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JIMIJOURNAL OF INTERNAL MEDICINE OF INDIA

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JOURNAL OF INTERNAL MEDICINE OF INDIA � JAN - MAR 2018 � VOL. 12 � NO. 1 � RNI No. 69152/98

© JIMI � JAN - MAR 2018 � VOL. 12 1

Dr. D. Himanshu

2

Chairman Dr. Sarita Bajaj

Chairman-Elect Dr. Virendra Atam

Vice-Chairman Dr. Kauser Usman

Dr. Veerendra Singh

Hon. Secretary Dr. D. Himanshu

Treasurer Dr. S. Chaudhary

Joint Secretaries Dr. Anupam Wakhlu

Dr. S. Chakravorty

Governing Body Members

Dr. Jalees Fa�ma

Dr. Sanjay Tandon

Dr. Anuj Maheshwari

Dr. Abha Gupta

Dr. Anjum Parvej

Dr. Jaya Chakravorty

Co-opted Members

Dr. R.R. Gupta

Dr. K.K. Sawlani

Dr. Kailash Kumar Gupta

Dr. A.K. Singh

Dr. Manoj Mathur

Dr. N.K. Soni

Dr. Om Kumari Gupta

Dr. Sudhir Agarwal

Governing Body

ASSOCIATION OF PHYSICIANS OF INDIA NOIDA CHAPTER

Governing Body

ASSOCIATION OF PHYSICIANS OF INDIA UP CHAPTER

© JIMI � JAN - MAR 2018 � VOL. 12


PatronDr. (Prof) B. C. BansalDr. (Prof) Om Kumari GuptaDr. S. K. Plaha

Former ChairmanDr. Subodh ChandraDr. K.C. SoodDr. G.C. VaishnavaDr. S. Chakravorty

ChairmanDr. R. K. Ga�ani

Vice ChairmanDr. G.C. Gupta

SecretaryDr. Meenakshi Jain

Joint SecretaryDr. Kuldeep Dhar Dr. Amitesh AggarwalDr. Kiran Seth

TreasurerDr. A.K. Shukla

Scien�fic AdvisorDr. Neeru GeraDr. L.K. JhaDr. Amitabh YaduvanshiDr. R.K. Prasad

Core Commi�ee MemberDr. Sanjay WadhawanDr. Vandana GargDr. Ajay Aggarwal Dr. N. K. SharmaDr. K.D. Kotlia Dr. S.K. SahooDr. P.K. GuptaDr. Sanjay MahajanDr. Manju TyagiDr. Vinay LabrooDr. Ambreen Zeenat Ahmad

Dr. Saurabh SrivastavaDr. Amit Kumar Gupta

Editorial

Dear all, Journal of internal Medicine of India (JIMI) continues its journey with well wishes of all its members. Constant efforts are on to improve the standard and content of the journal, which is only possible if the members contribute whole heartedly with upgraded articles to match international standards. In last 2 decades India has witnessed a rapid rise in non-communicable diseases with upliftment of the society coupled with large gap in doctor-patient ratio leading to overall inadequate healthcare of citizens of India. Considering lack of adequate trained manpower to deal with current situation, it becomes imperative to train every doctor the basic aspects of non-communicable diseases so that they can effectively manage such ailments even at primary health centre level and in the community.

With rapid advancement of the treatment modalities in diabetes & cardiovascular diseases lot of newer drug have been introduced. It is essential for us to know the pharmacokinetics and pharmacodynamics of each drug. Some of the agent may causes metabolic derangements in the process of controlling hyperglycaemia. Having an actual knowledge of various adverse effect of these may help us in proper selection of patients therapy avoiding those life threatening adverse situation.

Diabetic Ketoacidosis is a life threatening condition that develops as a result of profound deficiency of insulin action. It is characterized by marked hyperglycaemia and resultant dehydration. It can occur either in a state of moderate hyperglycaemia or in the setting of normal glucose concentration. DKA was originally defined with blood glucose concentration of < 300 mg/dl. But now it is recognized that DKA can develop with blood glucose concentration of <200 mg/dl. This condition is known as Euglycemic DKA (EU-DKA). It can develop both in type 1


© JIMI � JAN - MAR 2018 � VOL. 12 3

SGLT-2 inhibitor reduces glucose levels by increasing urinary glucose excretion which in turn reduces insulin secretion from pancreatic β-cell-. The decline in circulating insulin levels results in lowering of anti-lipolytic activity of insulin and consequent stimulation of production of free fatty acids which are converted to ketone bodies by β-oxidation in the liver. SGLT-2 inhibitors also stimulate secretion of glucogon which contributes overproduction of ketone bodies. Recently US-FDA issued a drug safety communication that warns of an increased risk of DKA with mild to moderate hyperglycemia associated with the use of newer anti-hyperglycemic agents.

The SGLT-2 inhibitors appear to be associated with EU-DKA as a consequence of their non-insulin dependent glucose clearance, hyperglucagonemia and volume depletion.

EU-DKA is an easily detectable condition in presence of currently available tools to measure ketoneuria & ketonemia. All patients taking SGLT-2 inhibitors should be recommended to measure ketones whenever they feel unwell regardless of ambient glucose levels. Patients should temporarily stop SGLT-2 inhibitors and take supplemental boluses of rapid acting insulin along with liquids and carbohydrates.

& type 2 diabetes individuals. EU-DKA is precipitated by certain conditions such as partial treatment of DKA, food restriction, alcohol intake & inhibition of gluconeogenesis. EU-DKA can also develop in individual without diabetes and in pregnant women as a result of ketogenic change in metabolism. Alcoholic Ketoacidosis is a subtype of EU- Ketoacidosis that occurs in individuals without diabetes. In this there is a decrease in insulin secretion in the setting of increased counter-regulatory hormone secretion.

Fig;1; Demonstration of the cascade of clinical events and metabolic changes that contribute sequentially to progressive clinical deterioration and development of full-blown episodes of EU-DKA. BG, blood glucose; CHO,

3carbohydrate; TGs, triglycerides.

ReferencesAnne L. Peters, Elizabeth O. Buschur,; Euglycemic Diabetic Ketoacidosis: A Potential Complication of Treatment With Sodium–Glucose Cotransporter 2 Inhibition, Diabetes Care Volume 38, September 2015; 38:1687–1693.

Henry RR, Rosenstock J, Edelman S, et al. Exploring the potential of the SGLT2 inhibitor dapagliozin in type 1 diabetes: a randomized, double-blind, placebo-controlled pilot study.Diabetes Care 2015;38:412–419.

1.

2.

Julio Rosenstock, and Ele Ferrannini, Euglycemic Diabetic Ketoacidosis: A Predictable, Detectable, and Preventable Safety Concern With SGLT2 Inhibitors; Diabetes Care Volume 38, September 2015

Erondu N, Desai M, Ways K, Meininger G. Diabetic ketoacidosis and related events in the canagliozin type 2 diabetes clinical program. Diabetes Care 2015;38:1680–1686

3.

4.

4 © JIMI � JAN - MAR 2018 � VOL. 12


Conclusion: All patients with type 1 and type 2 DM who are sick and experiencing nausea, vomiting , shortness of breath, malaise in the presence of SGLT-2 inhibitor therapy should be promptly evaluated for presence EU-DKA even if glucose levels are normal or slightly raised. The SGLT-2 inhibitor therapy should be withdrawn at once till the metabolic derangement is fully corrected and patient is clinically & metabolically normal.

Contents

ORIGINAL ARTICLE

1.

2.

3.

4.

REVIEW ARTICLE

5.

Dyslipidemia As A Predictor of Clinically Significant Macular Edemain Type 2 Diabetes Mellitus: A Cross Sectional Study

Abha Gupta, Charu Mithal, Kamlendra Verma

Study of Echocardiography in Normotensive Diabetic Patients:A North India Based Observational Study

Shri Krishna Gautam, Brijesh Kumar, Daya Shankar, Gulab Jha

Predictive Value of ECG Patterns in Acute MI

Chetan Chaturvedi, Smita Gupta and Sharat Johri

Vitamin D Deficiency: SymptomatologyVijay Verma, V Saxena, A K Shukla, Meenakshi Jain

Role of HbA1c In Diagnosis of Gestational Diabetes Mellitus

Virendra Atam, Prachi Daga, Arpit Gupta, Madhukar Mittal, Isha Atam

Armor Regime For Management of Rheumatic Fever &

Rheumatic Heart Disease : Easy And Painless

6.

Endoscopic Ultrasound: A Paradigm Shift in Management8.

Pollution of 21st Century : The Noise

Bhupendra Chaudhary, Aarati Pokale, Ansh Chaudhary

7.

Arati Dave Lalchandani

Kunal Das, Anando Sangupta, S K Sharma, Vibhu Mittal, P Kar

Diagnosis And Treatment of Multi Drug Resistant And

Rifampicin Resistant Tuberculosis

Rajendra Prasad, Nikhil Gupta, Amitabh Banka, Dr. Ram Manohar Lohia

9.

James Parkinson : The Real Hero

Bhupendra Chaudhary

MEDICAL HISTORY

10.

Short Sleep Duration, Diabetes Risk and Mood Disorder

KNOWLEDGE FORUM

Aditya Chakravorty

11.


© JIMI � JAN - MAR 2018 � VOL. 12 5

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Dyslipidemia As A Predictor Of Clinically SignificantMacular Edema In Type 2 DiabetesMellitus: A Cross Sectional Study

Original Article

1 2 3Abha Gupta , Charu Mithal , Kamlendra Verma

AbstractAims And Objectives: To determine the association between lipid profile and clinically significant macular edema (CSME) in Type 2 diabetes.

Methods : The study comprised a total of 70 patients of type 2 diabetes mellitus with diabetic retinopathy (DR) and divided two groups i.e. Group 1 of 14 patients of diabetic retinopathy with CSME and Group 2 of 56 patients of diabetic retinopathy without CSME. Ophthalmoscopic and biomicroscopic examination of ocular fundus was done. Grading of the severity of retinopathy was done according to the ETDRS classification along with the presence or absence of CSME. Laboratory investigations including fasting serum lipid profile and HbA1c estimation were done in both the groups.

Conclusion : Hypertriglyceridemia is a risk factor for the development of CSME in patients with type-2 diabetes.

Keywords: Diabetic retinopathy, (Dr.) CSME, lipid profile

Diabetes mellitus is estimated to affects about 4 percent of the world's population and almost half of them have some

1,2degree of diabetic retinopathy at any given time. Diabetic retinopathy (DR) is a very common long term microvascular complication of both type 1 and type 2 diabetes and probably the leading cause of loss of vision in

3,4the working age group in the current era. Diabetic macular edema (DME) is one of the important causes of

5vision loss in diabetes . In type 2 diabetic patients, the prevalence of DME is about 3% within 5 years of diagnosis and almost 28% after 20 years duration of diabetes while in type 1 diabetics, the prevalence is about 27% after 9

Introduction

1. Professor, Department of Medicine, LLRM Medical College, Meerut, Uttar Pradesh 2 . A s s o c i a t e P r o f e s s o r , D e p a r t m e n t o f Ophthalmology, L.L.R.M. Medical College, Meerut, Uttar Pradesh3. Senior Resident, Department of Medicine, L.L.R.M. Medical College, Meerut, Uttar Pradesh

Results : Serum triglyceride levels were found to be significantly higher in DR with CSME group as compared to DR without CSME (p=0.04). Other sub-fractions of lipid profile i.e. total cholesterol, HDL and LDL in both groups were not significantly different.

6,7years of diabetes. The term clinically significant macular edema (CSME), defined by the early treatment of diabetic

8retinopathy study (ETDRS) group , is used as an equivalent of DME to characterize the severity of macular edema and for the treatment guidelines. It is a complex disease of multifactorial origin. The most important pathway resulting in DME is disruption of the blood retinal barrier (BRB). While there are multiple risk factors which have been associated with the development and progression of diabetic retinopathy, the duration of the disease and the age of the patient are said to be strongest predictors. Poor glycemic control, dyslipidemia, microalbuminuria, increased body mass index (BMI) and smoking are some other factors supposed to be the p r e d i c t o r s f o r t h e d e v e l o p m e n t o f d i a b e t i c

9,10,11retinopathy . The early treatment diabetic retinopathy study (ETDRS) group8 and the Wisconsin Epidemiologic study of diabetic retinopathy6 found a statistically association between elevated serum total cholesterol and Low-density Lipoprotein (LDL) cholesterol and the severity of retinal hard exudation inpatients with diabetic

6 © JIMI � JAN - MAR 2018 � VOL. 12


The study was carried out in the department of Medicine and Ophthalmology, LLRM medical college, Meerut (U.P.) from August 2016 to August 2017. Ethical clearance was taken from LLRM medical College ethical committee. A total number of 70 patients of type 2 diabetes mellitus with diabetic retinopathy were included in the study. Out of them, 14 patients (8 males and 6 females) having CSME with diabetic retinopathy were taken as study group while the other 56 patients (30 males and 26 females) of diabetic retinopathy without CSME formed the control group.

retinopathy. Early detection and identification of the risk for the development of diabetic complications are important strategies to minimize the human suffering and costs incurred from the disease.

The current study was undertaken to determine the association of serum lipid profile with Clinically Significant Macular Edema in type 2 diabetes mellitus patients.

Materials and Methods

Accordingly, the patients were allocated to one of the following two groups: Group 1(study group; n=14): Type 2 diabetic patients with diabetic retinopathy along with CSME.

Group 2 (Control group; n=56): Type 2 diabetic patients with diabetic retinopathy without CSME.

Inclusion Criteria - Patients of Type 2 diabetes mellitus within the age group of 30 to 80 years - Duration of diabetes more than 6 months - Fitness to undergo a dilated fundus examination

Exclusion criteria 1. Co-existing ocular disorders like uveitis, opaque or hazy media, retinal vein/artery occlusion, retinitis pigmentosa, Vitreoretinal degenerations and dystrophies, high Myopia 2. Accelerated hypertension 3. Active infection 4. Patients on lipid lowering medications 6. Pupillary abnormalities which prevent adequate dilatation for fundus visualization 7. Recent ocular surgeries (< 6 month) 8. Pregnancy 11. Co-morbid conditions like diabetic nephropathy (grade 3 onwards), chronic Liver Disease or collagen vascular disease etc. 12. Psychiatric illnesses and substance abuse

For the presence of clinically significant macular edema: Patients were assessed by using slit-lamp biomicroscopic assessment with a 78D lens. The definition used for diagnosing CSME was the presence of one or more of the following as given by ETDRS8:

1. Retinal thickening at or within 500 micron of centre of macula2. Hard exudates at or within 500 micron of centre of the macula if associated with adjacent retinal thickening.3. Zone or zones of retinal thickening 1 disc area in size, at least part of which is within one disc diameter of centre of macula.

For the assessment of Best-corrected visual acuity (BCVA): It was assessed using illuminated Snellen's Chart. The BCVA of the worst eye was taken for analysis converting it to decimal equivalent for the purposes of statistical analysis. Detailed fundoscopy were done both with indirect ophthalmoscope with 20D lens and slit lamp biomicroscopy with 78D lens. Colour photograph centred on the macula were obtained using Zeiss fundus camera visucam lite.

For assessment of the severity of diabetic retinopathy (DR): Severity of DR was assessed according to the modified Early Treatment of Diabetic Retinopathy Study (ETDRS) protocol 7 as mild, moderate, severe non-proliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR).

The patients were subjected to fallowing series of laboratory investigations.

1. Complete Haemogram2. Fasting pasma glucose and post prandial plasma glucose profile3. HbAlc4. Fasting Serum Lipid profile:- Serum Total Cholesterol Serum High Density Lipoproteins (HDL) Serum Low Density Lipoproteins (LDL) Serum Very Low Density Lipoproteins (VLDL) Serum Triglycerides5. Liver function tests, Kidney function tests including urine analysis for microalubuminuria6. ECG7. Other investigations as per requirement.

Sampling method and Statistical tool: Patients were selected by Stratified random sampling after written informed consent. Data was analyzed using SPSS

(Statistical Presentation System Software) for windows software (version 20.0). All group data was presented as frequency distribution (proportion) and the average values were presented as means ± SD for the normal distribution data. p values of less than 0.05 were considered as statistically significant.


© JIMI � JAN - MAR 2018 � VOL. 12 7

Serum lipid profile : It was done using fasting blood samples to analyze total cholesterol, cholesterol components -and triglycerides utilizing the Dade Dimension Series using photometric enzymatic method. For the purpose of analysis dyslipidemia were defined as serum total cholesterol >200mg/dl, triglyceride levels >150mg/dl, LDL levels >100mg/dl and HDL<40 for men and <50 for women mg/dl according to NCEP, ATP III guidelines12.

Observations & ResultsPatients were divided into 2 groups as already described i.e. Group 1 (Study group): Diabetes with diabetic retinopathy with CSME (n=14) Group 2 (Control group): Diabetic retinopathy without CSME (n=56)

Table 1: Age, Duration of diabetes and BMI Distribution

Variable

Group 1 (Study

group,n=14)

Group 2 (Control group,n=56)

p-value

Age (Years)

53.1±12.85

54.77±7.98 0.55

Duration of

diabetes (Years)11.07±6.09 9.48±5.78 0.36

BMI (kg/m2) 22.76±2.94 22.86±3.03 0.90

Table 1 shows that mean age in Group 1 and 2 was 53.14±12.85 and 54.77±7.98 years, respectively and the difference was not statistically significant (p=0.55). The mean duration of diabetes in Group 1 and Group 2 was 11.07±6.09 and 9.48±5.78 years, respectively, which was also significantly not different from each other (p=0.36). The mean BMI value in Group 1 and Group 2 was 22.76±2.94 and 22.86±3.034, respectively which was not statistically significantly from each other (p=0.90).

Table 2: Mean value of various serum lipid sub-fractions and HbA1c in Group 1 and Group 2

VariableGroup 1

n=14

Group 2

n=56

p-value

Total SerumCholesterol

190.92 ± 48.82

185.18 ± 43.01

0.665

SerumTriglyceride 178.50 ±54.08 147.66 ± 48.43 0.041

Serum HDL 41.97 ± 9.81

41.21 ± 8.61

0.777

Serum LDL 112.54 ± 41.71 114.46 ± 34.85 0.914

HbA1c 10.01 ± 2.37 10.50 ± 2.10 0.439

Table 2 shows that mean triglycerides concentration in Group 1 and 2 was 178.50±54.08 and 147.66±48.43 mg/dl, respectively i.e. serum triglyceride levels were significantly higher in the DR subjects with CSME as compared to those without CSME (p=0.04). Other sub-fractions of lipid profile i.e. total serum cholesterol, HDL and LDL in both groups were not significantly different from each other. HbA1C levels were also not found to be significantly different in both the groups (p=0.43).

Fig. 1 shows association of CSME with various grades of severity of diabetic retinopathy. As it can be seen from this figure, 2 patients (6.25%) of CSME had mild NPDR, 6 patients (33.33%) had moderate NPDR , 5 patients (41.66%) had severe NPDR and 1 patient (12.5%) had PDR. On applying Chi- square test, this correlation of CSME with severity of diabetic retinopathy was found to be insignificant (p value=o.1826)

Fig. 1: CSME association with Severity of Diabetic Retinopathy

Table 3: Correlation of CSME with visual acuity

Visual acuityGroup 1(DR with

CSME, n = 14)

6/6 0(0%)

6/9 – 6/12 4(28.6%)

6/18 – 6/36 8 (57.1%)

��6/60

2(14.3%)

P value 0.0186

Table 3 shows association of visual acuity in CSME group. There was mild impairment of visual acuity (6/9 – 6/12) in 4 patients (28.6%), moderate (6/18 – 6/36) in 8 patients

(57.1%) and severe (� 6/60) in 2 patients(14.3%). This

association of diminution of visual acuity with CSME was found to be statistically significant with p value of 0.0186.

Table 4: Correlation of Severity of Diabetic Retinopathy without CSME with Visual acuity (Group 2, n=56)

Visual acuity Mild NPDR

(n=30)

Mod. NPDR(n=12)

Sev. NPDR

(n=7)

PDR(n=7)

6/6 0 0 0 06/9 – 6/12 12(40%)

3(25%)

2(28.3%)

1(14.3%)

6/18 – 6/36 16(53.3%)

7(58.3%)

4(57.1)

5(71.4%)

��6/60 2(6.7%) 2(16.7%) 1(14.3%) 1(14.3%)

8 © JIMI � JAN - MAR 2018 � VOL. 12


Table 4 shows the association of visual acuity with various grades of severity of diabetic retinopathy in the group having DR without CSME. As it can be seen from the table, though impairment of visual acuity was present in all the cases, the severity of impairment did not follow the linear trend for the severity of diabetic retinopathy. It can be because visual acuity depends on various other factors as well like presence of cataract, refractive errors etc.

Disturbances in lipid metabolism have been implicated in the pathogenesis of diabetic retinopathy. In the EURODIAB Prospective Study, a multicenteric cross-sectional study of diabetic complications and their risk factors, after adjustment for age, duration of diabetes, HbA1c and albumin excretion rate; elevated serum triglyceride levels were found to be a significant risk factor for moderate-severe nonproliferative retinopathy and

15proliferative retinopathy . DCCT investigators had also found that the severity of retinopathy was associated with increasing triglycerides and inversely associated with

13HDL levels . The present study have shown statistically significant correlation between CSME and raised total serum triglyceride levels (p=0.04) in type 2 diabetic patients. The mean values of serum triglycerides in Group 1 and Group 2 were 178.50±54.08 mg/dl and 147.66±48.43 mg/dl, respectively. However, other sub-fractions of serum lipid profile i.e. total cholesterol, HDL and LDL in both groups were not significantly different from each other, hence found to have no correlation with the

16development of CSME. In contrast, Miljanovic et al gives an insight into diabetes control and complications Trial (DCCT) study in which serum lipids levels of 1441 participants were studied and was found that there was a twofold increased risk of CSME with increased LDL cholesterol and a fourfold increased risk of CSME with increased total cholesterol to HDL ratio. Similarly, the risk of hard exudates increased more than twofold for subjects with total cholesterol, LDL cholesterol, or total to HDL cholesterol ratio and more than threefold for subjects with

16-17high triglycerides. Ucgun et al studied the importance of serum lipids in Exudative Macular Edema and found that total serum cholesterol and LDL levels were elevated in patients with macular edema and high hard exudates however serum triglyceride, HDL, VLDL levels were not different between the two groups. In India, study done by

17Rema et al in urban south Indians showed significant association of LDL cholesterol with DME (Diabetic macular edema).

