Guido Valle

99mTc HM-PAO brain perfusion SPECT in brain death.

Diagnosis of brain death must be certain to allow discontinuation of artificial ventilation and organ transplantation. Brain death is present when all functions of the brain stem have irreversibly ceased. Clinical and electrophysiological criteria may be misinterpreted due to drug intoxication, hypothermia or technical artefacts. Thus, if clinical assessment is suboptimal, reliable early confirmatory tests may be required for demonstrating absence of intracranial blood flow. We have easily carried out and interpreted99mTc HM-PAO SPECT in a consecutive series of 40 comatose patients with brain damage, without discontinuing therapy. Brain death was diagnosed in 7 patients, by recognising absence of brain perfusion, as shown by no intracranial radionuclide uptake. In patients in whom perfusion was seen on brain scans, HM-PAO SPECT improved assessment of the extent of injury, which in general was larger than suggested by CT.

Feasibility and Diagnostic Accuracy of a Gated SPECT Early-Imaging Protocol: A Multicenter Study of the Myoview Imaging Optimization Group

The aim of this study was to investigate whether early (time 1, or T1) myocardial tetrofosmin imaging is feasible and as accurate in detecting coronary artery disease as is standard delayed (time 2, or T2) imaging. Methods: One hundred twenty patients (100 men and 20 women; mean age ± SD, 61 ± 10 y) with anginal symptoms underwent tetrofosmin gated SPECT. Stress/rest T1 imaging was performed at 15 min and T2 at 45 min after injection. Image quality was visually evaluated using a 4-point scale (from 0 = poor to 3 = optimal). Myocardial perfusion analysis was performed on a 20-segment model using quantitative perfusion SPECT software, and reversible ischemia was scored as a summed difference score (SDS). Coronary angiography was performed within 1 mo on all patients, and stenosis of more than 50% of the diameter was considered significant. Results: Overall, quality was scored as optimal or good for 94% of T1 images and 95% of T2 images (P = not statistically significant). Heart, lung, liver, and subdiaphragmatic counts did not differ for stress and rest T1 and T2 imaging. A good linear relationship was seen between T1 and T2 SDS (r = 0.69; P < 0.0001), and Bland–Altman analysis showed good agreement between the 2 conditions. In terms of global diagnostic accuracy, areas under the receiver-operating-characteristic curve were comparable between T1 and T2 (0.80 vs. 0.81, P = not statistically significant). Discrepancies between T1 and T2 SDS were observed in 44% of patients (T1 − T2 SDS > 2). Linear regression analysis showed a good correlation between T1 and T2 SDS (r = 0.67; P < 0.0001), whereas the Bland–Altman method showed a shift in the mean value of the difference of +2.67 ± 2.73. In patients with a T1 − T2 SDS of more than 2, areas under the receiver-operating-characteristic curves were significantly higher for T1 than for T2 images (0.79 vs. 0.70, P < 0.001). Conclusion: T1 imaging is feasible and as accurate as T2 imaging in identifying coronary artery disease. However, in a discrete subset of patients, early acquisition strengthens the clinical message of defect reversibility by permitting earlier, more accurate identification of more severe myocardial ischemia.

Prevalence of Tako-Tsubo Syndrome among patients with suspicion of acute coronary syndrome referred to our centre

