Can euglycemic Diabetic Ketoacidosis Caused by SGLT2 Inhibitors be avoided in Covid-19 and other acute Infections?

Introduction: We present a case of anion gap euglycemic diabetic ketoacidosis (EuDKA) in a patient with COVID-19 infection. Patients with diabetes mellitus are at increased risk of severe illness, and hyperglycaemia is associated with higher morbidity and mortality in patients infected with COVID-19. Case Description: A 76-year-old male with diabetes mellitus treated with SGLT2 inhibitor tested positive for COVID-19 infection on day 3 after his admission. In the emergency room he had a high anion gap metabolic acidosis and a blood glucose of 248 mg/dl. His urine tested strongly positive for ketones. A diagnosis of euglycemic diabetic ketoacidosis was made and he was treated with intravenous insulin and normal saline; his antidiabetic medications were stopped. His metabolic acidosis gradually resolved, and he was discharged. Discussion: Euglycemic diabetic ketoacidosis is a rare complication of COVID-19 infection. It is defined by the American Diabetes Association as the triad of anion gap metabolic acidosis with arterial pH <7.3, serum bicarbonate <18 mmol/l and ketonuria or ketonemia. It is a life-threatening complication which usually occurs in type 1 diabetes mellitus patients but may also occur in type 2 diabetes mellitus patients. As described earlier, it is associated with hyperglycaemia but if blood glucose is low or near normal but <250 mg/dl it is then named euglycemic diabetic ketoacidosis. Patients treated with SGLT2 inhibitors are at increased risk of euglycemic diabetic ketoacidosis. Conclusions: COVID-19 infection precipitated euglycemic diabetic ketoacidosis in our patient. SGLT2 inhibitors must be stopped when this adverse reaction occurs. As their use increases, the risk of this adverse reaction is higher as well. Their prescription should be restricted to trained physicians who are able to educate their patients and treat them appropriately in situations that may arise. LEARNING POINTS: COVID-19 infected patients are at increased risk of developing diabetic ketoacidosis or euglycemic ketoacidosis when treated with SGLT-2 inhibitors.It is practical to discontinue the drug at the onset of any symptoms consistent with acute infection to prevent the development of euglycemic diabetic ketoacidosis.

FP-CIT SPECT does not predict the progression of motor symptoms in Parkinson's disease.

BACKGROUND/AIMS: FP-CIT (fluoropropyl-2ß-carbomethoxy-3ß-4-iodophenyl-nortroptane) SPECT is a well-established nuclear medicine method to support the clinical diagnosis of Parkinson's disease (PD). In this study, we examined the prognostic value of FP-CIT SPECT concerning the PD motor symptoms. METHODS: All 38 PD patients (age 57 ± 7 years, Hoehn & Yahr stage 1.6 ± 0.8, mean ± SD) underwent a baseline visit and a follow-up visit 3-7 years (5.2 ± 1.3 years) after the baseline visit. Cerebral [(123)I]FP-CIT SPECT was performed only once at the baseline visit. At both visits the motor symptoms bradykinesia, rigidity, resting tremor, postural tremor and axial symptoms were quantified by means of the UPDRS motor scale. RESULTS: There was no significant correlation between the initial striatal FP-CIT uptake and the annual progress of any motor symptom (= difference [(motor symptom at follow-up visit) - (motor symptom at baseline visit)]/time (in years) between assessments). CONCLUSION: The initial striatal FP-CIT SPECT does not predict the velocity of progress of PD motor symptoms within an interval of 3-7 years.

Prospective study of p-[123I]iodo-L-phenylalanine and SPECT for the evaluation of newly diagnosed cerebral lesions: specific confirmation of glioma.