Discussion Clinical Significant Macular Edema (CSME) is the major concern of visual loss in diabetic patients. In the present study as well, all the patients of CSME were having some or more degree of impairment of visual acuity. The pathophysiology of macular edema is complex and multifactorial. However, the common pathway that results in CSME is disruption of blood- retinal barrier leading to abnormal inow of uid into the neurosensory retina that can exceed the outow and cause residual accumulation of uid in the intraretinal layers of macula.

Numerous studies have shown an association of lipid fractions with macrovascular complications of diabetes but relatively less have looked at the association of serum lipids with microvascular complications such as diabetic retinopathy and probably further less have studied risk factors for CSME in patients with diabetes.

In the present study, the mean age in study group (Group1) and the control group (Group2) was not significantly different (p=0.55). The mean duration of diabetes in group 1 and group 2 was 11.07±6.09 and 9.48±5.78 years, respectively but the difference was also not statistically significant. However, there may be some bias in estimating the real duration of type-2 diabetes in these patients, as the diagnosis of diabetes could have been delayed due to lack of symptoms and the insidious onset of type-2 diabetes. Various studies have demonstrated age and duration of diabetes to be the strong risk factors for diabetic retinopathy but we could not find such association for the risk of developing CSME in type 2 diabetes.

In the present study, most of the subjects in both Group 1 and Group 2 were having poor glycemic control suggested by raised HbA1c levels and the difference in the mean values of HbAIc between the two groups was also not statistically significant. In contrast, glycemic control was effective in substantially reducing the incidence and progression of retinopathy in the diabetes control and

13complication Trial (DCCT) . The UKPDS (UK Prospective 14Diabetes Study) also showed that intensive glucose

control reduced the risk of a two step change in retinopathy by 21% at 12 years follow up.

The elevated lipid levels may be an additional risk factor for CSME, however, results have been inconsistent. Ozer et al conducted a study to evaluate the correlation of lipid profile and clinical presentation of macular edema in diabetes mellitus patient and found no correlation between serum lipid levels and macular edema severity in that study. Nonetheless, a relationship of lipids with CSME and hard exudates is biologically possible because elevated lipid levels are associated with endothelial dysfunction, which appears to play an important role in the pathogenesis of diabetic retinopathy, particularly in relation to breakdown of blood-retinal barrier. Elevated levels of LDL and triglycerides in diabetes mellitus have been linked with higher levels of advanced glycation end


© JIMI � JAN - MAR 2018 � VOL. 12 9

products, which are known to play an important role in the pathogenesis of diabetic complications. There may also be incorporation of triglycerides into the cell membrane leading to changes in membrane uidity and leakage of plasma constituents into the retina. This results in haemorrhage and edema in the retina. DCCT investigators had also found that the severity of retinopathy was associated with increasing triglycerides

13and inversely associated with HDL levels . Additionally, in a prospective study to investigate the inuence of serum lipids on the visual outcome of patients after central laser photocoagulation, Kremser et al found that patients with normal total cholesterol, LDL, HDL and triglyceride levels tended to have better results than those with abnormal lipid levels. They concluded that serum lipid fractions inuence both the course of diabetic macular

15-17edema as well as the success of laser photocoagulation .

ConclusionsOn the basis of present study, we conclude that there is a significant correlation between development of CSME in diabetic retinopathy and patient's serum triglyceride levels. Since CSME poses significant risk of diminution of vision and hence adversely affecting the quality of life of diabet ic pat ients , we recommend control l ing Hypertriglyceridemia via lifestyle modification and/or medical therapy to prevent the development and retard the progression of CSME in patients with diabetic retinopathy in type-2 diabetes.

Further studies are required to establish the causal relationship between serum lipid profile and CSME in diabetic retinopathy. If established, these data can lead to an additional support to current treatment guidelines for dislipidemia and diabetic retinopathy in diabetic patients. Rigorous triglyceride control for its other known health benefits may also lessen ocular morbidity and associated health care costs, thereby potentially improving quality of life and vision among patients with type 2 diabetes.

Limitations of the StudySmall sample size is the major drawback of this study. Moreover, in the present study CSME was diagnosed by Slit lamp biomicroscopy with 78D/ 90D lens. Because of the non-availability, the more sensitive method of assessing retinal thickening such as optical coherence tomography was not used.

Aiello L.M., “ Perspectives on diabetic retinopathy”,Am J Ophthalmol, 136,pp. 122-135,2003.Aiello L.P., Cahill M.T., Wong J.S.,“Systemic considerations in the management o f d iabet ic re t inopathy” , Am J Ophthalmol,132,pp.760 -776, 2001.Ciulla T.A., Amador A.G., Zinman B., “Diabetic retinopathy and diabetic macular edema: pathophysiology, screening, and novel therapies”,Diabetes Care,26,pp.2653-2664,2003.Klein R., Klein B.E.K., Moss S.E., Cruickshanks K.J., “The Wisconsin epidemiologic study of diabetic retinopathy: XV: t h e l o n g - t e r m i n c i d e n c e o f m a c u l a r e d e m a ” , Ophthalmology,102,pp.7-16,1995.White N.H., Sun W., Cleary P.A., Tamborlane W.V., Danis R.P., Hainsworth D.P., Davis M.D., DCCT-EDIC Research Group, “Effect of Prior intensive therapy in type 1 diadetes on 1 0 – y e a r p r o g r e s s i o n o f r e t i n o p a t h y i n t h e DCCT/EDIC:comparison of adults and adolescents”, Diabetes, 59,pp.1244-1253,2010.Chew E.Y., Klein M.E., Ferris F.E. 3rd, Remaley N.A., Murphy R.P., Chantry K. et al., “Association of elevated serum lipid levels with retinal hard exudate in diabetic retinopathy.Early Treatment Diabetic Retinopathy Study (ETDRS) Report 22”, Arch Ophthalmol., Sep.l 14,pp.1079-84, 1996.Muawyah D. Al-Bdour, Maha I. Al-Till, Khawla M. Abu Samra, “Risk factors for diabetic retinopathy among Jordanian diabetics”, Middle East African Journal of Ophthalmology, 15,pp. 77-80, 2008.Dornan T.L., Carter R.D., Bron A.J., Turner R.C., Mann J.I., 'Low density lipoprotein cholesterol: an association with the severity of diabetic retinopathy”, Diabetologia, 22,167-70, 1982.Miccoli R., Odello G., Giampetro O., Marchetti P., Cristofani R., Penno G. et al., “Circulating lipid levels and severity of diabetic retinopathy in type I diabetes mellitus”, Ophthalmic Res, 19,pp.52-6, 1987.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 High Blood Cholesterol in Adults. NIH Pub.No. 02--5215. Bethesda, MD: National Heart,Lung and Blood Institute, Sept, 284, 2002. Lyons T.J., Jenkins A.J., Zheng D., Lackland D.T., McGee D., Garvey W.T. et al., And The DCCT/EDIC Research Group, “Diabetic Retinopathy and Serum Lipoprotein Subclasses in the DCCT/EDIC Cohort”, Investigative Ophthalmology & Visual +Science, March, 45,pp. 910-918, 2004.Paromita K., Peacock I., Donnelly R., “The UK Prospective Diabetes Study (UKPDS): clinical and therapeutic implications for type 2 diabetes”, Br J Clin Pharmacol., November, 48(5),pp. 643–648, 1999 .

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ReferencesAiello L.P., Gardner T.W., King G.L., Blankenship G., Cavallerano J.D., Ferns F.L. 3rd, et al., “Diabetic retinopathy”, Diabetes Care, 21,pp. 143-56, 1998.Wild S., Roglic G., Green A., Sicree R., King H,“ Global prevelance of Diabetes. Estimates for the year 2000 and projections for 2030”, Diabetes Care, 27,pp.1047-1053, 2000.

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Sjolie A.K., Stephenson J., Aldington S. et al., “Retinopathy and vision loss in insulin-dependent diabetes in Europe. The EURODIAB IDDM Complications Study”, Ophthalmology, Feb;,104(2),pp.252-60, 1997. Miljanovic B., Glynn R.J., David M., Nathan, Joann E., Manson, Debra A. et al., “Prospective Study of Serum Lipids and Risk of Diabetic Macular Edema in Type1 Diabetes”, Diabetes , Nov, 53,pp. 2883-2902, 2003. Ucgun N.I., Yildirim Z., Kilic N., Giirsel E., “The importance of serum lipids in exudative diabetic macular edema in type 2 diabetic patients”,Annals of -the New York Academy of Sciences, Apr, 1100,pp. 213-217, 2007.

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10 © JIMI � JAN - MAR 2018 � VOL. 12


Study of Echocardiography In Normotensive Diabetic Patients:A North India Based Observational Study

Original Article

1 2 3 4Shri Krishna Gautam , Brijesh Kumar , Daya Shankar , Gulab Jha

AbstractAim: To study the left ventricular systolic and diastolic dysfunction with 2D Echaocardiography , M –mode, colour doppler in normotensive diabetic patients using . Also is there any correlation exist between diabetic nephropathy and LV dysfunction.

Material and Methods : We studied 50 patients of diabetes mellitus with no arterial hypertension ,and 10 healthy control .All participants underwent echocardiography. With Echo- Doppler techniques, lateral E' peak velocity, atrial velocity (A'), their ratio (E'/A') Isovolumic relaxation time (IVRT)(Normal 60-100 msec), Deceleration time of mitral 'E' curve (DT of E)(Normal 150-200msec)and systolic velocity (S') were measured. Diastolic dysfunction was diagnosed by tissue Doppler imaging, and the following criterion was met: E'/A' ratio <1.

Result and Discussion: Using 2D echo and colour doppler ,the majority of patients had Ejection fraction between normal value 31 (62%) with mean age group 41 years whereas 19(38%) patients had systolic dysfunction with mean age group 54 years . The mean Ejection fraction of patients was 57.56% with standard deviation 8.25. Ejection fraction in control group between normal value 7(70%) with mean age 42 years and 3(30%) had systolic dysfunction with mean age 56 years. Mean of ejection fraction 57.8 and standard deviation5.977 and P value of these group is 0.7694

The majority of patients had E/A ratio <1, 28(56%) accounting for diastolic dysfunction with mean age 56 years whereas 22(44%) had E/A ratio within normal limits with mean age 43 years ,1-2.E/A ratio being the most specific and sensitive indicator of diastolic dysfunctions. The mean E/A of patients was 1.10 with standard deviation 0.27. .28 (56%) patients had IVRT (msec) value >100 with mean age 46 years, denoting significant diastolic dysfunction, whereas 22(44%) of patients were within normal limits, 60-100. Only 20% in control group had IVRT >100 msec with mean age 58 years . The mean of IVRT (msec) of patients was 96.7(msec) with standard deviation 9.88.The mean of IVRT in control group 84.6 and standard deviation 15.94. Only 20% in control group had E/A ratio <1 with mean age 58 years .The mean E/A ratio of control group was 1.357 and standard deviation was 0.3036.28(56%) patients had value of DT of E (msec) >200 with mean age 47 years, denoting significant diastolic dysfunction, whereas 22(44%) of patients within normal limits, 150 - 200. The mean of DT of E(msec) of patients was 200.42(msec) with standard deviation 18.64. . Only 20%in control group had DT of E >200 (msec) with mean age 58 years .The mean of DT in control group 189.8 and standard deviation 17.44,No correlation between microalbuminuria and left ventricular dysfunction. that means microalbuminuria not associated with left ventricular dysfunction( p> 0.05).


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Diabetes mellitus is a disease known to mankind for the past 2500 years.Diabetes mellitus has become a leading cause of premature death, disability and high health care costs. It is a silent killer disease. The World Health Organisation estimates that the disease burden of diabetes mellitus world over would be more than 500 million in 21st century. Indians are genetically more susceptible to diabetes mellitus compared to other races .A relationship between diabetes and heart failure has been discussed for many years.Subclinical abnormalities of left ventricular function are recognized in both Type 1 and Type 2 diabetes mellitus. Studies using doppler echocardiography have confirmed the findings of abnormal diastolic function as an early indicator of cardiac involvement in asymptomatic patients with Type 1 or Type 2 diabetes mellitus.Diabetic subjects have been reported to develop congestive heart failure in the absence of coronary heart disease, hypertension or any known structural heart disease. The term 'diabetic cardiomyo-pathy' has been introduced for this condition. It has been suggested that microangiopathic lesions of the myocardium, altered composition and fibrosis of myocardial interstitium and accumulation of lipids in myocardial cells are involved in pathogenesis of diabetic cardiomyopathy.This study was carried to study the left ventricular systolic and diastolic dysfunction in normotensive diabetic patients. Also is there any correlation exist between diabetic nephropathy and LV dysfunction.

IntroductionInclusion criteria: 1. Age more than 21year, both males and females.2. Normotensive asymptomatic diabetic patients (diagnosed as per ADA guidelines 2010) a. HbA1C greater or equal to 6.5%. b. Fasting plasma glucose >126mg/dl.Fasting is define as no caloric intake for at least 8hrs. c. 2-hr plasma glucose>200mg/dl during OGTT. d. In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis ,a random plasma glucose>200mg/dl.

1. Associate Professor of Medicine GSVM Medical College Kanpur UP2. Associate Professor of Medicine GSVM Medical College Kanpur UP3. Senior Resident Medicine GSVM Medical College Kanpur UP4. Junior Resident Medicine GSVM Medical College Kanpur UP

Materials and MethodsThis cross-sectional study was conducted in the department of medicine GSVM Medical college, Kanpur, among the normotensive diabetic patients who attended the medical OPD of LLRH hospital, during the study period of January 2011 to January 2012.The study included fifty patients of diabetes mellitus with no arterial hypertensonwho were selected according to the following inclusion and exclusion criteria:

Exclusion criteria: Age less than 21year, both males and femalesHypertensive patients.Patient with symptoms of CHF and CAD.Patients with CKD.Patients with history suggestive of thyroid disorders.Patients on drug therapy with drugs known to cause cardiomyopathy (eg. Donorubicin, bleomycin, adriamycin, etc.)Patients of Autonomic Neuropathy.Patients associated with any comorbid conditions ( CLD, Malignancy, any steroid therapy).

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A comprehensive history and examination (including fundus examination) was conducted and the following investigations performed and systematically documented:

Complete blood count.

Urine- routine and microscopy

Urine sugar and ketones.

Kidney function test.

Fasting blood sugar

Post prandial blood sugar.

Glycated hemoglobin.

Chest X ray.

ECG

Microalbuminurea.

TMT (wherever indicated )

Thyroid profile (wherever indicated).

Lipid profile (wherever indicated).

Echocardiography

Fundus examination

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Statistical Analysis: Data was compiled using Microsoft Excel and analysed using SPSS 20.0. Categorical variables were analysed using percentages and Chi square test. Two-tailed p value less than 0.05 was considered significant.

Echocardiography:2D echocardiography, M-mode and colour doppler examination were done by Agilent Image Point machine with 2.5 to 5 mHz probes. All recordings were done with patients in supine and left lateral position. The transducer was placed in the left parasternal, apical and subcostal areas of chest and the parasternal long axis and short axis were taken to record various dimensions and measurements.

Figure 1: Showing grading of diastolic dysfunction

Figure 2: Showing normal parameters of diastolic function

Echocardiographic Measurements:For the systolic and diastolic function of the left ventricle following measurements were done (in four chamber view).A. Systolic Function: In the present study following parameters were used to assess left ventricular systolic function. 1. Fractional shortening (FS) 2. Ejection fraction (EF)

(a) Fractional shortening (FS): It is the percent change in left ventricular cavity dimensions and is derived from the following equation as:

FS =LVIDd – LVIDs x 100

LVIDd

WhereLVIDd= Left ventricular internal diameter at end diastoleLVIDs = Left ventricular internal diameter at end systoleNormal values of FS: 28 to 42%In the present study FS < 25% was taken as significant systolic dysfunction.

Figure 3: Showing stages of diastolic dysfunction

(b) Ejection fraction: It represents ratio of stroke value to end-diastolic volume. It is computed as follows.

EF = LVEDV – LVESV x 100%

EDV

WhereLVEDV = End diastolic volumeLVESV = End systolic volumeNormal values : 62-85%In the present study, EF < 50% was taken as significant.

(B) Diastolic FunctionDiastolic function of left ventricle is best assessed by evaluating the mitral inow velocity curves (MIVC) by Echo-Doppler techniques. In this study the following parameters were used to assess LV diastolic dysfunction.

Mitral 'E' velocity (Peak velocity of early mitral ow)Mitral 'A' velocity (Peak velocity of late (atrial) mitral ow)Mitral E/A ratio (Normal 1-2)Isovolumic relaxation time (IVRT) (Normal 60-100 msec)5. Deceleration time of mitral 'E' curve (DT of E) (Normal 150-200 msec). Mitral ow velocities were measured by pulsed wave doppler with sample volume placed between the leaet tips. It is important to keep it between the leaet tips as doppler parameters are dependent on the sample volume location.

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© JIMI � JAN - MAR 2018 � VOL. 12 13

5. Deceleration time of mitral 'E' curve (DT of E) (Normal 150-200 msec). Mitral ow velocities were measured by pulsed wave doppler with sample volume placed between the leaet tips. It is important to keep it between the leaet tips as doppler parameters are dependent on the sample volume location.

Results Fifty patients who are normotensive asymptomatic Type 2 diabetes were selected for the present study, during the study period of January 2011 to January 2012. 10 Age and sex match control group were also studied for valid comparison. All the patients were evaluated for left ventricular systolic and diastolic dysfunction.

A. Age distribution in present study.

Table 1: Showing age distribution in present study ( years)

AGE(YEARS) Patients(number and percentage)

Control(number and percentage)

20 – 30 6 (12%)

1(10%)31 -40 8 (16%) 2(20%)

41 -50 16 (32%)

3(30%)

>50 21 (42%) 4(40%)Total 50(100%) 10(100%)

The following observations can be made for the above table.The majority of patients were of age > 51 years of age of life

21(42%), whereas 16(32%) of patients were �41 -50 years.

The mean age of patients was 48.8yrs.The mean age of control group were 47.4.

B. Sex distribution of patients

Table 2: Showing sex distribution of patients in present study.

Sex Patients

(number and percentage)

Control


Male 28(56%) 6(60%)

Female 22(44%)

4(40%)

Total 50(100%) 10(100%)

Males were 28 (56%) as compared to females 22 (44%) in case group while in control group 6 (60%) were male and 4(40%) were female .

C. Duration of Diabetes:

Table 3: Showing duration of diabetes in present study.

duration of diabetes in (year) Patients(number and percentage)

< 3 2 (4%)3-6 19(38%)7 -9 14(28%)

>10 15(30%)

The majority of the patients are belonged to duration of diabetes between 3 -6 years. The mean duration of diabetes of patients was .8.12yrs with standard deviation 4.54.

Table 4 : Level of microalbuminuria in patient of present study

Microalbuminuria (mg/dl per 24 hrs) Patients (number and percentage)<30 19 (38%)

30 -60 14(28%)60-100 10(20)100-300 7(14%)

The following observations can be made for the above table. In the majority of patients, microalbuminuria was found. The mean of micro albuminuria was 209.16 and standard deviation 32.83.Showing micro albuminuria in patient of present study.

Table 5: Fundus changes in patients of present study

Retinopathy Patients (number and percentage)Yes 16(32%)No 34(68%)

In majority of patients, fundus changes were not found.

Table 6: Showing retinopathy

Nonproliferative retinopathy Patients (number and percentage)Very mild 6(12%)

Mild 4(8%)

Moderate 1(2%) Severe 1(2%)

Very severe 0

Proliferative retinopathy Patients (number and percentage)

NVD (NEOVASCULARISATION AT THE OPTIC DISC)

2(4%)

NVE(NEOVASCULARISATION AT ELSEWHERE)

2(4%)

G. Echocardiographic measurements in present study.(i) Systolic parameters1. Ejection Fraction (%)Table 7: Ejection Fraction (%)

Ejection fraction (%)

Patients(number and percentage)

Mean age in years

Control (number and percentage)

Mean age

<30 0 0 30 -44 2(4%) 57 0 45 -54 17(34%)

54

3(30%)

56

>55 31(62%) 41 7(70%) 42Total 50(100%) 10(100%)

14 © JIMI � JAN - MAR 2018 � VOL. 12


P-value =0.7694, which is statistically not significant.The following observations can be made for the above table. The majority of patients had Ejection fraction between normal value 31 (62%) with mean age group 41 years whereas 19(38%) patients had systolic dysfunction with mean age group 54 years . The mean Ejection fraction of patients was 57.56% with standard deviation 8.25.Ejection fraction in control group between normal value 7(70%) with mean age 42 years and 3(30%) had systolic dysfunction with mean age 56 years. Mean of ejection fraction 57.8 and standard deviation5.977 and P value of these group is 0.7694years and 3(30%) had systolic dysfunction with mean age 56 years. Mean of ejection fraction 57.8 and standard deviation5.977 and P value of these group is 0.7694

Only 20% in control group had E/A ratio <1 with mean age 58 years .The mean E/A ratio of control group was 1.357 and standard deviation was 0.3036

2. Fractional shortening (%)Table 8: Fractional shortening (%)

Fractional shortening(%)


Mean age (in years)


Mean age(in

years)<25 3(6%) 57 0 25-45 46(92%)

48

10(100%)

47>45 1(2%) 32 0Total 50(100%) 10(100%)

P-value =0.6514, which is statistically not significant.The following observations can be made for the above table. The majority of patients had Fractional shortening value between normal limits 46(92%) with mean age 48 yearsWhere as 3(6%) patients had fractional shortening <25, means systolic dysfunction with mean age 57 years. The mean fraction shortening of patients were 36.26 with standard deviation 5.34. In control group all had fractional shortening with in normal limit with mean age 47 years .The mean ejection fraction of control group was 33.6 and standard deviation was 4.477. and P value of these group was 0.6514.

(ii) Diastolic parametersTable 9: Diastolic parameters

E/A ratio Patients(number and percentage)

Mean age (in years)


Mean age(in years)

<1 28(56%) 56 2(20%) 581-2 22(44%)

43

8(80%)

42

>2 0 0Total 50(100%) 10(100%)

P-value =0.0377, which is statistically significant.The following observations can be made for the above table. The majority of patients had E/A ratio <1, 28(56%) accounting for diastolic dysfunction with mean age56 years. whereas 22(44%) had E/A ratio within normal limits with mean age 43 years ,1-2.E/A ratio being the most specific and sensitive indicator of diastolic dysfunctions. The mean E/A of patients was 1.10 with standard deviation 0.27.

