Type 2 diabetes mellitus (T2DM) is one of the most common chronic conditions encountered in primary care, affecting up to 10% of the Hong Kong population.1 It is also a leading cause of morbidity and mortality due to diabetic complications.2 Optimal control of cardiovascular risk factors can decrease the risk of developing diabetes-related complications.3 4 5

Hyperlipidaemia is one of the most important modifiable risk factors for cardiovascular disease (CVD) prevention. Studies have shown that optimal lipid control is associated with an improved cardiovascular outcome.6 7 8 9 Low-density lipoprotein (LDL) particles are considered more atherogenic than other cholesterol components and therefore stringent control of LDL is particularly important for the prevention of CVD in high-risk patients.10

Despite this evidence, lipid control among diabetic patients in the primary care setting, both locally and internationally, has been inadequate.11 The most recent study performed in Hong Kong found that 88.4% of diabetic patients had a suboptimal lipid level.12 Studies in Europe and the US found that the LDL control rate ranged from 30% to 55%.13 14 15 16 17 Similarly, a study of dyslipidaemia management in South Asia including China, South Korea, Malaysia, and Singapore revealed that only 48% of patients attained pre-defined low-density lipoprotein–cholesterol goals.18

Similar to other chronic conditions, the reasons for poor (lipid) control are multifactorial and may include patient, physician, and health care delivery factors. Among them, suboptimal medication augmentation has been identified as an important physician factor. This is known as therapeutic inertia (TI) and is said to exist whenever the health care provider does not initiate or intensify therapy appropriately when therapeutic goals are not reached: “recognition of the problem, but failure to act”.19 20 Such TI has become increasingly acknowledged as a major impediment to CVD risk factor control. Studies have suggested that TI is related to the management of diabetes and hypertension (HT) and may contribute to up to 80% of heart attacks and strokes.21 22

The prevalence of TI in chronic disease management has not been explored in Hong Kong. In this study, we specifically looked at the prevalence of TI in hyperlipidaemia management among diabetic patients. Internal statistical data (internal data from Hospital Authority [HA] Head Office) revealed that lipid control has been relatively poor in this cluster when compared with blood pressure and glycaemic control. Our study aimed to explore the prevalence of TI in the management of hyperlipidaemia among T2DM patients and to explore the underlying factors. By overcoming the barriers to adequate and appropriate treatment, it was expected that the long-term cardiovascular outcome of T2DM patients could be improved.

In this cross-sectional study, all T2DM patients with International Classification of Primary Care code T90 (Non-insulin Dependent Diabetes Mellitus), who had been regularly followed up in all General Outpatient Clinics (GOPCs) of Kowloon Central Cluster (KCC) from 1 October 2011 to 30 September 2013, and had blood lipid levels checked at least once during this period were recruited. In our clinics, blood and urine check-ups are usually carried out in patients with T2DM every 12 to 18 months. This 2-year retrieval period was therefore likely to cover all such patients regularly followed up in our cluster. The diagnosis of diabetes was based on the “Definition and description of diabetes mellitus” from American Diabetes Association (ADA) in 2013.23

The following patients were excluded: patients who had been incorrectly diagnosed with diabetes, type 1 diabetic patients, diabetic patients who had no regular blood or urine check-up during the study period, diabetic patients followed up in a specialist clinic, and patients who died during the study period.

Various studies and guidelines have recommended targets in the treatment of hyperlipidaemia. In the HA of Hong Kong, National Cholesterol Education Program Adult Treatment Panel III Guidelines (NCEP ATP III) and ADA guidelines were used to set up the manual for the risk assessment and management programme. In this study, we used the same set of guidelines to define the level of lipid control in T2DM patients. We focused on the control of LDL as it is the most important risk factor of the lipid profile.

According to NCEP ATP III 200224 and ADA 2013 Guidelines on Diabetes and Lipids,23 target LDL should be <2.6 mmol/L in diabetic patients without overt CVD and <1.8 mmol/L in diabetic patients with overt CVD. In this study, CVD is defined as established ischaemic heart disease (IHD), cerebrovascular accident (CVA), or peripheral vascular disease (PVD).

In this study, lipid control was defined as poor and escalation of treatment indicated if the last LDL level was ≥2.6 mmol/L in diabetic patients without CVD and ≥1.8 mmol/L in diabetic patients with established CVD. Consultation notes of the follow-up immediately after the last available lipid profile test were reviewed through the HA Clinical Management System (CMS). Therapeutic inertia was considered to be present when the attending doctor failed to initiate or intensify treatment if target LDL level was not achieved. If medical notes indicated a valid reason for non-escalation of treatment despite a clinical indication, it was not considered TI. Common justifications included:

(1) Diet and lifestyle modification advice was given to patients newly diagnosed with hyperlipidaemia.

(2) Statin was started following the previous visit and LDL level was improving.

(3) Patient was non-compliant with the existing statin regimen and advice on regular drug compliance was given.

(4) Patient refused to take a statin.

(5) Patient was unable to tolerate side-effects of statin.

(6) Statin was contra-indicated, eg in patients with deranged liver function.

According to the data drawn from Clinical Data Analysis and Reporting System of the HA, a total of 19 662 T2DM patients were attending GOPCs of KCC for regular follow-up with checking of blood lipid profile during the study period. Based on the definitions mentioned above, 9647 of them had suboptimal or poor LDL control. Using the internet sample size calculator (Survey Software from Creative Research System, http://www.surveysystem.com), a sample size of 369 would provide 95% confidence level and 5% margin of error. Thus, 400 patients were sampled to ensure adequate statistical power and allow room for case exclusion. A list of random numbers was then generated from the research randomiser (http://www.randomizer.org/form.htm), from which 400 patients were selected. Details of the visit with latest lipid profile result seen were recorded. Data were derived from the consultation notes in the CMS record of selected patients and recorded on a standard data collection form (Appendix). Data were collected by the principal investigator and counter-checked by another experienced doctor in the research team.

Age and gender of all patients as well as smoking status, body mass index (BMI), latest blood pressure, haemoglobin A1c (HbA1c) level, serum creatinine level, lipid profile, and urine albumin-to-creatinine ratio were retrieved from the CMS. The most recent blood or urine test was used for analysis if more than one test had been performed during the study period. The BMI was calculated as body weight/body height² (kg/m²). The patient was considered a smoker if he/she currently smoked or had stopped in the last 6 months.25 The abbreviated Modification of Diet in Renal Disease formula was used to calculate the estimated glomerular filtration rate.26

The working profile of the attending doctors was retrieved from the Central Office of Department of Family Medicine (FM) and GOPC, KCC. Duration of clinical practice was calculated as the number of years from registration with the Medical Council of Hong Kong. The training status of FM of doctors was documented and categorised according to the following criteria:

All data were entered and analysed using computer software (Windows version 21.0; SPSS Inc, Chicago [IL], US). Student’s t test and analysis of variance were used to analyse continuous variables and the Chi squared test for categorical data. Fisher’s exact test was used if the sample size was less than five. Multivariate stepwise logistic regression was used to determine the association between TI and the significant different variables from patient characteristics and doctor characteristics. All statistical tests were two-sided, and a P value of <0.05 was considered statistically significant.

The study protocol was reviewed and approved by the Research Ethics Committee of HA (Kowloon Central/Kowloon East Cluster) [Reference number: KC/KE-13-0247/ER-1].

A total of 21 960 T2DM patients were identified from the KCC GOPC Diabetes Mellitus registry from 1 October 2011 to 30 September 2013. Among them, 19 662 (89.5%) patients had their lipid profile checked at least once during the study period; 9647 (49.1%) cases had suboptimal lipid control based on the defined criteria above, including 1733 cases with co-existing CVD and 7914 cases without CVD.

Among 400 randomly sampled diabetic patients with suboptimal lipid control, 31 were excluded including 21 who were being followed up in other clinics for diabetic control, nine who died during the study period, and one who was wrongly diagnosed with diabetes. The remaining 369 cases were recruited for data analysis (Fig).

Table 1 summarises the demographic characteristics of the recruited patients. The mean (± standard deviation) age of the study population was 65.5 ± 11.9 years and 186 (50.4%) were female. The mean duration of diabetes was 9.1 ± 7.9 years. With regard to their co-morbidities, 306 (82.9%) patients had concomitant HT, 24 (6.5%) had IHD, 40 (10.8%) had CVA, and two (0.5%) had PVD. The mean LDL level was 3.12 ± 0.61 mmol/L and only 101 (27.4%) patients were prescribed a statin.

Table 2a summarises the demographic characteristics of the attending doctors. A total of 56 doctors, among whom 19 (33.9%) were female, attended the 369 diabetic patients. The mean duration of clinical practice was 13.6 ± 9.6 years. With regard to FM training status, 13 (23.2%) doctors had received no FM training, 18 (32.1%) received basic training or studied DFM, 13 (23.2%) were intermediate FM fellows, and 12 (21.4%) were FM specialists.

Subanalysis of attending doctors’ profile according to their duration of clinical practice and FM training status is shown in Table 2b. Training status of FM varied significantly with duration of clinical practice (P<0.001). Among 13 doctors who had worked for ≤5 years, all had been a basic FM trainee or had obtained a DFM. On the other hand, among 12 doctors who had worked for over 20 years, most (n=9, 75%) had not received any formal FM training.

Among the 369 recruited T2DM patients, treatment was escalated in 47 (12.7%). Justification for not intensifying treatment was provided in 78 (21.1%) cases. Justification was as follows: 19 patients were given dietary advice on lifestyle modifications as they were newly diagnosed with hyperlipidaemia; in 13 patients, a statin had been newly commenced at the previous visit and lipid level was lower compared with pretreatment; five patients were non-compliant with the existing treatment regimen and advice on compliance was given; 28 patients refused to start a statin despite medical advice; six patients had been unable to tolerate side-effects of statin. Statin therapy was contra-indicated in seven patients with impaired liver function. In the remaining 244 cases, TI was present with a prevalence rate of 66.1%.

Table 3 shows the characteristics of physicians in TI-positive and TI-negative patients. The duration of clinical practice of attending doctors was significantly longer in the TI group compared with the non-TI group (P=0.001), with doctors working for over 20 years having a particularly higher rate of TI (82.4%). Doctors without any FM training also had a higher rate of TI (77.7%; P=0.006).

Table 4 summarises the characteristics of T2DM patients in TI-positive and TI-negative groups. Patients in the TI-positive group had a longer duration of diabetes (9.8 ± 8.1 years in TI-positive group vs 7.8 ± 7.4 years in TI-negative group; P=0.024) and lower total cholesterol level and LDL level (both P<0.001). The co-existence of CVD (IHD, CVA, PVD) was more common in the TI-positive group (P=0.003). Other characteristics including patient gender, age, BMI, smoking status, blood pressure, HbA1c level, and type and dose of current statin use were comparable for both groups (all P>0.05).

Based on the results from Tables 3 and 4, multivariate stepwise logistic regression analysis was performed to identify any factors that contributed to TI (Table 5). Only variables that were significantly different in the univariate analysis were included in the regression model. As the FM training status varied significantly with the duration of clinical practice (Table 2b, P<0.001) and these two factors were interrelated, only one of these two variables was included in the logistic regression analysis. As the P value of FM training status (P=0.006) was smaller than that for years of clinical practice (P=0.007) in the univariate analysis (Table 3), FM training status was entered into the logistic regression analysis. Lack of FM training was positively associated with TI (odds ratio [OR]=2.170; P=0.008), whereas patient’s LDL level was inversely associated (OR=0.320; P=0.001).

This was the first clinical analysis of TI in lipid management among T2DM patients managed locally in the primary care setting. It has provided important background information about the prevalence of TI in this group of patients. It also explored possible underlying factors from both the doctor’s and patient’s perspective.

Our study found that lipid control among T2DM patients was far from satisfactory, with 49.1% suboptimally controlled. This is consistent with reports that a high proportion of patients with hyperlipidaemia do not achieve their LDL goal.27 28 It is important to note that TI was present in 66.1% of these cases, meaning that in over 60% of diabetic patients with dyslipidaemia, appropriate management including dietary advice or drug treatment was not provided. This relatively high TI rate should alert primary care physicians to the importance of lipid control among T2DM patients as greater TI leads to poorer clinical outcomes. A similar study carried out by Whitford et al29 has shown that TI was present in 80% of consultations when lipid control was addressed among diabetic patients managed in the primary care setting in Middle East countries. This rate was much higher than the TI in blood pressure control (68%) and glycaemic control (29%). A similar study of lipid management in high-risk patients at a large academic primary care practice in the US has shown that statin dose was augmented at only 16% of over 2000 patient visits where the patient was suboptimally controlled.30 Among the sampled 369 poorly controlled T2DM patients in this study, only 27.4% (n=101) were treated with simvastatin, which is the only statin available in Hong Kong GOPCs. In addition, most (74.3%, 75/101) were treated with a lower dose (5-10 mg daily) that is considered inadequate according to ATP-IV guidelines in which a moderate dose of statin, such as simvastatin 20-40 mg daily, is recommended for T2DM patients in order to achieve target LDL level.31 Thus, the low statin prescription rate and the inadequate dose of statin may together contribute to the suboptimal lipid control among T2DM patients in primary care.

