Métodos de caracterización

Although the evidence base relating to MIBG has encouraging implications for clinical practice, the important limitations of the research conducted thus far make translation of research data into routine use difficult.

The majority of MIBG studies to date have excluded patients prescribed any medications suspected to interfere with MIBG uptake (Oide et al., 2003; Hanyu et al., 2006; Yoshita et al., 2006; Wada-Isoe et al., 2007; Estorch et al., 2008; Noguchi-Shinohara et al., 2009; Novellino et al., 2010), citing guidelines by the European Association of Nuclear Medicine (Giammarile et al., 2008), or a review relating to MIBG use in the treatment of neuroblastoma (Solanki et al., 1992). As an analogue of noradrenaline, MIBG is transported into presynaptic terminals through a number of mechanisms; chiefly, the energy-dependent “Uptake-one” process mediated by the norepinephrine transporter (NET), a transmembrane protein (Streby et al., 2015). Other processes also influence noradrenaline transport across the cell membrane, including active transport into vesicles, granular uptake, and calcium channel-mediated reuptake. Disruption of any of these mechanisms has the theoretical potential to diminish noradrenaline, and therefore MIBG, uptake (Giammarile et al., 2008).

This practice of excluding patients on such medications, while important in accounting for confounding variables in an emerging evidence base, presents considerable difficulty in establishing MIBG in routine clinical practice. Among the medications identified as potentially interfering with MIBG are a number of commonly prescribed, clinically important agents that include analgesics, antidepressants, antipsychotics, cardiovascular medications and inhaled sympathomimetics used in the treatment of asthma and chronic obstructive pulmonary disease.

Marquié Sayagués et al. (2010) demonstrated the scale of exclusion of such patients in a 2010 non-controlled study investigating MIBG use in the diagnosis of DLB and PDD. Thirty one of the 77 patients (40%) recruited to the study were prescribed medications identified as potentially

interfering with uptake; these included antipsychotics (n=26), levodopa (n=29; 38%), venlafaxine (n=4; 5%), and amitriptyline (n=2; 3%). Twenty-seven participants (35%) were also prescribed antihypertensive medication. The study failed to identify a significant difference in HMR between patients prescribed potentially interfering medications (HMR 1.47 ± 0.23) and those that were not (HMR 1.40 ± 0.33). That such a high proportion of participants were prescribed such medications in this clinically representative sample indicates the impracticability of restricting MIBG use in these patients, both in research and clinical settings.

The argument against excluding patients prescribed medications identified as interfering was strengthened further by a comprehensive review, which assessed published data on drug

interactions with MIBG uptake (Jacobson and Travin, 2015). The authors noted that the majority of studies involved in vitro or non-human methodologies and recommended that only labetalol or tricyclic antidepressants should be withdrawn prior to MIBG imaging.

More recent MIBG utility studies have created inclusion and exclusion criteria with the intent of recruiting more clinically representative populations. Yoshita et al’s (2015) multicentre study excluded patients on the basis of reserpine or tricyclic antidepressants alone, while an Italian MIBG study withheld medications, rather than exclude their participants, prior to cardiac

scintigraphy (Tiraboschi et al., 2016). Withholding medications poses its own practical difficulties; restricting use of medications such as inhalers, analgesics or dopaminergic agents for even short periods could lead to an escalation in symptoms and deterioration in wellbeing.

41 3.4.3 MIBG and comorbidities

Similar concerns exist surrounding the exclusion of patients with medical comorbidities from MIBG utility studies. In determining the presence of impaired sympathetic uptake, MIBG studies in DLB diagnosis have presumed such findings to be attributable to neuronal denervation secondary to α- synuclein deposition; however, several common conditions are capable of producing similar findings. Early MIBG studies restricted the recruitment of patients with comorbidities. In order to prevent the possibility of reduced MIBG uptake in diabetic neuropathy, studies excluded patients with any history of diabetes mellitus (Hanyu et al., 2006; Yoshita et al., 2006; Wada-Isoe et al., 2007; Estorch et al., 2008; Noguchi-Shinohara et al., 2009). Patients with “heart disease” were excluded to account for the generalised reduction in noradrenergic uptake observed in left ventricular dysfunction and the more localised reduction secondary to both chronic and acute myocardial ischaemia (Hanyu et al., 2006; Yoshita et al., 2006; Estorch et al., 2008; Noguchi- Shinohara et al., 2009; Novellino et al., 2010; Wada-Isoe et al., 2012). Subjects with thyroid disease, capable of producing autonomic dysfunction, and therefore impaired MIBG uptake, were excluded in two of these studies (Hanyu et al., 2006; Yoshita et al., 2006).

Marquié Sayagués et al. (2010) demonstrated that medical comorbidities affected a substantial proportion of the population likely to benefit from MIBG and found no significant relationship between HMR and comorbidity status. Twenty-four of 77 subjects had a history of “diseases that may interfere with uptake”, including arrhythmias, MI and cardiac failure.

Two more recent studies have attempted to address the difficulty in translating the findings of early MIBG studies into clinical practice. Yoshita et al’s (2015) multicentre study did recruit a population with some comorbidities, including subjects with a history of ischaemic heart disease or myocardial blood flow abnormalities, provided they occurred more than six or twelve months respectively before consent. The same study did, however, also exclude patients with thyroid disease and insulin-controlled diabetes.

Tiraboschi et al. (2016) did not cite any medical illnesses in the exclusion criteria of their study, explicitly stating that they deliberately included subjects “with common illnesses in the elderly (including ischemic, hypertensive, dilated cardiomyopathy, and diabetes) that might reduce 123_I-

same paper failed to cite how many of its participants were affected by such illnesses, it did report that DLB and non-DLB subjects reported a mean of 0.8 and 0.5 conditions (as structured by the Cumulative Illness Rating scale) respectively.

To summarise, although early MIBG studies excluded large proportions of patients on the basis of both medical comorbidities and prescribed medications, the high prevalence of these factors severely restricts the translation of such findings into clinical practice (Marquié Sayagués et al., 2010). Although two more recent studies, conducted in Japan and Italy, have recruited more representative cohorts, the former reported the lowest overall accuracy of MIBG published to date, and the latter temporarily withdrew medications deemed capable of interacting with MIBG uptake (Yoshita et al., 2015; Tiraboschi et al., 2016).