Table 10: Isovolumetric Relaxation Time (IVRT)

IVRT(msec) Patients(number and percentage)

Mean age (in years)

Control


Mean age (in years)

<60 0 0 60-100 22(44%)

41

8(80%)

42

>100 28(56%)

46

2(20%)

58

Total 50(100%) 10(100%)

P-value =0.03693, which is statistically significant.The following observations can be made for the above table.28 (56%) patients had IVRT (msec) value >100 with mean age 46 years, denoting significant diastolic dysfunction, whereas 22(44%) of patients were within normal limits, 60-100. Only 20% in control group had IVRT >100 msec with mean age 58 years . The mean of IVRTmsec) of patients was 96.7(msec) with standard deviation 9.88.The mean of IVRT in control group 84.6 and standard deviation 15.94.

Table 11 : Deceleration Time of E (DT of E)

DT of E (msec) Patients(number and percentage)

Mean age (in years)

Control


Mean age (in years)

<150 0 0 150-200 22(44%) 43 8(80%) 42

>200 28(56%) 47 2(20%) 58Total 50(100%) 10(100%)

P-value =0.03647, which is statistically significant.The following observations can be made for the above table. 28(56%) patients had value of DT of E (msec) >200 with mean age 47 years, denoting significant diastolic dysfunction, whereas 22(44%) of patients within normal limits, 150 - 200. The mean of DT of E(msec) of patients was 200.42(msec) with standard deviation 18.64. . Only 20%in control group had DT of E >200 (msec) with mean age 58 years .The mean of DT in control group 189.8 and standard deviation 17.44,

Table;12: Duration of diabetes in present study with correlation of left ventricular dysfunction.

duration of diabetes in (year)


Left ventricular dysfunction found in

patients< 3

2 (4%)

0

3-6 19(38%) 5(26.3%)7 -9

14(28%)

6(42.8%)

>10 15(30%) 12(80%)

r value is 0.66 and P VALUE is<0.050, which is positive correlation between duration diabetes and left ventricular dysfunction, that means when duration of diabetes increases, left ventricular dysfunction also increases


© JIMI � JAN - MAR 2018 � VOL. 12 15

Table13: Correlation of microalbuminuria with left ventricular dysfunction

Microalbuminuria (mg/dl per 24 hrs) (number and percentage)

Left ventricular dysfunction found in patients

<30 19(38%)

14(73%)30 -60 14(28%)

10(71%)

60-100 10(20%) 8(80%)

100-300 7(14%) 4(28.5%)

P value >0.05No correlation between microalbuminuria and left ventricular dysfunction. that means microalbuminuria not associated with left ventricular dysfunction

DiscussionEpidemiological data indicate a greater risk of cardiovascular morbidity and mortality particularly heart failure, in diabetic patients compared to non-diabetic patients. Diabetic cardiomyopathy has been proposed as an independent cardiovascular disease and left ventricular diastolic dysfunction may represent the first stage of diabetic cardiomyopathy. Several studies have shown the evidence of left ventricular diastolic dysfunction in asymptomatic, normotensive, Type 2 diabetic patients. However, the exact causes and mechanisms remains unclear. Sanderson et al. and Shapiro et al. suggest that impairment of diastolic function of left ventricle, i.e. its filling abnormalities are far more common than systolic dysfunction. In the present study an attempt has been made to evaluate left ventricular function by m-mode, 2-D echo and colour doppler studies in type 2 diabetes patients was done.Fifty patients who are normotensive asymptomatic Type 2 diabetes were selected for the present study. 10 people age and sex match control group were also studied forvalid comparison, during the study period of January 2011 to January 2012. All patients were evaluated for the left ventricular systolic and diastolic dysfunction.

1. Age of the patients: In the present study age of the patients ranged from 30 to 60 years of life mean age was 48.8±12.4 years. The majority of patients belonged to mid fourties and beyond. In all previous studies, national and international, the relation of diabetes with cardiac abnormalties had grown stronger with passage of time i.e. years of life.In Rajesh Rajput et al 2002.study mean age was 50.12±7.75.

2. Sex Incidence: From the present study, it can be observed from the demographic data collected, male patients 28(56%) were more as compared to female patients 22(44%).In Rajesh Rajput et al.2002 study 54% were male and 46% were female

3. Duration of diabetes: In present study, the majority of patients had diabetes for duration of <10 years of life 35(70% which is positive correlation between duration diabetes and left ventricular dysfunction. That means when duration of diabetes increases, left ventricular dysfunction also increases) (J Am SocEchocardiogr2001 ). ). An inverse correlation was found between the duration of diabetes and both the ejection fraction (r = −0.53, P< 0.05) and E/A ratio (r = −0.4, P<.05)

4. Microalbuminuria: In the present study majority of patients were havingpoteinuria of different range 3 1 ( 6 2 % ) w h i l e 1 9 ( 3 8 % ) p a t i e n t n o t h a v i n g proteinuia.There is a no correlation of proteinuria with left ventricular dysfunction. MehtapCakir et al 2003 microalbuminuria is an independent marker for cardiovascular morbidity and mortality however its relation with diastolic dysfunction in normotensive, well-controlled type 2 diabetic patients is not clearly documented.J Am CollCardiol. 2003 stated that Albuminuria is independently associated with LV systolic and diastolic dysfunction in Type 2DM;

5. Fundus changes: Majority of patient were not having retinopathy 34(68%). 16(32%) of patients having retinopathy in which 12(24%) patients were having nonproliferative type retinopathy. 4 (8%) patient were developed proliferative type of retinopathy.

Echocardiographic Measurements1. Assessment of Systolic Function: In the present study, LV systolic function was assessed by using ejection fraction and fractional shortening as important parameters through m-mode and 2D echocardiography, left ventricular ejection fraction and fractional shortening has been calculated and analysed.

A - Ejection fraction: In the present study, majority of patients 31(62%), were within normal limit i.e>55%, whereas 1 9(38%), patients showed systolic dysfunction, i. e <55%. 17 (34%),having EF 45 -54 and 2(4%) patients with Ejection fraction 30 -44.In control group 3(30%) had ejection fraction <55 which showed systolic dysfunction .In both case and control group EF decreases with increasing age. This systolic dysfunction was due to ageing effect not due to diabetes. In this study P value =0.7694 which is statistically not significant.

B - Fractional shortening (%): In the present study, majority of patients 46(92%), had Fractional shortening value within in normal range, i. e 25-45%, whereas 3(6%), patients had significant reduction in Fractional shortening, thus, denoting systolic dysfunction and only 1(2%) of patients with value >45% of fractional

16 © JIMI � JAN - MAR 2018 � VOL. 12


shortening. In this study P value =0.6514 which is statistically not significant.

Abdul Khaliq M.H.Annonu 2001Patients with NIDDM and no symptoms of cardiovascular disease have a reduced LV systolic function as compared with healthy subjectsRajesh rajput et al 2002 functions of systolic LV were within normal range

2. Assessment of Diastolic parameters

A. E/A ratio: In the present study, majority of patients 28(56%), had value of E/A <1, thus denoting diastolic dysfunction and 22(44%) of patients had value between 1-2. 28 patients had E/A ratio of < 1 constituting 56% of study group. 22 patients had E/A ratio >1. E/A < 1 is very sensitive and specific indicator of LV diastolic dysfunction. In the present study more than half of the patients had LV diastolic abnormalities inspite of relatively normal LV systolic function . In this study P value =0.0369 which is statistically significant (J Am SocEchocardiogr 2001.)An inverse correlation was found between the duration of diabetes and both the ejection fraction (r = −0.53, P< .05) and E/A ratio (r = −0.4, P< .005).B.Isovolumetric Relaxation Time (IVRT):The prolongation of IVRT more than 100 msec is a significant indicator of early LV diastolic dysfunction. In the present study, 28(56%), patients had IVRT of > 100. All these patients also had E/A ratio of < 1. IVRT was within normal range, i. e 60-100, in 22(44%), of patient. In this study P value =0.03693 which is statistically significant.C. Deceleration time of E (DT of E): In the present study, DT of E was >200 m sec in 28(56%) patients. All these patients had E/A < 1 and IVRT > 100 msec suggestive of early diastolic dysfunction. 22 patients (44%) had DT of E between 150 m sec to 200 msec. In this study P value =0.03647 which is statistically significant.In the present study 28(56%) patient had diastolic dysfunction out of 50 patients.KhurshidA Khan et al was noted that in 30(60%) patient had diastolic dysfunction out of 50 patient.So therefore from the present study we here with conclude that in patients of diabetes mellitus without hypertension, echocardiography reveal diastolic dysfunction in 56% of patients. This is also correlated with longer duration of diabetes.We could not find any correlation with other stigmata of diabetes like microalbuminuria and retinopathy. Probable cause of diastolic dysfunction may be due to accelerated atherosclerosis and ageing in these patient

Fifty patients who are normotensive asymptomatic type 2 diabetes were selected for the present study. 10 people Age and sex match control group were also studied for valid comparison. All the patients were evaluated for left ventricular systolic and diastolic dysfunction.

Conclusion

Following conclusions are drawn from the present study-

Out of 50 cases 28 were male and 22 were female. While in control group 6 were male and 4 were female.The mean age in case group was 48.8year and in control group was 47.4 year.The mean duration of diabetes of patients in the study 8.12 years.Majority of cases were having microalbuminuria with mean 209.16 mg/dl/24hr.In majority of cases no retinopathy were found.LV diastolic dysfunction is commonly seen in asymptomatic normotensive Type 2 DM patientsL V systolic dysfunction was also seen in a small number of asymptomatic normotensive Type 2 DM which was also present in control group. Systolic dysfunction was increases with increasing age.Left ventricular dysfunction increases as the duration of diabetes increases.Left ventricular dysfunction had no correlation with microalbumiuria.

ReferencesAm SocEchocardiogr 2001;14:885-91.) Diastolic dysfunction in asymptomatic type 2 diabetes mellitus with normal systolic functionAppleton Christopher P. The echodoppler evaluation of left ventricular diastolic function – a current prospective. In: Cardiology Clinic – Diastolic Function and Dysfunction, Saunder J Kovascs (ed). Philadelphia: WB Saunders Company 2000; 600.Bell DS. Diabetic cardiomyopathy. A unique entity or a complication of coronary artery disease? Diabetes Care. 1995;18:708-14.Bella JN, Devereux RB, Roman MJ, et al. Separate and joint effects of systemic hypertension and diabetes mellitus on left ventricular structure and function in American Indians (the Strong Heart Study). Am J Cardiol. 2001;87:1260-5.Bergstrom A, Andersson B, Edner M, Nylander E, Persson H, Dahlstrom U. Effect of carvedilol on diastolic function in patients with diastolic heart failure and preserved systolic function. Results of the Swedish Doppler-echocardiographic study (SWEDIC). Eur J Heart Fail. 2004;6:453-61.

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Cosson S, Kevorkian JP. Left ventricular diastolic dysfunction; An early sign of diabetic cardiomyopathy. Diabetes Metab 2003; 29:455-466Dickstein K, Cohen-Solal A, Filippatos G, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur Heart J. 2008;29:2388-442GaniBajraktari. Non-insulin dependent diabetes as an independent predictor of asymptomatic left ventricular diastolic dysfunction. Croat Med J 2005; 46(5):225-231.Henry RM, Paulus WJ, Kamp O, et al. Deteriorating glucose tolerance status is associated with left ventricular dysfunction--the Hoorn Study. Neth J Med. 2008;66:110-7.J Am CollCardiol. 2003;41(11):2022-2028. doi:10.1016/S0735-1097(03)00403-0, association of albuminuria with systolic and d ias to l ic le f t ventr icular dysfunct ion in type 2 diabetes.vollume41,issue11,june2000Khurshid A Khan, Sheikh Jalal, Rauf M. Baba, Vicar M. Jan, Hilal A. Rather, Mohammad S. Alai, Nazir A. Lone, A.

RauoofMalik . Prevalence of diastolic dysfunction in normotensive asymptomatic patient with Type 2 diabetes mellitusjournal.9med.net/html/qikan/.../20080831185206708_205791.htmlMehtapCakir,NilgünBaskal, SevimGüllü, Murat Erdogan, ElhanAtilla,ÇetinErol,GürbüzErdogan,2003Microalb,uminuria is an independent marker for cardiovascularmorbidity andmortality however its relation with diastolic dysfunction in normotensive, Turkish Journal of Endocrinology and metabolism ,2003,1;23-29. Nagueh SF, Middleton KJ, Kopelen HA, Zoghbi WA, Quinones MA. Doppler tissue imaging: a noninvasive technique for evaluation of left ventricular relaxation and estimation of filling pressures. J Am CollCardiol. 1997;30:1527-33Poirier Paul, Peter Bogaty, Carline Garneall. Diastolic dysfunction in normotensive men with well controlled type 2 diabetes mellitus. Diabetes Care 2001; 24(1):5-10.R a j e s h R a j p u t , J a g d i s h , S i w a c h S B , R a t t a n A . Echocardiographic and Doppler assessment of cardiac functions in patients of non-insulin dependent diabetes mellitus. JIACM 2002; 3(2):164 168.

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1. Junior Resident, Department of Medicine, Sri Ram Murti Smarak Institute of Medical Sciences, Bareilly, UP, India.2. Associate Professor, Department of Medicine, Sri Ram Murti Smarak Institute of Medical Sciences, Bareilly, UP, India.3. Professor and Head of Department, Department of Medicine, Sri Ram Murti Smarak Institute of Medical Sciences, Bareilly, UP, India.

Predictive Value of ECG Patterns In Acute MI

Original Article

1 2 3Chetan Chaturvedi , Smita Gupta and Sharat Johri

AbstractObjectives: To investigate the accuracy and predictive value of the patterns of 12-lead ECG in acute myocardial infarction.

Methods: We reviewed abnormal ECGs obtained during myocardial infarction with angiographically documented single vessel disease. All the leads except aVR were evaluated individually according to a modification of the Minnesota code.

Results: A total of 70 patients with patients having documented CAD on angiography. The presence of Q waves, ST-segment elevation and T-wave inversion in leads I, aVL and V1-V4 were all highly correlated with the presence of left anterior descending coronary artery disease (p < 0.001), and the same ECG findings in leads II, III and aVF were associated with right (RCA) or circumex coronary artery (LCx) narrowings (p < 0.001). In contrast, ST depression alone was not useful in predicting the site of coronary artery narrowing. Q waves correctly predicted the location of the coronary disease in 93% of cases, ST elevation in 87%, T-wave inversion in 86%, and ST depression in 60%.

Conclusions: Our data show that these findings should lead to a better understanding of the value and limitations of the 12-lead ECG in localizing coronary artery disease. The ECG location of ST depression is not very useful in predicting the location of coronary artery disease. No electrocardiographic criteria distinguished RCA from LCx disease, even in patients with a right-dominant circulation.

KEY WORDS- Electrocardiogram patterns, coronary artery disease, predictive value, single vessel disease

IntroductionThe increased use of coronary angiography and the progress made in various diagnostic imaging techniques for the diagnosis of ischemic heart disease (IHD) currently allows highly accurate diagnosis and treatment during the early phase of myocardial infarction (MI). However, the standard 12-lead electrocardiogram (ECG) is still the most common, basic examination method in daily clinical practice. Because of the small number of lead

points and the absence of points on the right chest and the back, the location of the coronary artery lesions in IHD is roughly divided into the anterior wall and inferoposterior

1–3wall regions, and a more detailed diagnosis of the location is often more difficult.4 In addition, for anterior wall infarction, when the lesion is located more proximal than distal to the left anterior descending coronary artery (LAD), the infarct area extends further. In general, inferoposterior wall infarction related to the left circumex coronary artery (LCX) or right coronary artery (RCA) is viewed as having favourable prognosis,5 but an infarction of the proximal region of the RCA frequently involves the right ventricle and often the prognosis is

5,6poor. Therefore, bearing reperfusion therapy in mind, a more detailed diagnosis of the coronary artery lesions

7,8responsible for the MI is required.

Unfortunately, there is only limited documentation for these correlations between the location of coronary artery narrowings or occlusions and the findings of Q waves

9,10during myocardial infarction. There is even less


© JIMI � JAN - MAR 2018 � VOL. 12 19

documentation of the accuracy of electrocardiographic ST-segment or T-wave changes in identifying the site of injury or ischemia during infarction. Studies are often confounded by the inclusion of patients with multivessel coronary artery disease, which makes it difficult to

determine in which vascular distribution ischemia occurred. Nonetheless, patients who develop ST depression in leads II, III and aVF during angina are commonly referred to as having "inferior wall ischemia" and are often presumed to have RCA disease; similar associations are often drawn between ST depression in anterior precordial leads and LAD disease, and between ST depression in so-called lateral leads I and aVL and LCx

11disease.

Aims and Objectives of StudyCorrelation between the ECG leads and anatomic location of infarction has been repeatedly confirmed. We undertook the present study to evaluate the predictive value of various ECG changes in acute myocardial infarction in localising the site of coronary artery disease.

MethodsPatient Selection: The study was retrospective, controlled

trial in which patients of acute Myocardial Infarction were selected who had given informed consent for the procedure. The onset of a MI is diagnosed from typical chest pain with characteristic ECG findings and elevation of the cardiac enzymes in the serum. The present study enrolled 70 patients with a first episode of MI (49 anterior wall , 21 inferoposterior wall) who underwent revascularization of the coronary artery in the first 12 h by percutaneous transluminal coronary angioplasty (PTCA) in Department of Medicine, Sri Ram Murti Smarak Institute of Medical Sciences, Bareilly, Uttar Pradesh. Patients were considered to have one-vessel disease only if 70% or greater diameter narrowing in one of the three major coronary arteries (LAD, RCA or LCx) and without narrowing (> 40%) in the other two coronary arteries or their branches. No patient with significant narrowing in the left main coronary artery was included.

Inclusion Criteria: The study population consisted of all 70 patients of any age group who met the following criteria: one-vessel coronary disease as defined above with no significant valvular or congenital heart disease; no bundle branch block or left ventricular hypertrophy on resting ECG; and an abnormal 12-lead ECG recorded during myocardial infarction documented by cardiac enzyme elevations.

Electrocardiogram: Al l ECGs were reviewed independently only changes graded as abnormal by both were included. Serial ECGs recorded during the course of myocardial infarction were analyzed, and 11 leads (all except aVR) were evaluated individually according to a

12modification of the Minnesota code. Q waves were considered significant when their duration was at least 0.04 second in any lead or at least 0.03 second in association with a Q/R ratio greater than 1:3 in leads I, II and V2-V6. ST-segment elevation was considered significant if the J point was elevated more than 1 mm and the ST segment remained elevated more than 1 mm and 0.08 second beyond the J point. Similarly, ST-segment depression was considered significant if the J point was depressed by more than 1 mm and the ST segment was horizontal or down sloping and remained 1 mm below the baseline and 0.08 second beyond the J point. T-wave inversions were considered significant in leads I, II and V2-V6 when the net amplitude was negative; in leads III, aVF, and aVL, when the QRS was isoelectric or mainly upright and the net T wave amplitude was negative; and in lead aVL when the net amplitude was negative and represented a change from a previous tracing.

Statistical Evaluation : Data were tabulated comparing the prevalence of Q waves, ST elevation, ST depression and T-wave inversion in each electrocardiographic lead in patients with one-vessel disease involving the LAD, RCA and LCx. To examine the importance of "reciprocal" ST changes, additional tables were prepared showing the prevalence of ST depression in tracings with and without concomitant ST elevation in any lead. The prevalence of each ECG change was compared between patients with LAD and non-LAD (RCA or LCx) disease, lead by lead, with the chi-square test and, where appropriate, by Fisher's exact test.

ResultsPatient Population: The study group consisted of 52 men and 18 women, ages 27-73 years (mean + SD 48 ± 9 years). Of the total 70 patients 40 had isolated LAD disease,24 patients had one-vessel RCA disease and 6 patients had disease limited to the LCx. Four patients with LCx disease had a right-dominant circulation and two had a left-dominant circulation.

Myocardial Infarction: During the course of myocardial infarction, the location Of Q waves was highly predictive of the location of the obstructed coronary artery (table 1). Fifteen patients with LAD disease developed significant Q waves in one or more of leads I, aVL and V1-V4; with one

20 © JIMI � JAN - MAR 2018 � VOL. 12


Myocardial Infarction: During the course of myocardial infarction, the location Of Q waves was highly predictive of the location of the obstructed coronary artery (table 1). Fifteen patients with LAD disease developed significant Q waves in one or more of leads I, aVL and V1-V4; with one exception, Q waves did not develop in these leads in patients with RCA or LCx disease (p < 0.001 for each lead). In contrast, Q waves in leads II, III and aVF reected infarction in the RCA or LCx territory and occurred in

only one patient with LAD disease (p < 0.001). Q waves were found in leads V5 and V6 in patients with both LAD and non-LAD disease. Four of the six patients with LCx disease and Q waves during infarction had a right-dominant circulation; two had a left-dominant circulation. All six of these patients showed significant Q waves in at least two of the "inferior" leads (II, III and aVF), and none developed Q waves in lead I or aVL. ECG criteria did not distinguish between patients with infarction due to RCA disease and those with infarction due to LCx disease.

The associations between the location of ST-segment elevation during myocardial infarction and the location of the obstructed coronary artery were also quite strong, but exceptions were found more frequently than with Q waves (table 2). ST-segment elevation in leads I, aVL and V1-V5 during myocardial infarction correlated with the presence of LAD disease (p < 0.005 for each lead); ST-segment elevation in leads II, III and aVF was associated with RCA or LCx disease (p < 0.005). All patients with LCx disease and ST elevation during myocardial infarction had elevation in at least two of the inferior leads (II, III and aVF).

T-wave inversion in leads I, aVL and V2-V6 during myocardial infarction was strongly associated with LAD disease (p < 0.005 in each case) (table 3), and T-wave inversion in leads II, III and aVF occurred predominantly in patients with RCA or LCx disease (p < 0.005). All three patients with LCx disease and T wave inversions during infarction had inversion in at least two of the inferior leads. The exceptions to the electrocardiographic- angiographic associations were more frequent with T-wave inversion than with Q waves or ST-segment elevation, but the association was still strong.