A possible explanation for the TI in dose augmentation of simvastatin is the potential drug-drug interaction with calcium channel blockers (CCB) such as amlodipine.32 The maximum recommended dose for simvastatin in conjunction with amlodipine use is 20 mg/day. Since 306 (82.9%) sampled diabetic patients were found to have concomitant HT and among them 122 (40%) were prescribed amlodipine for blood pressure control, doctors might have hesitated to increase the dose of simvastatin. In our study, 10 diabetic patients in the TI-positive group were prescribed amlodipine and simvastatin 20 mg daily. In this scenario, either changing simvastatin to an alternative statin such as atorvastatin or changing amlodipine to an alternative CCB such as nifedipine is recommended if lipid control remains suboptimal. Failing to switch to another statin or CCB when clinically indicated is also considered to be TI. A more proactive approach to prescribing different drug combinations is required in order to achieve the target LDL in a timely manner.

Further studies of the physician profile relative to the presence of TI have revealed that doctors with longer duration of clinical practice have a higher rate of TI that is even more prominent in those with over 20 years’ clinical practice. These findings are contrary to an overseas study where more experienced doctors had a lower rate of TI33; nonetheless, this study was performed in a secondary care setting and involved cardiologists who managed hyperlipidaemia in patients with IHD. In our study, most doctors who had worked for over 20 years had no formal FM training (9 [75%] of 12 doctors; Table 2b). In addition, when training status was compared, doctors with no FM training had a higher rate of TI than those who had completed FM training (77.7% vs 60.0%; P=0.006). We postulate that doctors who have worked for over 20 years may be less familiar with the latest guidelines on lipid management, possibly due to a lack of FM or related training. If physicians lack appropriate training, there will be gaps in their knowledge of latest clinical management guidelines. This has been confirmed by review articles which showed that TI could be attributed to insufficient knowledge of guidelines.34

When patient’s profile was compared, surprisingly, TI was present in 51 of 62 diabetic patients with overt CVD, and only 11 cases were properly managed (Table 4). This is a considerable concern since lipid control is particularly important and as a secondary prevention strategy in this group of patients. The target for LDL control is much more stringent at <1.8 mmol/L in this group of patients, and more difficult to achieve clinically. Some doctors may not have been aware of this stricter/lower LDL target and have been satisfied with LDL level of 1.8 to 2.6 mmol/L. This is supported by our finding that among diabetic patients with overt CVD whose lipid profile was inadequately controlled (n=62), more than half (n=33, 53.2%) had LDL controlled at 1.8 to 2.6 mmol/L. Physicians should take a more proactive approach particularly in this high-risk group of patients and adhere closely to the prevailing management guidelines in CVD risk factor control.

Multiple variable logistic regression analysis revealed that patients with lower LDL or LDL level closer to normal was associated with TI (Table 5). This could be explained by the threshold effect, that is, the closer the LDL level is to target level, the less likely is the doctor to intensify treatment. This threshold effect has been commonly observed in other similar studies.30 35 Other factors that contribute to the threshold effect could be ‘overestimation of current care’ or ‘complacency with borderline values’, leading to the physician’s subjective misperception that the care provided is sufficient.34

Our study found that TI was common in lipid management among diabetic patients managed in the GOPCs of KCC, with a prevalence of 66.1%. Doctors with a longer duration of clinical practice and who had not received formal FM training had a higher rate of TI. Patients with a closer-to-target LDL were more common in the TI group. Considering that a large volume of diabetic patients are managed in the primary care setting, comprehensive strategies with a more proactive approach should be devised to combat TI so that the cardiovascular outcome of diabetic patients can be improved.

This is the first clinical analysis of TI in lipid management among diabetic patients managed locally in the primary care setting. It has provided important background information about the prevalence of TI in lipid management among diabetic patients and explored the possible underlying factors from both the doctor’s and patient’s perspective. These findings will help improve strategies to overcome TI in lipid control for these patients.

There are some limitations in this study. First, the study was carried out in one single cluster of HA and therefore selection bias might exist. These results from the public primary health care sector might not be applicable to the private sector or secondary care. In addition, the number of doctors with or without FM training was quite discrepant in this study (43 vs 13) and may affect the generalisation of findings. Nevertheless, the present results may lay the groundwork for similar studies in the future, both locally and internationally. Second, patients with diabetes who had not had any blood testing performed during the study period were excluded (n=2298, 10.5% of all diabetic cases). The lipid control status of this group of diabetic patients remained unknown. This might bias the accurate measurement of TI among our target population. Third, only TI in LDL management was explored in this study. Management of hypertriglyceridaemia was not addressed in view of its less-important role as a risk factor for CVD. Future studies exploring the TI in hypertriglyceridaemia management are needed to comprehensively assess lipid control among diabetic patients. Lastly, this study relied heavily on review of consultation notes to identify justification for submaximal therapy and determine presence of TI. Insufficient justification for a certain treatment may have resulted in an overestimation of the prevalence of TI.

This study found that TI was common in the lipid management of diabetic patients managed in GOPCs of KCC, with a prevalence rate of 66.1%. Doctors without FM training and a closer-to-target LDL level among T2DM patients were associated with the presence of TI. Comprehensive strategies should be devised to overcome TI so that the cardiovascular outcome of diabetic patients can be improved.

We are indebted to Ms Katherine Chan, statistical officer of Queen Elizabeth Hospital, for her expert statistical support in the data analysis.

Additional material related to this article can be found on the HKMJ website. Please go to <http://www.hkmj.org>, and search for the article.

All authors have disclosed no conflicts of interest.

1. Chan JC, Malik V, Jia W, et al. Diabetes in Asia: epidemiology, risk factors, and pathophysiology. JAMA 2009;301:2129-40. Crossref

2. Leung GM, Lam KS. Diabetic complications and their implications on health care in Asia. Hong Kong Med J 2000;6:61-8.

3. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004;364:685-96. Crossref

4. Collins R, Armitage J, Parish S, Sleigh P, Peto R; Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003;361:2005-16. Crossref

5. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348:383-93. Crossref

6. Waters DD, Ku I. Early statin therapy in acute coronary syndromes: the successful cycle of evidence, guidelines, and implementation. J Am Coll Cardiol 2009;54:1434-7. Crossref

7. Ward S, Lloyd Jones M, Pandor A, et al. A systematic review and economic evaluation of statins for the prevention of coronary events. Health Technol Assess 2007;11:1-160,iii-iv. Crossref

8. O’Regan C, Wu P, Arora P, Perri D, Mills EJ. Statin therapy in stroke prevention: a meta-analysis involving 121,000 patients. Am J Med 2008;121:24-33. Crossref

9. Vrecer M, Turk S, Drinovec J, Mrhar A. Use of statins in primary and secondary prevention of coronary heart disease and ischemic stroke. Meta-analysis of randomized trials. Int J Clin Pharmacol Ther 2003;41:567-77. Crossref

10. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ 2003;326:1423. Crossref

11. Fung CS, Chin WY, Dai DS, et al. Evaluation of the quality of care of a multi-disciplinary risk factor assessment and management programme (RAMP) for diabetic patients. BMC Fam Pract 2012;13:116. Crossref

12. Kung K, Chow KM, Hui EM, et al. Prevalence of complications among Chinese diabetic patients in urban primary care clinics: a cross-sectional study. BMC Fam Pract 2014;15:8. Crossref

13. Kotseva K, Wood D, De Backer G, De Bacquer D, Pyörälä K, Keil U; EUROASPIRE Study Group. Cardiovascular prevention guidelines in daily practice: a comparison of EUROASPIRE I, II, and III surveys in eight European countries. Lancet 2009;373:929-40. Crossref

14. Toth PP, Zarotsky V, Sullivan JM, Laitinen D. Dyslipidemia treatment of patients with diabetes mellitus in a US managed care plan: a retrospective database analysis. Cardiovasc Diabetol 2009;8:26. Crossref

15. Ferrières J, Gousse ET, Fabry C, Hermans MP; French CEPHEUS Investigators. Assessment of lipid-lowering treatment in France—the CEPHEUS study. Arch Cardiovasc Dis 2008;101:557-63. Crossref

16. Kotseva K, Stagmo M, De Bacquer D, De Backer G, Wood D; EUROASPIRE II Study Group. Treatment potential for cholesterol management in patients with coronary heart disease in 15 European countries: findings from the EUROASPIRE II survey. Atherosclerosis 2008;197:710-7. Crossref

17. Santos RD, Waters DD, Tarasenko L, et al. Low- and high-density lipoprotein cholesterol goal attainment in dyslipidemic women: The Lipid Treatment Assessment Project (L-TAP) 2. Am Heart J 2009;158:860-6. Crossref

18. Kim HS, Wu Y, Lin SJ, et al. Current status of cholesterol goal attainment after statin therapy among patients with hypercholesterolemia in Asian countries and region: the Return on Expenditure Achieved for Lipid Therapy in Asia (REALITY-Asia) study. Curr Med Res Opin 2008;24:1951-63. Crossref

19. Phillips LS, Branch WT, Cook CB, et al. Clinical inertia. Ann Intern Med 2001;135:825-34. Crossref

20. Okonofua EC, Simpson KN, Jesri A, Rehman SU, Durkalski VL, Egan BM. Therapeutic inertia is an impediment to achieving the Healthy People 2010 blood pressure control goals. Hypertension 2006;47:345-51. Crossref

21. Andrade SE, Gurwitz JH, Field TS, et al. Hypertension management: the care gap between clinical guidelines and clinical practice. Am J Manag Care 2004;10:481-6.

22. O’Connor PJ, Sperl-Hillen JM, Johnson PE, Rush WA, Biltz G. Clinical inertia and outpatient medical errors. In: Henriksen K, Battles JB, Marks ES, Lewin DI, editors. Advances in patient safety: from research to implementation. Vol 2: Concepts and methodology. Rockville (MD): Agency for Healthcare Research and Quality (US); 2005.

23. American Diabetes Association. Standards of medical care in diabetes—2013. Diabetes Care 2013;36 Suppl 1:S11-66. Crossref

24. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002;106:3143-421.

25. Centers for Disease Control and Prevention (CDC). Smoking-attributable mortality, years of potential life lost, and productivity losses—United States, 2000-2004. MMWR Morb Mortal Wkly Rep 2008;57:1226-8.

26. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;130:461-70. Crossref

27. Park JE, Chiang CE, Munawar M, et al. Lipid-lowering treatment in hypercholesterolaemic patients: the CEPHEUS Pan-Asian survey. Eur J Prev Cardiol 2012;19:781-94. Crossref

28. Khoo CM, Tan ML, Wu Y, et al. Prevalence and control of hypercholesterolaemia as defined by NCEP-ATPIII guidelines and predictors of LDL-C goal attainment in a multi-ethnic Asian population. Ann Acad Med Singapore 2013;42:379-87.

29. Whitford DL, Al-Anjawi HA, Al-Baharna MM. Impact of clinical inertia on cardiovascular risk factors in patients with diabetes. Prim Care Diabetes 2014;8:133-8. Crossref

30. Goldberg KC, Melnyk SD, Simel DL. Overcoming inertia: improvement in achieving target low-density lipoprotein cholesterol. Am J Manag Care 2007;13:530-4.

31. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults, Journal of the American College of Cardiology 2013. Available from: https://www.joslin.org/docs/2013-ACC-AHA-Guideline-Treatment-of-Blood-Cholestero-_to-Reduce-Atherosclerotic-Cardiovascular-Risk-in-Adults.pdf. Accessed Mar 2016.

32. Simvastatin summary of product characteristics. Available from: http://www.medicines.org.uk/emc/medicine/1201/SPC. Accessed Mar 2016.

33. Aujoulat I, Jacquemin P, Rietzschel E, et al. Factors associated with clinical inertia: an integrative review. Adv Med Educ Pract 2014;5:141-7. Crossref

34. Byrnes PD. Why haven’t I changed that? Therapeutic inertia in general practice. Aust Fam Physician 2011;40:24-8.

35. Berlowitz DR, Ash AS, Glickman M, et al. Developing a quality measure for clinical inertia in diabetes care. Health Serv Res 2005;40:1836-53. Crossref

Hong Kong has experienced a tremendous change in lifestyle and the consequent clinical problems pose a challenge to the medical profession. A good example of this is infant feeding. Almost half a century ago, the prevalence of breastfeeding in Hong Kong was at its lowest rate of 5% in 1978 after a dramatic fall from 44% in 1967.1 Following the joint efforts of doctors, nurses and mothers, the prevalence of the ever breastfeeding rate in Hong Kong has rapidly climbed from 20% in 1992 to 60% in 2002 and 86% in 2014.2 The efforts of both the UNICEF Baby-Friendly Hospital Initiative and the Department of Health should be applauded.