BACKGROUND The Tako-Tsubo Syndrome is a clinical entity characterized by acute but rapidly reversible left ventricular systolic dysfunction and triggered by emotional or psychological stress. The aim of our study was to determine the prevalence and characteristics of this syndrome among the patients presenting to our Centre with suspicion of acute coronary syndrome. METHODS AND RESULTS Over a 12-month period (May 2006 to April 2007), among 82 patients referred to our catheterization laboratory with suspicion of acute coronary syndrome, 4 confirmed Tako-Tsubo Syndrome (prevalence 4.87%). The patients referred to our Centre came from Foggias province above all. The mean age of the population was 65.5 +/- 18.48 years (range 49 to 82), with a ratio of men to women of 1:3. The syndrome characterized by acute chest pain with ST-segment elevation, absence of significant lesions in each of the 3 epicardial coronary arteries by angiography, systolic dysfunction (ejection fraction 35 +/- 9.12%) with abnormal wall motion of the mid and distal LV and hyperkinesia of the basal LV, and emotional or psychological stress immediately preceding the cardiac events. Among markers of cardiac necrosis, only serum Troponin-I increased in each patients without significant elevation of CPK and with mild elevation of CK-mb and LDH. 2 patients developed hemodynamic instability. Each patient survived with normalized ejection fraction (54.25 +/- 5.05%) and rapid restoration to previous functional cardiovascular status within 4 weeks. CONCLUSIONS A reversible cardiomyopathy triggered by emotional or psychological stress occurs in elderly women above all and mimic acute coronary syndrome. The diagnosis of Tako-Tsubo Syndrome is based mainly on coronary and left ventricular angiography, which excludes the diagnosis of coronary artery disease and recognizes the pattern of wall-motion abnormalities. The different epidemiology of this Syndrome reported in literature demonstrates which this cardiomyopathy is underdiagnosed.

Considerations of brain death on a SPECT cerebral perfusion study.

Brain death imaging is often a diagnostic challenge. Cerebral angioscintigraphy is extensively used for this analysis, but this test does not allow the perfusion evaluation of the posterior fossa. The authors report a case in which a SPECT study showed persistence of blood frow in infratentorial structures with total absence of cerebral (supratentorial) perfusion. This finding excluded the diagnosis of brain death.

Temozolomide and Radiotherapy versus Radiotherapy Alone in High Grade Gliomas: A Very Long Term Comparative Study and Literature Review

Temozolomide (TMZ) is the first line drug in the care of high grade gliomas. The combined treatment of TMZ plus radiotherapy is more effective in the care of brain gliomas then radiotherapy alone. Aim of this report is a survival comparison, on a long time (>10 years) span, of glioma patients treated with radiotherapy alone and with radiotherapy + TMZ. Materials and Methods. In this report we retrospectively reviewed the outcome of 128 consecutive pts with diagnosis of high grade gliomas referred to our institutions from April 1994 to November 2001. The first 64 pts were treated with RT alone and the other 64 with a combination of RT and adjuvant or concomitant TMZ. Results. Grade 3 (G3) haematological toxicity was recorded in 6 (9%) of 64 pts treated with RT and TMZ. No G4 haematological toxicity was observed. Age, histology, and administration of TMZ were statistically significant prognostic factors associated with 2 years overall survival (OS). PFS was for GBM 9 months, for AA 11. Conclusions. The combination of RT and TMZ improves long term survival in glioma patients. Our results confirm the superiority of the combination on a long time basis.