T-wave inversion in leads I, aVL and V2-V6 during myocardial infarction was strongly associated with LAD disease (p < 0.005 in each case) (table 3), and T-wave inversion in leads II, III and aVF occurred predominantly in patients with RCA or LCx disease (p < 0.005). All three

ST-segment depression during myocardial infarction followed a different pattern. Depression in leads I and aVL was associated with RCA or LCx disease, and depression in leads III and aVF was associated with LAD disease (all p < 0.001) (table 4). These ST depressions probably represent "reciprocal" changes. Of the 51 patients with ST depression during myocardial infarction, 44 also had

exception, Q waves did not develop in these leads in patients with RCA or LCx disease (p < 0.001 for each lead). In contrast, Q waves in leads II, III and aVF reected infarction in the RCA or LCx territory and occurred in

patients with LCx disease and T wave inversions during infarction had inversion in at least two of the inferior leads. The exceptions to the electrocardiographic- angiographic associations were more frequent with T-wave inversion than with Q waves or ST-segment elevation, but the association was still strong.

simultaneous ST elevation in other leads. Patients with ST elevation in leads I, aVL and V1-V5 tended to have ST depression in leads II,III and aVF, whereas patients with ST elevation in leads II, III and aVF tended to have ST depression in leads I and aVL.

When ECGs recorded during infarction, ST depression in leads I and aVL was associated with RCA or LCx disease (p < 0.001) (table 4), and ST depression in leads III and aVF with LAD disease (p < 0.001). These findings are opposite to those found with Q waves, ST elevation and T-wave inversion and are probably due to a high prevalence of "reciprocal" ST segment depression. If tracings with ST depression alone are examined (excluding tracings with ST elevation in some leads and depression in others), these significant associations disappear.

Of the 51 patients in whom ST depression was recorded during the course of myocardial infarction, 44 had ST elevations in other leads on the same tracing. These "reciprocal" changes were seen less often in patients with infarctions due to LAD occlusion than in patients with LCx or RCA disease. In patients with reciprocal changes, ST depression was noted in lead II, III or aVF in every case of LAD disease, and in lead I or aVL in every case of RCA disease. ST depression in the precordial leads was seen in six of 20 patients with RCA disease. In the five cases of reciprocal change due to LCx infarction, ST depression was found in at least three precordial leads in all five patients and in lead I or aVL in four of the five.

Predictive Value: Table 6 illustrates the usefulness of electrocardiographic location of Q waves and ST-T changes in localizing coronary artery disease in this selected patient population. The presence of a Q wave in two or more of leads I, aVL and V,-V4 during myocardial infarction was 93% predictive of LAD disease; ST elevation in two or more of these leads during infarction was 87% predictive; and T-wave inversion in two or more of these leads during infarction was 83% predictive. Similarly, the finding of Q waves in two or more of leads II, III and aVF during infarction was 94% predictive of RCA


© JIMI � JAN - MAR 2018 � VOL. 12 21

Although coronary angiography is the gold standard for determining the infarct-related artery in acute myocardial infarction, the ECG can be a clinically valuable tool in

13identifying the culprit artery. The early and accurate identification of the infarct-related artery on the ECG can help predict the amount of myocardium at risk and guide decisions regarding the urgency of revascularization. Accurate localization of infarct-related artery from surface electrocardiogram is crucial in formulation of management and need for early thrombolysis or primary percutaneous coronary intervention. The recent findings of masoudi et al. suggest that the failure to identify high-risk ECG patterns in patients with acute myocardial infarction (AMI) results in lower quality care in the emergency room and highlights the importance of system

14changes to enhance the accuracy of ECG interpretation.

The present study shows that (1) the development of Q waves, ST elevation or T-wave inversion in lead I, aVL or V1-V4 is highly predictive of LAD disease; (2) the development of Q waves, ST elevation or T-wave inversion in lead II, III or aVF is highly predictive of the presence of RCA or LCx disease, regardless of whether a right, left or balanced distribution is present; (3) RCA disease cannot be distinguished from LCx disease by ECG criteria; (4) "reciprocal" ST depression frequently develops during infarction; and (5) the ECG location of ST depression is not very useful in predicting the location of coronary artery disease.

These conclusions are based on a study of patients with one-vessel coronary disease in which many tracings were recorded during myocardial infarction. Although this study did not include a large number of patients with angina at rest and stress testing, the patterns of ST-segment and T-wave changes in this group paralleled those recorded during infarction. Investigation of patients with one-vessel coronary disease is important, because only in such patients can one be reasonably certain in which vascular distribution ischemia or infarction is occurring.

Discussion

or LCx disease; ST elevation in two or more of these leads during infarction was 93% predictive; and T-wave inversion in two or more of these leads during infarction was 86% predictive. Excluding patients who had simultaneous ST elevation and depression, ST depression in two or more of leads I, aVL and V1-V4 during infarction was 60% predictive of LAD disease; ST depression in two or more of leads II, III and aVF was 50% predictive of RCA or LCx disease. By these criteria, the ECG location of Q waves, ST elevation and T-wave inversion were highly predictive of the anatomic location of coronary disease (p < 0.001 in each case), but ST depression was not predictive (p > 0.25).

The correlation between the leads in which pathologic Q waves occur and the anatomic location of the infarction was noted as long ago as 193515 and has been repeatedly

16-20confirmed. With the advent of coronary angiography, these correlations were extended to include coronary

9,10artery anatomy. Early studies were limited, however, by the frequent occurrence of multivessel disease; furthermore, ECGs were not examined lead by lead, and leads I and aVL were not evaluated in many cases. Our data from a more homogeneous patient

population show that infarctions termed anterior, anteroseptal, anterolateral and lateral are all caused by LAD occlusion, whereas inferior or diaphragmatic infarctions are due to RCA or LCx disease. Contrary to

21some suggestions, "lateral" infarctions with changes in leads I and aVL did not occur in patients with LCx occlusions. Q waves in these leads may reect infarction of the LAD diagonal territory.

Experimental studies have shown that ST-segment elevation on the surface ECG develops during epicardial

22-27or transmural myocardial injury. ST-segment mapping 28studies during myocardial infarction and analyses of

electrocardiographic-angiographic correlations during 29-31coronary spasm have generally supported the belief

that ST elevation in precordial leads indicates transmural ischemia or injury in the LAD distribution, and ST elevation in the "inferior" leads (II, III and aVF) indicates transmural ischemia or injury in the RCA or LCx distribution. In the present study, we confirmed these findings and further analyzed the correlations lead by lead.

Although T-wave changes have long been recognized as a 21-23marker for myocardial ischemia and infarction, few

data are available as to their usefulness in locating the anatomic site of the perfusion deficit. The present study shows that the location of new T-wave inversions on the resting ECG during myocardial infarction is useful in predicting the site of coronary artery disease;

Our finding of the non-specificity of the site of ST depression during stress testing for localizing the likely region of myocardial ischemia (i.e., the region perfused by the vessel with significant stenosis) is in accord with some

32-37 38-40studies but at variance with others. We believe that the nonspecificity of ST-segment depression in localizing the site of is chemia or infarction is due to the multiple ways in which ST depression can be produced. Animal experiments have shown that subendocardial ischemia or injury can produce ST depression in leads overlying the area of damage, and transmural ischemia or injury can

24-26,41,42produce ST depression in distant "reciprocal" leads. Thus, ST depression in lead II, III or aVF might be due to subendocardial ischemia in the

22 © JIMI � JAN - MAR 2018 � VOL. 12


In patients with acute transmural myocardial infarction, several authors have attempted to predict the presence of a second jeopardized vascular territory by the presence of ST depression in "opposite" electrocardiographic leads, often with disparate results. For example, anterior precordial ST-segment depression in the setting of acute inferior myocardial infarction has been variously

45,46attributed to concomitant anterior (LAD) disease or to 47,48extensive posterolateral (RCA or LCx) infarction.

However, the high prevalence of "reciprocal" ST depression in patients with one vessel disease suggests that localization of additional regions at risk for ischemia or infarction may not be possible by examining ST-segment depression alone. This is particularly important in populations with a high prevalence of multivessel disease, such as patients with myocardial infarction. Our data suggest that the presence of ischemia or infarction in more than one vascular territory may only be reliably identified when Q waves, ST elevation or T-wave inversion are present in both anterior and inferior leads.

We examined the correlation between ECG changes and coronary anatomy, but did not directly examine which myocardial region was ischemic or injured. Given the moderate degree of interpatient variability in the myocardial area supplied by a given coronary artery,49 it is not surprising that abnormalities in certain leads - notably V5 and V6 -were not very useful in localizing the site of myocardial infarction, even when Q waves occurred in these leads. Changes in the other leads correlated strongly with narrowings in specific coronary arteries.

ConclusionWe emphasize the specificity of electrocardiographic-anatomic correlations in patients with Q waves, ST-segment elevation and T-wave inversion during myocardial infarction and ischemia. We suggest greater caution in the use of such terms as "anterior" and "inferior" ischemia based solely on ST-segment depression.

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Vitamin D Deficiency: Symptomatology

Original Article

1 2 3 4Vijay Verma , V Saxena , A K Shukla , Meenakshi Jain

Abstract

Till now we know that vitamin D deficiency cancause rickets in children and osteomalacia in adults.Previously it was thought that vitamin D deficiency iscommon in children only. Recently more frequentmeasurement of vitamin D in adults, has shown thatvitamin D deficiency is much more common withoutthe typical features of

1,2 osteomalacia. The lack of sunexposure being the most prominent cause of vitaminD deficiency there also exists other causes likemalabsorption and inadequate dietary intake. The general population and the medical-practitioners in particular are not well aware of vitaminD deficiency. There are so many patients takinganalgesic drugs for their bodily pain without any relief.Mere supplementation of vitamin D give them relief oftheir symptoms. There are minimal literature on signsand symptoms of isolated vitamin D deficiency. Thepresent study is designed to know the signs andsymptoms of isolated Hypovitaminosis D.

Introduction

1. Assistant Professor, Department of Medicine, Government Institute of Medical Sciences, Greater Noida. 2. Associate Professor, Department of Orthopedics, Government Institute of Medical Sciences, Greater Noida. 3. Sr. Consultant Physician & Diabetologist, Kailash Hospital, Noida4. Sr. Consultant Physician & Diabetologist, Max Hospital, Noida

Several studies has shown varying prevalence rateof 3vitamin D deficiency. Forrest et al has studiesvitamin

deficiency in US adults and has found 41.6%overall prevalence rate. They found obesity, illiteracy,low HDL cholesterol, poor health and “no daily milkconsumption”

4were all associated with hypovitaminosisD. Choi EY has studied 25(OH) vitamin D status anddemographic and life style determinants of 25(OH)vitamin D among Korean adults and has found lowvalues in spring, young urban residents, sedentaryworkers and non-alcoholics.

5Tolppanen et al hasstudied the vitamin D concentration in children andfound 29% prevalence and correlate lowsocioeconomic position, female gender, less time spent outdoors, older age and winter season with low vitaminD level. Catherine et al6 in their study found 42% of the307 normal healthy adolescents had vitamin Ddeficiency.

The present study was undertaken to find out the symptoms of isolated 25 (OH) vitamin D deficiency.The data were collected on 46 patients who had non osteomalacic symptoms along with isolated 25(OH) vitamin Ddeficiency. All these patients were subjected to detailed investigations. Those patients who were detected to be havingsome other associated diseases were excluded from this study. The study included 31 (67%) female and 15 (33%) malepatients of all age groups. Thirtythree (72% ) patients complained of joint pain, 27 (59%) patients had backache, 18(39%) patients had proximal muscle weakness, 13 (28%) patients had pain in legs and thighs, 9 (19%) patients hadnumbness over different part of body, 9 (19%) had muscular twitchings, 2 (4%) patients had tetany. Many patients hadcombination of more than one symptoms. The significance of isolated 25 (OH) vitamin D deficiency in non specificmusculoskeletal and some other symptoms has been established in this study. A large scale future study can beundertaken for further strengthening this study. Imrovement in Vitamin D level in human being can lead to good healthfor all.

Background

Materials and MethodsThe study involves analysis of 46 patients seenfrom December 2016 to March 2018 in the district ofGautam Budha Nagar. Patients with low level ofvitamin D and normal level of serum calcium wereincluded in this study. Patients with associated illnesseslike diabetes mellitus, hypothyroidism, COPD etc andthose with evidence of osteomalacia were excludedfrom this study. A chart was prepared with details ofpatients complaints, age, sex, dietary habits,occupation, mobile number, weight,


© JIMI � JAN - MAR 2018 � VOL. 12 25

height, associatedillness, sun exposure, history of drug intake especiallyINH, Rifampicin, Phenobarbitone, Ketoconazole, placeof living-urban/rural and detailed investigations to ruleout any associated illnesses. They were asked for theircomplaints like 1) Back pain, 2) Proximal muscleweakness, 3) Lower limb pain, 4) Muscular twitchings,5) Tetanic spasm 6) Fatigue, 7) Numbness, 8)Generalized bodyache. The signs were elicited in theform of sternal or rib tenderness. The serum level of 25(OH) vitamin D and Calcium were measured pre andpost vitamin D therapy. Initially total of 53 patient’sdata were collected. After detailed analysis of the data,9 patients were excluded from the study as thesepatients had associated diseases or calcium deficiency.Thus the data of 46 patients were analysed. The25(OH) vitamin D level of <20 ng/ml is considered asVitamin D deficiency and level between 20 to 29.9 ng/ml is taken as vitamin D insufficiency. The 25 (OH)vitamin D level of 30 to 100 ng/ml is considered asnormal. In this study all those patients who had lessthan 20.0 ng/ml of 25 (OH) vitamin D are included.

ResultsThe demographic analysis of these patientsshowed 14 (30%) patients were of the age group 21-30years and 13 patients (28%) of age group 41-50 years.There were 5 patients (%) each in the age gruop 51-60and 61-70 years age group and one patients each in agegroup 71-80 and less than 20 years.

Table 1: Age Distribution (n=46)

Age Group

(years)

Number of Patients Percentage

<20 1 2.5

21-30 14 30

31-40 7 15

41-50 13 28

51-60 5 11

61-70 5 11

71-80 1 2.5

>80 0 0

There were 31 (67%) female patients as comparedto 15 (33%) male patients.

Table 2: Sex Distribution (n=46)

Sex Number of Patients Percentage

Male 15 33

Female 31 67

The presenting symptoms and signs are depictedin table 3. Many patients had more than one symptomsand signs. The joint pain was the most prominent symptom.A total of 33 (77%) patients had joint pains. Backachewere presented in 27 (59%) patients. The proximalmuscle weakness was present in 18 (39%) patients. Atotal of 15 (33%) patients had bone tenderness in theform of sternal or rib tenderness. Thirteen (28%) ofpatients had pain legs or thighs, 9 (19%) patients hadnumbness over different part of body. A similarnumber (9 patients ) complained of fatigue. Fourpatients reported muscular twitchings. Two patients (4%) had Tetany. Two patients (4%), both male,complained of decreased sexual activity in the form oferectile dysfunction and this was their single complaint.

Table 3: Presenting Symptoms and Signs (n=46)**

Sr

No

Symptoms and Signs Number of patients Percentage

1 Proximal Muscle Weakness

18 39

2 Pain joints 33 72

3 Backache 27 59

4 Pain legs 13 28

5 Numbness 9 19

6 Muscular Twitchings

4 9

7 Tetany 2 4

8 Fatigue 9 20

9 Decreased sexual activity

2 4

10 Bone Tenderness

15 33

** Patients had one or more than one symptoms.

26 © JIMI � JAN - MAR 2018 � VOL. 12


DiscussionMany patients presenting to physician complainsof var ious bodi ly and jo int pain . There rout ine clinicalexamination and pathological investigations includingserum calcium did not reveal any positive findings.Many of these patients when their 25 (OH) vitamin D ismeasured they showed it below normal level. Thesefindings were an eye opener for postulatingsym-ptomatology of isolated vitamin D deficiency. Kanekar et al7 reported 69% of patients hadArthralgia in their study as compared to 77% in thisstudy. Kanekar7 et al had shown muscle weakness in8% of the patients as compared to 18% in this study.Grimaldi et al9 , ceglia L8, Ziambaras et al10 and Zittermann et al11 had given similar opinion on muscleweakness in their reviews and study. Raidh et al12 hasdepicted the role of vitamin D in erectile dysfunction All these patients showed improvement in theirsymptoms after 3 month of weekly dose of 60,000 IUof Cholecalciferol.

ConclusionAlthough the study size was small, the studyshows that vtamin D deficiency is very common.Several non osteomalacic patients can present with nonspecific musculoskeletal and other symptoms. Therecan be isolated vitamin D deficiency state with normalserum calcium level. Vitamin D deficiency has apreponderence for females and common in all agegroups. Vitamin D estimation is essential in many nonspecific and relatively asymtomatic patients. A futurestudy can be undertaken to explore vitamin Ddeficiency in urban vs rural population and fair vs darkcomplexioned persons.

Holick MF, High Prevalence of Vitamin DInadequacy and Implications for Health. Mayo ClinProc. March 2006;81(3):353-373.Holick MF, Sunlight and vitamin D for bonehealth and prevent ion of autoimmune diseases , cancers ,and cardiovascular disease. Am J Clin Nutr. 2004; 80(6,suppl) :1678S -1688S.Forrest KY, Stuhldreher WL. Prevalence andcorrelates of vitamin D deficiency in US adults. NutrRes. 2011 Jan;31(1):48-54. Choi EY. 25(OH)D status and demographic andlifestyle determinants of 25(OH)D among Koreanadults. Asia Pac J Clin Nutr. 2012;21(4):526-35. Tolppanen AM, Fraser A, Fraser WD, LawlorDA. Risk factors for variation in 25-hydroxyvitaminD3 and D2 concentrations and vitamin D deficiency inchildren. L Clin Endocrinol Metab. 2012Apr;97(4):1202-10Catherine M Gordon MD MSc, Kermin CDePeter BA, Henery A Feldman PhD, Estherann GraceMD, S Jean Emans MD. Arch Pediatr Adolesc Med.2004;158(6):531-537.Kanekar Amar & Sharma Manoj & R Joshi V.Vitamin D Deficiency—A Clinical Spectrum: Is Therea Symptomatic Nonosteomalacic State?. Int JEndocrinol. 2010; 521457. 10.1155/2010/521457.Lisa Ceglia. Vitamin D and its role in skeletalmuscle: Current Opinion in Clinical Nutrition andMetabolic Care. Nov 2009;12(6):628-633.Adam S. Grimaldi, Beth A. Parker, Jeffrey A.Capizzi, Priscilla M. Clarkson, Linda S. Pescatello, C.Michael White, Paul D. Thompson. 25(OH) Vitamin Dis Associated with Greater Muscle Strength in HealthyMen and Women. Med Sci Sports Exerc. 2013January;45(1): 157-162.Ziambaras K, Dagogo-Jack S. Reversiblemuscle weakness in patients with vitamin D deficiency.West J Med 1997;167:435-439.Armin Zittermann, Jan F. Gummert.Nonclassical Vitamin D Actions. Nutrients 2010;2:408-425.Raidh A Talib, Kareim Khalafalla, OnderCanguven. The role of Vitamin D supplementation onerectile function. Turk J Urol. 2017 Jun;43(2):105-111

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© JIMI � JAN - MAR 2018 � VOL. 12 27

Role of HbA1c In Diagnosis ofGestational Diabetes Mellitus

Review Article

1 2 3 4 5Virendra Atam , Prachi Daga , Arpit Gupta , Madhukar Mittal , Isha Atam

AbstractIntroduction: Gestational Diabetes Mellitus (GDM) is defined as 'carbohydrate intolerance with recognition or onset during pregnancy', irrespective of the treatment with diet or insulin. HbA1C has been used as a marker for diagnosing Type 2 Diabetes Mellitus, but in Gestational Diabetes Mellitus it is not used as diagnosing marker. The aim of this study was to evaluate the role in diagnosing GDM, based on OGTT as reference diagnosing test.

Gestational Diabetes Mellitus (GDM) is defined as 'carbohydrate intolerance with recognition or onset during pregnancy', irrespective of the treatment with diet or insulin. HbA1C has been used as a marker for diagnosing Type 2 Diabetes Mellitus, but in Gestational Diabetes Mellitus it is not used as diagnosing marker. Traditionally, the OGTT has been the test of choice for this condition. It can be preceded by a screening strategy such as fasting glycemia (FG) or a glucose load test. However, there are still divergences as to the OGTT cut-offs which should be used for the diagnosis of GDM and also a recent review concluded that the evidence is insufficient to

Introduction

1. Professor Department of medicine, KGMU2. Junior resident 3, Medicine, KGMU3. Junior resident 3, Medicine, KGMU4. Associate Professor and Head of Department of Endocrinology, KGMU5. MBBS Final professional student, KGMU

permit assessment of which strategy is best to diagnose 1, 2GDM . In 2010, the American Diabetes Association

(ADA) included the HbA1c test as a diagnostic criterion for diabetes (DM) in the general population. The cut-off of HbA1c _48 mmol/mol (6.5%) was established for the diagnosis and was endorsed by the World Health

3, 4Organization (WHO) in 2011 . This cut-off has high 5,6,7specificity in diagnosing DM . However, HbA1c and

glucose tests show very weak agreement, and it seems that these two tests may identify different populations of

5patients . Although OGTT is accepted as the diagnostic test for GDM by international organizations, it requires at least 8h fasting, extensive patient preparation, lacks reproducibility, it is time-consuming and unpalatable. Unlike, HbA1c may be measured any time of the day, has less biological variation, higher reproducibility, and better analytical stability as compared to glucose

8measurements . Additionally, HbA1c test does not need fasting and would be more comfortable for pregnant women than the OGTT. Nevertheless, its use for the

Materials and Methods: The study population was derived by screening pregnant females attending for their routine antenatal check-up from 24 to 28 weeks of gestation. The diagnosis of GDM was made on the basis of OGTT cut off given by IADPSG and DIPSI criteria.Those who were diagnosed by IADPSG criteria, HbA1C levels were measured in them.

Results: On comparing the HbA1C in GDM and non-GDM cases diagnosed by IADPSG criteria values were found to be higher among GDM as compared to non-GDM and differences were found to be statistically significant for HbA1c, but the mean values were very low that the diagnostic cut-off.

Conclusion: HbA1C can't be used as the criteria for diagnosis as its value is much lower in pregnancy and lowering the cut-off to that level would have many false positives, so it better to use the gold standard criteria for the diagnosis of GDM.