Breast milk is the best for babies. Mothers should be encouraged to breastfeed fully for 6 months, followed by introduction of solid foods and continuation of breastfeeding for 2 years or more. Recent data have shown that only 27% of mothers can sustain breastfeeding for 4 to 6 months.2 There are areas where we, as medical professionals, can provide support. For historical reasons, however, not many local doctors and nurses have been trained to manage the clinical problems encountered by breastfeeding mothers. One such problem is breast pain.

Breast pain, which may lead to cessation of breastfeeding, is the most common complaint of lactating mothers seen in a private general paediatric clinic run by a doctor (author) trained in 2000 as an International Lactation Consultant. This study aimed to analyse the reasons for breast pain and how it can be relieved.

Clinical records of lactating mothers who presented with breast pain over a 6-month period (January to June 2015) were retrieved. Patients were self-referred after chatting online with other breastfeeding mothers. During consultation, patients were asked about the history of pain, prior treatment, breastfeeding practices, and their own diet. Breast examination was then performed, including the nipple and areola, to identify any redness or tenderness. In particular, any blockage was identified.

If redness or tenderness was generalised in either or both breasts, it was diagnosed as engorgement (Fig a). If it was confined to a segment, this implied only a lobule was involved. If gentle massage and milk expression provided relief, a blocked duct was diagnosed (Fig b). The ability to express pus (Fig c) or an area of fluctuation or skin thinning (Fig d) was indicative of breast abscess. Mastitis was diagnosed in the presence of fever and tenderness/mass that could not be relieved but had not progressed to an abscess.3 Nipples were examined for cracks (Fig e). Feeding position and latch were checked when appropriate and corrected accordingly. When there was a white spot in the nipple, it was cleared by simple expression or by using a needle to open up the blockage. If there was a shinny reddish colour of the nipple and areola together with burning, stinging, and itchiness then fungal infection was diagnosed. In such case, the baby’s mouth was also examined for the presence of oral thrush.

A total of 69 patients were seen of whom 45 had been breastfeeding for more than 1 month. All except six were in their 30s. The age of the baby was less than 1 month in 24 (35%) women, 1 to 6 months in 27 (39%), and over 6 months in 18 (26%). Only 13 (19%) used complementary infant milk formula.

Breast pain was present for less than 3 days in 35 (51%) women but for longer in the remaining 34 (49%). Pain duration exceeded 7 days in 22 (32%); 15 (22%) of whom had intermittent pain for 14 to 30 days. In 31 (45%) patients, earlier treatment had been received from various sources including Maternal and Child Health Centres (MCHCs), family doctors, general practitioners, obstetricians, doctors at an accident and emergency department, surgeons in a breast surgery clinic, or lactation consultants. Antifungal or antibacterial medication, either local or systemic, was prescribed.

Apart from breast pain, there were other additional complaints: nipple pain in eight (12%) women, sharp needle pain after feeding in eight (12%), white spot at nipple in 15 (22%), and fever in 14 (20%). All had decreased milk production by the affected breast despite frequent feeding or pumping.

The following diagnoses were made: nipple cracks (n=2), poor positioning and latch (n=7), engorgement (n=5), blocked duct (n=35), mastitis (n=13), breast abscess (n=6), and skin infection (n=1). One had all pus drained via the milk duct. Another had pus formed in the sebaceous gland at the areola and was fully drained. The remaining four were referred to a surgeon for further management. Oral antibiotics were prescribed to 21 (30%) women. Fungal infection was suspected in only one woman. Clinical details of four patients chosen for illustration are shown in the Table.

Subjects in this study represent mothers who were very dedicated to breastfeeding. Most had been breastfeeding for more than 1 month and had not given up, despite experiencing pain for quite a number of days.

Blocked duct was the most common cause of breast pain in this study group. Delay in diagnosing and treating a blocked duct can lead to a more serious condition of mastitis and breast abscess.

Engorgement, blocked duct, mastitis, and breast abscess reflect progression from a common original problem of inadequate drainage that can be due to poor positioning and latching, inadequate emptying, or overproduction.3 Obtaining a good history, performing a thorough breast examination, and milk expression can help to make the diagnosis.

Engorgement usually involves the whole breast whereas a blocked duct involves a lobule. In the latter, redness and tenderness are apparent and examination of the areola may reveal a tender swelling representing a blockage of the duct near the opening. Gentle massage and milk expression will relieve the pain and tenderness. A simple blocked duct can be relieved immediately. Nonetheless, when the swelling can only be partially relieved, it may represent tissue inflammation indicative of mastitis. Mothers were encouraged to feed more often on the affected breast. If this failed after one or two feeds, antibiotics were prescribed to prevent progression to breast abscess.

Milk is a very good medium for bacterial culture. Stasis of milk for too long may lead to infection (mastitis) and pus formation (abscess). The common guideline is to relieve a blocked duct as soon as possible, especially in the presence of fever. Once fever has persisted for longer than 24 hours, antibiotics are required. In one woman in this study, however, breast abscess was evident within the first few hours of fever and in another woman without fever, thus fever should be considered a non-specific sign. Clinical assessment was the most important. The ratio of breast abscess to mastitis was higher in this series (46.2%) compared with that reported in the literature (11.1%).3 This may have been due to a difference in sampling methods or different diagnostic criteria for mastitis. The difference between a blocked duct and mastitis can be very subtle. Presence of redness and tenderness in the breast with little effort to clear the blockage may be classified as mastitis. What is of more concern is the possible delay in management that allows untreated mastitis to progress to breast abscess. An abscess can be drained through the duct manually, but needle aspiration under ultrasound guidance or incision may be required in some cases. If there is an incision, the wound must be left open for continuous drainage and the mother may be forced to stop breastfeeding.

Since most of these infections are due to Staphylococcus aureus, Streptococcus, or Escherichia coli, antibiotics chosen should be amoxicillin with clavulanate, cloxacillin, or cefuroxime; all of which are compatible with continuation of breastfeeding.3

Nipple pain may indicate a blocked duct because the duct beneath the areola is swollen. There should be some tenderness although not as much as that of the affected breast lobule. After relief of the blockage, nipple pain will resolve.

A white spot at the nipple may also indicate a blocked duct. Blockage of a lobule and then stasis of milk at the opening of the duct can lead to further blockage by milk that has a high fat or high calcium content. This spot will be white in colour, sometimes referred to as a bleb. It can be removed by milk expression, needle or local application of vegetable oil. This should not be confused with thrush.

Concern has already been raised about the general overdiagnosis of fungal infection as a cause of breast pain, nipple pain, or white spot.4 Patients treated for a presumed ‘yeast infection’ might have shown improvement in symptoms as a result of the anti-inflammatory effect of the antifungal drugs or because the blocked duct resolved on its own. Fungal infection of the breast and nipple may be considered if a blocked duct has been excluded and is often associated with other risk factors. Examples are consuming a diet with high sugar content that promotes growth of fungus, mother having received antibiotics, a maternal history of vaginal candidiasis, or baby’s oral mucosa with thrush.4 All these risk factors were not found in any of the mothers in this study. Excruciating pain after a feed is a non-specific sign. It is more likely to be due to a blocked duct or inadequate emptying of the breast, as shown in this study. These patients had failed to improve after being given local or systemic antifungal treatment in their previous consultations prior to presentation to this clinic. Pain was relieved only after the blocked duct was cleared.

There was a general misunderstanding among the lactating mothers that eating more animal foods could improve milk supply. Previous studies have shown that the protein intake of local lactating mothers is much higher than that of those in other countries. At 3 months postpartum, Hong Kong mothers had a protein intake of 98 g/day5 compared to 81 g/day in the UK6 and 80 g/day in Japan.7 In the first month after delivery (known locally as the confinement period), the protein intake was even higher (133 g/day)5 than at 3 months. During this month, local mothers usually consume a special diet consisting of much more pork, fish, chicken, egg, and milk.

The practice of eating a special diet with additional animal foods during confinement may be unique to Hong Kong Chinese population and is likely a long Chinese tradition. The original rationale was to replenish the blood loss of childbirth and may have been necessary at a time when the general population had barely enough food. Prior to the 1960s, our ancestors usually ate a plant-based diet, with pork available only in the Chinese New Year or during some festivals. There was very little over-nutrition. Time has changed. The diet of adults today is generally high in animal protein8 and fat. Further increase will lead to new clinical problems, not just weight gain in mothers but also increased risk of blockage and inflammation in breastfeeding mothers. A diet that contains much more meat has been shown to be associated with higher inflammatory index scores9 and one of these is C-reactive protein.10

The quantity and quality of fat in breast milk can be affected by the fat in the maternal diet. Lactating mothers in Chongqing (a major city in Southwest China) consumed a diet wherein fat came from lard. Total fat in the breast milk was higher in Chongqing: 38 g/L compared with 32 g/L in Hong Kong.11 Chongqing mothers did not appear to have problems of blocked ducts or mastitis. Thus, a high-fat diet per se may not cause mastitis, it is the quality of fat that matters. Mothers who consume a diet high in saturated fat may be more prone to duct blockage.3 Mothers with a recurrent blocked duct were often advised to change their diet to one with more polyunsaturated fat or use a supplement, lecithin.3 A dietary source of lecithin is mainly soy or eggs. It would appear to be a good practice for lactating mothers in Chongqing to eat lots of eggs. However, in view of the possibility of egg allergy, Hong Kong mothers may be better advised to eat more soy products. Mothers in this study group appeared to eat very few soy products.

High milk production together with inadequate emptying definitely poses a problem. Many Hong Kong mothers took both Chinese remedies (herbs, fish soups) and drank western teas (eg fenugreek) to increase milk production. Nearly all breastfeeding mothers had a breast pump. Some mothers pumped milk more often to produce an excess for later use. Indeed quite a number of the studied mothers had plenty of stored milk in their refrigerator. Working mothers may have stopped pumping during weekends. Such irregular breast emptying may cause the problem of milk stasis. The presence of fatigue, stress, and an imbalanced diet can encourage inflammation that can easily progress to mastitis. Recurrence of blocked duct/mastitis may occur if the mother’s diet and practice of feeding or pumping are not corrected.

A diet rich in white sugar or corn syrup, pastries, and cakes can enhance the growth of fungus but was generally not observed in our subjects. This may explain why fungal infection was rare. A natural well-balanced diet with whole grains, plenty of vegetables and fruits, and no excessive animal products should be recommended. Refined sugary foods, foods with chemicals, colouring agents, and preservatives should be avoided.

A substantial number of nurses had passed the examination that qualified them as an International Lactation Consultant. They worked mainly in the maternity wards of hospitals and MCHCs in Hong Kong. They were very successful in initiating breastfeeding. Some hospitals ran a breastfeeding clinic to support mothers after discharge from the maternity ward but they were not available round the clock. Most mothers with breastfeeding problems attended a MCHC to seek for help. Other mothers chose to see their family doctors. In general, doctors had little training in dealing with problems related to breastfeeding. In 2011, the Department of Health produced a self-learning kit on breastfeeding for any doctor who was interested, but it is difficult for the public to identify such doctors.

Breast pain can sometimes be unbearable. Some patients described it as worse than labour pain. It is unknown from this study how many mothers had stopped breastfeeding because of the pain or how many ended up in hospital with a high fever and abscess that required surgery. Many patients in this study stated that after earlier treatment failed, they had no idea where else to seek further help. Others hesitated to seek medical help because they were afraid they would be told to stop breastfeeding. The mothers in this study were perhaps exceptional. They had tried very hard to find a solution for their pain even though it might have taken a number of days. These mothers deserve a better medical service. The Secretary for Food and Health has stated that the government is very supportive of breastfeeding and is ready to collaborate with health care professional bodies or non-governmental organisations in training personnel and promoting breastfeeding.12 Setting up breastfeeding clinics is the correct approach. These clinics can be run by MCHCs or a Baby-Friendly Hospital and should be full time and open to all. Doctors and lactation consultants can accumulate clinical experience faster and can then act as professional trainers. There is also a need for more local research on the diet and health of lactating mothers, especially those in confinement, so that appropriate education can be delivered to doctors, lactation consultants, midwives, peer counsellors, confinement nannies, and the public.

This study was limited by its retrospective nature. There was a lack of standard protocols for data recording and retrieval. Not all women were followed up to determine if they had completely recovered since it is difficult to do so in a private clinic. What is certain is that those with engorgement and a blocked duct felt immediate relief the moment they left the clinic. It is also quite possible that many cases of breast pain were treated by other doctors and lactation consultants. The data of this study may thus not be representative of Hong Kong in general.

Blocked duct was the most common cause of breast pain in lactating mothers. Without prompt relief it may progress to mastitis/breast abscess or the mother may choose to stop breastfeeding. It may be a suitable time for Hong Kong to set up one or more public full-time breastfeeding clinics in order to provide a better service for lactating mothers and to facilitate professional training and research.

The author has disclosed no conflicts of interest.

1. Baber FM. The current situation in Hong Kong. Hong Kong Pract 1981;5:132-7.

2. Baby-Friendly Hospital Initiative Hong Kong Association. Available from: http://www.babyfriendly.org.hk/en/breastfeeding-in-hk/breastfeeding-trend/. Accessed Feb 2016.

