Lee, D.K., Kim, J.S., Kwon, S.U., Yoo, S.H., & Kang, D.W. (2005) Lesion patterns and stroke

mechanism in atherosclerotic middle cerebral artery disease: early diffusion-

S.H., & Chung, C.S. (2003) Combined extracranial and intracranial atherosclerosis

Chimowitz, M.I. Collaterals dramatically alter stroke risk in intracranial

embolism in the brain: a clinicopathologic analysis of 15 autopsy cases. *Neurology,*

(2006) Prospective study of symptomatic atherothrombotic intracranial stenoses:

extracranial-intracranial bypass surgery in patients with symptomatic

atherosclerotic occlusion of the internal carotid artery. *Acta Neurochir (Wien), 146*, 95-101. ISSN 0001-6268

**15**

*Greece*

Elisabeth Andreadou

 *"Aeginition Hospital", Athens*

**Neuroimaging in Multiple Sclerosis**

*Department of Neurology, Athens National and Kapodistrian University,*

Multiple sclerosis (MS) is a chronic disabling autoimmune disorder of the central nervous system histopathologically characterized by inflammation, multifocal demyelination, axonal damage and neuronal loss. Focal intensive demyelination and white matter infiltration by lymphocytes and mononuclear cells are pathological hallmarks of the disease (Ferguson et

Complementary to the clinical evaluation, conventional magnetic resonance imaging (cMRI) plays a prominent role for diagnosis and assessment of patients with multiple sclerosis. It provides reliable detection and quantitative estimation of focal white matter lesions in vivo. Modern criteria involve MRI parameters for the diagnosis of MS and for predicting conversion to clinically definite MS in patients who present with a first clinical episode (eg, unilateral optic neuritis) suggestive of disease onset. A diagnosis of multiple sclerosis is based on showing disease dissemination in space and time and excluding other neurological disorders that can clinically and radiologically mimic multiple sclerosis. However, neurological impairment of patients with MS is poorly associated with the lesion load observed on conventional MRI scans. The discrepancy between clinical and conventional MRI findings in MS is explained, at least partially, by the low sensitivity of conventional MRI in the detection of grey-matter involvement and diffuse

In order to overcome these limitations new uses of conventional MRI methods have evolved and nonconventional MRI techniques have been developed. These advances are expected to help in understanding the underlying disease processes and the accumulation of irreversible disability and therefore are promising tools in studies of disease evolution

Optical coherence tomography (OCT) -a new, sensitive and non-invasive transpupillary imaging method- is able to provide accurate and quantitative measurements of axonal loss

This chapter reviews the use of cMRI techniques to diagnosis and follow-up of patients with MS. It also summarizes the evolving non-conventional MRI and non-invasive optical techniques, which are sensitive to different aspects of MS pathology and are promising to further increase our understanding of disease pathophysiology and the mechanisms

in retina and therefore holds promise as a biomarker for neurodegeneration in MS.

accounting for the accumulation of irreversible disability.

**1. Introduction**

al., 1997; Lucchinetti et al., 2000).

damage in white matter.

and clinical trials.

### **Neuroimaging in Multiple Sclerosis**

#### Elisabeth Andreadou

*Department of Neurology, Athens National and Kapodistrian University, "Aeginition Hospital", Athens Greece*

#### **1. Introduction**

316 Neuroimaging – Clinical Applications

Torvik, A., & Skullerud, K. (1982) Watershed infarcts in the brain caused by microemboli.

Turan, T.N., Bonilha, L., Morgan, P.S., Adams, R.J., & Chimowitz, M.I. Intraplaque

Turtzo, L.C., Gottesman, R.F., & Llinas, R.H. (2009) Diffusion-weighted imaging showing

Wintermark, M., Thiran, J.P., Maeder, P., Schnyder, P., & Meuli, R. (2001) Simultaneous

Wityk, R.J., Lehman, D., Klag, M., Coresh, J., Ahn, H., & Litt, B. (1996) Race and sex differences in the distribution of cerebral atherosclerosis. *Stroke, 27*, 1974-1980. ISSN 0039-2499 Wong, K.S., Li, H., Chan, Y.L., Ahuja, A., Lam, W.W., Wong, A., & Kay, R. (2000) Use of

Wong, K.S., Gao, S., Chan, Y.L., Hansberg, T., Lam, W.W., Droste, D.W., Kay, R., &