PURPOSE: The differentiation between gliomas, metastases and gliotic or inflammatory lesions by imaging techniques remains a challenge. Gliomas frequently exhibit increased uptake of radiolabelled amino acids and are thus amenable to PET or SPECT imaging. Recently, p-[123I]iodo-L-phenylalanine (IPA) was validated for the visualization of glioma by SPECT and received orphan drug status. Here we investigated its diagnostic performance for differentiating indeterminate brain lesions. METHODS: This prospective open study included 67 patients with newly diagnosed brain lesions suspicious for glioma (34 without and 33 with contrast enhancement in the MRI scan). Patients received 250 MBq IPA intravenously after overnight fasting. SPECT images at 30 min and 3 h post-injection were iteratively reconstructed and visually interpreted after image fusion with an MRI brain scan (fluid-attenuated inversion recovery sequence or T1-weighted contrast-enhanced image). Findings were correlated with results of stereotactic or open biopsies or serial imaging. RESULTS: Twenty-seven low-grade (2 WHO I, 25 WHO II) and 24 high-grade gliomas (1 WHO III, 23 WHO IV), 3 metastases originating from lung cancer as well as 13 non-neoplastic lesions were proven. All non-neoplastic lesions and all metastases were negative with IPA SPECT. Forty gliomas were true-positive (TP) and 11 false-negative (FN) findings (8 WHO II, 1 WHO III, 2 WHO IV) occurred. There were no false-positive (FP) findings. For the differentiation of primary brain tumours and non-neoplastic lesions, sensitivity and specificity were 78 and 100%. In 34 lesions without contrast enhancement in MRI, IPA SPECT resulted in 17 TP, 8 true-negative, 9 FN and no FP findings (sensitivity 65%, specificity 100%). CONCLUSION: In patients with suspected glioma, IPA SPECT shows a high specificity, but especially in low-grade gliomas FN findings may occur. Due to the high positive predictive value a positive finding allows a suspected glioma to be confirmed.

Improved synthesis of no-carrier-added p-[124I]iodo-L-phenylalanine and p-[131I]iodo-L-phenylalanine for nuclear medicine applications in malignant gliomas.

This work describes the synthesis and the tumor affinity testing of no-carrier-added (n.c.a.) p-[(124)I]iodo-L-phenyalanine ([(124)I]IPA) and n.c.a. p-[(131)I]iodo-l-phenyalanine ([(131)I]IPA) as radiopharmaceuticals for imaging brain tumors with PET and for radionuclid-based therapy, respectively. Parameters for labeling were optimized with regard to the amount of precursor, temperature and time. Thereafter, n.c.a. [(124)I]IPA and n.c.a. [(131)I]IPA were investigated in rat F98 glioma and in primary human A1207 and HOM-T3868 glioblastoma cells in vitro, followed by an in vivo evaluation in CD1 nu/nu mice engrafted with human glioblastoma. No-carrier-added [(124)I]IPA and n.c.a. [(131)I]IPA were obtained in 90+/-6% radiochemical yield and >99% radiochemical purity by iododestannylation of N-Boc-4-(tri-n-butylstannyl)-L-phenylalanine methylester in the presence of chloramine-T, followed by hydrolysis of the protecting groups. The total synthesis time, including the HPLC separation and pharmacological formulation, was less than 60 min and compatible with a clinical routine production. Both amino acid tracers accumulated intensively in rat and in human glioma cells. The radioactivity incorporation in tumor cells following a 15-min incubation at 37 degrees C/pH 7.4 varied from 25% to 42% of the total loaded activity per 10(6) tumor cells (296-540 cpm/1000 cells). Inhibition experiments confirmed that n.c.a. [(124)I]IPA and n.c.a. [(131)I]IPA were taken up into tumor by the sodium-independent L- and ASC-type transporters. Biodistribution and whole-body imaging by a gamma-camera and a PET scanner demonstrated a high targeting level and a prolonged retention of n.c.a. [(124)I]IPA and n.c.a. [(131)I]IPA within the xenotransplanted human glioblastoma and a primarily renal excretion. However, an accurate delineation of the tumors in mice was not possible by our imaging systems. Radioactivity accumulation in the thyroid and in the stomach as a secondary indication of deiodination was less than 1% of the injected dose at 24h p.i., confirming the high in vivo stability of the radiopharmaceuticals. In conclusion, n.c.a. [(124)I]IPA and n.c.a. [(131)I]IPA are new promising radiopharmaceuticals, which can now be prepared in high radiochemical yields and high purity for widespread clinical applications. The specific and high-level targeting of n.c.a. [(124)I]IPA and n.c.a. [(131)I]IPA to glioma cells in vitro and to glioblastoma engrafts in vivo encourages further in vivo validations to ascertain their clinical potential as agent for imaging and quantitation of gliomas with PET, and for radionuclid-based therapy, respectively.