3. Lawrence RA, Lawrence RM. Breast feeding: a guide for the medical profession. 5th ed. St Louis: Mosby; 1999: 273-83.

4. Wilson-Clay B, Hoover K. The breastfeeding atlas. 5th ed. US: LactNews Press; 2013: 57-8.

5. Chan SM, Nelson EA, Leung SS, Cheng JC. Bone mineral density and calcium metabolism of Hong Kong Chinese postpartum women—a 1-y longitudinal study. Eur J Clin Nutr 2005;59:868-76. Crossref

6. Black AE, Wiles SJ, Paul AA. The nutrient intakes of pregnant and lactating mothers of good socio-economic status in Cambridge, UK: some implications for recommended daily allowances of minor nutrients. Br J Nutr 1986;56:59-72. Crossref

7. Takimoto H, Yoshiike N, Katagiri A, Ishida H, Abe S. Nutritional status of pregnant and lactating women in Japan: a comparison with non-pregnant/non-lactating controls in the National Nutrition Survey. J Obstet Gynaecol Res 2003;29:96-103. Crossref

8. Leung SS, Woo J, Ho S, Lam TH, Janus ED. Hong Kong dietary survey. Aust J Nutr Diet 1988;55(Suppl):S11-4.

9. Morimoto Y, Beckford F, Cooney RV, Franke AA, Maskarinec G. Adherence to cancer prevention recommendations and antioxidant and inflammatory status in premenopausal women. Br J Nutr 2015;114:134-43. Crossref

10. Turner-McGrievy GM, Wirth MD, Shivappa N, et al. Randomization to plant-based dietary approaches leads to larger short-term improvements in Dietary Inflammatory Index scores and macronutrient intake compared with diets that contain meat. Nutr Res 2015;35:97-106. Crossref

11. Chen ZY, Kwan KY, Tong KK, Ratnayake WM, Li HQ, Leung SS. Breast milk fatty acid composition: a comparative study between Hong Kong and Chongqing Chinese. Lipids 1997;32:1061-7. Crossref

12. Hong Kong Paediatric Society, Hong Kong Paediatric Foundation. Summit on Breastfeeding and Early Childhood Nutrition in the First 1000 Days 2015; Abstract: 18.

With ageing of the world’s population, the prevalence of dementia increases: 46.8 million people worldwide were living with dementia in 2015. This is projected to reach 74.7 million in 2030 and 131.5 million in 2050, with 60% suffering from Alzheimer’s disease (AD).1 In Hong Kong, the prevalence of mild dementia has been reported to be 8.9% for adults aged 70 years or over, with 64.6% suffering from AD.2 Appropriate management of demented patients begins with correct diagnosis of dementia subtype that allows earlier implementation of disease-specific treatment. In particular, cholinesterase inhibitors (ChEIs) or N-methyl-D-aspartate receptor antagonists are mostly suitable for the treatment of AD. The current clinical diagnostic guidelines for various types of dementia have limited sensitivities and specificities, however. The sensitivity and specificity of clinical diagnostic criteria for AD, dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD) have been reported as 81% and 70%, 50% and 80%, 85% and 95%, respectively.3 4 5 6 In the most recent diagnostic criteria for AD, additional use of biomarkers of AD has been recommended by the National Institute on Aging and Alzheimer’s Association to improve the accuracy of AD diagnosis.3 Biomarkers for the diagnosis of AD include cerebrospinal fluid (CSF), amyloid pathological imaging (eg carbon 11–labelled Pittsburgh compound B [¹¹C-PIB] positron emission tomography [PET]), and functional imaging (eg [¹⁸F]-2-fluoro-2-deoxy-D-glucose [¹⁸F-FDG] PET) that yield sensitivities and specificities of at least 90% and 85%, respectively in the diagnosis of AD, DLB, and FTD.3 7 8 9 10 11 Because of the invasive nature of lumbar puncture in the collection of CSF, neuroimaging modalities such as ¹⁸F-FDG PET and ¹¹C-PIB PET are more accepted in routine clinical practice to improve the diagnosis of dementia subtype.

The most common functional neuroimaging is with ¹⁸F-FDG12 and the most common pathological neuroimaging is with ¹¹C-PIB.13 These molecular imaging markers are imaged using PET. The ¹⁸F-FDG measures metabolic activity of the brain; ¹⁸F-FDG PET distinguishes well between AD and non-AD dementia.11 In a systematic review, the sensitivity and specificity for ¹⁸F-FDG PET in distinguishing between AD and DLB was 83%-99% and 71%-93%, respectively; and the sensitivity and specificity for ¹⁸F-FDG PET in distinguishing between AD and FTD was 97.6%-99% and 65%-86%, respectively.11 In the same systematic review, ¹⁸F-FDG PET predicted patients with mild cognitive impairment (MCI) deteriorating into dementia with sensitivity and specificity of 81%-82% and 86%-90%, respectively.11 Besides, ¹¹C-PIB can detect the presence of fibrillar amyloid plaques that are a neuropathological marker of AD.13 Correlation studies with neuropathology have shown a sensitivity of 90% and specificity of 100%; ¹¹C-PIB can reasonably distinguish AD from other types of dementia, eg FTD.13 Using neuropathology as the gold standard, the sensitivity and specificity was 89% and 83%, respectively.13 The presence of ¹¹C-PIB retention also predicts the progression of patients with MCI: 50% progress to AD in 1 year and 80% progress to AD within 3 years.14

Previous studies with ¹⁸F-FDG and ¹¹C-PIB PET have focused on highly selected diagnostic groups, and only a few studies have studied their impact in the routine clinical setting of a memory clinic at a tertiary university hospital. The latter are referral centres, and often encounter patients with complicated diagnostic issues. Ossenkoppele et al15 reported a cohort of 145 patients who underwent ¹⁸F-FDG and ¹¹C-PIB PET after clinical assessment. Change in clinical diagnosis was required in 23% with the diagnostic confidence increased from a mean of 71% to 87%. Diagnosis remained unchanged in 96% after PET over the next 2 years.15 In seven patients with MCI and positive amyloid deposition on ¹¹C-PIB PET, six progressed to AD during follow-up (5 had AD pattern of hypometabolism on ¹⁸F-FDG PET).15 In a retrospective study of 94 patients with MCI or dementia, Laforce et al16 showed that ¹⁸F-FDG PET brain scan led to a change in diagnosis in 29% of patients, and reduced the frequency of atypical or unclear diagnoses from 39.4% to 16%.

To the best of our knowledge, there are no published data on the impact of molecular neuroimaging on accuracy of diagnosis of AD or other dementias in the Chinese population. We hypothesised that brain ¹⁸F-FDG with or without ¹¹C-PIB PET imaging can improve the accuracy of diagnosis of common dementia subtypes in a memory clinic. The objective of this study was to investigate the impact of brain ¹⁸F-FDG with or without ¹¹C-PIB imaging in improving the accuracy of diagnosis of dementia subtype in a local memory clinic in Hong Kong.

This was a retrospective study conducted at the Memory Clinic of Queen Mary Hospital, the University of Hong Kong. Patients were referred by general practitioners, neurologists, geriatricians, surgeons, or psychiatrists. All patient records between January 2007 and December 2014 were reviewed. Inclusion criteria were a clinical diagnosis of MCI, dementia of any type, or unclassifiable dementia; and ¹⁸F-FDG with or without ¹¹C-PIB PET performed within 3 months after the initial clinical diagnosis. The initial clinical assessment was performed by a geriatrician experienced in dementia care and included detailed history taking from primary carers of the patient, physical examination, cognitive assessment, and laboratory studies (including thyroid function test, vitamin B₁₂ level, folate level, and syphilis serology [Venereal Disease Research Laboratory]). Clinical criteria for AD, FTD, DLB, and vascular dementia (VaD) were employed to establish the clinical diagnosis initially, without using any biomarker. The diagnosis of different dementia subtype before neuroimaging was based on the respective diagnostic guidelines. Patients with AD were diagnosed according to the NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer’s Disease and Related Disorders Association) diagnostic criteria.17 Patients with DLB were diagnosed by the McKeith criteria.4 Behavioural variant (bv) of FTD was diagnosed by revised diagnostic criteria reported by the International bvFTD Criteria Consortium5 and language variant of FTD was diagnosed by latest published criteria.6 Patients with VaD were diagnosed according to the criteria of the NINDS-AIREN (National Institute of Neurological Disorders and Stroke/Association Internationale pour la Recherche et l’Enseignement en Neurosciences).18 In this study, we reviewed the medical records of eligible subjects and collected data including age, sex, education level, Mini-Mental State Examination score, Clinical Dementia Rating scale score, molecular imaging report including the standardised uptake value ratio (SUVR) of ¹¹C-PIB PET, and the pre- and post-imaging diagnoses. For patients who were diagnosed with MCI, their progression during subsequent follow-up visits was also reviewed.

The need for ¹⁸F-FDG with or without ¹¹C-PIB PET was determined by the geriatrician who performed the initial clinical assessment. The images were evaluated by a radiologist with more than 10 years of experience in reading PET scans. Dementias were classified using the generally accepted criteria. Patients were fasted for at least 4 hours before the PET. The serum glucose level was measured in all patients. For ¹⁸F-FDG PET, the patient was rested in a dimly lit room with eyes closed for 30 minutes prior to injection of ¹⁸F-FDG via a venous catheter. Another 30 minutes of rest was observed before starting the acquisition. The acquired data were semi-quantitatively compared with age-stratified normal controls using three-dimensional stereotactic surface projections. For PIB imaging, acquisition was performed at 5 minutes and 35 minutes after ¹¹C-PIB injection via a venous catheter, and SUVR images of ¹¹C-PIB between 5 and 35 minutes were generated. Cerebellar grey matter was chosen as reference tissue. In this study, ¹¹C-PIB PET scans were rated as positive (PIB+; if binding occurred in more than one cortical brain region; ie frontal, parietal, temporal, or occipital) or negative (PIB–; if predominantly white matter binding).

The pattern of ¹⁸F-FDG PET hypometabolism that is suggestive of each subtype of dementia is as follows6 12 19:

(1) AD—uni- or bi-lateral parietotemporal hypometabolism with posterior cingulate gyrus involvement or bilateral parietal and precuneal hypometabolism.

(2) DLB—same as AD with added hypometabolism in occipital lobes.

(3) bvFTD—uni- or bi-lateral frontotemporal hypometabolism with or without less-severe parietal hypometabolism.

(4) Semantic dementia—anterior temporal lobe hypometabolism.

(5) Progressive non-fluent aphasia—left posterior frontoinsular hypometabolism.

(6) VaD—well-defined focal defects not fitting the above described patterns.

Descriptive statistics were used for data analyses. Continuous variables were expressed as mean ± standard deviation or median (interquartile range) as appropriate. Categorical data were expressed as number and percentages. The agreement between pre- or post-imaging diagnoses of dementia subtype was analysed by the Cohen’s kappa (κ) statistic. The Cohen’s κ reflected the degree of agreement: <0 = no agreement, 0-0.20 = slight agreement, 0.21-0.40 = fair agreement, 0.41-0.60 = moderate agreement, 0.61-0.80 = substantial agreement, and 0.81-1.00 = almost perfect agreement. All analyses were performed with the Statistical Package for the Social Sciences (Windows version 18.0; SPSS Inc, Chicago [IL], US).

A total of 109 patients (56.9% were female) were recruited of whom 102 had dementia and seven had MCI. Both ¹⁸F-FDG and ¹¹C-PIB PET data were available for 45 (41.3%) patients, and 64 patients underwent ¹⁸F-FDG only. The final diagnosis of the 102 demented patients after neuroimaging is shown in Table 1.

The accuracy of clinical diagnoses is summarised in Table 2. Overall, PET scans confirmed the clinical impression in 63.7% of patients, and corrected the diagnosis in 36.3%. Using the result of PET scan as the gold standard, the frequency of accurate initial clinical diagnosis was low for FTD, VaD, and mixed dementia (14.3%, 28.6%, and 0%, respectively). The accuracy of clinical diagnosis for AD and DLB was 81.5% and 44.4%, respectively. After excluding subjects with an initial MCI diagnosis, the agreement between the initial and final post-imaging dementia diagnosis was only fair, with a Cohen’s κ of 0.25 (95% confidence interval, 0.05-0.45).

Table 3 lists the diagnosis of subjects before and after the availability of ¹⁸F-FDG with or without ¹¹C-PIB PET neuroimaging. For subjects with a final diagnosis of AD (n=65), 18.5% (n=12) were initially diagnosed with non-AD dementia (including 3 with DLB, 2 with FTD, 4 with VaD, and 3 with other dementia) and subsequently received symptomatic AD therapy (ie ChEIs and/or memantine). For the 21 subjects who underwent PIB PET imaging, 19% (n=4) of those with AD (PIB+) were initially diagnosed with non-AD dementia. For subjects with an initial diagnosis of AD (n=74), 28.4% (n=21) had a change in diagnosis (including 4 DLB, 6 FTD, 4 VaD, 3 mixed AD plus VaD, and 4 with other dementia). Excluding subjects with DLB and mixed AD plus VaD, 13.7% of all subjects (14 out of 102) had discontinued their previous symptomatic AD therapy. For subjects with a final diagnosis of FTD (n=7), 85.7% (n=6) were initially misdiagnosed as AD. For subjects with a final diagnosis of DLB (n=9), 44.4% (n=4) were misdiagnosed as AD.