28 © JIMI � JAN - MAR 2018 � VOL. 12


diagnosis of GDM has not yet been recommended by any current guidelines.The aim of this study was to evaluate the role in diagnosing GDM, based on OGTT as reference diagnosing test.

Materials and MethodsThis was a cross-sectional observational study, conducted at King George's Medical University, Lucknow, Uttar Pradesh between Aug 2016 and Sept 2017. The participants were recruited from the Outpatient departments of Department of Endocrinology, Medicine and Obstetrics & Gynaecology. Pregnant women between 24 to 28 weeks of gestation fulfilling the inclusion and exclusion criteria were included in the study after obtaining a written informed consent. The study population was derived by screening pregnant females attending for their routine antenatal check-up from 24 to 28 weeks of gestation. The diagnosis of GDM was made on the basis of OGTT cut off given by IADPSG and DIPSI criteria.Those who were diagnosed by IADPSG criteria, HbA1C levels were measured in them.

Results A total of 36 patients were diagnosed as GDM on the basis of IADPSG criteria and 21 patients were diagnosed on the basis of DIPSI and in both these groups, HbA1C levels were measured.

TABLE1: Association HbA1Cwith GDM (IADPSG Criteria)

GDM (n=36)

Non GDM

(n=123)

'p' value

HbA1c 4.90 0.47 4.66 0.43 <0.001

TABLE 2: Association of HbA1C with GDM (DIPSI Criteria)

GDM (n=21)

Non GDM (n=138)

'p' value

HbA1c 4.87 0.52 4.70 0.44 0.034

TABLE 3: Association of HbA1C with GDM (Any Criteria)

GDM (n=45)

Non GDM (n=114)

'p' value

HbA1c 4.84 0.49 4.67 0.43 <0.001

On comparing the HbA1C in GDM and non-GDM cases diagnosed by IADPSG criteria values were found to be higher among GDM as compared to non-GDM and differences were found to be statistically significant HbA1c (4.84±0.49 vs. 4.67±0.43%; p<0.001).

In GDM cases diagnosed by DIPSI criteria, the difference is also found to be statistically significant HbA1c (4.87±0.52 vs. 4.70±0.44; p=0.034). Also in GDM cases diagnosed by any of the above criteria, the difference is found to be Significant HbA1c (4.84±0.49 vs. 4.67±0.43%; p<0.001). The mean value HbA1C for diagnosing GDM was found to be 4.84 ( IADPSG), 4.87 (DIPSI) and 4.84 ( any criteria ).

DiscussionWe evaluated the role of HbA1C in diagnosing the GDM. We found that the correlation in HbA1C was significant in GDM and non-GDM cases. BUT the mean value for the diagnosing the GDM was lower i.e., 4.84±0.49, which is much lower than the value used for diagnosing the Type 2 Diabetes Mellitus. The presence of anemia can cause a reduction in HbA1c values, and some studies suggest that this may be one of the reasons for the lower HbA1c levels observed during pregnancya. but anemia alone cannot explain the low levels of HbA1C as they were also lower in the non-GDMcases, so there have to other physiologic processes that need to be studied further. So in case of HbA1C, if we lower the cut-off of HbA1C to 5.0, we would be able to diagnose GDM, but the levels in non-GDM cases were also much lower, so we can't lower the cutoff to this level. It implies that not feasible to use HbA1C over OGTT for diagnosing of GDM. Studies done to evaluate the role HbA1C in GDM are

9A study done by Paula Breitenbach Renz et al suggested that combined HbA1c and OGTT measurements may be useful in diagnosing GDM, and not HbA1C alone is helpful in the diagnosis of GDM. Alhossain Khalafallah et

10al suggested that pregnant women with an HbA1c of�5.4% (36 mmol/mol) should proceed with an OGTT. This may result in a significant reduction in the burden of testing on both patients and testing facility staff and resources. Further investigations are required to integrate and optimize the HbA1c as a single, non-fasting,

11screening tool for GDM. LENE R. NIELSEN et al suggested that HbA1c was lower early in pregnancy and further decreased in late pregnancy compared with age-matched non-pregnant women using a DCCT-aligned method.

ConclusionHbA1C can't be used as the criteria for diagnosis as its value is much lower in pregnancy and lowering the cut-off to that level would have many false positives, so it better to use the gold standard criteria for the diagnosis of GDM.


© JIMI � JAN - MAR 2018 � VOL. 12 29

Buckley BS, Harreiter J, Damm P, Corcoy R, Chico A, Simmons D et al. Gestational diabetes mellitus in Europe: Prevalence, current screening practice and barriers to screening. A review. Diabet Med 2012; 29:844–854. doi: 10.1111/j.1464-5491.2011.03541.x PMID: 22150506Farrar D, Duley L, Medley N, Lawlor DA. Different strategies for diagnosing gestational diabetes to improve maternal and infant health. Cochrane Database Syst Rev. 2015 Jan 21; 1:CD007122. doi: 10. 1002/14651858.CD007122.pub3American Diabetes Association. Classification and diagnosis of Diabetes. Diabetes Care 2015; 38 (suppl.1):s8–s16.World Health Organization. Use of glycated haemoglobin (HbA1c) in the diagnosis of diabetes mellitus. Abbreviated r e p o r t o f a W H O c o n s u l t a t i o n 2 0 1 1 . A v a i l a b l e : h t t p : / / w w w . w h o . i n t / d i a b e t e s / p u b l i c a t i o n s / diagnosis_diabetes2011/en/index.html. Accessed 5 October 2014.Cavagnolli G, Comerlato J, Comerlato C, Renz PB, Gross JL, Camargo JL. HbA1c measurement for the diagnosis of diabetes: is it enough? Diabet Med 2011; 28:31–35. PMID: 21210540

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Kramer CK, Araneta MR, Barrett-Connor E. HbA1c and diabetes diagnosis: The Rancho Bernardo Study. Diabetes Care 2010; 33:101–103. doi: 10.2337/dc09-1366 PMID: 19837792Carson AP, Reynolds K, Fonseca VA, Munter P. Comparison of HbA1c and fasting glucose criteria to diagnose diabetes among U.S. adults. Diabetes Care 2010; 33:95–97. doi: 10.2337/dc09-1227 PMID: 19808920Sacks DB. HbA1c versus glucose testing: a comparison. Diabetes Care 2011; 34:518–523. doi: 10. 2337/dc10-1546 PMID: 21270207Renz P, Cavagnolli G, Weinert L, Silveiro S, Camargo J. HbA1c Test as a Tool in the Diagnosis of Gestational Diabetes Mellitus. PLOS ONE. 2015;10(8):e0135989.Khalafallah A, Phuah E, Al-Barazan A, Nikakis I, Radford A, Clarkson W et al. Glycosylated haemoglobin for screening and diagnosis of gestational diabetes mellitus. BMJ Open. 2016;6(4):e011059.Nielsen L, Ekbom P, Damm P, Glumer C, Frandsen M, Jensen D et al. HbA1c Levels Are Significantly Lower in Early and Late Pregnancy. Diabetes Care. 2004;27(5):1200-1201.

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Abstract

Armor Regime For Management Of Rheumatic Fever &Rheumatic Heart Disease Easy And Painless

Review Article

ARMOR ie Arati's Regime for Management Of Rheumatic fever. The ARMOR regime basically consists of diagnosis and management of rheumatic fever/ rheumatic heart disease in today's context and in a very easy and simplified way. For eradication of RF/RHD we must have a simplified diagnosis, treatment must be painless, easily available and safe, and prophylaxis must be painless, safe, easily available, readily administered, weekly oral single dose. The seven-and-odd-decades-old Jones criteria for diagnosis and management of rheumatic fever should only form a skeletonbase for today's way of diagnosis and management of rheumatic heart disease and not copied ad verbatim. We have seen that out of all the major, minor and essential criteria for diagnosis of Rheumatic Feverand Rheumatic Heart Disease the most common, frequent, and sufficient criteria are arthralgia or arthritis,carditis or organic heart valvular disease and any evidence of streptococcal infection especially history of sore throat, along with the most essential and irrefutable evidence by echocardiography Doppler study.

disease clinical profile of 550 cases in India,arthritis and carditiswas found in in 169 (67.6%) and 105 cases (42%), respectively and chorea in 47 cases (18.8%) and erythema marginatum in four only. The Jones criteria is too complicated therefore to simplify the diagnosis of rheumatic fever it was suggested by Lalchandani etal to include patients with arthralgia or arthritis,carditis/ cardiac involvement suggestive of rheumatic heart disease and echocardiographic evidence of rheumatic heart disease.If the diagnosis of RF and RHD was simplified and only migratory arthritis, endocarditis with history of sore throat, were given sufficient importance to start early prophylaxis more cases would be cured before serious organic heart disease could occur.Jones criteria make sense only when applied along with a strong clinical suspicion and judgement.In India it is always better to overdiagnose RF rather than underdiagnoseby strict adherence to the Jones criteria.In a study of 200 patients of RF by Lalchandani et al it was shown that out of all the Jones criteria only arthritis and arthralgia and carditis was present in the patients.No patient had chorea and erythema marginatum or subcutaneous nodules all of which are major Jones criteria.This is the pattern from most cases of rheumatic fever.Echocardiography in rheumatic fever: Diagnosis of carditis with valvular regurgitation increases with the use of echo in patients of a RF. Echo is an extremely useful tool for detection of rheumatic heart disease. In Echo-based screening of school children Carapetis et al

Arati Dave Lalchandani

IntroductionARMOR criteria :So actuallyarthritis,carditis and echocardiographic evidence of rheumatic heart valve involvement is quite sufficient to diagnose Rheumatic Fever and Rheumatic Heart Disease with high specificity and sensitivity. As regards treatment for rheumatic fever and Rheumatic Heart Disease we need a drug which is highly efficacious against Group A Beta Hemolytic Streptococcus (GABHS) which is the causative agent for Rheumatic Fever and Rheumatic Heart Disease for primary prevention, treatment and secondary prophylaxis.The best drug discovered till date for GABHS is AZITHROMYCIN.In ARMOR Azithromycin must be given in a dose of 500 mg one tablet daily for 5 days followed by 1 tablet once a week for one year for primary prevention, treatment and secondary prophylaxis of RF / RHD.ARMOR for arthritis :Further in ARMOR, Aspirin, the drug used for Rheumatic arthritis in high doses is replaced by Aceclofenac 200mg twice a day or even Nimesulide 200mg twice a day for 5 days only or more according to physician's discretion. The detailed explanation and work-up with evidencein support of each and every aspect of ARMOR is mentioned and substantiated in detail in the following text.ARMOR FOR DIAGNOSIS OF RF RHD : In a study by Ravisha MS et al of Rheumatic fever and rheumatic heart

Ex Director Professor & Head PG Institute of Medical GSVM Medical Collage, Kanpur


© JIMI � JAN - MAR 2018 � VOL. 12 31

The age-old treatment with aspirin should be discouraged as it is a very toxic drug causing peptic ulcer, hematemesis,haemorrhage, rhinitis, bronchial asthma, Reye's syndrome and even death. Moreover, aspirin has to be given for 6 weeks to 6 months and then tapered over a few weeks. It has to be given in very high doses of 8–12 g/day due to which the compliance is very poor especially in children. Aceclofenac is a very effective and safe drug with good antiarthritic, anti-inammatory and analgesic properties. It can be stopped suddenly and does not need to be tapered. It is largely free of side effects and is easily available and affordable. It is more cost effective.

ARMOR FOR TREATMENT AND PROPHYLAXIS: The standard and age-old treatment of RF/ RHDie GABHS is a single injection of Benzathine Penicillin G given intramuscular after sensitivity test in a dose of 1.2 million units. For secondary prophylaxis, this is followed by Injection Benzathine Penicillin given intramuscular, each time after sensitivity test, after every 21 days (3weeks), in the same dose of 1.2 million units. The treatment and prophylaxis of RF/ RHD has never seriously been reviewed in the light of newer drugs discovered for GAS (Group A Streptococcus) after Penicillin. All the other drugs mentioned above are oral forms which could never be an alternative to Benzathine Penicillin due to the daily dose required, except for Azithromycin which has a long half-life and several other pharmacological properties which make it an ideal drug for treatment and prophylaxis of RF/ RHD. Benzathine Penicillin G is in use for past 60 years due to convenience of dosing, its undoubted efficacy in eradication of the GABHS, and the low cost. But the scene is changed now.We must replace the use of Penicillin with a suitable drug, and never look back, for reasons detailed below. Acute Rheumatic Fever (ARF) usually affects children aged 5 to 15 years, but recurrences of attacks with rheumatic activity or ongoing inammation and intervals of rapid progression of valvular disease continue up to age 40 and even beyond. Rarely may it be detected for the first time even at the age of 50 years and beyond. ARF begins with a respiratory tract infection usually a sore throat caused by Group A Beta Haemolytic Streptococci (GABHS).

As there is no specific or definitive test for ARF, diagnosis is made by a combination of clinical features and to great extent the physician's discretion. For Rheumatic Heart Disease (RHD), the single most confirmatory evidence is the Echo Doppler Study. For prevention of Rheumatic Fever (RF) there is no treatment of ARF that has been proven to alter the likelihood of developing, or lessened the severity of RHD. In a study by an International RF Study Group of 1790

patients from 11 countries, RF recurred in 8 (.45%) in those who received Benzathine Penicillin prophylaxis compared with 11 of 96 (11.5%) who did not comply. This shows that recurrence may occur even with best prophylaxis and that compliance is very important. So at best, our attempt should be to eradicate the GABHS infection at the outset and give maximum symptomatic relief possible to the patient. The non-drug prevention of RF / RHD, like improving socio economic Conditions, housing, sanitation, overcrowding has not been possible in developing nations where RF /RHD is a major health problem. So the mainstay of primary prevention is timely and appropriate drug treatment.The drug of choice for the past 60 odd years has been Penicillin in different forms namely: Phenoxymethyl Penicillin 500mg oral twice daily or Amoxycillin 1g daily divided in 3 doses, Injection Procaine Penicillin IM twice a day, or Benzathine Penicillin G single dose IM 1.2 million u n i t s . A l t e r n a t i v e t o a b o v e d r u g s a r e ErythromycinjCephalosporins l ike Cefadroxil , Cephalex in , Cefuroxime axet i l , Cefpodoxime proxetil, Cefdinir, and Tetracyclines, Sulphisoxazole, Sulphadiazine, macrolides and Azalides etc. All above drugs have a big list of disadvantages of using in RF / RHD.

Best drug for the GABHS to date is AZITHROMYCIN which if started within 9 days of onset of sore throat almost all cases of ARF will be prevented. Hence the best drug for RF RHD is AZITHROMYCIN for primary prevention and also to treat recurrent attacks of ARF as well as for the secondary prevention in terms of safety, availability, compliance, efficacy, affordability and tolerability. In fact he only drug with all these properties is Azithromycin. Ordinarily, sore throat whether viral or Streptococcal (GAS - Group A Streptococcus), resolves in 3 to 5 days but if we have to prevent RF/ RHD, then all cases of sore throat even if cured or relieved of symptoms must be given the full course of Azithromycin 500mg (12mg/Kg) once daily for 5 days. Secondary Prevention of RF: Long term secondary prophylaxis is advocated in RF/RHD, as a known patient of RF is at higher risk for recurrent attacks of RF and progression of valvular heart disease than the general population. The best known antibiotic up till now has been Benzathine Penicillin G 1.2 million units given at interval of 3 to 4 weeks (with more

found that echocardiography woulduncover 10 subclinical rheumatic heart disease cases for every clinical case.In a Cambodian study published in 2007 and reported by Hardwire it was suggested that all cases of RF even on suspicion must be screened by echocardiography compulsorily.ARMORFOR RHEUMATIC ARTHRITIS: Aceclofenac 200mg twice a day or even Nimesulide 200mg twice a day for 5 days only or more according to physician's discretion must be the drug regime of choice.

32 © JIMI � JAN - MAR 2018 � VOL. 12


data to support 3-weekly intervals). The treatment and prophylaxis of RF/ RHD has never seriously been reviewed in the light of newer drugs discovered for GAS (Group A Streptococcus) after Penicillin. All the other drugs mentioned above are oral forms which could never be an alternative to Benzathine Penicillin G is in use for past 60 years due to convenience of dosing, its undoubted efficacy in eradication of the GABHS, and the low cost. But the scene is changed now.

We must replacethe use of Penicillin with a suitable drug, and never look back, for the following reasons:

Patients of RF/RHDare usually from the villages who first go to their family doctor or CHC for treatment. For the past two decades, with the gradually increasing distrust of the patients for the doctors and with the Consumer Protection Law for medical practice, the doctors, paramedics and the nurses have become very fearful of giving injections of Penicillin due tothe severe fatal reactions which occur in more than 1 in 10,000 patients, which is not a small number by any means considering that there may be more than 20 million people affected by RF/ RHD in the world today (AHA Scientific Statement Circulation March 24, 2009).

Also, this drugBenzathine penicillin has become very difficult to procure and the patients have many a times to buy it in the black paying many times the cost of the drug.

They have to travel long distances in search of some person who will be ready to give them the injection, knowing the hazards. Even big hospitals, district hospitals and medical college hospitals refuse to give these injections due to the sudden severe reaction causing death of the patient or, they do so only after getting signed consents of the relative saying that they, are well aware and are prepared for the fact that their child (relation) may well drop down dead after the prick (even after-proper sensitivity test each time that the injection is administered).

We have come a long way from those days when there was no option apart from penicillin oral or injectable and it was a 'take or die' situation. Today when the patient's parents askDoctor, is there any other option? - then one can't say - no, that's the only drug if you wantto save your child.

After an injection of Benzathine Penicillin, invariably the patient, usually asmall child suffers from aches and pains all over and especially at the site of injection; fever, which does not recover any sooner than it's time for next injection.

The injection itself is oily and painful and more than 2 ml in quantity. It has to be given deep intramuscular whereas the patients of RHD are usually from poor soc ioeconomic s t ra ta , very cachect ic and malnourished with poor muscle mass.

There are frequent cases of patients showing transientvalvulitis of mitral and aortic valve after injection of Benzathine Penicillin. So ironically this becomes a cause for continuing the injection for say another 5 years and then the patient ends up with the injection being prescribed lifelong. [May be this is the reason that there are recommendations for giving it lifelong]!

Some drugs which interact with penicillin include warfarin, aspirin, tetracycline, diuretics etc. These are commonly coprescribed drugs in patients of RF / RHD. Benzathine penicillin is not for IV use at all. Inadvertent IV injection can cause cardiorespiratory arrestanddeath.

Hypersensitivityand allergic reactions, immediate and delayed are common. It should not be injected near a nerve, artery orvein.

Pseudomembranous colitis is common with penicillin.

Clostridium difficile associated diarrhoea (COAD) occurs which can increase the morbidity and mortality.

There is enoughevidence and experience with Benzathine Penicillin to show that it itself causes all features of ARF like fever, arthritis and even valvulitis, not to mention the well known fatal anaphylaxis risk.

There is ample scientific supporting literature for all of the above. Al l the above problems resul t in tota l noncompliance leading to the progression of valve destruction anddeath of the patient. Any amount of counselingalso does not help as the patients and attendants are more terrified of the injection and its consequences compared to the pains and agony of the disease itself, which they realize will progress relentlessly sometimes irrespective of years of painful prophylaxis.


© JIMI � JAN - MAR 2018 � VOL. 12 33

The solutionis to give tablet Azithromycin 500 mg once daily for 5 days consecutively as initial treatment, andthen 1 tablet of Azithromycin 500 mg only once a weeki.e. say every Sunday morning for,1 year only.

In our institution this antibiotic with more or less similar regime has been in use for over 9 years and found to be nearly 100% effective in terms of almost no relapse, recurrence or new cases of RF and RHD, nearly 100% compliance and freedom from side effects. It may be given for more than 1 year if at all there is sore throat or relapse of the disease i.e. any of the symptoms of disease or any suspicion thereof, for an extended period according to the discretion of the treating doctor.

This regime has been worked out with the following facts for backup andrationalization:

The basis of giving Azithromycin only once a week is the long half-life of the drug which is sufficient to eradicate GAS,and suppress any autoimmune inammatory process in the heart which may start mid-week, when the drug is given at weekend. Azithromycin is acid-stable and so can be taken orally without damage from gastric acids. It is readily absorbed, but its absorption is greater on an empty stomach. Azithromycin can be taken with or without food.Time to peak concentration is 2.1 to 3.2 hours for oral dosage, and 1-2 hours for IV forms.Due to high concentrat ion in phagocytes Azithromycin is actively transported to site of infection. During active phagocytosis large concentration of Azithromycin is released. The concentration of Azithromycin can be 50 times higher in the tissues than in plasma. This is due to ion-trapping and high lipid solubility of the drug. Concentrations in target tissues such as lungs and tonsils exceed the MIC 90 after a single dose of 500 mg. The single daily dose administration is a big advantage. Azithromycin is the first of a class of antibiotics designated chemically as azalides. The chemical name of Azithromycin is 9-deoxy9-za9-a-methyl-9-ahomoerythromycin. The molecularweight is 749.0. The mode of action of Azithromycin is inhibition of proteinsynthesis in bacteria by binding to 50s ribosomal subunit and preventing translocation of peptides Azithromycin's long half-life allows a large single dose to be administered and yet maintain bacteriostatic levels in the infected tissue for several days.

Following a single 500mg dose, plasma concentration of Azithromycin declines in a polyphasic pattern with a mean apparent plasma clearance of 630 mL/min and a terminal elimination half-life of 68 hours. The prolonged terminal half-life is thought to be due to extensive uptake and subsequent release of drug from tissues. The drug persists in the tissues for 6 days if started with continuous 5-days treatment. Hence Azithromycin needs to be given only once a week as it has a long life of 6 days if given after loading dose for 5 days. Thereafter it can be given in a dose of 1 tablet weekly only. All other antibiotics need to be given daily, therefore Azithromycin is the best choice. Each time, the drug must be started with 1 tablet of 500mg continuously for 5 days even when switching over from other antibiotics. Azithromycin also has immune-suppressant properties. Azithromycin is freely available, safe in children and adults alike, cost effective, and has excellent anti-streptococcal activity. It is effective in complete eradication of streptococci from oropharynx and subsequent prevention of RF RHD. Caut ion-should be exerc i sed when administered to patients with renal failure. It can be safely given even in moderate hepatic impairment. In children it can be given as a single dose of 10 mg/kg or 20mg/kg for 3 days only, with good efficacy. A daily dose of 500 mg may be given to any child more than 5 years of age.During pregnancy no evidence of harm to the fetus due to Azithromycin was found. Azithromycin was discovered in 1991 and is in constant use for GAS since then with excellent results. In a systematic review of 21 randomized controlled trials Azithromycin 20 mg/kg/day (3-day) achieved bacteriological eradication in 95% cases in acute streptococcal tonsillopharyngitis.