Wong, K.S., Ng, P.W., Tang, A., Liu, R., Yeung, V., & Tomlinson, B. (2007) Prevalence of

Wong, K.S., Chen, C., Fu, J., Chang, H.M., Suwanwela, N.C., Huang, Y.N., Han, Z., Tan, K.S.,

open-label, blinded-endpoint trial. *Lancet Neurol, 9*, 489-497. ISSN 1474-4422 Yamauchi, H., Nishii, R., Higashi, T., Kagawa, S., & Fukuyama, H. (2009) Hemodynamic

Yong, S.W., Bang, O.Y., Lee, P.H., & Li, W.Y. (2006) Internal and cortical border-zone

Yuan, C., Kerwin, W.S., Yarnykh, V.L., Cai, J., Saam, T., Chu, B., Takaya, N., Ferguson, M.S.,

Zhao, M., Amin-Hanjani, S., Ruland, S., Curcio, A.P., Ostergren, L., & Charbel, F.T. (2007)

large-artery occlusive disease. *Stroke, 31*, 2641-2647. ISSN 0039-2499

a validation study. *AJNR Am J Neuroradiol, 22*, 905-914. ISSN 0195-6108 Wintermark, M., Sesay, M., Barbier, E., Borbely, K., Dillon, W.P., Eastwood, J.D., Glenn, T.C.,

techniques. *J Neuroradiol, 32*, 294-314. ISSN 0150-9861

monitoring study. *Ann Neurol, 52*, 74-81. ISSN 0364-5134

clinical trials. *NMR Biomed, 19*, 636-654. ISSN 0952-3480

*Neuroradiol, 28*, 1470-1473. ISSN 0195-6108

hemorrhage in symptomatic intracranial atherosclerotic disease. *J Neuroimaging, 21*,

'pearls' predicts large-vessel disease as stroke etiology. *Cerebrovasc Dis, 28*, 49-54.

measurement of regional cerebral blood flow by perfusion CT and stable xenon CT:

Grandin, C.B., Pedraza, S., Soustiel, J.F., Nariai, T., Zaharchuk, G., Caille, J.M., Dousset, V., & Yonas, H. (2005) Comparative overview of brain perfusion imaging

transcranial Doppler ultrasound to predict outcome in patients with intracranial

Ringelstein, E.B. (2002) Mechanisms of acute cerebral infarctions in patients with middle cerebral artery stenosis: a diffusion-weighted imaging and microemboli

asymptomatic intracranial atherosclerosis in high-risk patients. *Neurology, 68*, 2035-

Ratanakorn, D., Chollate, P., Zhao, Y., Koh, A., Hao, Q., & Markus, H.S. (2010) Clopidogrel plus aspirin versus aspirin alone for reducing embolisation in patients with acute symptomatic cerebral or carotid artery stenosis (CLAIR study): a randomised,

compromise as a cause of internal border-zone infarction and cortical neuronal damage in atherosclerotic middle cerebral artery disease. *Stroke, 40*, 3730-3735. ISSN

infarction: clinical and diffusion-weighted imaging features. *Stroke, 37*, 841-846.

Underhill, H., Xu, D., Liu, F., & Hatsukami, T.S. (2006) MRI of atherosclerosis in

Regional cerebral blood flow using quantitative MR angiography. *AJNR Am J*

*Clin Neuropathol, 1*, 99-105. ISSN 0722-5091

e159-161. ISSN 1051-2284

ISSN 1015-9770

2038. ISSN 0028-3878

0039-2499

ISSN 0039-2499

Multiple sclerosis (MS) is a chronic disabling autoimmune disorder of the central nervous system histopathologically characterized by inflammation, multifocal demyelination, axonal damage and neuronal loss. Focal intensive demyelination and white matter infiltration by lymphocytes and mononuclear cells are pathological hallmarks of the disease (Ferguson et al., 1997; Lucchinetti et al., 2000).