Five patients were diagnosed with unclassifiable dementia following neuroimaging, which comprised four females and one male with a mean age of 78 ± 9.4 years. All presented with amnesia. In addition, one patient presented with apraxia and dysexecutive syndrome and another presented with hyperorality. All of them were PIB^-. An AD pattern of hypometabolism was present in four patients (2 with hypometabolism in posterior cingulate gyrus and 2 with hypometabolism in temporoparietal lobes). Isolated hypometabolism in the temporal lobes was present in one patient.

The clinical information of the seven amnesic MCI subjects are summarised in Table 4. None of the three subjects without imaging risk factors for AD deteriorated over a follow-up period of 1 to 5 years. Of the four amnesic MCI subjects with imaging risk factors, two deteriorated into AD over a follow-up period of 5 years.

In this study, we showed that ¹⁸F-FDG with or without ¹¹C-PIB PET clarified and improved the accuracy of dementia diagnosis in 36.3% of patients, and confirmed the initial diagnosis in 63.7%. Using the results of PET scan as the gold standard, the accuracy of clinical diagnosis was low for FTD, VaD, and mixed dementia collectively. On the one hand, 11.7% of patients (ie 12 out of 102) were started on symptomatic AD therapy after the ¹⁸F-FDG with or without ¹¹C-PIB PET neuroimaging investigations. On the other hand, 13.7% of patients (ie 14 out of 102) discontinued symptomatic AD therapy after ¹⁸F-FDG with or without ¹¹C-PIB PET because they did not have AD.

We also showed that the accuracy of clinical diagnosis of DLB and FTD was low (44.4% and 14.3%, respectively). This finding was in agreement with a previous study.20 Both DLB and FTD are commonly misdiagnosed clinically as AD (50% for DLB and 85.7% for FTD).20 We have previously reported that 100% of our patients with biomarkers that confirmed DLB and FTD presented with memory impairment in our memory clinic.20 A previous study also reported that 26% of DLB patients were initially misdiagnosed with AD, and 57% of these DLB patients presented with memory impairment.21 We understand that an accurate diagnosis of DLB is very important for subsequent management. Patients with DLB are particularly sensitive to neuroleptics.21 Neuroleptic sensitivity can present as drowsiness, confusion, abrupt worsening of parkinsonism, postural hypotension, or neuroleptic malignant syndrome.21 Other clinical features of DLB that need to be observed and tackled include well-formed visual hallucinations, rapid eye movement sleep behavioural disorder, and autonomic symptoms (including postural hypotension, sialorrhoea, and urinary and bowel symptoms).21 By accurately establishing the diagnosis of DLB, careful observation of classic DLB symptoms may reduce unnecessary investigations. Regarding therapeutic implications, DLB is characterised by far greater cholinergic deficits than AD. Hence, most DLB patients will benefit from ChEIs, and the extent of symptomatic improvement should be monitored after such therapy.22

Similarly, FTD may be misdiagnosed as AD. The former can also present initially with memory impairment, as illustrated by our FTD patients. There is increasing evidence that elderly patients with FTD often present with memory impairment.5 23 24 In one autopsy study, 64% (n=7) of 11 elderly patients with FTD had anterograde memory loss.23 Current treatment guidelines do not advise giving ChEIs or memantine treatments to FTD patients. Thus, such medications should be stopped to prevent unnecessary adverse effects.25

In the past few years, disease-modifying treatments (eg bapineuzumab) have failed to demonstrate their efficacy in clinical trials with AD patients.26 Detailed post-hoc analyses with AD biomarkers have shown the problem of diagnosing AD in subjects recruited in these studies. Only approximately 80% of these subjects had AD amyloid pathology, according to the presence of amyloid PET scan.26 Thus, including ¹¹C-PIB PET to confirm brain amyloid in study inclusion criteria can help ensure recruitment of genuine AD patients to future clinical trials of disease-modifying treatments for AD.27 Given the minimally invasive nature of ¹¹C-PIB PET compared with CSF amyloid-beta (Aβ) 42 measurements,7 it is likely to be a more acceptable choice for patients in clinical trials. At present, there are ongoing clinical trials of AD treatments including secretase inhibitors, Aβ aggregation inhibitors, Aβ and tau immunotherapy.27 We believe that ¹¹C-PIB PET will play an important role in these clinical trials.

It is considered that ¹⁸F-FDG and ¹¹C-PIB PET may detect underlying AD in patients with MCI.28 In the present study, 50% of MCI patients (ie 2 out of 4) with ¹⁸F-FDG and ¹¹C-PIB PET imaging findings positive for AD showed deterioration over a follow-up period of 5 years. Although recommending PET brain imaging in MCI patients is still debatable, we believe that this investigation can help clinicians to better plan future and long-term treatments. In particular, disease-modifying drugs for AD or MCI due to AD may prove to be effective in the coming decade. Finally, in the present study, five patients were diagnosed with unclassifiable dementia. In the four patients with an AD pattern of hypometabolism, AD may still be present as they may have diffuse plaques or amorphous plaques that do not bind well to PIB. Alternatively they may have another type of dementia that requires pathological confirmation, eg argyrophilic grain disease or neurofibrillary tangle–only dementia.29 We will follow up the remaining patient with isolated hypometabolism in the temporal lobes to see whether additional FTD features develop.

There were several limitations to the present study. This was a retrospective case series and as such we were unable to collect further information such as the pre-imaging or post-imaging confidence of diagnosis. The diagnosis of dementia relied on the clinical diagnostic criteria without pathological confirmation. Therefore, we were also unable to compare the relative accuracy of clinical diagnosis and PET diagnosis with pathological diagnosis. For patients with MCI, some were not followed up for sufficiently long to ascertain whether or not they had deteriorated and developed dementia. Structural imaging (including computed tomography or magnetic resonance imaging) of the brain was not analysed as a separate variable but integrated into the pre-functional imaging clinical diagnoses of dementia subtypes. Our case series is likely to have selection bias as PET imaging is mostly a self-paid service in Hong Kong. The exception is for patients who are retired civil servants or recipients of Comprehensive Social Security Assistance. Demented patients who could not afford PET may differ to the patients selected. Although the PET images were analysed and read by radiologists experienced in PET, the interpretations depended heavily on individual experience and training; also, radiologists were not blinded to clinical information written on the request form. Despite these limitations, our study should be more reflective of day-to-day practice in a memory clinic and how ¹⁸F-FDG with or without¹¹C-PIB PET imaging may assist clinical diagnosis.

In this study, ¹⁸F-FDG with or without ¹¹C-PIB brain imaging improved the accuracy of diagnosis of dementia subtype in 36% of patients with underlying AD, DLB, VaD, and FTD who presented to our memory clinic.

All authors have disclosed no conflicts of interest.

1. Alzheimer’s Disease International World Alzheimer Report 2015: executive summary. Available from: http://www.alz.co.uk/research/WorldAlzheimerReport2015-sheet.pdf. Accessed Sep 2015.

2. Lam LC, Tam CW, Lui VW, et al. Prevalence of very mild and mild dementia in community-dwelling older Chinese people in Hong Kong. Int Psychogeriatr 2008;20:135-48. Crossref

3. McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging and Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011;7:263-9. Crossref

4. McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 2005;65:1863-72. Crossref

5. Rascovsky K, Hodges JR, Knopman D, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 2011;134:2456-77. Crossref

6. Harris JM, Gall C, Thompson JC, et al. Classification and pathology of primary progressive aphasia. Neurology 2013;81:1832-9. Crossref

7. Shea YF, Chu LW, Zhou L, et al. Cerebrospinal fluid biomarkers of Alzheimer’s disease in Chinese patients: a pilot study. Am J Alzheimers Dis Other Demen 2013;28:769-75. Crossref

8. Duits FH, Teunissen CE, Bouwman FH, et al. The cerebrospinal fluid “Alzheimer profile”: easily said, but what does it mean? Alzheimers Dement 2014;10:713-723.e2. Crossref

9. Sinha N, Firbank M, O’Brien JT. Biomarkers in dementia with Lewy bodies: a review. Int J Geriatr Psychiatry 2012;27:443-53. Crossref

10. Harris JM, Gall C, Thompson JC, et al. Sensitivity and specificity of FTDC criteria for behavioral variant frontotemporal dementia. Neurology 2013;80:1881-7. Crossref

11. Davison CM, O’Brien JT. A comparison of FDG-PET and blood flow SPECT in the diagnosis of neurodegenerative dementias: a systematic review. Int J Geriatr Psychiatry 2014;29:551-61. Crossref

12. Schöll M, Damián A, Engler H. Fluorodeoxyglucose PET in neurology and psychiatry. PET Clin 2014;9:371-90. Crossref

13. Vandenberghe R, Adamczuk K, Dupont P, Laere KV, Chételat G. Amyloid PET in clinical practice: Its place in the multidimensional space of Alzheimer’s disease. Neuroimage Clin 2013;2:497-511. Crossref

14. Cummings JL. Biomarkers in Alzheimer’s disease drug development. Alzheimers Dement 2011;7:e13-44. Crossref

15. Ossenkoppele R, Prins ND, Pijnenburg YA, et al. Impact of molecular imaging on the diagnostic process in a memory clinic. Alzheimers Dement 2013;9:414-21. Crossref

16. Laforce R Jr, Buteau JP, Paquet N, Verret L, Houde M, Bouchard RW. The value of PET in mild cognitive impairment, typical and atypical/unclear dementias: A retrospective memory clinic study. Am J Alzheimers Dis Other Demen 2010;25:324-32. Crossref

17. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984;34:939-44. Crossref

18. Román GC, Tatemichi TK, Erkinjuntti T, et al. Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology 1993;43:250-60. Crossref

19. Waldö ML. The frontotemporal dementias. Psychiatr Clin North Am 2015;38:193-209. Crossref

20. Shea YF, Ha J, Chu LW. Comparisons of clinical symptoms in biomarker-confirmed Alzheimer’s disease, dementia with Lewy bodies, and frontotemporal dementia patients in a local memory clinic. Psychogeriatrics 2014;15:235-41. Crossref

21. Zweig YR, Galvin JE. Lewy body dementia: the impact on patients and caregivers. Alzheimers Res Ther 2014;6:21. Crossref

22. Gauthier S. Pharmacotherapy of Parkinson disease dementia and Lewy body dementia. Front Neurol Neurosci 2009;24:135-9. Crossref

23. Baborie A, Griffiths TD, Jaros E, et al. Frontotemporal dementia in elderly individuals. Arch Neurol 2012;69:1052-60. Crossref

24. Hornberger M, Piguet O. Episodic memory in frontotemporal dementia: a critical review. Brain 2012;135:678-92. Crossref

25. Portugal Mda G, Marinho V, Laks J. Pharmacological treatment of frontotemporal lobar degeneration: systematic review. Rev Bras Psiquiatr 2011;33:81-90. Crossref

26. Blennow K, Mattsson N, Schöll M, Hansson O, Zetterberg H. Amyloid biomarkers in Alzheimer’s disease. Trends Pharmacol Sci 2015;36:297-309. Crossref

27. Wisniewski T, Goñi F. Immunotherapeutic approaches for Alzheimer’s disease. Neuron 2015;85:1162-76. Crossref

28. Langa KM, Levine DA. The diagnosis and management of mild cognitive impairment: a clinical review. JAMA 2014;312:2551-61. Crossref

29. Kovacs GG. Tauopathies. In: Kovacs GG, editor. Neuropathology of neurodegenerative diseases: a practical guide. Cambridge: Cambridge University Press; 2015: 125-8.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome. Mutation of the ryanodine receptor 2 (RyR2) gene and infrequently the calsequestrin (CASQ2) gene is identified in approximately 60% to 70% of patients.1 2 Patients with CPVT usually present with syncope and sudden cardiac death. The symptoms are due to bidirectional polymorphic ventricular tachycardia (VT) induced by adrenergic stress.1 Onset of arrhythmia syndrome is usually in childhood. Many affected children are considered to have vasovagal syncope or epilepsy before a correct diagnosis is made.1 2 3 4 If left untreated, the mortality of CPVT is up to 31% by the age of 30 years.1 3 5

In this study, we reviewed the clinical characteristics, genetic profile, and outcome of CPVT in Hong Kong Chinese children.

Our study included children diagnosed with CPVT from January 2008 to October 2014 at Queen Mary Hospital, a university-affiliated teaching hospital in Hong Kong. The hospital records were retrospectively reviewed. Demographic data, clinical presentation, diagnostic methods, and genetic tests were reviewed. In all patients, the heart rate–corrected QT interval of the resting electrocardiogram was normal and the presence of structural heart disease was excluded by echocardiography (n=10) and/or magnetic resonance imaging (n=5). We also summarised the treatment modalities, response to treatment, and clinical outcome up to October 2014.