In a study downloaded from http:\circ.ahajournals.org/ dec16, 2011,730 patients were given Azithromycin for ARF in dose of 500 mg once a day for 5 days then 500 mg on 2 consecutive days of the week i.e. only 2 days in a week. No patients showed relapse or rebound rheumatic activity or reinfection with streptococci, there was no worsening of cardiac valve disease either. Compliance was 100%. Patients who had no new problem attributable to RF/RHD were given Azithromycin prophylaxis for one year only. Thus it was shown thatAzithromycin is very effective in treatment and prevention of RF/ RHD due to efficacy of treatment and high compliance.

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In a communication to Prof A Lalchandani, Dr Stephen Marko of World Heart Federation, University of Connecticut has mentioned that there is great concern over the use of Benzathine Penicillin G due to significant issueswith quality and quantity of the drug with reports of shortages and poor quality penicillin. He echoes the sentiments that the treatment guidelines should be less stringent and according to the needs of the community. ([email protected] -Dec6,2011-survey based study on BPG).

According to an article in Paediatric Cardiology, 2010 August, from the Division of Cardiology, Department of Paediatrics of University of Virginia, a retrospective review of patients of ARF <21 years was performed. 144 patients of RF/RHD showed n recurrence rate of 38%, mean level of compliance with Benzathine penicillin was 59% in patients without recurrence of ARF, and 57% in patients with recurrence of ARF. This suggests that improved methods of primary and secondary antibiotic prophylaxis for ARF must be researched.

The recurrence rate for RF in various studies is 3% to 8% over 5-6 yearsbut rate of recurrence of RF in studies with Azithromycin was less than 3% consistently. A serum penicillin concentration of more than 0.02 μgm/ml is required to prevent recurrence8 but since Azithromycin persists in tissues in high concentrations therefore its efficacy is greater in preventing recurrences. There is no rationale for giving RF /RHD prophylaxis for more than 1 year after an episode of sore throat, recurrence, relapse of evidence of progression of disease. If Azitrhomycin is started within 9 days of sore throat, it will prevent all cases of RF/RHD. Various studies have proved that it takes at least two weeks after a streptococcal infection /sore throat for autoimmune destruction leading to RF /RHD. Even in post streptococcal reactive arthritis valvular heart disease is seen only several months after the streptococcal infection in a small proportion of patients. These patients should receive secondary prophylaxis for up to 1 year after symptoms (Class llb, LOE C - AHAScientific Statement).The duration of prophylaxis according to American Heart Association Recommendations is from 5 years after last attack to lifelong prophylaxis in patients with persistent valvulardisease, with a footer that the recommendations be modified by individual circumstances as warranted.It is very obvious from the footer that the duration of treatment recommended has been arbitrarily decided and not after serious deliberations over the strep infection, a possible time-interval for causing an autoimmune damage, its time gap for presenting as carditis or organic heart valve destruction, its persistence and disappearance from the blood stream, its susceptibility to the drug and comparison with other drugs.

Canany benefit be attributed to a drug which has to be taken lifelong and can it truly be called 'prophylaxis'. An ethical prescription should be based on the principle of 'greater benefit of thedrug than the risk from its use' and what greater risk than death!as can occur with injection Benzathine Penicillin; and what greater benefit than 95% eradication of causative organism! What are we waiting for? There cannot bea better, more effective drug for GAS than Azithromycin (CIassl, LOE-C). Should we not all shift to Azithromycin for prophylaxis?Can therebe better proof than over 9 years of consistent and exclusive use of this drug for treatment and prophylaxis of RF and RHD in our GSVM Medical College and associated hospitals catering to a huge urban and rural population in and around Kanpur districts where mostof the patients are from lower socioeconomic strata and the incidence of RF/RHD is not less than 4 perthousand, still significantly high. A s w e s t r o n g l y c o n s i d e r e d t h e u s e o f Benzathine·Penicillin injections unethical, dangerous, less effective and even harmful, with probability of fatal reactions, a direct comparison of Benzathine Penicillin and Azithromycin could not be done but in vitro comparison result show Azithromycin to be a superior drug for GABHS, the causative organism of RF/ RHD.

ARMOR: Azithromycin must be given in a dose of 500 mg one tablet daily for 5 days followed by 1 tablet once a week for one year for primary prevention, treatment and secondary prophylaxis of RF / RHD.

ReferencesRavisha MS, Tullu MS, Kamat JR. Department of Pediatrics, Seth G.S. Medical College and KEM Hospital, Parel, Mumbai, Maharashtra, India.PMID: 14602504 [PubMed - indexed for MEDLINE].Arch Med Res. 2003 Sep-Oct;34(5):382-7 A Lalchandani, M Shameem, P Sondhi, AAgarwal, V Agarwal, P Neelam, G Preethi, U Pandey. A Paradigm Shift in Diagnosis of RF : A Review of 200 patients of RF with a view to Scrap Jones Criteria. Indian Heart J 2005;57:463.SaxenaA : Diagnosis of rheumatic fever : current status of Jones Criteria and role of echocardiography. Indian JPediatr 2000; 67 (3 Suppl) : S11-4.Use of Acelofenac Instead of Aspirin in Arthritis of Rheumatic Fever AratiLalchandani, MukeshRana, MayankMehrotra, MriduRawat, GianRai, ShashiFirmal, Pinky Talreja, TaruniLalchandani, AlokSangam, Kundan. Circulation 2010;122;e115; originally published online Jun 14, 2010;International Rheumatic Fever Study GroupM. Markowitz and E. Kaplan (USA); R. Cuttica (Argentina); X. Berrios (Chile); Z. Huang and X. Rao(People's Republic of China); P. L Wahi and H. K. Bali (India); D. Millard (Jamaica); J. Y. Choi and C. Y. Hong (Korea); H. A Majeed (Kuwait); P. Clarkson and J. Neutze (New Zealand), H. C. Lue (Taiwan); C. Vongprateep and C . Phornphutkul (Tha i land) , and S . Munoz (Venezuela).1991, Elsevier Ltd.

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ShaantanuDonde, Mishra A, Kochhar P: Indian J O t o l a r y n g o l o g y a n d H e a d N e c k s u r g e r y , 7 J a n 2012:Azithromycin in Acute Bacterial URTI: An Indian Noninterventional Study.AHA Scientific Statement: Michael A, Gerber, Chair Robert S.Baltimore MD, Charles B, Eaton; Michael Gewitz FAHA, Anne H. Rowley; Stanford T Shulman, Kathryn A Taubert :Prevention of Rheumatic Fever and Diagnosis and Treatment of Acute Streptococcal Pharyngitis. Circulation2009 Mar 24;119(11):1541-51. Thomson WO: Late Resident Medical Officer, Belvidere Infec Dis Hosp;Glasgow: Sudden Death Followinginjection Penicillin: British Medical Journal, July12, 1952. Altamimi S, Khalil A, Khalaiwi KA, Milner R, Pusic MV, AI Othman MA (2009)Short versus standard duration antibiotic therapy for acute StreptococcaI pharyngitis in children. Cochrane Database Systemic Review. Doi: 10.1002/146515858. CD004872. pub2 AratiLalchandani, MukeshRana, MayankMehrotra, Prabhu K, TaruniLalchandani :Benzathine Penicillin must be substituted with Azithromycin for treatment and prophylaxis of Rheumatic fever . Downloaded from http:// circ . ahajournals.org/December 16, 2011.

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Seckeler, Hoke TR, Gurka MJ, Barton LL : No demonstrable effect of benzathine penicillin on recurrence of rheumatic fever in pacific island population. Pediatric Cardiology. 2010 Aug; 31(6) : 849-52. Epub 2010 April. 22. Harrison's Principles of Internal Medicine 18th Edition, Ch 322, Acute Rheumatic Fever.D a n i e l s : E D , M o h a n l a l D , P e t t i f o r J M : S A f r MedJ.1994Aug;84:477- 81 :RF prophylaxis in SA.A Lalchandani, M Shameem, S Chandra, P Sondhi, AAgarwal, V Agarwal, P Neelam, G Preethi, U Pandey: Use of Alternative Drugs for Rheumatic Fever Prophylaxis in Place of Injection Benzathine Penicillin. Indian Heart Journal 2005; 57: 462.Abstract. Schaad UB (2004) Acute Streptococcal tonsillopharyngitis : A review of clinical efficacy and bacteriological eradication. Journal of Internal Medicine 32: 1-13.Azithromycin (ARMOR) must replace benzathine penicillin for treatment ...https://www.omicsonline.org/.../azithromycin-armor-must-replace-benzathine-penicillin

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Pollution of 21st Century : The Noise

Review Article

1 2 3Bhupendra Chaudhary , Aarati Pokale , Ansh Chaudhary

AbstractNoise is an unwanted and disharmonic sound pollutant which has a direct and indirect effect on human health. It is an environmental pollutant but does not affect the air, soil or water environment. With increasing industrialization and modernization over the last decade, the health hazard of this measurable pollutant has increased to label it a "Silent Killer" with lots of health related issues. According to WHO, around 63 million people i.e. around 6.3% of total population is affected by hearing loss in India due to noise pollution. Despite our ability to precisely measure noise, its effects on health have been largely neglected until recently in most countries and unfortunately this neglect continues in most developing countries, including India. Worldwide it is estimated that hundreds of millions of people suffer a range of health effects due to noise pollution but there is no national plan in India to reduce environmental noise pollution.

Keywords : Noise, Pollution, Environment, Health Problems, Hearing loss.

IntroductionNoise is defined as any unpleasant or loud undesired sound interfering with one's hearing and concentration. Acoustic signals producing a pleasant sensation are referred to as 'sound' whereas the unpleasant sounds are referred to as 'noise'. World Health Organisation regards Noise as an underestimated threat that can cause a number of short and long term health problems such as stress, sleep disruption, cardiovascular effects, poorer work and school performance, hearing impairment, endocrine effects and increased incidence of diabetes. In 21st Century, the noise has emerged as a modern day pollutant and an environmental stressor. Source can be both indoors (audio and video devices, musical toys, games, electrical gadgets, kitchen appliances, classroom noises etc.) or outdoors (vehicular traffic ranging from aircrafts to road traffic, factory sirens, loud speakers, environmental noises in play grounds etc.). Increasing pollution and industrialization has contributed to the

1menace .Noise affects all vital organs adversely. Central nervous system, Cardiovascular, Endocrine and Immune systems are the most vulnerable & all life style diseases are aggravated by exposure to loud sounds.

1.Director and Head, Deptt. of Neurosciences, Jaswant Rai Speciality Hospital, Meerut (U.P.)2. Deptt. of Community MedicineBharati Vidhyapeeth University, Medical CollegePune Satara Road, PUNE-43 (Maharashtra)3.Deptt. of Community MedicineBharati Vidhyapeeth University, Medical CollegeMaharashtra

Noise : A Health Hazard for All Ages1. Impact of Noise on Foetal Life: Harmful effects of noise may start even from the intrauterine period and children

are passive consumers of harmful noise, and are more susceptible to its damaging effects. A functional vestibular system develops by 28-29 weeks of gestation. That fetus is able to hear, is indicated by observations of blink-startle responses to vibro-acoustic stimulation during antenatal ultrasonography around 24 weeks of gestation. Fetus can respond to auditory stimulus originating both inside and outside the womb. Sources of sound in the materno-fetal unit include heartbeat of mother, placental ow, mother's voice, and vibroacoustic st imulat ions from antenatal ultrasonography.

Intrauterine exposure to excessive sound can have long-lasting effects. Studies have documented high frequency hearing loss in children who were exposed to noise in the range of 85 to 95 decibels (dB) during intrauterine period. In utero exposure to loud noise can also cause cochlear damage. Besides auditory damage, intrauterine exposure

2to noise may contribute to prematurity and birth defects .


© JIMI � JAN - MAR 2018 � VOL. 12 37

2. Impact of Noise on Neonatal & Infantile Period: In neonatal period high intensity sounds may cause damage to the cochlear cilia leading to hearing loss. Repeated arousal of the baby as a result of the sounds produced by equipment may lead to fatigue and irritability. Preterm infants are more vulnerable to adverse physiological effects of noise. New born exposed to sound above 45 decibels may experience increase in blood pressure, heart rate, respiratory rate, and decreased oxygen saturation, increase in caloric consumption. Neonatal intensive care unit (NICU) environment is characterized by continuous sounds from monitors, ventilators, alarms, infusion pumps, incubators, and conversations between doctors, staff and family. The American Academy of Pediatrics (AAP) Committee on Environmental Health has recommended that sounds levels should be at or below 45

3-4dB in neonatal intensive care units (NICU) .

2. Impact of Noise on Neonatal & Infantile Period: In neonatal period high intensity sounds may cause damage to the cochlear cilia leading to hearing loss. Repeated arousal of the baby as a result of the sounds produced by equipment may lead to fatigue and irritability. Preterm infants are more vulnerable to adverse physiological effects of noise. New born exposed to sound above 45 decibels may experience increase in blood pressure, heart rate, respiratory rate, and decreased oxygen saturation, increase in caloric consumption. Neonatal intensive care unit (NICU) environment is characterized by continuous sounds from monitors, ventilators, alarms, infusion pumps, incubators, and conversations between doctors, staff and family. The American Academy of Pediatrics (AAP) Committee on Environmental Health has recommended that sounds levels should be at or below 45 dB in neonatal intensive care units (NICU).

3. Impact of Noise on Childhood Period: School children spend most of their time in classroom and playground. Noise in schools is multipronged originating from the poor acoustics of the room, slamming of doors, noisy corridors, ventilation systems and computers. In addition there is external noise from road traffic particularly from schools built on highways or near congested roads. Background noise is found to be higher in classrooms with natural ventilation as compared to those with mechanical ventilation. Children in noisy environments have poor

4. Impact of Noise on Adult Health: Hearing impairment as a result of noise exposure presents a serious public health problem; it is estimated that, worldwide, 1.3 billion people suffer from this condition and the World Health Organisation (WHO) estimates that 10% of the global population is currently exposed to noise levels that could lead to hearing impairment. It has been estimated that 50% of the population in the USA had an annual exposure to traffic noise that were high enough to be harmful to health.

school performance, which leads to stress and misbehavior. They also have decreased learning, lower

5reading comprehension, and concentration deficits .There is significant drop in children's reading performance when background noise interfered with

speech. Teenagers & young people frequently visit discotheques and concerts where a very high sound pressure level is generated; this increases the chances of hearing loss. Youths also turn up the volume of their car stereo while driving, which is damaging not only for ears it further increases the chances of traffic accidents.The source of noise in children can be both indoors and outdoors. Rural homes are less burdened with sound exposure compared to urban homes. Machines used in agriculture are less distressing compared to traffic noise. Due to lack of proper planning and lack of space in urban areas, particularly the metropolitan cities, residential colonies and schools are placed close to busy roads, airports, railway stations and even factories. Sources of noise inside the houses include air conditioners, coolers, washing machine, televisions, music systems, vacuum cleaners, video and computer games. Noise from social, cultural and recreational activities is another nuisance, particularly in densely populated cities. Many toys produce noise and children love to play with them. Preschool children who spend quite a good amount of time in day care institutions are also exposed to noise originating from toys, overcrowding, and air conditioners.The body response to noise is in terms of fight or ight, thus resulting in adverse nervous, hormonal and vascular changes. Exposure to noise during sleep increases the adrenaline, noradrenaline and Cortisol excretion which are associated with insulin resistance, hypertension, stress ulcers and cardiovascular diseases. Another side effect of noise is enhanced pain sensation, which may increase the requirement of dose of analgesics.Noise-induced hearing loss is particularly more pronounced in children with learning disabilities, attention difficulties and children on ototoxic medications. Noise-induced hearing impairment is usually accompanied with loudness recruitment, paracussis and tinnitus. These changes may be temporary or permanent. Noise-induced sleep deprivation suppresses the rapid eye movement (REM) sleep pattern.

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1. Stress: Environmental noise is not only a health risk to people who report being annoyed by noise, but these individuals are also at risk for additional health effects. The effects of noise on conscious subjects are insidious and result at least in part from increased psychosocial stress. Annoyance from continuous sound appears to vary substantially by individual, and there are a number of factors that may inuence annoyance and subsequent stress. Annoyance increases sympathetic tone, especially in noise-sensitive individuals, and may be the non-sleep mediated pathway that is present in individuals with high occupational noise exposures who subsequently develop heart disease.2. Cardiovascular Diseases & Sleep Disturbance: Those who live in surrounding of noisy environments experience a subjective habituation to it, but their cardiovascular system does not habituate with the time and they still experience activations of the adrenergic nervous system and changes from deep sleep to a lighter stage of sleep in response to noise. The body's initial startle response to noise is due to activation of the sympathetic nervous system. Although blood pressure normally drops during sleep, people experiencing sleep fragmentation from noise have difficulty achieving a nadir for any length of time because blood pressure rises with noise transients and heart rate increases with increase in noise levels. Decreased quality and quantity of sleep elevates cardiovascular strain, which manifests as increased blood pressure and disruptions in cardiovascular circadian rhythms alongwith increased levels of stress hormones. Microarousals appear to be associated with increased lipids and Cortisol levels. Increased blood lipid, heart rate, blood pressure, and stress levels from noise lead to atherosclerosis, which is causally related to heart disease. The priming of the neuroendocrinal stress response in some individuals make them vulnerable to depression,

6distraction and masking effects . 3. Noise induced Hearing Loss: Noise induced hearing loss is a function of sound level and duration of exposure. Noise Induced Hearing Loss (NIHL) can be caused by a onetime exposure to an intense impulse sound (such as explosives) or more commonly by a steady long-term sustained exposure with sound pressure levels in excess of 80-85dBHL. Long-term exposures to noise levels > 75 dBA can cause metabolic changes in sensory hair cells within the cochlea, eventually leading to their loss and increasing inability to perceive sound (e.g., NIHL). Neuronal destruction may also occur; in such cases, the ability to perceive sound may remain undiminished, but the ability to understand the meaning of sound deteriorates.The characteristic pathology of NIHL is the loss of auditory sensory cells (hair cells) in the Organ of Corti in the cochlea. Since mammals have lost the ability to

regenerate, NIHL is irreversible. Inammatory and immune responses are central mechanisms in cochlear defensive response to noise but if unregulated, they contribute to inner ear damage and hearing loss. Extreme exposures can cause direct mechanical damage (acoustic trauma) to cochlear hair cells. Noise exposure is also associated with tinnitus (ringing in the ears) and hyperacusis. NIHL has traditionally been associated with occupational noise, but there is increasing evidence that music may play an important role as well.The auditory effects of noise probably represent a complex interplay of genetic and environmental factors which leads to oxidative stress at a molecular level. The identification of NOX-3 and CDH-23 gene are identified as

7key genes for susceptibility to NIHL .

Environment Noise : The Legal IssuesA National Ambient Noise Monitoring Network on the pattern of existing Air and Water Networks was created in the country. The network will result in creation of base line data and facilitate its analysis for policy makers and implementing agencies to take appropriate actions for noise control at regional and national level. The Supreme Court of India gave a significant verdict on noise pollution in 2005. Unnecessary honking of vehicles makes for a high decibel level of noise in cities. The use of loudspeakers for political purposes and for sermons by temples and mosques makes noise pollution in residential areas worse. In January 2010, Government of India published norms of permissible noise levels in urban and rural areas.

Facts & Strategies to Prevent Noise PollutionFacts :1. Noise is a health hazard and zero dB is the quietest audible sound a healthy hearing person can hear in absolute noise free environment and each 10 dB increment will double the sound intensity.2. Never expose a child to a sound above 120 decibels.3. Safe limit for short time exposure is 75 dB. Exposure to less loud sounds for longer times is also harmful for our health. The damage may develop at a later period & slowly.4. A whisper is 30 dB, conversational speech is 60 dB, and someone shouting at you from an arm's length away is 85 dB.5. Exposure to noise greater than 120-125 dB can cause hearing loss or pain in the ears.6. The permissible work limit for noise is 8 hours for 90 dB, 4 hours for 95 dB and 2 hours for 100 dB.7. Silence zone are areas up to 100 metres around hospitals, educational institutions and courts.8. Permissible noise : Industrial area 75 dB in day time and 70 dB in night time; Commercial area 65 dB in day time and 55 dB in night time; Residential area 55 dB in day time


© JIMI � JAN - MAR 2018 � VOL. 12 39

and 45 dB in night time and silence zone 50 dB in day time and 40 dB in night time.9. Noise-induced hearing loss usually happens slowly, with no pain and it is also the commonest cause of preventable permanent deafness.10. One can complain to the authorities if the noise levels exceed more than 10 dB than the allowable limit.

Measures to Minimise Noise Pollution :Outdoor Measures :

Encourage safe driving and avoid honking. By honking you are disturbing and damaging not only fellow citizen's health but yours also. Honking is to be used only to avoid an accident.If intended to use – Use soundless fire crackers.

Indoor Measures :Home noise is also dangerous. Even use of fan at very high speed produce 60 dB sounds. Reduce the fan speed to minimum needed.TV and Radio volume should be kept at minimum.Pregnant ladies and children should not be permitted to sit near TV and Radio. Loud sound is more dangerous to foetus and young children.Discard or exchange high noisy home appliances for more modern silent equipments even though they may be little more costly. The damage to your health is much more costlier.

Personal Measures :Break for a few minutes when you use ear phones or head phones to listen to music. It will help in recovery of fatigued hair cells and restore normal enzymatic activity of cochlea and brain neurones.

If only we remember "Your Joy Can Be Someone's Noise" 8the noise pollution can be checked .

ReferencesBerglund B, Lindvall T. Community noise. Arch Center Sensory Res.l995;2:1-195.Babisch W. Noise and health. Environ Health Perspect. 2005;113:A14-5.Zimmerman E, Lahav A. Ototoxicity in preterm infants: effects of genetics, aminoglycosides, and loud environmental noise. J Perinatol. 2013;33:3-8.Saunders AN. Incubator noise: a method to decrease decibels. PediatrNurs. 1995; 21:265-8.Hetu R, Truchon-Gagnon, Bilodeau SA. Problems of noise in school settings: a review of literature and the results of an exploratory study. J Speech Lang Pathol Audiol 1990;14:31-8.Lisa Goines RN, Louis H. Noise pollution: A modern plague. South Med J. 2007; 100:287-94.Harrison RV. The prevention of noise induced hearing loss in children. Int J Pediatr. 2012;2012:473541.Taljaard DS, Leishman NF, Eikelboom RH. Personal listening devices and the prevention of noise induced hearing loss in children: The Cheers for Ears Pilot Program. Noise Health. 2013-15:261-8.