Pain palliative therapy in women with breast cancer osseous metastatic disease and the role of specific serum cytokines as prognostic factors.

PURPOSE: To evaluate the efficacy of radionuclide palliative therapy (RPT) in women suffering from painful metastatic bone disease (MBD) due to breast cancer (BrCa), and to investigate the possible relationship between the RPT efficacy and cytokines levels. METHODS: Sixty-three BrCa women patients with MBD enrolled in a prospective, nonrandomized study. Thirty were treated with Rhenium-186-hydroxyethylidenediphosphonic acid ((186)Re-HEDP), 21 with Strontium-89-Chloride ((89)Sr-Cl2), and 12 with Samarium-153-thylenediaminetetramethylenephosphonic acid ((153)Sm-EDTMP). Blood samples were collected pre- and post-therapy to assess the interleukin (IL)-2, IL-6 and tumor necrosis factor (TNF)-a titers. The palliative effect of the treatment was evaluated using a modified Wisconsin test. RESULTS: All three radiopharmaceuticals were equally effective in pain relief. Pain palliation was complete in 52% of patients, partial in 31%, and absent in 16%. Responders to therapy had higher IL-2 and lower IL-6/TNF-a concentrations, compared with nonresponders, even though statistically significant difference in cytokines levels between responders and nonresponders before treatment was noted only for IL-6. CONCLUSION: All used radiopharmaceuticals had the same therapeutic effect. Pretherapy low titers of IL-6 levels seems to have a favorable prognostic value for the therapeutic outcome, while IL-2 and TNF-a alterations pre- and post-therapy can only serve as markers of a better RPT response.

Evaluation of transcranial sonographic findings and MIBG cardiac scintigraphy in the diagnosis of idiopathic Parkinson's disease.

The diagnosis of idiopathic Parkinson's disease (IPD) is based on clinical criteria. In the last two decades several neuroimaging methods using transcranial sonography (TCS) or radiolabelled tracers such as the myocardial MIBG scintigraphy were applied to support diagnosis of IPD. They have been used independently of each other and their interrelation is not yet clear. In the present study we analyzed the relation between findings of TCS, MIBG scintigraphy, and clinical presentation in 42 patients with IPD who were clinically diagnosed and underwent clinical follow-up over ≥3 years in order to confirm IPD diagnosis throughout the clinical course. The extent of substantia nigra hyperechogenicity (SN+) contralateral to the clinically more affected body side (SN(contra)) was compared to myocardial (123)I-MIBG uptake. SN(contra) did not correlate with the myocardial MIBG uptake (r = -0.10; p = 0.52). Both myocardial MIBG uptake and TCS did not correlate significantly with Hoehn and Yahr stage (r = -0.03; p = 0.87 and r = -0.10; p = 0.54, respectively). Sensitivity of TCS in the diagnosis of IPD was 79%, of MIBG scintigraphy 81%. The combination of both measurements reached a sensitivity of 95%. TCS and MIBG scintigraphy may disclose complementary aspects of IPD. The combined use of both neuroimaging methods might improve the diagnostic sensitivity regarding IPD.

Myocardial MIBG scintigraphy may predict the course of motor symptoms in Parkinson's disease.