Blood samples of seven patients were sent to the Molecular Genetics Laboratory of Victorian Clinical Genetic Services, Australia where testing for mutations of the RyR2 gene was performed. The assay involved sequencing of 17 hotspot exons (exons 1, 8, 14, 15, 44, 46, 47, 49, 88, 93, 95, 97, 101, 102, 103, 104, 105), their splice junctions and 20 bps into the introns. Since 2014, the Laboratory has made use of a cardiac next-generation sequencing panel to analyse the 28 arrhythmia genes: AKAP9, ANK2, CACNA1C, CACNA2D1, CACNB2, CASQ2, CAV3, GJA5, GPD1L, HCN4, KCNA5, KCND3, KCNE1, KCNE1L, KCNE2, KCNE3, KCNH2, KCNJ2, KCNJ5, KCNJ8, KCNQ1, NPPA, RYR2, SCN1B, SCN3B, SCN4B, SCN5A, and SNTA1. In two patients, the samples were tested by the local Laboratory Genetic Service (Department of Pathology, Princess Margaret Hospital, Hong Kong), where direct sequencing of selected hotspot exons and the flanking introns (10 bps) was performed. Cascade testing was offered for first-degree relatives of genotype-positive subjects.

During the study period, 10 patients were diagnosed to have CPVT. Their demographic data and clinical features are summarised in Table 1. The group comprised five female and five male patients; two of whom were brothers. The mean (± standard deviation) age at first presentation was 11.0 ± 2.9 (range, 6.2-14.2) years. The mean age at diagnosis was 12.5 ± 2.8 (range, 6.9-15.1) years. The mean delay time from first presentation to diagnosis was 1.5 ± 1.3 years.

Six patients presented initially with syncope while the other four presented with aborted cardiac arrest. At the end of the study, a total of six patients had aborted cardiac arrest. The triggering event for syncope or cardiac arrest was either exercise or emotion. Nonetheless, no such event was evident in three patients.

Four patients were initially misdiagnosed with epilepsy, one of whom was treated with an anticonvulsant prior to the diagnosis of CPVT.

Of the four patients who presented with aborted cardiac arrest, three required repeated cardioversion because of recurrent VT immediately following successful termination of ventricular arrhythmias. The case of patient 4 has been reported previously.6

Diagnosis of CPVT in two patients was based on the presence of bidirectional polymorphic VT in the cardiac arrest electrocardiogram. In the remaining patients, diagnosis was made when polymorphic or bidirectional VT was induced during provocation tests by exercise (n=2) or catecholamine infusion (n=6). Heart rate at the induction of ventricular premature beats ranged from 90 to 150 beats/min. Polymorphic VTs were induced when heart rate was increased to 126 to 170 beats/min (Fig).

Of the nine patients with genetic study, six were confirmed to have mutations of the RyR2 gene as shown in Table 2. One patient (patient 9) did not undergo genetic study because his brother (patient 5) was confirmed to have no mutation of RyR2. Only two (brothers of the same family) of 10 patients had a family history of cardiac arrhythmic events. There was no RyR2 mutation identified in the first-degree relatives of any patient with a RyR2 mutation.

The treatment modalities and response are summarised in Table 3. All patients were started on a beta-blocker as first-line medication. One patient initially refused medical treatment. She then had recurrent syncope and subsequently agreed to treatment with nadolol.

Metoprolol was prescribed to three patients as initial medical treatment, although all switched to nadolol with or without flecainide due to unsatisfactory control (aborted cardiac arrest in one and exercise-induced polymorphic VT in another) or intolerable side-effects (tiredness and significant bradycardia at 38 beats/min).

Of the six patients prescribed nadolol as the first medication, five had no more syncope and no VT on treadmill exercise testing. Nadolol was changed to flecainide in one patient (patient 7) due to significant resting bradycardia of 35 beats/min. Nadolol was later resumed at a lower dose.

Atenolol was started in one girl as initial medical treatment but failed to prevent recurrent syncope. After changing to nadolol, she remained symptomatic and subsequently underwent left cardiac sympathetic denervation (LCSD).

Left cardiac sympathetic denervation was performed via a video-assisted thoracoscopic approach in five patients. The lower half of the stellate ganglion and the sympathetic trunk of T2 to T4 were resected. After LCSD, one patient (patient 1) still had recurrent syncope. The other four patients had no more syncope. Dual-chamber implantable cardioverter defibrillator (ICD) implantation was performed in one patient (patient 7) who experienced an aborted cardiac arrest despite flecainide. She had no complications related to the ICD implantation. After implantation, she had one episode of syncope while she was swimming slowly in the pool with her mother. She was taken out of the water and was able to stand unaided soon after. The ICD interrogation noted an episode of VT/ventricular fibrillation that was successfully aborted by electric shocks from the ICD. She had no inappropriate shocks from the ICD during the follow-up period of 30 months.

The median duration of follow-up was 3.7 ± 2.0 (range, 0.7-6.7) years. Six (60%) patients became asymptomatic after drug treatment. Two patients had recurrent syncope; one of whom was without drug treatment. Two patients experienced aborted cardiac arrest, one received ICD implantation and another one refused. There was no mortality during the study period.

Catecholaminergic polymorphic ventricular tachycardia is uncommon in Hong Kong Chinese children. Our centre treated most of the serious local paediatric cardiac arrhythmia cases. Over a period of 7 years we identified only 10 patients. Our case series is, to date, the largest in Chinese children.

Many of our patients (6 out of 10) had experienced aborted cardiac arrest as the near-fatal arrhythmic event during the study. The diagnosis of CPVT can be challenging and requires documentation of typical bidirectional polymorphic VT at presentation, or induction of polymorphic VT by exercise test or catecholamine infusion test.1 2 3 7 8 Studies show that diagnosis of CPVT can be made in 69% and 75% of patients by exercise test and catecholamine infusion test, respectively.9 10

Misdiagnosis and delay in diagnosis of CPVT is common. Our patients had a mean delay of 1.5 years from first presentation to diagnosis. Four of our patients were initially misdiagnosed with epilepsy, one of whom was prescribed anticonvulsant therapy. Of the 10 patients, four were not diagnosed until they presented with aborted cardiac arrest.

Genetic mutations are identified in 60% to 70% of patients with CPVT, and more than 90% of the mutations affect the RyR2 gene.1 3 Mutation of the CASQ2 gene is rare (<2%). Very recently, mutation of triadin, a transmembrane sarcoplasmic reticulum protein, was found to be the cause of CPVT in two families.11 In these mutations, the defective proteins cause excessive calcium release from the sarcoplasmic reticulum to the cytoplasm leading to polymorphic VT.1 5 Similar to overseas studies, mutation of the RyR2 gene was evident in the majority (60%) of our patients.

Patients with CPVT must be restricted from exercise to avoid the adrenergic trigger. A beta-blocker serves as first-line medical therapy.1 2 4 10 Nonetheless, CPVT is a very malignant arrhythmic disease and many patients remain symptomatic despite such therapy.1 3 4 10 In a systematic analysis of 354 CPVT patients treated with beta-blockers, the estimated 8-year arrhythmic event rate was 37.2%.12 Our study also showed that a high proportion of patients still developed arrhythmic events despite beta-blocker treatment (syncope in one and aborted cardiac arrest in two out of 10 patients).

In the early period of study, we prescribed metoprolol in three patients, although all experienced treatment failure due to recurrent symptoms or intolerance. In the later period, nadolol was the initial medication and five out of six patients became asymptomatic.

Flecainide, a class 1c anti-arrhythmic drug with dual action of direct ryanodine receptor blockage and blockage of sodium channels,1 12 may be effective in CPVT patients. Flecainide has been evaluated in a multicentre study of 33 CPVT patients. In 22 (76%) out of 29 patients, flecainide suppressed exercise-induced ventricular arrhythmia either partially (n=8) or completely (n=14).1 12 13 In our study, flecainide was used in four patients who had failed treatment with a beta-blocker. Three patients still had arrhythmic events, however.

Studies showed that LCSD, which prevents noradrenaline release in the heart, is highly effective in severely affected CPVT patients.14 15 It can be performed with a minimally invasive approach by video-assisted thoracic surgery. In our study, five patients underwent LCSD. All recovered well and no complications were noted at follow-up. Four had no more syncope. Large studies are needed to further evaluate its efficacy in CPVT patients.

An ICD has been recommended in patients who fail optimised medical therapy.1 12 14 16 Some recent studies have suggested that ICD may be harmful to CPVT patients, however, because both appropriate and inappropriate ICD shocks can potentially induce VT storms and cardiac arrest.16 17 Therefore, ICD implantation should be restricted to patients with symptoms refractory to optimised medical treatment and LCSD.18

Catecholaminergic polymorphic ventricular tachycardia is an uncommon but malignant cardiac arrhythmia that presents as syncope, seizure, or sudden cardiac death in childhood. In our study, 60% of patients experienced aborted cardiac arrest. One should suspect the diagnosis when syncope occurs during exercise or emotional stress. Similar to overseas studies, RyR2 mutation is the most common genetic mutation and affected 60% of our patients. Despite optimised medical therapy, 60% of patients still required LCSD or ICD implantation.

The expenses of genetic analysis were sponsored by the Children’s Heart Foundation of Hong Kong.

All authors have no relevant conflicts of interest to disclose.

1. Ylänen K, Poutanen T, Hiippala A, Swan H, Korppi M. Catecholaminergic polymorphic ventricular tachycardia. Eur J Pediatr 2010;169:535-42. Crossref

2. Priori SG, Napolitano C, Memmi M, et al. Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia. Circulation 2002;106:69-74. Crossref

3. Leenhardt A, Lucet V, Denjoy I, Grau F, Ngoc DD, Coumel P. Catecholaminergic polymorphic ventricular tachycardia in children. A 7-year follow-up of 21 patients. Circulation 1995;91:1512-9. Crossref

4. Çeliker A, Erdoğan I, Karagöz T, Özer S. Clinical experiences of patients with catecholaminergic polymorphic ventricular tachycardia. Cardiol Young 2009;19:45-52. Crossref

5. Swan H, Piippo K, Viitasalo M, et al. Arrhythmic disorder mapped to chromosome 1q42-q43 causes malignant polymorphic ventricular tachycardia in structurally normal hearts. J Am Coll Cardiol 1999;34:2035-42. Crossref

6. Kung SW, Yung TC, Chiu WK. Successful resuscitation of out-of-hospital ventricular fibrillation cardiac arrest in an adolescent. Hong Kong J Emerg Med 2010;17:482-7.

7. Lahat H, Eldar M, Levy-Nissenbaum E, et al. Autosomal recessive catecholamine- or exercise-induced polymorphic ventricular tachycardia: clinical features and assignment of the disease gene to chromosome 1p13-21. Circulation 2001;103:2822-7. Crossref

8. Postma AV, Denjoy I, Kamblock J, et al. Catecholaminergic polymorphic ventricular tachycardia: RYR2 mutations, bradycardia, and follow up of the patients. J Med Genet 2005;42:863-70. Crossref

9. Marjamaa A, Hiippala A, Arrhenius B, et al. Intravenous epinephrine infusion test in diagnosis of catecholaminergic polymorphic ventricular tachycardia. J Cardiovasc Electrophysiol 2012;23:194-9. Crossref

10. Sumitomo N, Harada K, Nagashima M, et al. Catecholaminergic polymorphic ventricular tachycardia: electrocardiographic characteristics and optimal therapeutic strategies to prevent sudden death. Heart 2003;89:66-70. Crossref

11. Roux-Buisson N, Cacheux M, Fourest-Lieuvin A, et al. Absence of triadin, a protein of the calcium release complex, is responsible for cardiac arrhythmia with sudden death in human. Hum Mol Genet 2012;21:2759-67. Crossref

12. van der Werf C, Zwinderman AH, Wilde AA. Therapeutic approach for patients with catecholaminergic polymorphic ventricular tachycardia: state of the art and future developments. Europace 2012;14:175-83. Crossref

13. van der Werf C, Kannankeril PJ, Sacher F, et al. Flecainide therapy reduces exercise-induced ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. J Am Coll Cardiol 2011;57:2244-54. Crossref

14. Wilde AA, Bhuiyan ZA, Crotti L, et al. Left cardiac sympathetic denervation for catecholaminergic polymorphic ventricular tachycardia. N Engl J Med 2008;358:2024-9. Crossref

15. De Ferrari GM, Dusi V, Spazzolini C, et al. Clinical management of catecholaminergic polymorphic ventricular tachycardia: the role of left cardiac sympathetic denervation. Circulation 2015;131:2185-93. Crossref

16. Miyake CY, Webster G, Czosek RJ, et al. Efficacy of implantable cardioverter defibrillators in young patients with catecholaminergic polymorphic ventricular tachycardia: success depends on substrate. Circ Arrhythm Electrophysiol 2013;6:579-87. Crossref

17. Mohamed U, Gollob MH, Gow RM, Krahn AD. Sudden cardiac death despite an implantable cardioverter-defibrillator in a young female with catecholaminergic ventricular tachycardia. Heart Rhythm 2006;3:1486-9. Crossref

18. van der Werf C, Wilde AA. Catecholaminergic polymorphic ventricular tachycardia: from bench to bedside. Heart 2013;99:497-504. Crossref

Click here to watch a video clip showing colorectal endoscopic submucosal dissection

For many years, conventional endoscopic mucosal resection (EMR) and surgery were the only options for treating a large (>20 mm) sessile or flat colorectal lesion. Conventional EMR, however, often results in piecemeal removal and there is a significant local recurrence rate ranging from 7.4% to 17%.1 2 3 Full histological evaluation is also difficult.