Complementary to the clinical evaluation, conventional magnetic resonance imaging (cMRI) plays a prominent role for diagnosis and assessment of patients with multiple sclerosis. It provides reliable detection and quantitative estimation of focal white matter lesions in vivo. Modern criteria involve MRI parameters for the diagnosis of MS and for predicting conversion to clinically definite MS in patients who present with a first clinical episode (eg, unilateral optic neuritis) suggestive of disease onset. A diagnosis of multiple sclerosis is based on showing disease dissemination in space and time and excluding other neurological disorders that can clinically and radiologically mimic multiple sclerosis. However, neurological impairment of patients with MS is poorly associated with the lesion load observed on conventional MRI scans. The discrepancy between clinical and conventional MRI findings in MS is explained, at least partially, by the low sensitivity of conventional MRI in the detection of grey-matter involvement and diffuse damage in white matter.

In order to overcome these limitations new uses of conventional MRI methods have evolved and nonconventional MRI techniques have been developed. These advances are expected to help in understanding the underlying disease processes and the accumulation of irreversible disability and therefore are promising tools in studies of disease evolution and clinical trials.

Optical coherence tomography (OCT) -a new, sensitive and non-invasive transpupillary imaging method- is able to provide accurate and quantitative measurements of axonal loss in retina and therefore holds promise as a biomarker for neurodegeneration in MS.

This chapter reviews the use of cMRI techniques to diagnosis and follow-up of patients with MS. It also summarizes the evolving non-conventional MRI and non-invasive optical techniques, which are sensitive to different aspects of MS pathology and are promising to further increase our understanding of disease pathophysiology and the mechanisms accounting for the accumulation of irreversible disability.

Neuroimaging in Multiple Sclerosis 319

compared with past Criteria (Table 2). However, even these latest revisions do not address issues of lesion morphology except to emphasize the importance of Gd enhancement and insufficiently deal with lesion location. Distribution and morphology provide important clues to the suspected nature of the detected lesions. In addition, misapplication of the McDonald criteria can lead to misdiagnosis in subjects without relevant clinical symptoms. Therefore, a diagnosis of MS based on incidental findings on MRI alone, should be avoided

**Clinical Presentation Additional Data Needed**

MRI

site

MRI

MRI

MRI

Positive CSF

*and*

*and*

*and*

Table 1. 2001 McDonald diagnostic criteria for multiple sclerosis (from McDonald et al.,

MRI

None; clinical evidence will suffice

consistent with MS)

consistent with MS

or second clinical attack

consistent with MS

or second clinical attack

spinal cord lesion

(additional evidence desirable but must be

Dissemination in space, demonstrated by:

Dissemination in time, demonstrated by:

Dissemination in space demonstrated by:

Dissemination in time demonstrated by:

Dissemination in space demonstrated by: MRI evidence of 9 or more T2 brain lesions

Dissemination in time demonstrated by:

or continued progression for 1 year

or positive VEP with <4 brain lesions plus 1

 or 2 or more spinal cord lesions or 4-8 brain and 1 spinal cord lesion or positive VEP with 4-8 MRI lesions

or a positive CSF and 2 or more MRI lesions

or further clinical attack involving different

or positive CSF and 2 or more MRI lesions

(Polman et al., 2011).

2 or more attacks

1 attack

1 attack

1 objective clinical lesion

 1 objective clinical lesion (monosymptomatic presentation)

Insidious neurological progression

suggestive of MS

(primary progressive MS)

2001; with permission)

2 or more objective clinical lesions

 2 or more attacks (relapses) 2 or more objective clinical lesions

#### **2. MRI and the diagnosis of multiple sclerosis**

Since multiple sclerosis is a histopathological diagnosis, clinical criteria have been developed for the diagnosis of MS during life. Initial diagnostic criteria were based on clinical features alone to show disease dissemination in space and in time (Schumacher et al., 1965). The introduction of MRI in clinical practice resulted in improved investigation of multiple sclerosis (Young et al., 1981). Paraclinical evidence to support clinical findings in cases of diagnostic uncertainty was first proposed by Poser and colleagues (Poser et al., 1983). Given that MRI is the most sensitive paraclinical test and that comparable MRI abnormalities may be found in a variety of other diseases and in healthy volunteers, criteria have been developed by which MRIs can be classified as suggestive of multiple sclerosis or not (Fazekas et al., 1988; Paty et al., 1988; Barkhof et al., 1997; Tintore et al., 2000).

