Brain perfusion imaging using 99mTc-Ethyl cysteinate dimer with acetazolamide challenge reveals “steal phenomenon” in suspected stroke: A case report

Introduction

Chronic cerebral ischaemia (CCI) is a potentially life-threatening condition caused by carotid artery occlusion, hypotension, and other causes. Moyamoya Syndrome (MMS) is an example of CCI in which there is progressive narrowing of the branches of the internal carotid artery (ICA). Initially, Moyamoya Disease (MMD) was identified as presence of occlusion of the proximal ICA, leading to formation of small vessels at the base of skull to overcome the blockage, giving rise to the pathognomonic feature of a ‘puff of smoke’ on digital subtraction angiography (DSA). MMD is of unknown aetiology but believed to have a genetic predisposition. On the other hand, MMS is referred to as the Moyamoya-like vasculopathy with associated risk factors that can be heritable or acquired such as cranial irradiation, atherosclerosis of skull base arteries, sickle cell anemia, type I neurofibromatosis, and Down syndrome. ¹

MMS can frequently be difficult to diagnose because the vascular alterations or anomaly often resemble other aging-related disorders, such as atherosclerosis. CCI is caused by atherosclerosis involving vascular constrictions as a result of cholesterol plaques formation, but MMS is due to the blockage or stenosis of the ICA branches that can be of variable aetiology. In view of variable outcomes in post-surgical intervention of MMS, there is a need to properly investigate the regional cerebrovascular reserve. ² Therefore, the role of imaging is needed to help visualise the areas of the brain that are underperfused but still viable and amenable to surgical intervention.

Conventionally, magnetic resonance angiography (MRA) or digital subtraction angiogram (DSA) are utilised to visualise the vascular abnormalities. However, nuclear medicine imaging can help to give more functional information to better manage the patient’s condition and evaluate the regional cerebrovascular reserve. There is a need to highlight the role of single-photon emission computed tomography/computed tomography (SPECT/CT) imaging using ^99mTc-Ethyl Cysteinate Dimer (^99mTc-ECD) with Acetazolamide (ACZ) challenge to diagnose MMS and decide on further surgical or medical intervention.

We illustrate a case of a young woman with MMS, who benefited from SPECT/CT brain perfusion imaging using ^99mTc-ECD with ACT challenge for the management of her condition.

Case report

A 32-year-old woman with underlying hypertension for the past 3 years, presented with sudden onset of right-sided hemiplegia. Patient also revealed a history of several months of having recurring headaches preceding the attack. She was noted to have elevated blood pressure upon arrival to hospital. Neurological test revealed motor power of 3/5 on the right, in keeping with right hemiplegia. No facial asymmetry and no slurred speech. Cranial nerves examination was normal. Other vital signs were unremarkable.

Initially, the patient was diagnosed with acute ischaemic stroke. However, computed tomography angiography (CTA) Brain showed acute left anterior cerebral artery (ACA) territory infarction with a calcified vascular malformation of the M1 segment of left middle cerebral artery (MCA), however there was no aneurysm noted. This was further supported by DSA of cerebral vessels. The angiogram findings included detection of total occlusion of proximal left MCA M1 segment, with distal neovascularization by collateral from left PCA. The left ICA is noted to be in smaller caliber compared to the right ICA. There was also calcification noted in the region of M1 segment of the left MCA. There is no aneurysmal dilation, fistula communication or arteriovenous malformation seen in the cerebral arteries. The patient was diagnosed to have MMS in view of young age, fairly recent onset of hypertension, and chronic occlusion of proximal branch of ICA leading to neovascularization. A decision was made by the referring team to proceed with brain perfusion imaging to assess regional cerebrovascular reserve (rCBR) to evaluate whether the patient would benefit from a flow augmentation bypass surgery.

Subsequently, the patient was referred to the nuclear medicine department in our hospital for brain perfusion imaging using ^99mTc-ECD SPECT/CT with ACZ challenge. A single-day protocol was utilised, whereby a baseline scan was performed using 14.81 mCi of ^99mTc-ECD. Following this, IV ACZ 1000 mg was administered as a slow bolus over 2 min and another dose of 29.8 mCi ^99mTc-ECD was given. Post-challenge brain perfusion imaging was performed at 20 min post-ACZ injection. Comparison was made between the baseline perfusion images with the 20 min post challenge images.

In the baseline scan, there was reduced basal cerebral perfusion (BCP) at the left lateral prefrontal cortex (Figure 1(a)). In the post challenge images, there was further decrease in the perfusion at the lateral prefrontal cortex with paradoxical increase perfusion to the contralateral cerebral hemisphere (Figure 1(b)). In the quantitative SPECT (qSPECT) composite image of baseline scan (Figure 2(a)) and post challenge scan (Figure 2(b)), Stage 3 BCP and poor vascular reserve was identified at the left lateral prefrontal cortex in keeping with ‘steal phenomenon’ (Table 1).OPEN IN VIEWER

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Figure 2.

Composite image of qSPECT brain perfusion imaging. (a) Baseline image demonstrating reduced perfusion at the left prefrontal cortex. (b) Post challenge image demonstrating further reduction at the left prefrontal cortex perfusion indicating poor rCVR (‘misery perfusion’), with paradoxical increase in perfusion at the contralateral cerebral hemisphere consistent with ‘steal phenomenon’.

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Table 1.

Stages of cerebral hemodynamic impairment in cerebrovascular occlusive disease.