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Avoid continues use of mobile phones. Those who have to use mobile phones continuously, may use speaker phones whenever possible.Mp3 players including iPods can be turned up to a maximum of around 103 dB using standard iPod earphones.Use personal sound protection devices (ear plugs and mufer) when exposed to loud sounds above 80-85 dB.

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1. Principal Consultant, department of gastroenterology, Max super speciality hospital, Vaishali2. DNB- Gastroenterology Resident, department of gastroenterology, Max super speciality hospital, Vaishali3. DNB- Gastroenterology Resident, department of gastroenterology, Max super speciality hospital, Vaishali4. Senior Consultant, department of gastroenterology, Max super speciality hospital, Vaishali5. Director and Head, department of gastroenterology, Max super speciality hospital, Vaishali

Endoscopic Ultrasound: A Paradigm shift in management

Review Article

AbstractEndoscopic Ultrasound (EUS) is a new age tool combining the powers of endoscopy and Ultrasound. EUS, first conceived and developed as a research tool in the early 1980'sis today an essential tool to visualize difficult to reach anatomical regions, and also, because of its interventional role in modern Gastro-intestinal (GI) practice. Echoendoscopes can be broadly divided into two types:-(i) Radial scope produces an ultrasound image which extends outwards in a plane that transects the axis of the scope and is preferred for diagnostic imaging (ii) Linear scope produces an ultrasound image in a plane that lies along the axis of the scope and is used for fine needle aspiration (FNA), fine needle biopsy (FNB) or EUS guided interventions. Diagnostic indication for EUS are recurrent acute pancreatitis, pancreatic divisum, chronic pancreatitis, benign & neoplastic pancreatic cysts, pancreatic adenocarcinoma, pancreatic neuroendocrine tumors, bile duct stones, biliary microlithiasis, bile duct tumors, and sphincter of oddi dysfunction.EUS is an ideal technique for the investigation of submucosal lesions like lipoma, GIST, stromal tumors, leiomyomas etc. EUS is the most accurate method for the T and N staging of upper GI malignancies and has significant impact on its diagnosis and management. EUS is also useful in mediastinal lymph nodes for diagnosis confirmation by EUS-FNA / FNB. The major focus and success in the last decade has been the EUS guided interventions. EUS guided Pancreatic Pseudocyst drainage, Celiac Plexus Neurolysis, Biliary drainage – either by rendezvous or Duodeno-choledochostomy or Hepatico-gastrostomy techniques. Some of the other upcoming techniques are EUS guided angiotherapy like injection of glue along with coils in gastric varices or pancreatic pseudoaneurysms, EUS guided Fine Needle Injection using Radio-Frequency ablation (RFA) probes, cryothermal probes, and photodynamic therapy. EUS-guided fiducial placement to facilitate image-guided radiotherapy has been used, most commonly for pancreatic cancer. EUS guided gastro-enterostomy and EUS guided gall bladder drainage are very promising techniques which are set to revolutionize the future of EUS guided interventions. Thus, Endoscopic Ultrasound has now no more a research tool but is changing managements due to its practical diagnostic and therapeutic applications.

Endoscopic Ultrasound (EUS) is a combination of the two most powerful image acquisition instruments of the 20th Century, the endoscopy and Ultrasound. EUS was first conceived and developed in the early 1980's by

1DiMagnoetal . Slowly and steadily from the research laboratory in the 1990's, it has now become indispensable of any modern gastro-intestinal services unit. EUS is anessential tool as it not only provides superior visualization of a difficult to reach anatomical regions, but also because of its valuable role as a problem-solving tool and ever-improving ability in an interventional capacity'' 2. In addition, the ever-increasing application of EUS has improved the diagnosis of other gastrointestinal and non-

Introductiongastrointestinal diseases and provided a delivery system for therapies. EUS was shown to outperform endoscopic retrograde cholangiopancreatography (ERCP), computed tomography (CT) , catheter angiography, and

3transabdominal ultrasound .Echoendoscopes can be broadly divided into two types. The radial type produces an ultrasound image which extends outwards in a plane that transects the axis of the scope. This type of device was the first to be developed and is still generally the preferred type for diagnostic imaging. In contrast, the linear configuration produces an ultrasound image in a plane that lies along the axis of the scope. Linear echoendoscopes are used when image guided fine needle aspiration (FNA), core biopsy or intervention is required. (fig 1)

EUS has an important role in the evaluation of Barrett's esophagus, cancer of the esophagus, stomach, and rectum, gastr ic lymphoma, submucosal les ions , feca l incontinence, perianal disease, lymph nodes, mediastinal

4adenopathy, and heart and vascular structures . Therapeutic EUS is increasingly used to treat pancreatic diseases, including intratumoral chemotherapy drug

1 2 3 4 5Kunal Das , Anando Sangupta , S K Sharma , Vibhu Mittal , P Kar


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5,6 7delivery , EUSguided endoscopic cystogastrostomy , 8 9EUS-guided celiac plexus blockade , or neurolysis . The

usage for EUS can be divided into 2 major Indications: Diagnostic and Therapeutic Indications

Diagnostic IndicationsEUS was initially invented to assess the difficult of image organs like pancreas, distal CBD and mediastinum. EUS is presently indicated both as an primary (ie, initial imaging modality) as well as secondary diagnostic imaging investigation (ie, in the assessment of abnormalities identified with other imaging modalities). It has an important role in staging of a many cancers of the gastrointestinal and respiratory tracts, particularly in those patients being considered for surgery and chemotherapy. Indications of diagnostic EUS includes:

Acute PancreatitisThe major role of EUS in acute pancreatitis is evaluation of etiology of recurrent acute pancreatitis and non-invasively assess CBD for stones before subjecting the patient to ERCP (Endoscopic Retrograde Cholangio-Pancreatography). More than 80% patients of acute pancreatitis are caused by gall bladder stones or alcohol which can be assessed by routine Transabdominal Ultrasound and LFT (Liver Function Test). In the rest 20%, EUS can help detect bile duct stones, pancreatic divisum, early chronic pancreatitis, Biliary microlithiasis, bile duct t u m o r s , a n d s p h i n c t e r o f o d d i d y s f u n c t i o n . Microlithiasisis defined as presence of calculi < 3mm in diameter. The proximity of the EUS probe to the Gall Bladder and biliary tree provides a better spatial resolution and higher sensitivity and thus small calculi

10can be detected . Incase of small CBD stones, EUS has an edge over MRCP in diagnosis. In relation to ERCP, EUS is non-invasive and does not cause post-procedure pancreatitis and other complications. Overall, EUS can diagnose positive etiology in 2/3rds cases of Idiopathic

11acute pancreatitis .

Chronic PancreatitisEUS has been shown to be sensitive and specific in the diagnosis of non-calcific chronic pancreatitis (calcific

12chronic pancreatitis is easily diagnosed at CT) . EUS can look at both the parenchymal changes like hyper echoic dots and strands, lobulations etc and pancreatic ductal changes like dilatation, irregularity, stricture, stones etc. EUS criteria have recently been established for the

13diagnosis of chronic pancreatitis .

Submucosal LesionsEUS is an ideal technique for the investigation of submucosal lesions identified during conventional endoscopy. EUS can identify the bowel wall into five layers with alternating black and white layers: Mucosa

(White), Muscularis mucosa (Black), Submucosa (White), Muscularis propria (Black), and Adventitia or surrounding tissues (White). This also helps in identification of the probable cause of origin of the submucosal lesions. For eg: GIST or stromal tumors arise from the second hypoechoic layer while leiomyomas arise from the 4th hypoechoic layers. Also the echogenicity of

14the lesion is sometimes critical . Also EUS-FNA / FNB can be used to acquire tissue and examination of the same by conventional strains and immune-histochemistry helps to plan treatment.

Pancreatic Cystic LesionsEUS is the diagnostic procedure of choice in the evaluation

15of the cystic pancreatic lesion . After identification of a pancreatic cystic lesion with other imaging modalities viz USG, CT or MRI, EUS not only helps in detailed image based analysis due to the higher spatial resolution of theimages but also can be used to guide aspiration of the cyst contents. Cytological and biochemical analysis of the uid (for carcinoembryonic antigen and amylase) aids the differentiation of benign entities from malignant or premalignant lesions.

Pancreatic Adenocarcinoma and Pancreatic Neuro-Endocrine Tumors (NET)EUS is useful in both diagnosis and planning of treatment for Pancreatic Adenocarcinoma. EUS is the most sensitive

16modality to diagnose small < 2 cm pancreatic SOL's . EUS can further help in determining resectibility for Whipple's surgery and also help start chemotherapy after establishing diagnosis by EUS-FNA. EUS elastography and EUS contrast Ultrasound (EUS-CEUS) are other 2 EUS based tests that help in distinguishing chronic pancreatitis related head SOL's from pancreatic adenocarcinoma

17related SOL .Pancreatic neuroendocrine tumors can be localized by EUS, and confirmed by EUS-FNA. Also EUS-CEUS helps in diagnosis as these are hyper vascular after injection of ultrasound contrast agents (USCA) while pancreatic

18adenocarcinoma is hypo vascular .

EUS for StagingEUS is the most accurate method for the T and N staging of

19upper GI malignancies . It has been shown to have a 20significant impact on diagnosis and management . EUS-

FNA is cost effective in establishing the accurate 21pretreatment staging of upper GI malignancies .

Patients undergoing resection of upper GI tumours will often require a preoperative EUS for the reasons described above. Tumours where EUS has a role include oesophageal, pancreatic and ampullary, biliary and gastric lesions. EUS alone is not sufficient for M staging. Despite this, EUS-FNA can be used to identify and obtain tissue from metastases in certain locations, particularly the left adrenal gland, liver, spleen, and non-regional lymph nodes. It is also a very sensitive method for

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detecting small volumes of pleural uid and ascites, which can have significant prognostic implications.Lower GI malignancies can be staged using EUS to assess depth of wall invasion and to look for malignant lymph nodes (ie, T and N staging). EUS is best reserved for local staging of rectal cancer in those patients where MRI is

22contraindicated .In the preoperative staging of lung cancer, positron emissiontomography-computed tomography (PET-CT) is the initial investigation of choice. After PET-CT suggests mediastinal node involvementthen this must be confirmed by tissue sampling which is easiest by EUS / EBUS-FNA as compared to the traditional invasive surgical mediastinoscopy. In this concept of 'medical' mediastinoscopy a combined approachusing both EUS

23and endobronchial ultrasound (EBUS) .

�erapeutic IndicationsPancreatic Pseudoscyst DrainageEUS guided pseudoscyst drainage has become the therapeutic procedure of choice for drainage of

24pseudocyst pancreas . This is due the several safety and therapeutic advantages of this procedure. The advantages include: detection and puncturing the cyst in the avascular plane as detected with EUS-Doppler guidance. The tail and body cysts or those cysts with no compression defect can be detected with EUS and punctured under its guidance. The cyst cavity shrinks and collapses after puncture which can be monitored real time by use of EUS. Also there are newer single stage lumen opposing metallic stents (LAMS) which can be used under EUS guidance for pseudocyst drainage. Its is very useful to detect the amount of walled off necrosis (WON) in the pancreatic pseudocyst as its great relevance in prognosis and future management of pancreatic WON.

Celiac Plexus NeurolysisCoeliac plexus neurolysis (CPN) has been used for the treatment of abdominal pain in pancreatic cancer and chronic pancreatitis since the 1970s. EUS-CPN has a low rate of complications in comparison to other image guided CPN techniques. EUS-CPN has been shown in a small study to be superior to CT-CPN in terms of initial and

25medium term reduction in analgesia requirements . EUS-CPN entails the delivery of either alcohol (for the palliation of pancreatic carcinoma) or corticosteroid (for the treatment of chronic pancreatitis) to the coeliac plexus via an echoendoscope.

EUS guided Biliary DrainageEUS-directed pancreaticobiliary access and drainage procedures primarily represent potential alternatives to percutaneous or surgical interventions after failed ERCP. EUS-guided pancreaticobiliary interventions broadly fall into the following 3 categories: (1) wire rendezvous procedures to facilitate retrograde pancreatic or biliary

access, (2) antegrade introduction of a balloon or stent through a pancreaticobiliary-enteric fistula with subsequent dilation or antegrade stent deployment across a native or surgically created pancreatic or biliary orifice, and (3) creation and stenting of a transluminal

26pancreaticobiliary- or cholecystoentericfistula .

EUS guided angiotherapyBleeding gastric varices are the most commonly reported

27indication for EUS-guided angiotherapy . Varices are visualized sonographically, and blood ow before, during, and after treatments is monitored with a duplex Doppler mode. Most commonly use of 19G or 22G FNA needles for delivery of therapeutic agent(s) into the variceal lumen, and targeting of the afferent feeding vein into a varix has also been described. One or more embolization coils, cyanoacrylate glue, or both coil(s) and glue, are injected to induce variceal thrombosis. EUS-guided angiotherapy has also been used for esophageal varices and a variety of ectopic varices including rectal

28duodenal, choledochal, and parastomal EUS-guided angiotherapy has also been used in the treatment of nonvariceal GI bleeding from arterial pseudo-aneurysms, bleeding tumors, Dieulafoy lesions, and refractory

28bleeding ulcers .

EUS guided Fine Needle Injection (FNI) (26)EUS-FNI of an antitumor agent (allogeneic mixed lymphocyte culture) into pancreatic adenocarcinoma was first described in2000.EUS-guided ethanol injection of pancreatic endocrine tumors has been described. EUS-guided ablation of solid pancreatic malignancies has been described using radiofrequency ablation probes, cryothermal probes (capable of both radiofrequency ablation and cryogenic cooling), and photodynamic therapy. Brachytherapy to treat advanced pancreatic adenocarcinoma using iodine-125 (125I) seeds delivered using EUS has been reported in small trials, with and without adjuvant chemotherapy. EUS-guided interventions on nonpancreatic malignancies, including esophageal and hepatocellular carcinoma and metastatic lymph nodes, have also been reported. All EUS-guided treatment of neoplasia remains investigational, and best indications and techniques have not been fully established.EUS-guided fiducial placement to facilitate image-guided radiotherapy has been used, most commonly for pancreatic cancer. A 19G or 22G FNA needle is preloaded with 1 or more appropriate-caliber fiducial(s) by retracting the needle stylet several centimeters and back-loading the fiducial(s) into the needle tip. The needle tip may be sealed with sterile bone wax to prevent fiducial loss during needle advancement through the echoendoscope.


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Anastomosis creation and other emerging interventions.EUS-guided creation of gastroenterostomies has been

SummaryIn the current scenario, endoscopic Ultrasound has now no more a research tool but is changing managements due to its practical diagnostic and therapeutic applications. Diagnostic applications include evaluation of recuurent acute pancreatitis and diagnosing CBD stones and GB microlithiasis in those patients. It is also useful in diagnosing early chronic pancreatitis and in evaluation of other pancreatic disorders like distinguishing benign pancreatic cysts and from cystic neoplasms of pancreas. EUS-FNA is useful for confirming of the diagnosis of pancreatic adenocarcinoma before chemotherapy and also in Pancreatic Neuroendocrine tumors (P-NET). Also diagnostic EUS is useful in suspected sub-mucosal lesions of the stomach.The real surprise is the addition of the therapeutic role of the EUS in management of various cases like EUS guided Pancreatic Cyst drainage, EUS guided biliary drainage, EUS guided angiotherapy, EUS guided gastro-enterostomies, and even EUS guided Gall bladder drainage. The future is bright for many new indications for EUS guided diagnostic and therapeutic applications.

reported for the management of gastric outletobstruction 29and afferent loop syndrome . Small series describe

advancing a balloon device over a previously placed oro-jejunal guidewire to a point beyond the obstruction. After small bowel puncture with a 19G needle or cystotome, a long .035-inch wire is coiled in the bowel lumen, and tract dilation is performed to accommodate placement of a lumen-apposing SEMS. Both the original AXIOS and HOT AXIOS stent systems have been used for this indication.EUS-guided puncture into the excluded stomach of patients who have undergone Roux-en-Y gastric bypass has been reported to facilitate subsequent ERCP. Placement of a lumen apposing SEMS across an EUS-created gastrogastric or jejunogastric fistula to facilitate transfistula ERCP in Roux-en-Y gastric bypass patients

30has also been reported .

EUS guided Gall Bladder Drainage EUS-guided gallbladder drainage (EUS-GBD) has been reported using both transantral and transduodenal approaches, with drainage attained using nasobiliary drains, double-pigtail plastic stents, covered SEMSs, and lumen-apposing SEMSs. The indication for the vast majority of EUS-GBD procedures is acute cholecystitis in

31patients unsuitable for surgery .

Fig 1

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Diagnosis And Treatment Of Multi Drug Resistant AndRifampicin Resistant Tuberculosis

Review Article

1 2 3Rajendra Prasad , Nikhil Gupta , Amitabh Banka

AbstractMultidrug resistant tuberculosis (MDR-TB) and Rifampicin resistant Tuberculosis (RR-TB) has been area of growing concern and has become a major threat to control of tuberculosis (TB) worldwide and in India. Early suspicion, diagnosis and treatment of MDR-TB and RR-TB are essential to prevent the morbidity, mortality and transmission of MDR-TB and RR-TB. Treatment of MDR-TB and RR-TB is difficult, complicated, much costlier and challenging. For treatment of MDR-TB, standardised, empirical and individualized approaches have been laid down. For standardised treatment approach, conventional and shorter regimens are available. The outcome of treatment of MDR-TB is not very favourable and varied from 50-80% in different studies. Identification and treatment of MDR TB are the top priorities for the proper control of MDR TB. Sound infection control measures to avoid further transmission of MDR TB and research towards development of new diagnostics, drugs and vaccines should be promoted for prevention and control of MDR-TB and RR-TB,Key words: Multidrug resistant tuberculosis (MDR-TB), Rifampicin resistant tuberculosis (RR-TB), conventional regimen, shorter regimen, diagnosis, treatment.

IntroductionMultidrug Resistant Tuberculosis (MDR-TB) is defined as disease due to M.Tuberculosis that is resistant to Isoniazid (H) and Rifampicin (R) with or without resistance to other drugs. Rifampicin resistant TB (RR-TB) defined as resistance to rifampicin detected using genotypic or phenotypic methods with or without resistance to other first line anti TB drugsMDR-TB has been an area of growing concern to human health worldwide and posing a threat to the control of tuberculosis. The Global Tuberculosis Report 2017 estimated that 4.1% of newly diagnosed and 19% of previously treated Tuberculosis cases had MDR-TB. It has been estimated that 490,000 new cases of MDR-TB and additional 110,000 cases of rifampicin resistant tuberculosis (RR-TB) emerged causing death to 240,000 people globally in 2016. Out of estimated 600,000 MDR-TB cases, only 153119(25.5%) were detected and even fewer 129,689(22%) started treatment and only 54% of them were treated successfully.

In India, it is estimated that the prevalence of MDR-TB among new and previously treated patients was 2.8% and 12% respectively. It is estimated that 147,000 cases of MDR-TB emerge every year of which 84,000 were among notified cases of TB in 2016. Out of 84000 MDR –TB cases, only 37,258(44%) were diagnosed, 32,914(39%) were started on treatment and treatment success rate was only

146% . The present write up aims to give an overview of diagnosis and treatment of multi drug resistant and rifampicin resistant tuberculosis

Diagnosis of MDR-TB/RR-TBA presumptive case of MDR-TB is defined as a TB patient who fails new treatment regimen and retreatment regimens with first-line Anti-TB drugs who is sputum smear positive at the end of the fourth month of treatment

2or later and Close contacts of drug-resistant TB cases. , Diagnosis of MDR TB is based on clinical, radiological and bacteriological evidences.Clinical evidence comprises of the symptoms and signs suggestive of TB and past history of anti -tubercular treatment. History of prior treatment with antitubercular drugs (ATD) is most important. The main predictor of resistance to a particular drug is the demonstration of its prior use in monotherapy for more than one month. To obtain evidence of possible inadvertent or direct monotherapy, it

1. Department of Pulmonary Medicine Era's LucknowMedical college and Hospital, Lucknow2. Department of Medicine Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow3. Department of Pulmonary Medicine Era’s LucknowMedical college and Hospital

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is essential to be meticulous in obtaining the historyof anti-tuberculosis treatment in all patients suspected of MDR-TB.There should be a detailed evaluation into the drugs used, the drug dosages if previous drug prescriptions are available, whether the drugs were fixed dose combinations or separate drugs, their reliability in terms of WHO approved bioavailability, whether the patients were compliant to these drugs, supervised or unsupervised treatment and any drug intolerance that included partial or complete drug defaulting. Any real masked monotherapy previously received by the patient can be identified with reasonably good accuracy and one can accurately predict resistance to specific drugs and

3prevent their inclusion in the retreatment plan . The other important aspects of history include contacts with known case of resistant tuberculosis and patient's place of residence which may have a high prevalence of drug resistance. Though radiological worsening is not a very reliable indicator for predicting drug resistance, it serves to compliment the clinical and bacteriological evidence of the patient. Change in size of cavities and increase in size of existing lesions and appearance of new lesions are signs of disease progression and activity.

The bacteriological evidence serves as the gold standard in the detection of MDR-TB. This is based on sputum smear microscopy and culture of M. tuberculosis anddrug susceptibility testing (DST).Sputum smear microscopy, after starting standard chemotherapy can show a positive, negative or suboptimal response. While positive response is characterized by sputum conversion at 2 to 3 months of chemotherapy, a negative response could mean persistent smear positivity at the end of 3 months of adequate chemotherapy and a suboptimal response by an initial fall in the sputum grade followed by a gradual rise - the so called 'fall & rise' phenomenon while the patient is on anti-tubercular therapy. The last two patterns increase the probability of drug resistant tuberculosis. Diagnosis is confirmed by DST from reliable and reputed laboratories under constant quality control. However, one has to keep in mind the limitation of highly specific DST because the technique is complex, difficult to perform accurately even when skilled personnel are available and laboratory

4facilities are of high standard . Further one should realize that laboratories vary in reliability; errors do occur in labs, different DST reports are obtained from the same patient from different labs. Susceptibility testing for isoniazid, rifampicin, ouroquinolones and the injectables is very reliable. For other drugs, it is less reliable and individualized treatments based on DST for these drugsshould beused with great caution. The Effectiveness or ineffectiveness of a drug cannot be predicted by DST

5with 100% certainty .Furthermore, the DST to second line drugs (SLD'S) is very variable. Keeping above facts in mind it is pertinent that DST should not be accepted

uncriticallyand quality assured labs performing DST is needed.