With the increased availability of MRI scanners and the high sensitivity and ability of MRI to provide evidence for disease dissemination in both space and time, subsequent consensus criteria relied on MRI findings to complement clinical and other paraclinical data for the diagnosis of MS (McDonald et al., 2001). The 2001 McDonald diagnostic criteria for multiple sclerosis included MRI evidence of dissemination in space (DIS) and dissemination in time (DIT), which allowed a diagnosis of multiple sclerosis to be made in patients with clinically isolated syndrome (CIS) (McDonald et al., 2001). The DIS criteria were those developed for brain MRI by Barkhof and colleagues (1997) and Tintore and colleagues (2000), in addition to allowing one spinal-cord lesion to substitute for a brain lesion. Evidence for DIT requires either a gadolinium enhancing lesion after at least 3 months from CIS onset, or a new T2 lesion developing on a scan subsequent to a reference scan obtained at least 3 months after CIS onset (Table 1).

The incorporation of MRI findings to the diagnostic criteria improved the ability to diagnose MS and exclude alternative diagnoses. Apparently MRI started to play a prominent role in establishing a firm and clear diagnosis of multiple sclerosis and predicting conversion to clinically definite MS in patients who present with a first clinical episode (eg, unilateral optic neuritis) suggestive of disease onset. The necessity of early and accurate diagnosis became particularly important with the advent of disease modifying treatments. Subsequently, the McDonald criteria were revised in 2005 by Polman and colleagues, to simplify their use and increase their sensitivity while maintaining their specificity. These revised criteria strengthen the use of spinal cord lesions in MS diagnosis, allowing a spinal cord lesion to substitute for an infratentorial brain lesion. In 2006, new simpler imaging criteria were proposed with similar high specificity for clinically definite MS (CDMS) and increased sensitivity (Swanton et al., 2006), in which DIS requires at least one T2 lesion in at least two of four locations (juxtacortical, periventricular, infratentorial, and spinal-cord) and DIT requires a new T2 lesion on a follow-up scan. Thereafter, new data and consensus underlined the need to simplify the revised McDonald Criteria in order to improve their comprehension and utility. Accumulating evidence resulted recently in specific recommendations for revisions to the McDonald Criteria. These proposals concerned the use and interpretation of imaging criteria for DIS and DIT and were based on the simplified criteria of Swanton and colleagues (Polman et al., 2011). The 2010 revisions to the McDonald Criteria simplify the diagnostic process with fewer required MRI examinations, allowing a more rapid diagnosis of MS, with preserved or improved specificity and sensitivity

Since multiple sclerosis is a histopathological diagnosis, clinical criteria have been developed for the diagnosis of MS during life. Initial diagnostic criteria were based on clinical features alone to show disease dissemination in space and in time (Schumacher et al., 1965). The introduction of MRI in clinical practice resulted in improved investigation of multiple sclerosis (Young et al., 1981). Paraclinical evidence to support clinical findings in cases of diagnostic uncertainty was first proposed by Poser and colleagues (Poser et al., 1983). Given that MRI is the most sensitive paraclinical test and that comparable MRI abnormalities may be found in a variety of other diseases and in healthy volunteers, criteria have been developed by which MRIs can be classified as suggestive of multiple sclerosis or

With the increased availability of MRI scanners and the high sensitivity and ability of MRI to provide evidence for disease dissemination in both space and time, subsequent consensus criteria relied on MRI findings to complement clinical and other paraclinical data for the diagnosis of MS (McDonald et al., 2001). The 2001 McDonald diagnostic criteria for multiple sclerosis included MRI evidence of dissemination in space (DIS) and dissemination in time (DIT), which allowed a diagnosis of multiple sclerosis to be made in patients with clinically isolated syndrome (CIS) (McDonald et al., 2001). The DIS criteria were those developed for brain MRI by Barkhof and colleagues (1997) and Tintore and colleagues (2000), in addition to allowing one spinal-cord lesion to substitute for a brain lesion. Evidence for DIT requires either a gadolinium enhancing lesion after at least 3 months from CIS onset, or a new T2 lesion developing on a scan subsequent to a reference scan obtained at least 3 months after