Endoscopic submucosal dissection (ESD), pioneered in Japan for treating early upper gastro-intestinal malignancy, was introduced in the late 1990s by Yamamoto et al4 and Fujishiro et al5 to treat colorectal lesions. The technique has an advantage over EMR in that its effectiveness is not limited by size or shape of the lesion. In the past decade, colorectal ESD has been shown to be superior to EMR, in terms of higher en-bloc resection rate and lower recurrence rate.6 Colorectal ESD can be applied not only to adenoma, but also to intramucosal carcinoma and low-risk submucosal carcinoma, as defined by the Paris classification7 and the Japanese Society for Cancer of the Colon and Rectum.8 Recently, a large-scale multicentre study has shown that ESD alone is adequate in the management of patients with low-risk submucosal carcinoma and achieves an excellent 5-year recurrence-free survival of 98% and 5-year overall survival of 94%.9

Despite the growing evidence to support the use of colorectal ESD, it is not established as a standard treatment outside Japan. The drawbacks of colorectal ESD include longer operating time6 and higher complication rates, especially perforation. Although the perforation rate of ESD is much higher than that of EMR, most ESD perforations can be treated conservatively by clip closure during endoscopy.10 11 In a multicentre study of iatrogenic perforations in Japan, the respective EMR and ESD perforation rate was 0.58% and 14% in 15 160 therapeutic colonoscopies.12 Endoscopic clipping failed in 43.5% of ESD perforations and surgical intervention was necessary.12

Perhaps one of the major hurdles to its general application is that it is a technically demanding procedure that is difficult to set up at a low-volume district hospital. We would like to share our experience of applying this novel technique in a district hospital in Hong Kong.

North District Hospital was a district hospital serving 700 000 population with a case volume of 15 to 20 cases of ESD per year. Since the introduction of the ESD technique at the hospital in 2009, all lateral spreading tumours larger than 2 cm or those unable to be resected en bloc by conventional polypectomy were referred to a single endoscopist to determine the appropriateness of ESD. Colonoscopy was repeated by a single endoscopist to determine the location, size, and nature of each tumour by white-light and narrow band imaging (NBI). Benign polyps not amendable to removal by EMR were triaged to ESD. Target biopsy was performed on Sano III lesions that were triaged to conventional laparoscopic colectomy. No tumours were excluded based on location.

Evaluation of the depth of invasion is important to determine the treatment strategy. To predict the depth of invasion, we used NBI colonoscopy, based on Sano’s capillary pattern classification. The underlying principle is that angiogenesis is critical for transition of a premalignant lesion to a malignant one and the microcapillary pattern changes in this process. Sano et al13 focused on this microcapillary difference based on their histopathological findings and devised three classifications: types I, II, and III. Type III was further subdivided into IIIA and IIIB.14

The diagnostic accuracy of NBI colonoscopy in differentiating a neoplastic from non-neoplastic lesion is superior to conventional colonoscopy and equivalent to chromoendoscopy using indigocarmine.15 For estimation of the depth of invasion, the sensitivity, specificity, and diagnostic accuracy of capillary pattern type III for differentiating pM-ca (intramucosal) or pSM1 (superficial) from pSM2-3 (deep) was 84.8%, 88.7% and 87.7%, respectively.14 We preferred NBI colonoscopy because it is fast and easy to use, without the need to spray dye as in chromoendoscopy.

The procedure was performed in the operating theatre with the patient under conscious sedation. All patients were assessed by an anaesthetist in a preoperation clinic.

Patients were instructed to eat a low-residue diet 2 days before the procedure and a fluid diet on the day before ESD. Bowel preparation with 4 L polyethylene glycol solution was given on the day before ESD. Prophylactic antibiotics were not prescribed.

All procedures were performed in the operating theatre. This ensured that all equipment was on hand should conversion to an open procedure be required, for example, if there was full-thickness perforation that could not be closed endoscopically.

In our hospital, ESD was performed using a single-channel colonoscope (CF-H180AL; Olympus, Tokyo, Japan). This colonoscope was a high-density television compatible with a wide angle of 170°, 3.7-mm instrument channel, and auxiliary water jet. A short transparent hood was fitted to the tip of the endoscope so that the whole ring could be seen in endoscopic view. Carbon dioxide was used for insufflation to decrease patient discomfort. We used a high-frequency electrosurgical generator (ESG-100; Olympus, Tokyo, Japan) with a peristaltic pump (AFU-100; Olympus, Tokyo, Japan). The energy setting used for incision and dissection was “forced coagulation 2” 30W, whereas “soft coagulation” 100W was used for haemostasis.

In our initial practice, we used the Flex Knife (KD-630L; Olympus, Tokyo, Japan) to perform the procedure. It had a loop-shaped tip that allowed easy control in any direction, as it was soft and flexible. Nonetheless, we found it difficult to adjust the length of the tip and there was frequent accumulation of debris around the tip. We then changed to Dual Knife (KD-650L; Olympus, Tokyo, Japan) with a fixed length (1.5 mm) and hence a more stable knife movement. More recently, we have used Flush Knife BT (DK2618JB/DK2618JN; Fujifilm, Saitama, Japan) for dissection. It has a ball tip of fixed length that touches a wider part of tissue and enhances haemostasis. The knife has a water jet channel and achieves two purposes: (1) it can wash away any tissue that accumulates around the tip, thereby maintaining the sharpness of the knife; and (2) submucosal normal saline injection can be performed without the need to change the instrument for further hyaluronate injection.

We used a mixture of 10% sodium hyaluronate (LG Chemical, South Korea) and 1:200 000 adrenaline saline at a ratio of 1:1.5. This solution was chosen for three reasons: the addition of adrenaline can produce a haemostasis effect; dilution of sodium hyaluronate made it less viscous and thus easier to inject; and it reduced the amount used of the relatively more expensive sodium hyaluronate.

All ESD procedures were performed by a single experienced endoscopist who had performed more than 500 therapeutic colonoscopic procedures and more than 200 laparoscopic colectomies. The ESD procedure was implemented by the endoscopist following completion of training on an animal model in the Second Master Workshop on Novel Endoscopic Technology & Endoscopic Submucosal Dissection in 2009 at Prince of Wales Hospital in Hong Kong, which was organised by the Department of Surgery, The Chinese University of Hong Kong (http://www.surgery.cuhk.edu.hk/events/2009-07-22-ESD.pdf). The workshop included both lecture sessions and hands-on sessions to perform ESD in a pig. The endoscopist had no experience in gastric or colorectal ESD. He received further overseas training in ESD in 2011 at Osaka Medical Center for Cancer and Cardiovascular Diseases in Japan as a clinical observer with hands-on animal model training.

With the patient initially lying in the left lateral position, a full colonoscopy was first performed to confirm and locate the site of pathology. Patients were then re-positioned such that the lesion was at an anti-gravitational position in the endoscopic view at 6 o’clock. This could be easily achieved by seeing the injected water pooling opposite to the lesion. In this position, the gravitational force aided in retracting the lesion away from the submucosal plane during dissection. We then injected 1:100 000 adrenaline saline at 1 cm distal to the lesion, aiming at the submucosal layer. This could be ascertained by seeing the formation of a dwell. With the injecting needle still in situ, the solution was then changed to the mixture of adrenaline saline and sodium hyaluronate to provide a precipitous elevation of sufficient height. After elevating the lesion, a mucosal incision was made proximal to the lesion. The mucosal incision was started at the proximal two thirds of the lesion. After mucosal incision, the submucosal plane was dissected with the submucosa dissected away from the muscle layer. Care was taken to manipulate the dissection plan parallel to the intestinal wall to prevent perforation. When a more than 1-mm diameter vessel was detected, it was coagulated using haemostasis forceps (Radial Jaw 4; Boston Scientific, US). When the flap was sufficient for retraction, the mucosal incision was completed. In case of perforation, the defect was closed with endoscopic clipping (EZ Clip; Olympus, Tokyo, Japan). The resected area was not closed as healing usually occurred in a few weeks without complications.16

All specimens were pinned on a piece of foam and fixed in formalin. Histological type, depth of invasion, as well as lateral and vertical resection margins were recorded. En-bloc resection was defined as one-piece resection of an entire lesion as observed endoscopically. R0 resection was defined as clear lateral and vertical resection margin.

All patients were allowed to resume a full diet on the same day. We performed no routine blood tests or imaging and patients were discharged the next day if there were no signs of perforation or haemorrhage. Postoperative haemorrhage was defined as clinical evidence of bleeding manifested by melena or haematochezia that required endoscopic haemostasis within 0 to 14 days of the procedure.11

All patients were followed up in clinic 2 weeks later to review the pathology report. Additional surgery would be offered in case of carcinoma with one of the following criteria: (1) margin involved; (2) >1 mm submucosal invasion; (3) positive lymphovascular permeation; (4) poorly differentiated adenocarcinoma, signet ring cell carcinoma, or mucinous carcinoma; or (5) high-grade tumour budding.17 Surveillance colonoscopy was performed 1 year after ESD.

All continuous variables were described as median and range. To study the learning curve, all patients were grouped chronologically into two periods: group 1 with cases 1 to 35; and group 2 with cases 36 to 71. Comparisons between non-parametric data were done with Mann-Whitney U test, while Chi squared test was used for categorical variables. A P value of <0.05 was considered statistically significant.

From March 2009 to December 2013, a total of 71 ESDs were performed. Characteristics of the patients are shown in Table 1.

There was one conversion to laparoscopic colectomy due to intra-operative bleeding that could not be controlled endoscopically (40 mm x 15 mm tumour at the transverse colon). For perforation, there were 11 (15.5%) perforations: eight in the colon and three in the rectum, all were noticed during the ESD. Endoscopic clipping was successful in 10 of the perforations. The median number of clips used was 2 (range, 1-6). One perforation required conversion to laparoscopic colectomy (30 mm x 5 mm tumour at the sigmoid colon). Both laparoscopic operations were uneventful and patients were discharged without any surgical complications. The overall morbidity rate was 16.9% including bleeding and perforation and there was no mortality. The median postoperative stay was 1 day (range, 0-11 days).

Of the 69 patients who completed the endoscopic procedure, en-bloc resection was successful in 56 (81.2%) patients, of whom 19 (27.5%) required additional snare (SD-210U-25, Snare Master; Olympus, Tokyo, Japan) to complete the en-bloc resection. Conversion to piecemeal resection by snare occurred in 14 (20.3%) patients.

In these 69 patients, the resection margin was unclear in 15 patients as it was too close to the cauterised edge. These, together with piecemeal resection, were classified as R1 (29 patients in total). R0 resection was achieved in 40 (58.0%) patients. The histopathological diagnosis was tubular adenoma for 26 (36.6%) tumours, tubulovillous adenoma for 28 (39.4%), villous adenoma for two (2.8%), serrated adenoma for six (8.5%), carcinoid for one (1.4%) with involved margin, intramucosal carcinoma for two (2.8%), and carcinoma with submucosal invasion for six (8.5%). The ESD procedure was considered curative for the two patients with intramucosal carcinoma. One patient who had submucosal carcinoma refused further treatment because of a subsequent diagnosis of primary lung cancer. All other patients with submucosal carcinoma had curative interval laparoscopic surgeries. There was no residual tumour and no lymph node involvement found in the surgical specimen for any of these patients. The patient with rectal carcinoid also underwent subsequent interval laparoscopic total mesorectal excision: the pathology was well-differentiated carcinoid with invasion to the muscularis propria. There was one lymph node metastasis out of 11 lymph nodes retrieved.

After excluding the six interval surgeries and two conversions to laparoscopic colectomy, the remaining 63 patients were offered colonoscopy surveillance of whom four refused and one defaulted from follow-up. Until August 2014, 51 patients had undergone surveillance colonoscopy and seven were awaiting colonoscopy. Recurrence of polyp occurred in seven (13.7%) out of 51 patients: three recurrences occurred after piecemeal resection, another three recurrences occurred after additional snare to complete the en-bloc resection. All three cases had uncertain margin due to proximity to the cauterised edge. In one patient, recurrence occurred after successful en-bloc resection by ESD, in which the deep margin was clear but the circumferential margin was not certain.

All patients were grouped chronologically into two periods: group 1 with cases 1 to 35; and group 2 with cases 36 to 71. The comparison between the two groups is shown in Table 2. The median procedure time per unit area of tumour improved significantly from 31.5 min/cm² to 21.5 min/cm² (P=0.032).

