Brain Perfusion

3.1.1 Radiopharmaceuticals

• [^99mTc]Tc-ECD (Ethyl Cysteine Dimer), ECD
• [^99mTc]Tc-HMPAO (Hexamethyl Propylene Amine Oxime, possibly stabilized), HMPAO

3.1.2 Uptake mechanism / biology of the tracer

Because of the lipophilic nature of both tracers, they cross the blood brain barrier (BBB) and become stable due to a conversion into hydrophilic compounds.

The mechanism of hydrophilic conversion is, however, different for the two tracers:

• ECD: de-esterification is the reaction leading to hydrophilic conversion
• HMPAO: instability of the lipophilic form and glutathione interaction are probably responsible for the hydrophilic conversion.

These differences in uptake may account for the fact that HMPAO seems better correlated with cerebral blood flow, while ECD seems to be more closely correlated with metabolic activity. As a consequence, although frequently used interchangeably in evaluation of suspected dementia, they may not be interchangeable in other diagnostic fields such as localization of epileptogenic foci and cerebrovascular diseases.

3.1.3 Indications

Main indications:

• Assessment of brain death (BD).
• Presurgical lateralization and localization of epileptogenic foci.
• Evaluation of cerebrovascular disease (chronic ischemia, preoperative evaluation).
• Evaluation of CNS involvement in patients with autoimmune vasculitis and atypical neurologic or neuropsychiatric manifestations when MRI is inconclusive.
• Evaluation of suspected dementia (detection and differential diagnosis). It should be clarified that in the era of PET/CT, PET/MR and amyloid tracers a proper balance between sensitivity of methods and costs should be made on a case per case basis, considering reimbursement and availability issues.

Less common indications:

• Evaluation of traumatic brain injury;
• Evaluation of suspected inflammation.

3.1.4 Contra-indications

Absolute contraindications are:

• Pregnancy
• inability to cooperate
• It is not recommended to interrupt breast feeding, although an interruption of 4 h during which one meal is discarded can be advised to be on the safe side [3].

3.1.5 Clinical performances

• Clinical performances for main indications are summarized below:
  Assessment of BD: HMPAO SPECT improved assessment of the extent of injury is general greater than suggested by CT as shown in a series of 40 comatose patients, in 20 patients comparing brain SPECT and contrast angiography, and in 50 comatose patients confirmed the reliability of SPECT in the diagnosis of BD [14,41,42].  Perfusion SPECT has also been successfully used as confirmation test of BD in the process of organ donation for transplant [43].
• Presurgical lateralization and localization of epileptogenic foci: in a prospective IAEA multi-centre study comparing MR, ictal SPECT and EEG confirmed that ictal perfusion SPECT is an effective modality (sensitivity:84%) for identifying seizure origin in temporal lobe epilepsy [44], and a review concerning paediatric neurology found similar results (sensitivity: 85-90%) [45]. However, it should be noticed that a recent review including 3163 patients in 27 studies states that the “current evidence does not support the prognostic importance of SPECT in patients undergoing temporal lobe surgery” as compared to MRI and PET [46].
• Evaluation of cerebrovascular disease: The historical work of Richard E. Latchaw shows that “there is a linear relationship between rCBF measured by ECD-SPECT and that measured with PWI, which has a linear relationship with absolute CBF measured with PET. The volume of hypoperfusion detected by HMPAO-SPECT has been shown to correlate significantly with that demonstrated by PWI (class II)” [47].  A number of papers have shown sensitivity in acute stroke ranging 61-74%, with a specificity of 88- 98% (class I).
• Evaluation of suspected dementia: Although somewhat dated, the analysis of the Optima study (Oxford Project to Investigate Memory in Aging) showed a 63% sensitivity and 93% specificity for SPECT alone, while the combination of SPECT (temporoparietal hypoperfusion) and a clinical diagnosis of possible or probable Alzheimer’s Disease (AD) led to 96% sensitivity and 84% specificity. In another study with histopathologic confirmation sensitivity of 86% and a specificity of 73% for SPET were reported [48].
• As previously stated, a proper balance between sensitivity of methods (SPECT versus PET versus MR) and tracers (perfusion, metabolism, amyloid) and costs should be made on a case per case basis.

3.1.6 Activities to administer:

The suggested activities to administer for adults are:

• [^99mTc]Tc-ECD: 740 MBq
• [^99mTc]Tc-HMPAO: 740 MBq

In paediatric nuclear medicine, the activities should be modified according to the EANM paediatric dosage card (https://www.eanm.org/publications/dosage-calculator/). The minimum recommended activity is 100 MBq.