Mithridates VI Eupator of Pontus and mithridatism

We greatly appreciated the paper by Ring and Gutermuth, ‘100 years of hyposensitization: history of allergen-specific immunotherapy (ASIT)’ (1). Some points referring to Mithridates VI of Pontus deserve, in our opinion, to be further addressed (e.g. ‘... King Mithridates... used increased doses of snake venom to make himself immune against the toxin...’). Mithridates VI (132-63 BC), who ruled the northern part of Anatolia and waged a hard-fought war against the Romans, was interested, like other hellenistic sovereigns, in science, particularly poisons and antidotes (Fig. 1). His celebrated ‘universal antidote’ later came to be known as ‘Mithridatium’ (2). Aulus Gellius (Attic Nights 17.16) states that Mithridates used to mix the blood of Pontic ducks, whose flesh was toxic from their ingestion of plants poisonous to humans, with other substances reputed to ‘expel’ poisons. He also apparently obtained immunity to otherwise fatal doses of arsenic by ingesting tiny amounts over many years. His ‘theriac’ recipe was said to contain more than 50 ingredients, consisting of poison counteracting ‘drugs’ (3). He was known to display his ‘immunity’ to poison plots at banquets, inviting his guests to sprinkle his food and drink with deadly substances. Dio Cassius (Roman History 37.13) reports that Mithridates protected himself by taking his secret ‘antidote’ formula every day. Pliny the Elder (Natural History 25.3) states that Mithridates, through experiments, came up with a daily regimen of taking poison along with ‘remedies’. Appian (Mithridatic Wars 12.16) says that Mithridates accustomed himself to poisons by taking small doses every day. The original formula of the famous mithridatium has not survived, but it is unlikely that a snake venom was employed, as stated by Ring and Gutermuth. In fact, because of the enzymatic/proteic nature of their lethal active principia, reptile venoms taken orally are inactivated by proteolysis in the gut, being able to exert their effects only in the presence of lesions of the inner surface of the first digestive tract. The fact that snake venom could be safely ingested was known in antiquity. For example, the Roman writer Lucan (Bellum Civile/Pharsalia 9.614) stated that ‘snake venoms are dangerous only when mixed to the blood’. The word ‘mithridatism’ is currently used to mean tolerance or unresponsiveness to a toxin, which is acquired by taking gradually larger doses of it. The reported continuous per os assumption of ‘hemetics, antidotes, poisons, remedies and/or (unspecified) drugs’ probably determined Mithridates’ resistance to toxins more by functional and/or metabolic changes than by immune mechanisms. In this regard, gut irritation (impairing the absorption of the poison itself as in the case of chronically taken low doses of arsenic) and/or induction/activation of drug-biotransforming enzymes are likely to have been involved. Such resistance was said to have resulted in an unwonted effect when, in 63 BC, Mithridates tried unsuccessfully to empoison himself to avoid to be captured alive by his enemies. Appian states that Mithridates ‘mixed’ the poison and shared the dose with his two young daughters, then swallowed the rest. The two girls died immediately, but Mithridates only became weak (Fig. 2). The composition of this suicide poison is unknown. The effectiveness of poison in rapidly killing Mithridates’ daughters following oral ingestion suggests a nonproteic nature of the poison itself and, therefore, it is unlikely that Mithridates’ tolerance was based on an immunological mechanism. He had shared the single dose with his two daughters and the remaining amount was sublethal, also due to his tolerance. Figure 1 Portrait of Mithridates VI Eupator by Cristiano M. Ferretti. Mithridates is represented as Hercules wearing a lionskin. The sketch was inspired by the sculpture at Louvre museum (courtesy of the artist). Allergy

Cardiac Arrest caused by Barlow's Syndrome or by Stress Cardiomyopathy?

We describe a case of out-of-hospital Cardiac Arrest (CA) in a patient with Barlows Syndrome (BS) and features of Stress Cardiomyopathy (SC) (or Apical Ballooning Syndrome or Tako-Tsubo). The patient experienced CA during physical stress and was resuscitated thanks to DC-Shock. The Electrocardiogram (ECG) after resuscitation was unremarkable. In the reported case the documented severe hypokalemia, with the physical stress, could have triggered the CA, probably of tachyarrhythmic origin. However, in the reported case, the echocardiographic, coronarographic and ventriculographic features, were surprisingly indistinguishable from those of the SC. In conclusion it is impossible to say if, in our patient, the CA has been caused by BS or by SC. However, even if CA has been probably caused by the BS, we hypothesize that the CA, in its turn determined, might have caused the SC via stress mechanisms. In few words, the CA is a complication of SC, but should probably be regarded also as a cause of SC.

Volume overload modulates effects of cardiac resynchronization therapy independently of myocardial reperfusion: results of the RESYNC study.

Objectives Cardiac resynchronization therapy (CRT) may induce significant changes in regional wall motion and perfusion. However, the link between these variables in patients with heart failure has not been investigated. Methods Thirty-six patients with idiopathic (n = 22) or ischemic (n = 14) cardiomyopathy (mean age 70 ± 8 years, 24 male) were studied by echocardiography and gated single-photon emission computed tomography (SPECT) before and within 2 months after CRT. Results New York Heart Association class improved in all but four patients. The perfusion analysis indicated that, in all but three patients, there was a significant improvement of tracer uptake. Baseline end-diastolic volume index obtained by gated SPECT modulated increase of ejection fraction (P < 0.001), reduction of end-systolic volume index (P < 0.01) and improvement of motion (P < 0.001), as well as of left ventricular wall thickening (P < 0.002). Finally, despite CRT inducing significant reperfusion independently of volume overload (P < 0.05), extension of perfusion defect correlated with global improvement in the follow-up (P < 0.05). Conclusions Volume overload may identify responders to resynchronization therapy. CRT induced a significant ‘reperfusion’ both in ischemic and idiopathic cardiomyopathies, even if this is not sufficient to improve left ventricular function in patients with more severe volume overload. Finally, simultaneous evaluation of volume overload and perfusion defects may result useful in identifying CRT responders.