There were three (8.6%) perforations in group 1; one of them required conversion to laparoscopic colectomy. There were eight (22.2%) perforations in group 2; all managed successfully by endoscopic clipping. There was no significant difference in perforation rate (P=0.054). The intra-operative bleeding that required a conversion to laparoscopic colectomy also belonged to group 1.

For the 33 patients in group 1 who completed the endoscopic procedure, en-bloc resection was successful in 26 (78.8%), while 30 (83.3%) out of 36 patients in group 2 had successful en-bloc resection. This trend of improvement, however, did not reach statistical significance (P=0.15). Among these successful en-bloc resections, 15 (57.7%) out of 26 patients in group 1 and four (13.3%) out of 30 patients in group 2 required additional snare to complete the en-bloc resection (P<0.01).

R0 resection rate had improved significantly in group 2 despite a lower rate of snare application: 13 (39.4%) of 33 patients in group 1 had R0 resection, whereas in group 2, 27 (75.0%) of 36 patients had R0 resection (P<0.01).

The median postoperative stay was 1 day in both groups and was not significantly different (P=0.25). The median postoperative stay in patients with perforation in group 1 and group 2 was 1 day (range, 1-7 days) and 2 days (range, 1-11 days), respectively (P=0.73).

Colorectal ESD has been shown to be feasible and safe when performed at expert centres in Japan. In a recent prospective multicentre cohort study involving 1111 patients in Japan, the reported en-bloc resection rate was 88% and R0 resection rate was 89%.11 The total perforation rate was only 5.3% and postoperative bleeding was 1.5%.11 Nonetheless, these excellent results are largely reported from Japan. Colorectal ESD is technically difficult, as the lumen is narrow and angulated and the very thin wall presents a high risk of perforation. In Japan, endoscopists are first required to gain experience in gastric ESD, which is technically less demanding, before they move on to colorectal ESD.18 This is not possible in western and Asian countries outside Japan, where early gastric cancer is much less prevalent. In a recent review of 82 rectosigmoid ESD from a tertiary centre in Germany, the en-bloc resection rate and R0 resection rate was only 81.6% and 69.7%, respectively.19 This reflects the difficulty in generalising this novel procedure in other counties outside Japan, and an even greater challenge to low-volume district centres that lack local expertise.

The low case volume and the absence of expertise in western countries leads to the development of untutored colorectal ESD when it is impossible to have a step-up approach in ESD training starting from the stomach before proceeding to colon. The reported learning curve for untutored colorectal ESD has an acceptable outcome, however. Berr et al20 reported a case series of 48 colorectal ESDs with 76% en-bloc resection, 14% perforation, and 4% requirement for surgical intervention. This compared favourably with results in Japan.11 Another learning curve study of colorectal ESD found procedure time could be significantly shorter after 25 procedures.21

With a similar situation in Hong Kong, this study showed that untutored colorectal ESD is safe and feasible. Results demonstrated obvious improvement after 35 procedures, as evidenced by the significant reduction in combined ESD and EMR with snare from 45.5% to 11.1%. Procedure time per unit area of tumour as well as R0 resection rate also significantly improved after 35 cases. Although there were more perforations in group 2, it did not determine adverse outcome. None of the perforations in group 2 required conversion to laparoscopic colectomy. There was no significant impact on hospital stay. The higher perforation rate in group 2 may reflect a second learning curve to perform a complete ESD procedure without the assistance of a hybrid technique to achieve a reasonable R0 resection rate. A perforation rate comparable with the Japanese series11 is expected in the third tranche of 35 patients.

Contrary to perforations in traditional therapeutic colonoscopies, all perforations in ESD were only 1 to 2 mm in size and were noticed intra-operatively, thus immediate endoscopic repair was possible. No patient required surgical intervention solely for treatment of perforation. The only conversion to laparoscopic colectomy in the initial learning curve aimed to offer one-stop treatment rather than treating perforations. In a multicentre review of colonoscopic perforations by Teoh et al,22 43 (0.113%) perforations were found in 37 971 colonoscopies. Only seven (43.8%) out of 16 therapeutic colonoscopic perforations were noticed during the endoscopic procedure. The mean size of perforation was 0.98 cm. The overall 30-day morbidity and mortality rate was 48.7% and 25.6%, respectively and the stoma rate was 38.5%. This showed clearly that surgical outcome was much worse in conventional colonoscopic perforations compared with perforations in ESD, despite a much higher perforation rate of 15.7% in ESD group.22

After implementation of the ESD service, the following were noted:
(1) Venue of procedure—operating theatre was chosen instead of an endoscopic unit to enable conversion to conventional laparoscopic colectomy without the need to change location as well as the ready availability of an anaesthetist to give conscious sedation.
(2) Mode of anaesthesia—in the first few patients, we performed ESD under general anaesthesia for patient comfort and in the event conversion to laparoscopic colectomy was necessary. Positioning of patients was clumsy particularly when a prone position was needed to perform the procedure. Subsequently conscious sedation by an anaesthetist was used instead. Patients could follow instructions for positioning and deeper sedation could be achieved if necessary. There were no complaints from patients about any discomfort during the procedure.
(3) Choice of injecting agents—albumin 20% (Albumex 20; CSL, Australia) was used as submucosal injecting agent in the first few patients when sodium hyaluronate was not available. Albumin 20% has both a good cushioning effect without any inflammatory effect and the cost was much cheaper at HK$2.7/mL compared with commercially available sodium hyaluronate at HK$68/mL.23 Yet sodium hyaluronate has the longest lasting cushioning effect among all injecting agents. We recommend its use whenever available.
(4) A mixture of adrenaline saline and sodium hyaluronate was favourable for the assistant to inject and a lesser volume of sodium hyaluronate was required. Moreover, there were no instances of postoperative haemorrhage, although it was difficult to conclude whether this was due to the addition of adrenaline saline.
(5) Endoscopic technique—in our initial practice, we performed a full circumferential mucosal incision before submucosal dissection. We noticed it was technically more difficult compared with a two-third circumferential incision, because firstly, the submucosal elevation was lost quickly due to faster leakage of injecting agent, and secondly, it was difficult to retract the lesion at the end of dissection, and we had to complete the en-bloc resection with snare. After changing to two-third circumferential incision in the second period of the study, the need for additional snare to complete the en-bloc resection was significantly decreased (from 57.7% to 13.3%).
(6) Postoperative management—it was feasible and safe to resume diet immediately after the procedure and discharge patients the day following ESD without the need for routine blood taking or imaging. In one study from Japan, abdominal computed tomography was performed on day 1 and blood tests were carried out for 2 consecutive days. Oral intake was gradually stepped up and patients were discharged 5 days after ESD.10 In contrast, we allowed full diet on the same day after ESD and did not perform computed tomography or blood tests routinely. Our overall median postoperative stay was 1 day. Further development of ESD as a day procedure can be explored.

There are a number of limitations in this study. First, this was the learning curve of a single endoscopist and 35 procedures may not be a typical number required for such a learning curve. Second, the inclusion criteria for colorectal ESD were less strict than those in Japan. Lesion less than 2 cm that could not be removed en bloc would be subjected to ESD instead of piecemeal resection. These kinds of lesion were expected to be easier with shorter operating time. Third, this was a retrospective comparison of two chronological groups which might not have been directly comparable. Lastly, the 7.9% patient default rate may lead to underestimation of recurrence in this series.

Untutored colorectal ESD at a low-volume centre was an option in the absence of enough experts to supervise the procedure. Training on an animal model and clinical observation of real-time demonstrations was useful to start ESD without supervision. A cut-off at 35 procedures showed an acceptable R0 resection rate at a significantly improved procedure time per unit area. There was a second learning curve to achieve a complete ESD procedure without EMR at a higher perforation rate. Colorectal ESD performed by a colorectal surgeon enables any complications to be managed by the same operator, or any lesion unresectable by ESD to be surgically removed. It was not necessary to first perform gastric ESD as the start of ESD training. When more endoscopists have gained experience in colorectal ESD, a structured training programme with accreditation can be established.

All authors have disclosed no conflicts of interest.

1. Tanaka S, Haruma K, Oka S, et al. Clinicopathological features and endoscopic treatment of superficially spreading colorectal neoplasms larger than 20 mm. Gastrointest Endosc 2001;54:62-6. Crossref

2. Walsh RM, Ackroyd FW, Shellito PC. Endoscopic resection of large sessile colorectal polyps. Gastrointest Endosc 1992;38:303-9. Crossref

3. Uraoka T, Fujii T, Saito Y, et al. Effectiveness of glycerol as a submucosal injection for EMR. Gastrointest Endosc 2005;61:736-40. Crossref

4. Yamamoto H, Kawata H, Sunada K, et al. Successful en-bloc resection of large superficial tumors in the stomach and colon using sodium hyaluronate and small-caliber-tip transparent hood. Endoscopy 2003;35:690-4. Crossref

5. Fujishiro M, Yahagi N, Kakushima N, et al. Outcomes of endoscopic submucosal dissection for colorectal epithelial neoplasms in 200 consecutive cases. Clin Gastroenterol Hepatol 2007;5:678-83. Crossref

6. Saito Y, Fukuzawa M, Matsuda T, et al. Clinical outcome of endoscopic submucosal dissection versus endoscopic mucosal resection of large colorectal tumors as determined by curative resection. Surg Endosc 2010;24:343-52. Crossref

7. The Paris endoscopic classification of superficial neoplastic lesions: esophagus, stomach, and colon: November 30 to December 1, 2002. Gastrointest Endosc 2003;58(6 Suppl):S3-43.

8. Watanabe T, Itabashi M, Shimada Y, et al. Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2010 for the treatment of colorectal cancer. Int J Clin Oncol 2012;17:1-29. Crossref

9. Yoda Y, Ikematsu H, Matsuda T, et al. A large-scale multicenter study of long-term outcomes after endoscopic resection for submucosal invasive colorectal cancer. Endoscopy 2013;45:718-24. Crossref

10. Yoshida N, Wakabayashi N, Kanemasa K, et al. Endoscopic submucosal dissection for colorectal tumors: technical difficulties and rate of perforation. Endoscopy 2009;41:758-61. Crossref

11. Saito Y, Uraoka T, Yamaguchi Y, et al. A prospective, multicenter study of 1111 colorectal endoscopic submucosal dissections (with video). Gastrointest Endosc 2010;72:1217-25. Crossref

12. Taku K, Sano Y, Fu KI, et al. Iatrogenic perforation associated with therapeutic colonoscopy: a multicenter study in Japan. J Gastroenterol Hepatol 2007;22:1409-14. Crossref

13. Sano Y, Muto M, Tajiri H, et al. Optical/digital chromoendoscopy during colonoscopy using narrow-band image system. Dig Endosc 2005;17(Suppl):S43-8. Crossref

14. Ikematsu H, Matsuda T, Emura F, et al. Efficacy of capillary pattern type IIIA/IIIB by magnifying narrow band imaging for estimating depth of invasion of early colorectal neoplasms. BMC Gastroenterol 2010;10:33. Crossref

15. Machida H, Sano Y, Hamamoto Y, et al. Narrow-band imaging in the diagnosis of colorectal mucosal lesions: a pilot study. Endoscopy 2004;36:1094-8. Crossref

16. Iguchi M, Yahagi N, Fujishiro M, et al. The healing process of large artificial ulcers in the colorectum after endoscopic mucosal resection [abstract]. Gastrointest Endosc 2003;57:AB226.

17. Asano M. Endoscopic submucosal dissection and surgical treatment for gastrointestinal cancer. World J Gastrointest Endosc 2012;4:438-47. Crossref

18. Tanaka S, Tamegai Y, Tsuda S, Saito Y, Yahagi N, Yamano HO. Multicenter questionnaire survey on the current situation of colorectal endoscopic submucosal dissection in Japan. Dig Endosc 2010;22 Suppl 1:S2-8. Crossref

19. Probst A, Golger D, Anthuber M, Märkl B, Messmann H. Endoscopic submucosal dissection in large sessile lesions of the rectosigmoid: learning curve in a European center. Endoscopy 2012;44:660-7. Crossref

20. Berr F, Wagner A, Kiesslich T, Friesenbichler P, Neureiter D. Untutored learning curve to establish endoscopic submucosal dissection on competence level. Digestion 2014;89:184-93. Crossref

21. Białek A, Pertkiewicz J, Karpińska K, Marlicz W, Bielicki D, Starzyńska T. Treatment of large colorectal neoplasms by endoscopic submucosal dissection: a European single-center study. Eur J Gastroenterol Hepatol 2014;26:607-15. Crossref

22. Teoh AY, Poon CM, Lee JF, et al. Outcomes and predictors of mortality and stoma formation in surgical management of colonoscopic perforations: a multicenter review. Arch Surg 2009;144:9-13. Crossref

23. ASGE Technology Committee, Kantsevoy SV, Adler DG, Conway JD, et al. Endoscopic mucosal resection and endoscopic submucosal dissection. Gastrointest Endosc 2008;68:11-8. Crossref