BACKGROUND: The metaiodobenzylguanidine (MIBG) scintigraphy is a well established nuclear medicine method to support the clinical diagnosis of Parkinson's disease. In this study we examined the predictive value of the MIBG scintigraphy concerning the severity and progression of the parkinsonian motor symptoms. PATIENTS AND METHODS: This study included 40 patients with idiopathic Parkinson's disease (age 56 ± 9 years, Hoehn and Yahr stage 1.4 ± 0.7, mean ± standard deviation). All patients underwent a baseline visit and a follow-up visit 3-8 years (5.3 ± 1.6 years) after the baseline visit. (123)I-MIBG scintigraphy was performed only once at the baseline visit. At both visits the motor symptoms bradykinesia, rigidity, resting tremor, postural tremor and axial symptoms were quantified by means of the motor part of the Unified Parkinson's disease rating scale. RESULTS: The myocardial MIBG uptake correlated significantly with the annual progress of rigidity (r=-0.41, p<0.05; Pearson's correlation) and axial symptoms (r=-0.49, p<0.01). There was no significant correlation (p>0.05) between the initial myocardial MIBG uptake and the annual progress of the other motor symptoms. CONCLUSION: The MIBG scintigraphy may predict the velocity of progress of rigidity and axial symptoms in the following 3-8 years. Such a prediction is not possible for the other motor symptoms resting tremor, postural tremor and bradykinesia.

Myocardial sympathetic degeneration correlates with clinical phenotype of Parkinson's disease.

In idiopathic Parkinson's disease (PD), different clinical subtypes are distinguished due to predominant motor symptoms: a tremor-dominant type (TDT), an akinetic rigid type (ART), and a mixed type (MT). We compared myocardial sympathetic innervation, measured by MIBG scintigraphy, in different subtypes of PD at early and advanced stages of PD. We applied MIBG scintigraphy in 102 patients with PD. About 57 patients were at Hoehn and Yahr (H&Y) stage 1, 22 at H&Y stage 2, and 23 at H&Y stages 3 and 4. For quantification of myocardial MIBG uptake, the heart-to-mediastinum (H/M) count-ratio was calculated. At all H&Y stages, myocardial MIBG uptake was significantly higher in TDT patients than in ART or MT patients (P < 0.05; ANOVA). Furthermore, at each H&Y stage, myocardial MIBG uptake correlated significantly with severity of hypokinesia (P < 0.05; Spearman's correlation) and rigidity (P < 0.05), but not with severity of resting or postural tremor. The significant correlation between myocardial sympathetic degeneration and severity of hypokinesia and rigidity suggests that myocardial sympathetic degeneration and hypokinetic-rigid symptoms develop in a closely coupled manner in early as well as advanced PD. No such correlation can be found between myocardial sympathetic degeneration and parkinsonian tremor.

Cerebral and Extracranial Neurodegeneration are Strongly Coupled in Parkinson's Disease.

In idiopathic Parkinson's disease (PD), a generalized Lewy body type-degeneration in the brain as well as extracranial organs was identified. It is unclear, whether cerebral and extracranial Lewy body type-degeneration in PD are coupled or not. To address this question, cerebral [(123)I]FP-CIT SPECT - to quantify cerebral nigrostriatal dopaminergic degeneration - and myocardial [(123)I]MIBG scintigraphy - to quantify extracranial myocardial sympathetic degeneration - were performed in 95 PD patients and 20 healthy controls. At each Hoehn and Yahr stage separately, myocardial MIBG uptake correlated significantly with striatal FP-CIT uptake. No such correlation was found in the controls. Cerebral and extracranial Lewy body type-degeneration in PD do not develop independently from each other but develop in a strongly coupled manner. Obviously cerebral and extracranial changes are driven by at least similar pathomechanisms. Our findings in controls contradict a physiological correlation between nigrostriatal dopaminergic and myocardial sympathetic function.