European Nuclear Medicine Guide
[123I]iobenguane also known as Meta-[123I]iodobenzylguanidine (MIBG).
Norepinephrine (NE) the neurotransmitter of the sympathetic system is synthesized from the amino acid tyrosine and stored in high concentration in presynaptic vesicles. Upon stimulation, NE is released into the synaptic space binding to postsynaptic receptors β1, β2 and promoting sympathetic response that is stopped by postsynaptic re-uptake mechanism with uptake-1 and 2 pathway that take back NE into the presynaptic terminal.
Guanethidine is a false neurotransmitter analogue of NE that can be radiolabelled with iodine, most commonly [123I]
. MIBG’s molecular structure is similar to that of NE and presents the same uptake and storage mechanism, but, in contrast, is not catabolized by monoamine oxidase or catechol-O-methyltransferase. Subsequently, it is retained and localized in the myocardial sympathetic nerve terminal endings [33].
Off-label
Many drugs modify the uptake and storage of MIBG and should be discontinued: tricyclic antidepressants, sympathomimetics, antipsychotics, antihypertensive agent (reserpine, calcium channel blockers, labetalol), tramadol, opioids, cocaine [38].
In addition, it is also important that patients stop eating food that may interfere with MIBG uptake such as catecholamine-like compounds (e.g. chocolate and blue cheese) [38].
Unintentional radioactive iodine uptake in the thyroid must be avoided by administration for 2-3 days of sodium or potassium iodide (100-150 mg per day) or sodium or potassium perchlorate (200-400 mg per day) at least 30 minutes before administration of the radiopharmaceutical.
[123I] physical half-life is 13.2 hours.
The appropriate dosage of MIBG has not been definitively established. For planar images, in several published studies an activity of 111-185 MBq by slow (over 1 to 2 min) secure peripheral intravenous injection flushed with saline to avoid rare (<1%) adverse events (dizziness, rash, pruritus, flushing and injection site haemorrhage) is suggested. In case of adult patients with systolic heart failure a dose of 10 mCi (370 MBq) ±10% may be appropriate in order to obtain single-photon emission computerized tomographic (SPECT) images [35].
The effective radiation dose is 0.013 mSv/MBq: an increased radiation dose from CT in case of SPECT/CT protocols (volume CT dose index: 3–5 mGy depending on acquisition parameters) [40]. Organs with the highest absorbed dose per unit activity administered (mGy/MBq) are the liver, bladder, gallbladder, spleen, heart, and adrenals: ample hydration should be encouraged as well as frequent urinary voiding in the first 48 hours following administration [35].
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."
Planar and SPECT images are routinely obtained 15 minutes (early) and 4 hours (delayed) after MIBG administration, using low-energy high-resolution (LEHR) parallel hole collimator and energy window of 159 keV±20% [38].
On planar images, acquired for 10 min in the anterior view and stored in a 128×128 or 256×256 matrix, both qualitative and quantitative analysis are performed. Qualitative evaluation involves the location, pattern and intensity of cardiac MIBG uptake to guide quantitative analysis through heart/mediastinum ratio (H/M) that reflects the integrity of cardiac sympathetic nerves.
The H/M is calculated dividing the mean counts per pixel in the heart by the mean counts per pixel in the mediastinum obtained by drawing regions of interest (ROI) on anterior planar image over the heart, including or not including the cavity, and over the upper mediastinum (avoiding the thyroid gland) [38].
Another quantitative index is myocardial washout rate (WR), calculated as percentage of decrease in myocardial MIBG counts over time from early to delayed images, is an important measure of cardiac sympathetic innervation reflecting turnover of catecholamines that relates to the degree of sympathetic drive [33].
Normal values for late H/M ratio and WR vary in relation to age (inversely for the late H/M ratio, directly for the WR) and image acquisition protocols. Improvement in the standardization of cardiac MIBG imaging protocols would contribute to increased clinical applicability of this procedure [38].
SPECT images, stored in a 64×64 matrix, and derived polar maps (bull’s eye) display facilitates assessment of the presence, extent and location of sympathetic abnormalities. All three image planes (short axis, horizontal long axis and vertical long axis) should be inspected of both late and early images displayed in a continuous colour scale, preferably the same as that employed for myocardial perfusion imaging [38].
Patients with CHF present reduced cardiac MIBG uptake, and among these patients, those with the lowest uptake tend to have the poorest prognosis [38]. Furthermore, some studies have also revealed that abnormalities of cardiac MIBG uptake may be predictive of increased risk of ventricular arrhythmia and sudden cardiac death and thereby may guide the use of ICD. Myocardial scar represents an important substrate for the occurrence of potentially fatal ventricular arrhythmias and patients with LVEF <30%-35% present an increased risk for sudden cardiac death requiring ICD implantation to reduce the risk [33].
The largest published prospective study ADMIRE-HF [11] study has provided validation of the independent prognostic value of cardiac MIBG imaging in the assessment of patients with heart failure. A total of 961 patients with CHF, NYHA class II or III and LVEF ≤35% were included. All patients underwent MIBG myocardial imaging and were then followed up for up to 2 years.
The cardiac event risk was significantly lower for subjects with H/M ≥1.60, with hazard ratio of 0.40 (97.5% CI: 0.25 to 0.64; p < 0.001); two-year event rate was 15% for H/M ≥ 1.60 and 37% for H/M <1.60. Hazard ratios for individual event categories were as follows: HF progression, 0.49 (p = 0.002); arrhythmic events, 0.37 (p = 0.02); and cardiac death, 0.14 (p =0.006). Combined “arhythmic” events (self-limited ventricular tachycardia, resuscitated cardiac arrest, appropriate ICD discharges, sudden cardiac death) were more common in subjects with H/M <1.60 (p < 0.01) and the highest prevalence of arrhythmic events was in the H/M range of 1.30 to 1.39 [34].
Recent data showed that this cut-off of H/M < 1.60 is also suitable for a follow-up of patients with heart failure up to 5 years after MIBG imaging (3).
Standardization of MIBG cardiac sympathetic imaging should contribute to increasing its clinical applicability and integration into current nuclear cardiology practice [38].
Regarding the two principal off-label applications of [123I]-mIBG imaging, in case of neurodegenerative disorder, MIBG cardiac uptake is reduced in around 80–90% of patients while is preserved in other parkinsonian syndromes allowing the differential diagnosis [37]. H/M ratio can be variable depending of gamma camera system and collimator; therefore, standardization is needed to perform multicentre studies.
In case of ischemic heart failure, MIBG could be a diagnostic tool in risk assessment of lethal ventricular arrhythmic events (ArEs) and could guide ICD implantation decision [36]. Clinical evidences demonstrated that regions of innervation/perfusion mismatch (MIBG, [99mTc]Tc-tetrofosmin or [99mTc]Tc-sestamibi) predispose to arrhythmias: cardiac region with denervated but perfused viable myocardium may exhibit denervation supersensitivity and predispose to potentially lethal arrhythmias [33]. Further prospective multicentre studies are required to explore the relationship between ArEs and regional innervation defects and innervation/perfusion mismatches.