Mithridates VI Eupator, father of the empirical toxicology.

We read with pleasure the article by Gunduz et al., titled “Clinical review of grayanotoxin/mad honey poisoning past and present,” that offers an overview of the toxicological aspects of the “mad honey.” However, from a historical point of view and in a toxicological context, an observation seems mandatory. The king of Pontus (in northeast Anatolia), whose allies used grayanotoxin-containing honey against the troops of Pompey the Great, was Mithridates VI Eupator (132–63 BC), not Mithridates IV Philopator Philadelphus, who died circa 150 BC (more than 80 years before the Roman conquest of Pontus) and brother of the grandfather of Mithridates VI. The mistake probably reflects the fact that in ancient Middle East, many kings bore the name “Mithridates” and should be corrected because Mithridates VI Eupator king of Pontus was one of the pioneers of clinical toxicology. Mithridates VI was the author of a book on roots and plants that at those times were one of the most important sources on venoms, which he used to secretly kill his enemies. The interest of Mithridates VI in empirical clinical toxicology is also demonstrated by the experiments that he carried out on prisoners condemned to capital punishment to test poisons and antidotes. Moreover, as he was afraid to be poisoned, he started to protect himself against poisons by taking progressively increasing sublethal doses. The chemical toxicology of them is unknown but there probably was no additive effect. In this way, Mithridates VI acquired resistance to poisoning possibly by enzymatic activation or metabolic functional changes (mithridatism). This, paradoxically, resulted in an unwanted effect: when he understood that he was falling in his enemies’ hands, he attempted to commit suicide, but because of his acquired tolerance, the amount of poison he swallowed did not kill him despite the fact that he walked around rapidly to hasten its action. Consequently, he looked for death by sword. Besides mithridatism, Mithridates VI gave the name to “mithridatum,” a general antidote whose recipe was found in his cabinet by Roman soldiers and carried to Rome by Pompey. Despite Pliny’s criticism, the “mithridatum”, with some modifications, was given the name “theriaca” and used in medicine until the nineteenth century. The intentional use of mad honey to overwhelm enemy forces is one of the first recorded uses of a biotoxin in warfare and is perfectly correspondent to the personality and to the scientific interests of Mithridates VI Eupator king of Pontus.

Anomalous origin of the left coronary artery from the pulmonary artery in an elderly patient, football player in youth.

Anomalous origin of the left coronary artery from the pulmonary artery is a rare congenital defect. Without surgical treatment, approximately 90% of infants die within the first year of life. Late presentation in the adult or elderly is rare. Factors that may lead to survival in advanced age include the development of intercoronary collaterals. Furthermore, the risk of sudden cardiac death due to ischaemic malignant ventricular dysrhythmias exists even in asymptomatic adult patients and, classically, is precipitated by exercise. We report the case of a 67-year-old man, a football player in his youth, always asymptomatic until presentation at our centre for symptomatic sustained ventricular tachycardia and shortness of breath on exertion. We show the features of the ECG, transthoracic echocardiography, angiography study of the coronary and the pulmonary system, myocardial basal and stress gated single photon emission computed tomography with Tc-tetrofosmin and cardiac CT 64 slices. The patient was referred to cardiac surgery. We believe that this patients favourable course may be ascribed to the large network of collaterals from the right coronary artery supplying the entire heart. However, the exact reason why these favourable evolutions (both vascular and clinical) occur only in some individuals remains largely unknown.