3.1.7 Dosimetry

The effective doses per administered activity are [3]:

• [^99mTc]Tc-ECD: 7.7 µSv/MBq
• [^99mTc]Tc-HMPAO: 9.3 µSv/MBq

The range of the effective doses for the suggested activities is: 5.7 mSv - 6.9 mSv.

Caveat

“Effective Dose” is a protection quantity that provides a dose value related to the probability of health detriment to an adult reference person due to stochastic effects from exposure to low doses of ionizing radiation. It should not be used to quantify the radiation risk for a single individual associated with a particular nuclear medicine examination. It is used to characterize a certain examination in comparison to alternatives, but  it should be emphasized that if the actual risk to a certain patient population is to be assessed, it is mandatory to apply risk factors (per mSv) that are appropriate for the gender, the age distribution and the disease state of that population."

3.1.8 Interpretation criteria/major pitfalls

Data interpretation must consider relevant structural information (CT, MRI) also with image fusion, if available, taking into account possible effects of atrophy and partial volume effect. For epilepsy evaluation, correlation with the relevant electroencephalography data and clinical observations is mandatory (report exact timing of tracer injection relative to observed behavioural or electrical seizure activity). Ictal and interictal studies should be compared when available.

Semi quantification could be accomplished using:

• ROI analysis to compare blood flow abnormalities with those in the contralateral hemisphere or other reference regions;
• Spatial normalization, comparison to normal databases and voxel-based analysis;
• Subtraction analysis (after image count normalization to an appropriate reference region or the whole brain) provides a tool for subtracting an activation study from a baseline study.

Major pitfalls include:

• Interference with drugs.
• Sedating medications at the time of tracer injection may alter tracer distribution. Therefore, when sedation is necessary, record type, dose of the sedative and the time at which the sedative was administered in relation to the time of tracer injection.
• Phenytoin could determine cerebellar hypoperfusion.
• Psychoactive drugs (such as benzodiazepines) could determine hypoperfusion more prominent in the frontal cortex.
• Artefacts: patient motion during data acquisition may produce blurring; camera related; inappropriate processing.
• Unintended cerebral activation during uptake period (usually acoustic or visual stimuli).

3.1.9 Patient preparation

Before arrival, patients should be instructed to avoid smoking, xantinic drugs (cocoa, coffee, tea, cola), alcohol, and other drugs known to affect cerebral blood flow.

Before injection:

• check that the patient is able to cooperate.
• A stable environment (quiet, dimly lit room, patient seated or reclining comfortably with eyes and ears open) must be maintained from the positioning of intravenous access (10-15 min before injection) to 5-10 min after injection. Instruct the patient not to speak or read during the uptake period.
• Record events that might influence rCBF during the uptake (motion, talking, etc.).
• In uncooperative patients, conscious sedation (e.g. short-acting benzodiazepine) should be administered at least 5 min after tracer injection and preferably immediately before data acquisition.

When assessing BD, patient should have a stable blood pressure.

3.1.10 Methods

Detailed methods and recommendations regarding brain perfusion SPECT are available in the EANM procedure guideline for brain perfusion SPECT using ^99mTc-labelled radiopharmaceuticals, version 2 [49].

Quick methodological reference:

• Quality control of labelling and stability of the tracers is mandatory to prevent false- results. In particular, poor radiopharmaceutical labelling or stability could result in minimal concentration of tracer in the brain, an issue particularly critical when assessing BD.
• Try to keep the same time delay from injection to the start of data acquisition (30-60 min for ECD and 30-90 min for HMPAO). Imaging should be preferably completed within 4 h after injection.
• Use preferably a multi-head gamma camera to reach 5 million total events (without scatter correction) with the highest resolution collimation available (usually Low-energy High-Resolution (LEHR), Low-energy Ultra High-Resolution LEUHR or fan-beam).
• Rotational radius: smallest possible (less than 15 cm ensures best image quality) with appropriate patient safeguards. Use pan and zoom to reduce radius.
• Matrix: 128x128 or greater.
• Angular sampling: <3° (360° rotation).
• Typical scan time for triple head cameras is around 20-25 min (e.g. 120 projections, 40 projections per head, 20-25 s/projection). For dual head cameras it is closer to 30-35 min (e.g. 120 projections, 60 projections per head, 30 sec /projection).
• Use an iterative, e.g. ordered subset expectation maximization (OSEM), maximum-likelihood expectation maximization (MLEM), reconstruction (filtered back projection (FBP) is more affected by artifacts) after checking unprocessed projection data for artifacts.
• Reconstructed data are generally filtered using low-pass (e.g. Butterworth) filters with proper cut-off and order.
• Attenuation correction is highly recommended.
• Data should be then reformatted into at least three orthogonal planes (at least in the classical anterior commissure and posterior commissure anatomic orientation and using a section parallel to the long axis of the temporal lobe).