The incorporation of MRI findings to the diagnostic criteria improved the ability to diagnose MS and exclude alternative diagnoses. Apparently MRI started to play a prominent role in establishing a firm and clear diagnosis of multiple sclerosis and predicting conversion to clinically definite MS in patients who present with a first clinical episode (eg, unilateral optic neuritis) suggestive of disease onset. The necessity of early and accurate diagnosis became particularly important with the advent of disease modifying treatments. Subsequently, the McDonald criteria were revised in 2005 by Polman and colleagues, to simplify their use and increase their sensitivity while maintaining their specificity. These revised criteria strengthen the use of spinal cord lesions in MS diagnosis, allowing a spinal cord lesion to substitute for an infratentorial brain lesion. In 2006, new simpler imaging criteria were proposed with similar high specificity for clinically definite MS (CDMS) and increased sensitivity (Swanton et al., 2006), in which DIS requires at least one T2 lesion in at least two of four locations (juxtacortical, periventricular, infratentorial, and spinal-cord) and DIT requires a new T2 lesion on a follow-up scan. Thereafter, new data and consensus underlined the need to simplify the revised McDonald Criteria in order to improve their comprehension and utility. Accumulating evidence resulted recently in specific recommendations for revisions to the McDonald Criteria. These proposals concerned the use and interpretation of imaging criteria for DIS and DIT and were based on the simplified criteria of Swanton and colleagues (Polman et al., 2011). The 2010 revisions to the McDonald Criteria simplify the diagnostic process with fewer required MRI examinations, allowing a more rapid diagnosis of MS, with preserved or improved specificity and sensitivity

not (Fazekas et al., 1988; Paty et al., 1988; Barkhof et al., 1997; Tintore et al., 2000).

**2. MRI and the diagnosis of multiple sclerosis**

CIS onset (Table 1).

compared with past Criteria (Table 2). However, even these latest revisions do not address issues of lesion morphology except to emphasize the importance of Gd enhancement and insufficiently deal with lesion location. Distribution and morphology provide important clues to the suspected nature of the detected lesions. In addition, misapplication of the McDonald criteria can lead to misdiagnosis in subjects without relevant clinical symptoms. Therefore, a diagnosis of MS based on incidental findings on MRI alone, should be avoided (Polman et al., 2011).

Neuroimaging in Multiple Sclerosis 321

**Clinical Presentation Additional Data Needed**

1 An attack is defined as patient-reported or objectively observed events typical of an acute

for 1 past attack can include events with symptoms and evolution characteristic for a prior inflammatory demyelinating episode; at least 1 attack, however, must be supported by objective

inflammatory demyelinating event in the CNS, current or historical, with duration of at least 24 hours,

2 Clinical diagnosis based on objective clinical findings for 2 attacks is most secure. Historical evidence

3 No additional tests are required. However, it is desirable that any diagnosis of MS be made with

4Gadolinium-enhancing lesions are not required; symptomatic lesions are excluded from consideration

Hydrogen protons of water are highly abundant in our body. Conventional MRI measures alterations in tissue water content and dynamics by proton excitation, thus enabling visualization of edema, inflammation, demyelination and axonal damage in MS lesions. Conventional MRI techniques include T2-weighted, fast fluid-attenuated inversion recovery (FLAIR), and T1-weighted imaging with and without gadolinium (Gd) administration. In routine evaluation of patients with suspected or known MS, the most useful image acquisition clinical protocols for cMRI are axial dual spin-echo or single late echo T2 weighted imaging, axial and sagittal FLAIR, and pre- and post-gadolinium (Gd)-enhanced axial spin-echo T1-weighted imaging (Bakshi et al., 2004). On cMRI scans, detected MS lesions are presented as hyperintensities on T2- weighted images, hypointensities on T1-

T2-weighted MRI is sensitive in detecting white matter lesions. In T2-weighted images, MS lesions appear as bright areas against a gray or more neutral background; this hyperintesity reflects an increase in water content and thus is not specific for the underlying pathology.

Table 2. The 2010 McDonald Criteria for Diagnosis of MS (from Polman et al., 2011; with

criteria: 4

cord

1 year of disease progression (retrospectively or prospectively determined) plus 2 of 3 of the following

 Evidence for DIS in the brain based on 1 or more T2 lesions in the MScharacteristic (periventricular,

 Evidence for DIS in the spinal cord based on 2 or more T2 lesions in the

Positive CSF (isoelectric focusing

elevated IgG index)

juxtacortical, or infratentorial) regions

evidence of oligoclonal bands and/or

Insidious neurological progression

suggestive of MS (PPMS)

in the absence of fever or infection.

access to imaging based on these Criteria.