Stage	Description
Stage 1	Drop in rCPP is followed by drop in rCBR. Vasodilatation occurs to raise the rCBV. This occurs as homeostasis to stabilize rCBF.
Stage 2	Reduction in rCBF occurs concurrently with drop in rCPP. Maximum vasodilatation achieved but unable to raise the rCBV (rCVR is constant). There is compensatory increase in OEF. There occurs failure of hemodynamic vasodilatory compensation leading to “misery perfusion”.
Stage 3	At this stage, rCBF continues to drop (despite ACZ challenge, there is significant >10% drop in rCBV, with paradoxical increase in rCBF to and rCBV in the contralateral brain regions – “steal phenomenon”). At this point, the brain is unable to compensate by increasing the OEF, leading to end-organ dysfunction (TIA). If the situation persists, there will occur permanent end-organ damage, i.e., stroke.

Abbreviations: rCPP: regional cerebral perfusion pressure, rCBR: regional cerebrovascular reserve, rCBF: regional cerebral blood flow, rCBV: regional cerebral blood volume, OEF: oxygen extraction factor. (Sourced from Kuwabara et. al. 1995 and Vagal et. al. 2009).

Although there was a potential to reverse the patient’s haemodynamic impairment by performing an external carotid-internal carotid (EC-IC) bypass surgery, a decision was made to conservatively follow-up the patient and defer cerebral revascularisation surgery to respect the patient’s choice. The patient’s condition was stable at 6-month follow-up with progressive improvement of her hemiplegia with the aid of physiotherapy. She did not complain of any episode of a second stroke event.

Discussion

Chronic cerebral ischemia with impaired regional cerebrovascular reserve (rCVR) increases the risk of stroke and surgical complications in cervical steno-occlusive disease patients.^3,4 These patients have occluded or stenotic proximal branches of ICA, however the external carotid artery (ECA) branches are often preserved. Thus, it is important to assess for cerebrovascular reactivity to ACZ challenge as determined by quantitative cerebral perfusion SPECT/CT. ⁵ Brain SPECT/CT study with ACZ challenge is frequently used to guide suitable treatments and anticipate surgical difficulties in patients with CCI. This approach may enhance clinical outcomes or reduce surgical risks.^6–8

Basal perfusion can sometimes be normal even with the presence of carotid artery stenosis due to the compensation of brain collateral arteries, which results in an increase in cerebral blood volume (CBV). ⁹ CBV and subsequent cerebral blood flow (CBF) are also raised locally or globally during task-related brain engagement ¹⁰ or in response to ACZ or elevated CO₂ pressure challenges. ¹¹ ACZ is known to inhibit carbonic anhydrase, which is widespread in tissues and blood, that leads to increased CO₂ in the regional blood circulation. This implies that if ACZ is injected, CO₂ is not converted to bicarbonate ion, resulting in an increase in CO₂ pressure that mimics the ventilator supply of air with a higher concentration of CO₂. When extracranial/intracranial ICA or ACA/MCA undergo progressive stenosis, CBF is supplemented by capillary recruitment or vasodilation, resulting in an increase in CBV, at an early stage of the compensated state.^9–11 Hence, vasodilatory challenge using ACZ will reveal the distinction between entirely normal, i.e., preserved vascular reserve, and the spectrum of decline in vascular reserve according to artery stenosis severity. For example, basal perfusion may appear normal, as it does in remote non-stenosed arterial territories, however, if vascular reserve is inadequate, the ACZ challenge can reveal the difference between afflicted areas with inadequate reserve and remote areas with normal reserve.

In terms of choosing a radiopharmaceutical, ^99mTc hexamethylpropyleneamine oxime (HMPAO) and ^99mTc-ECD are two radiopharmaceuticals that are often utilised for brain perfusion imaging. ^99mTc-ECD has a superior target-to-background ratio in comparison to ^99mTc-HMPAO. ¹² According to a study by Ting-Syuan Lin et al., which comprised a total of 70 patients, ^99mTc-ECD Brain SPECT/CT also can be utilised to examine the heterogeneity of brain perfusion in CCI and is suitable to be utilised for a 1-day protocol imaging. ¹³

The pattern of basal perfusion and vascular reserve was characterised according to earlier research by Kuroda and colleagues. ¹⁴ These researchers employed Xe-133 SPECT to characterise the types of cerebral perfusion patterns. Type 1 was characterised by normal basal perfusion and normal preserved rCVR, type 2 by normal basal perfusion and reduced rCVR, type 3 by low basal perfusion and reduced rCVR, and type 4 by low basal perfusion and maintained reserve, according to Kuroda et al. ¹⁴ In type 3 perfusion pattern, once the basal perfusion begins to decrease indicating hemodynamic failure, the likelihood of progression to a second event of stroke increases if left untreated.

Moreover, as SPECT/CT with ACZ challenge provides a non-invasive method for evaluating CBF and rCVR, this diagnostic imaging tool should be performed in all patients having CCI who are planned for surgical intervention, such as carotid endarterectomy or cerebral artery IC-EC bypass surgery. In patients demonstrating reduced CBF and poor rCVR, the ‘steal phenomenon’ is considered present when the regional CBF values decreases by more than 10% after the administration of ACZ in a large cerebral area or multiple regions of interest.^8,15 In such patients, surgical intervention would not be considered as feasible.

Conclusion

Brain perfusion imaging using SPECT-CT with ACZ challenge is an inexpensive, and vital investigation to aid in the characterisation of cerebral haemodynamics. It is an indispensable tool for the management to strategise surgical interventions in CCI. The imaging is important to determine the degree of autoregulatory vasodilatation and can become a prognostic indicator of rCVR and response to surgery.