**2.1.1 T2-weighted imaging**

in subjects with brainstem or spinal cord syndromes.

**2.1 Characteristic findings on conventional MRI techniques**

weighted images, and Gd-enhancing foci on postcontrast images.

findings.

permission)

**Clinical Presentation Additional Data Needed**

cord) 4

or

or

or

or

and For DIT:

or

or

None3

Dissemination in space, demonstrated by: 1 T2 lesion in at least 2 of 4 MS-typical regions of the CNS (periventricular, juxtacortical, infratentorial, or spinal

 Await a further clinical attack1 implicating a different CNS site

A new T2 and/or gadolinium-

Await a second clinical attack1

 Await a second clinical attack1 implicating a different CNS site;

Simultaneous presence of

A new T2 and/or gadolinium-

Await a second clinical attack1

to a baseline scan;

to a baseline scan;

demonstrated by:

For DIS:

Simultaneous presence of

Dissemination in time, demonstrated by:

asymptomatic gadolinium-enhancing and nonenhancing lesions at any time;

enhancing lesion(s) on follow-up MRI, irrespective of its timing with reference

Dissemination in space and time,

asymptomatic gadolinium-enhancing and nonenhancing lesions at any time;

enhancing lesion(s) on follow-up MRI, irrespective of its timing with reference

1 or more T2 lesion in at least 2 of 4 MStypical regions of the CNS (periventricular, juxtacortical, infratentorial, or spinal cord) 4

2 or more attacks (relapses;

 2 or more objective clinical lesions or Objective clinical evidence of 1 lesion with reasonable historical evidence of a

Objective clinical evidence of 1 lesion

Objective clinical evidence of 2 or more

 Objective clinical evidence of 1 lesion (clinically isolated syndrome)

exacerbations) 1

prior attack 2

2 or more attacks1

1 attack1

1 attack1

lesions

1 An attack is defined as patient-reported or objectively observed events typical of an acute inflammatory demyelinating event in the CNS, current or historical, with duration of at least 24 hours, in the absence of fever or infection.

2 Clinical diagnosis based on objective clinical findings for 2 attacks is most secure. Historical evidence for 1 past attack can include events with symptoms and evolution characteristic for a prior inflammatory demyelinating episode; at least 1 attack, however, must be supported by objective findings.

3 No additional tests are required. However, it is desirable that any diagnosis of MS be made with access to imaging based on these Criteria.

4Gadolinium-enhancing lesions are not required; symptomatic lesions are excluded from consideration in subjects with brainstem or spinal cord syndromes.

Table 2. The 2010 McDonald Criteria for Diagnosis of MS (from Polman et al., 2011; with permission)

#### **2.1 Characteristic findings on conventional MRI techniques**

Hydrogen protons of water are highly abundant in our body. Conventional MRI measures alterations in tissue water content and dynamics by proton excitation, thus enabling visualization of edema, inflammation, demyelination and axonal damage in MS lesions. Conventional MRI techniques include T2-weighted, fast fluid-attenuated inversion recovery (FLAIR), and T1-weighted imaging with and without gadolinium (Gd) administration.

In routine evaluation of patients with suspected or known MS, the most useful image acquisition clinical protocols for cMRI are axial dual spin-echo or single late echo T2 weighted imaging, axial and sagittal FLAIR, and pre- and post-gadolinium (Gd)-enhanced axial spin-echo T1-weighted imaging (Bakshi et al., 2004). On cMRI scans, detected MS lesions are presented as hyperintensities on T2- weighted images, hypointensities on T1 weighted images, and Gd-enhancing foci on postcontrast images.

#### **2.1.1 T2-weighted imaging**

T2-weighted MRI is sensitive in detecting white matter lesions. In T2-weighted images, MS lesions appear as bright areas against a gray or more neutral background; this hyperintesity reflects an increase in water content and thus is not specific for the underlying pathology.

Neuroimaging in Multiple Sclerosis 323

(b) Axial FLAIR scan revealing

(d) Axial T2 scan showing characteristic

infratentorial involvement

Fig. 1. (a-d). Axial and sagittal FLAIR and T2 images showing common sites of MS

juxtacortical lesions

(a) Axial FLAIR image showing typical

ovoid periventricular hyperintense MS

(c) Sagittal T2-weighted image demonstrating lesions in the corpus callosum and periventricular white matter with characteristic extensions (Dawson's

lesions

fingers)

involvement.

The T2 hyperintense lesions represent processes ranging from edema and inflammation to demyelination, remyelination, Wallerian degeneration, axonal loss and gliosis (Fillipi & Agosta, 2009; Markovic-Plese & McFarland, 2001). Once detected, a lesion typically persists in the T2 hyperintense stage for many years. The techniques that are commonly used for the identification of T2 hyperintense lesions are conventional spin echo, fast spin echo, and fluid-attenuated inversion recovery (FLAIR) (Filippi et al., 2006). FLAIR imaging is a technique that suppresses the CSF signal, being more sensitive to periventricular and cortical/juxtacortical lesions and less sensitive to infratentorial lesions than T2-weighted MRI (Bakshi et al., 2001).

Given the lack of specificity of hyperintensities on T2-weighted MRI, lesion location and morphology plays a prominent role in distinguishing demyelinating lesions from the common and incidental presence of non-specific white-matter abnormalities, microvascular ischemia, or enlarged perivascular spaces (Fig. 1). MS lesions are primarily found in white matter but also in gray matter and usually affect the periventricular regions, corpus callosum, juxtacortical gray-white matter junction in the white matter, and infratentorial brain regions (brain stem, middle cerebellar peduncles and cerebellar white matter in the posterior fossa) (Bakshi et al., 2004; Barkhof et al., 1997). In some cases, direct involvement of the cerebral cortex also may be apparent (Bakshi et al., 2001). Corpus callosum is commonly affected in MS due to the large amount of myelinated fibres it contains. Callosal demyelinating lesions are usually multiple, small, nodular and characteristically involve callosal-septal interface. Infratentorial lesions are considered specific for multiple sclerosis and are typically located at the surface of the pons, the base of the fourth ventricle, and in the intra-axial trigeminal tract. It is important to note however that they can also be found in small-vessel disorder, with characteristic involvement of the central part of the pons (Kwa et al., 1997). Demyelinating lesions are larger (> 3mm) than punctuate non-specific white matter abnormalities associated with migraine and microvascular ischemia. Characteristically, they have an ovoid shape and appear perpendicular to the long axis of the ventricles in the axial plane. These typical MRI findings reflect the histopathological findings in multiple sclerosis. The periventricular lesions, especially in the corpus callosum, and the ovoid abnormalities with extensions (Dawson' fingers) into the adjacent white matter correlate with the perivenular distribution of multiple sclerosis plaques (Gean-Marton et al., 1991).

Between 50% and 90% of MS patients show hyperintense T2 lesions in the spinal cord, more frequently located in the cervical and the thoracic area (Lycklama et al., 2003; Agosta & Filippi, 2007). Cord lesions are usually located peripherally, occupy less than one half of the cord cross-sectional area and rarely involve more than two contiguous vertebral segments in length. Acute lesions may be associated with cord swelling. The presence of characteristic spinal cord abnormalities on MRI increases both sensitivity and specificity to the diagnosis of MS (Fillipi & Agosta, 2009).

In 50–70% of patients presenting with CIS clinically silent MRI lesions suggestive of MS are found. The extent of T2 lesions on brain MRI in CIS patients can predict the future risk of MS. The majority of CIS patients with T2 abnormalities (56–88%), develop clinically definite MS (CDMS) after prolonged (7–14 years) follow-up, whereas a minority of those with normal MRI (approximately 20%) have a risk for conversion to definite MS (Barkoff et al., 1997; Tintoré et al, 2006). Moreover, brain T2 hyperintense lesion load early in the clinical course of MS is also a predictor of long-term disability (Di Filippo et al., 2010).

The T2 hyperintense lesions represent processes ranging from edema and inflammation to demyelination, remyelination, Wallerian degeneration, axonal loss and gliosis (Fillipi & Agosta, 2009; Markovic-Plese & McFarland, 2001). Once detected, a lesion typically persists in the T2 hyperintense stage for many years. The techniques that are commonly used for the identification of T2 hyperintense lesions are conventional spin echo, fast spin echo, and fluid-attenuated inversion recovery (FLAIR) (Filippi et al., 2006). FLAIR imaging is a technique that suppresses the CSF signal, being more sensitive to periventricular and cortical/juxtacortical lesions and less sensitive to infratentorial lesions than T2-weighted