Molecular diagnostictechniques have been used for identification of resistance associated mutation. WHO with stop TB partnership endorsed line probe Assays in low resource countries in 2008which can do rapid

6screening of patients with MDR-TB risk within 2 days . The Xpert MTB RIF assay endorsed by WHO in 2010 enables simultaneous detection of mycobacterium tuberculosis and rifampicin resistance (reliable proxy for MDR –TB) directly from sputum and other extra

7pulmonary specimen except blood in less than 2 hours . The assay is robust enough to be performed outside of conventional laboratories at district and sub district level of health system but requires uninterrupted power supply. It provides accurate results and can allow rapid initiation of MDR –TB treatment pending results from

8conventional culture and DST .WHO recently recommended 2nd Line probe assay (2nd LPA), a rapid diagnostic test MTBDRsL that identifies genetic mutation in MDR strains that detect resistance to ouroquinolones

9and injectable second line anti-TB drugs .

Treatment of MDR-TB/RR-TBFor treatment of MDR-TB, standardised, empirical and

10individualizedapproaches have been laid down . Individualized treatment based on individual DST and prior treatment history is costly and needs skilled professionals and quality assured bacteriological and molecular diagnostic labs whereasstandardized treatment is simple, less costly and same treatment is given to all patients. Treatment of MDR-TB is very difficult in the hands of many physicians with restricted knowledge who dare to treat these patients and create worsening problems. Therefore individualized treatment needs specialized physicians experienced in dealing with such cases since these treatments represent the patient's last chance of a cure. There can be two types of treatment regimen - conventional or shorter regimen according to recent update from WHO in which they have also reclassified ATD for MDR-TB11. Drugs and doses according to new classification is given in TABLE-1. In patients with MDR-TB/RR-TB, a conventional regimen of least five effective Ant i -TB drugs during the intens ive phase i s recommended, including pyrazinamide and four core s e c o n d - l i n e A T D - o n e c h o s e n f r o m g r o u p A(ouroquinolones: levooxacin, moxioxacin and gatioxacin ), one from group B(Second line injectable drugs : Kanamycin, Amikacin, Capreomycin), and at least two from group C(Other core second-line drugs: ethionamide/prothionamide, cycloserine/terizidone, Linezolid and clofazimine). If the minimum of effective ATD cannot be composed as above, one drug from group


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D2 (Bedaquiline and Delamanid) and other drugs from D3 (PAS, Imipenem-cilastatin, Meropenem, Amoxicillin-clavulanate and Thioacetazone) may be added to bring the total number of drugs to five. The regimen may be further strengthened with rest of Group D1 (high-dose isoniazid and/or ethambutol). While streptomycin is not usually included with the second-line drugs it can be used as the injectable drug of the core MDR-TB regimen if none of the three other injectable drugs can be used and if the strain can be reliably shown not to be resistant. Thioacetazone should not be used if the patient is HIV seropositive11. Intensive phase including injectables should be given for atleast 8 months for most patients which can be modified depending upon the response of the patient.The total duration of treatment is atleast 20 months which can be prolonged upto 24 months depending upon the response of the patient. Pyrazinamide is usually continued for the entire treatment especially if there is extensive disease. If the patient has minimal disease, pyrazinamide can be stopped with injectables at end of intensive phase. Bedaquiline or delamanid are used for 6 months in intensive phase and are presently not recommended for whole treatment duration.

Shorter regimen for treatment for subset of MDR TB/RR-TB patients have been introduced recently. In patients with MDR TB/RR-TB who have not been previously treated with second-line drugs and in whom resistance to ouroquinolones and second-line injectable agents has been excluded or is considered highly unlikely, a shorter MDR-TB regimen of 9-12 months may be used instead of a conventional regimen of 20-24months. The intensive phase of 4 months which may be extended to 6 months in case of lack of sputum smear conversion consists of gatioxacin or moxioxacin, Kanamycin, prothionamide, clofazimine, high-dose isoniazid, pyrazinamide, and ethambutol. This is followed by a continuation phase of 5 months which consist of gatioxacin or moxioxacin, clofazimine, ethambutol, and pyrazinamide. Doses of drugs given in shorter regimen is given in TABLE-2It is important that a single drug should never be added to a failing regimen and it is ineffective to combine 2 drugs of the same group or to add a drug potentially ineffective because of cross resistance. No drug should be kept in reserve and the most powerful drugs should be used initially and in maximum combination so as to ensure that first battle is won and won permanently. All patients initiated on treatment and their family members should be intensively counseled prior to treatment initiation and during all follow up visits. To reduce the risk of development of resistance to second line ATD and promote optimal treatment outcomes, all efforts should be made to administer treatment under direct observation (DOT) over the entire course of treatment. If DOT is not possible, attempts to ensure treatment adherence should

be made by checking empty blister packs during follow up 12visits every month . All measures should be taken to

persuade and encourage patients not to stop treatment despite all its discomforts as it is the last resort that stands between life and death. Extrapulmonary MDR TB/RR-TB is treated with the same regimen and duration as pulmonary MDR TB/RR-TB. If the patient has symptoms suggestive of central nervous system involvement and is infected with MDR TB/RR-TB, the regimen should use drugs that have adequate

13penetration into the central nervous system . Rifampicin, isoniazid, pyrazinamide, prothionamide /ethionamide and cycloserine have good penetration into the cerebrospinal uid (CSF); Kanamycin, amikacin and capreomycin do so only in the presence of meningeal inammation; PAS and ethambutol have poor or no penetration. The ouroquinolones have variable CSF penetration, with better penetration seen in the later generations. Linezolid is believed to penetrate the central nervous system, and has been used in meningitis treatment. Imipenem has good central nervous system penetration, but children with meningitis treated with imipenem had high rates of seizures and meropenem is

13-15preferred for meningitis cases and children . There is no data on central nervous system penetration of clofazimine, clarithromycin, Bedaquiline and delamanid. Surgical treatment should be considered as an adjunct to chemotherapy whenever applicable and when results of chemotherapy are very unpredictable. Adjuvant use of corticosteroids can be beneficial in conditions like severe central nervous system or pericardial involvement. Corticosteroids do not increase mortality when the patient is on effective regimen and should be used with tapering

16of doses over several weeks . The immunomodulators may have the potential to improve outcomes in all TB including MDR-TB/RR-TB as seen in evidence reviewed

17by expert group in 2007 but still evaluation of efficacy and safety of such therapy is needed before any recommendation is madeMDR-TB/RR-TB treatment should include nutritional assessment and counseling of the all patients. Because of disease process, patient appetite is reduced and tends to be malnourished, in addition, second line Anti-TB drugs can further reduce appetite. Patients should be properly counseled for adequate food intake. One such step is to provide free food which is thought to improve quality of

18life and may improve treatment adherence but further research is necessary. Addition of vitamins probably does not improve weight gain and also no studies have

18assessed their effect on quality of life but they may be added to treat specific deficiencies like vitamin A. Furthermore, Vitamin B6 should be given if treatment regimen consists of cycloserine, terizidone, high dose Isoniazid or linezolid to prevent neurological side effects.

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Monitoring of treatment should be done with bacteriological, radiological and clinical methods. Sputum specimens should be obtained for semi quantitative smear and culture every month from third month onwards during the intensive phase of therapy. Sputum conversion is defined as two sets of consecutive negative smears and cultures, from samples collected at least 30 days apart. Both bacteriological techniques (smear and culture) should be used to monitor patients throughout therapy. After sputum conversion smear examination and culture are done once in three months until the end of therapy10. If such a large number of smears and cultures for follow-up are not possible, then at least five smears and cultures must be done for follow up (4, 6, 12, 18 and 24 months), X-rays should be done every 6 months whereas clinical monitoring preferably should be

19done every month .

Monitoring of Treatment

Outcome of TreatmentThe outcome of treatment of MDR-TB is not very favourable and varied from 50-80% in different studies.In a retrospective analysis of 171 immunocompetent-patients treated over a ten year period (1973-83) atthe National Jewish Hospital in Denver, the overall favourable outcome was only a little over 50%20. All Patients were treated with individually tailored regimensin which they received at least 3 or 4 drugs that they hadnot received previously, or to which they were known to be susceptible. Of the 134 patients evaluated forefficacy, 65% became culture negative and 35% failed to respond. Of those who became culture negative, 14%eventually relapsed giving an overall favourable-outcome in 56% of patients. Of the patients who failed, 46% died of tuberculosis. In Cape Province South Africa, the 5-yearoutcome of 240 MDR-TB patients was death in 48%, cure in 33%, 15% were respiratory disabled and 13%were still bacteriologically positive21. However, not all the reports are so grim. In a retrospective analysisreported from South Korea, of 107 patients with MDR-TBtreated with at least four drugs to which they hadnot been exposed to before, or to which they wereknown to be susceptible, in 63 patients with sufficientfollow up data, 52 (82.5%) responded to chemotherapy.There was no subsequent relapse among the patientswho responded, and there were no tuberculosis relateddeaths. The author concluded that, MDR-TB respondsrelatively well to carefully selected regimens. However,the mean period of follow up was only 17 months22. Khanna. 23 used kanamycin (6 months), cycloserine, ethionamide and sodium PAS for 18 monthsin hospital ized pat ients and observed bacteriologicalconversion in 71% of MDR-TB patients. Purohit et al.24 used kanamycin (6 months), ethionamide,

sodiumPAS and isoniazid for 18 months on a domiciliarybasis and bacteriological conversion was achieved in73% of the patients. In another study by Rupak

25Singla et al. bacteriological quiescence was achieved in78% of the patients who completed the full

19, 26therapy.Prasad, et al. observed 75.5% sputum smearand culture conversion rate at the end of two years in45 patients of MDR-TB patients, using kanamycin, ethionamide, PAS and cycloserine regimen. Out of 45patients 34 (75.5%) patients were declared cured, thesepatients were followed for an average 17.4 months (3-60 months) two patients relapsed (5.7%) so long termoutcome was around 70%. A systematic review andmeta-analysis of the available therapeutic studies on the treatment of MDR-TB showedoverall treatment success rate was 62%, however, the heterogeneity in study characteristicsled to significant variation in reported

27treatmentoutcomes . Individualized treatment regimens hadhigher treatment success (64%) thanstandar -dized regimens (54%), althoughthe difference was not significant. The proportion ofpatients treated successfully improved when treatmentduration was at least 18 months, and if patients receiveddirectly observed therapy throughout treatment. Studiesthat combined both factors had significantly higherpooled success proportions (69%) than other studies of treatment outcomes (58%). In another prospective study by Prasadet al. of 98 MDR-TB patients treated as per modified DOTSPLUS protocol it was observed that the default anddeath rates were 7.1% and 10.2% respectively and sputum smear and culture conversion rate at the end of 24 months was 92.5% and

2887.7% respectively . It is observed that inadequate treatment duration willresult in relapses, may lead to treatment failure andadditional acquired drug

29resistance . In a study byChan et al. on treatment and outcome analysis of 205patients with MDR-TB, it was observed that surgicalresection and ouroquinolones therapy was associatedwith improved microbiological

30and clinical outcome . Flouroquinolone resistance was associated witha higher proportion of treatment failures and deaths inMDR patients than non-ouroquinolone-resistant cases.Addition of ouroquinolones was associated with less chance of relapse and improved

31-36 37 38treatment outcomes . Kanamycin , capreomycin andstreptomycin resistance is associated with poor treatmentoutcomes. The outcome for patients with MDR-TB isnot very favourable in non- immunocompetent patients; and the response in HIV positive patients is even bleaker. In the outbreaks of MDR-TB in and aroundNew York City, between 1988 and 1992, predominantly in HIV infected individuals, mortality was in the orderof 80% and the mean duration from diagnosis to death was 4 to 16 weeks. In patients having concomitant HIVand MDR-TB, response rate


© JIMI � JAN - MAR 2018 � VOL. 12 50

appeared to be poor withhigh rates of treatment failure 39and mortality . InMDR-TB patients with localized

disease, surgery, as anadjuvant to chemotherapy, can improve outcomes andshould be considered when there

4 0is poor response toappropriate chemotherapy . Programmatic studies evaluating the shorter MDR regimen have been carried out in the countries across the world involving more than 1200 patients showed the cure

41-44rate of 82% and overall success rate of 84.5%11, .

ConclusionTreatment of MDR-TB and RR-TB is difficult , complicated, much costlier, challenging and needs experience and skills. MDR-TB is a man-made problem and its emergence can be prevented by prompt diagnosis and effective treatment of all TB case. Effective use of first line anti tuberculosis drugs in every new patients of tuberculosis to prevent the MDR-TB and RR-TB and proper use of second line drugs to treat patients with MDR-TB and RR-TB are the top priorities for the proper control of MDR-TB. Sound infection control measures to avoid further transmission of MDR-TB and RR-TB and research towards development of new diagnostics, drugs and vaccines should be promoted for prevention and control ofMDR-TB and RR-TB.

References:World Health Organization. Global Tuberculosis Report 2 0 1 7 . W H O / H T M / 2 0 1 7 . 1 3 . G e n e v a W o r l d H e a l t h Organization 2017. Companion Handbook to the WHO guidelines for the programmatic management of drug resistant tuberculosis.WHO/HTM/TB/2014.11Caminero J A. Management of multidrug-resistant tuberculosis and patients inretreatment. Eur Respir J 2005; 25: 928–36.Kim S J.Drug susceptibility testing in tuberculosis: methods and reliability of results.E Rr J 2005;25:564-9. Treatment of tuberculosis :guidelines for national programmes-4th ed.WHO\HTM\TB\2009.420.Lund DI, Zwerling AA, Pai M. Genotype MTB DR Assays for the diagnosis of multi drug resistant tuberculosis: a meta analysis. ERJ 2008;32;1165-74Banada PP, Sivasubramani SK, Blakemore R, Boehme C, Perkins MD, Fennelly K, Alland D. Containment of bioaerosol infection risk by the Xpert MTB/RIF assay & its applicability to point of care settings. J clin Microbio 2010;48:3551-7

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Small PM, Pai M. Tuberculosis diagnosis—time for a game change. New Engl J Med 2010;363:1070-1The use of molecular line probe assays for the detection of resistance to second-line anti-tuberculosis drugs. WHO/HTM/TB/2016.07World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis. Emergency update 2008 and 2011. WHO/HTM/TB/2008.402/2011/6. G e n e v a , S w i t z e r l a n d , 2 0 0 8 / 2 0 1 1 . http://whqlibdoc.who.int/publications/2008/9789241547581 _ e n g . p d f a n d http://whqlibdoc.who.int/publications/2011/9789241501583_eng.pdf (accessed 28-08-2017).WHO treatment guidelines for drug-resistant tuberculosis 2016 update. WHO/HTM/TB/2016.04.Prasad R, Singh A, Srivastava R, kushwaha RAS, Garg R , Verma SK et al. Treatment outcome of multi drug resistant tuberculosis patients in modified DOTS PLUS. ERJ 2012; 40, suppl56 p 3321(abstract)Holdiness MR. Cerebrospinal uid pharmokinetics of antituberculosis drugs. Clinical Pharmacokinetics, 1985, 10:532–4.Tuberculosis drug information guide. 2nd edition. California: Curry International Tuberculosis Center and California Department of Public Health; 2012.Daley CL. Mycobacterium tuberculosis complex. In: Yu VL, Merigan TC Jr, Barriere SL, editors. Antimicrobial Therapy and Vaccines. Williams & Wilkins; 1999. 531–6.PIH guide to medical management of multidrug-resistant t u b e r c u l o s i s . B o s t o n : P a r t n e r s I n H e a l t h ; 2 0 0 3 (http://www.pih.org/publications/entry/pih-guide-to-the-medical-management-of-multidrug-resistant tuberculosis/).Report of the expert consultation on immunotherapeutic interventions for tuberculosis. Geneva: World Health Organization; 2007:1–56.Sinclair D, Abba K, Grobler L, Sudarsanam TD. Nutritional supplements for people being treated for active tuberculosis. Cochrane Database Systematic Review;2011:1–139Prasad R, Verma S K, Sahai S, Kumar S, Jain A. Efficacy and safety of kanamycin, ethionamide, PAS, and cycloserine in multidrug resistant pulmonary tuberculosis patients. Ind J Chest Dis Allied Sci. 2006; 48:183-6.Goble M, Iseman MD, Madsen LA, Waite I, Ackerson L, Horsburgh CR. Treatment of 171 patients with pulmonary tuberculosis resistant to isoniazid and streptomycin. N Engl J Med. 1993; 328:527-32.Schaaf HS, Botha P, Beyers N, Gie RP, Vermeulen HA,Groenewald P, Coetzee GJ, Donald PR. The 5-yearoutcome of multi drug resistant tuberculosis patients inthe Cape Province of South Africa. Trop Med Int Health.1996; 1:718-22.

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Park SK, Kim CT, Song SD. Outcome of chemotherapyin 107 patients with pulmonary tuberculosis resistant toisoniazid and rifampicin. Int J Tuber Lung Dis. 1998;2:877-84.Khanna BK. Treatment of long-term tuberculosistreatment failures. Ind J Tub. 1985; 32:171-5.Purohit SD, Gupta M, Agnihotri SP, Madan A, GuptaPR. Management of chemotherapy failures. Ind J Tub.1991; 37:383.Singla R, Myneedu VP, Jaiswal A, Puri MM, Jain RC.Ethionamide, cycloserine, isoniazid, sodium PAS a n d k a n a m y c i n i n r e - t r e a t m e n t o f d r u g f a i l u r e pulmonarytuberculosis patients. Ind J Tub. 1995; 42:23-6.Prasad R. Long term treatment outcome in multidrugresistant tuberculosis (MDR-TB). Chest. 2004;126:836A.

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Orenstein EW, Basu S, Shah NS, Andrews JR, FriedlandGH, Moll AP, Gandhi NR, Galvaniet AP. Treatmentoutcomes among patients with multidrug-resistanttuberculosis: Systematic review and meta-analysis.Lancet Infect Dis. 2009; 9:153-61.Prasad R, Singh A, Srivastava R, Kushwaha RS, Garg R, Verma S K, Jain A. Treatment outcomes of multi-drug resistant tuberculosis patients in modified DOTS-PLUS: A two year experience. Int J Tuberc Lung Dis. 2013;17:S332.Prasad R, Srivastava DK. Multi-drug and extensivelydrug-resistant TB (M/XDR-TB) management: Currentissues. Clinical Epidemiology and Global Health. 2013;1:124-8.Chan ED, Laurel V, Strand MJ, Chan JF, Huynh ML,Goble M, Iseman MD. Treatment and outcome analysisof 205 patients with multidrug-resistant tuberculosis. AmJ Respir Crit Care Med. 2004; 169:1103-9.Jiang RH, Xu HB, Li L. Comparative roles ofmoxioxacin and levooxacin in the treatmentof pulmonary multidrug-resistant tuberculosis: Aretrospective study. Int J Antimicrob Agents. 2013;42:36-41.Chiang CY, Enarson DA, Yu MC, Bai KJ, HuangRM, Hsu CJ, Suo J, Lin TP. Outcome of pulmonarymultidrug-resistant tuberculosis: A 6-yr follow-up study.Eur Respir J. 2006; 28:980-5.Migliori GB, Lange C, Girardi E, Centis R, Besozzi G,Kliiman K, Codecasa LR, Spanevello A, Cirillo DM;SMIRA/TBNET Study Group. Fluoroquinolones: Arethey essential to treat multidrug-resistant tuberculosis?. Eur Respir J. 2008; 31:904-5.Ahuja SD, Ashkin D, Avendano M, et al. Multi-drugresistant pulmonary tuberculosis treatment

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D'Ambrosio L, Lange C, Bauer M, MenziesD. Resistance to uoroquinolones and second-lineinjectable drugs: Impact on multidrug-resistant TBoutcomes. Eur Respir J. 2013; 42:156-68.Jeon CY, Hwang SH, Min JH, et al. Extensively drugresis-tanttuberculosis in South Korea: Risk factors andtreatment outcomes among patients at a tertiary referralhospital. Clin Infect Dis. 2008; 46:42-9.Migliori GB, Lange C, Centis R, Sotgiu G, MütterleinR, Hoffmann H, Kliiman K, De Iaco G, Lauria FN,Richardson MD, Spanevello A, Cirillo DM; TBNETStudy Group. Resistance to second-line injectablesand treatment outcomes in multidrug-resistant andextensively drug-resistant tuberculosis cases. Eur RespirJ. 2008; 31:1155-9.Fischl MA, Daikos GL, Uttamchandani RB, PobleteRB, Moreno JN, Reyes RR, Boota AM, Thompson LM,Cleary TJ, Oldham SA, Saldana MJ, Lai S. Clinicalpresentation and outcome of patients with HIV infectionand tuberculosis caused by multi-drug resistant bacilli.Ann Intern Med. 1992; 117:184-90.Prasad R. Multidrug and extensively drug-resistanttu-berculosis management: Evidences and controversies.Lung India. 2012; 29:154-9.Van Deun A, Maug AKJ, Salim MAH, Das PK, Sarker MR, Daru P, et al. Short, highly effective, and inexpensive standardized treatment of multidrug-resistant tuberculosis. Am J Respir Crit Care Med. 2010;182:684–9.Kuaban C, Noeske J, Rieder HL, Aït-Khaled N, Abena Foe JL, Trébucq A. High effectiveness of a 12-month regimen for MDR-TB patients in Cameroon. Int J Tuberc Lung Dis 2015;19:517–24.Piubello A, Harouna SH, Souleymane MB, Boukary I, Morou S, Daouda M, et al. High cure rate with standardised short-course multidrug-resistant tuberculosis treatment in Niger: no relapses. Int J Tuberc Lung Dis. 2014;18:1188–94.Ahuja SD, Ashkin D, Avendano M, Banerjee R, Bauer M, Bayona JN, et al. Multidrug resistant pulmonary tuberculosis treatment regimens and patient outcomes: an individual patient data meta-analysis of 9,153 patients. PLoS Med. 2012;9:e1001300.

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© JIMI � JAN - MAR 2018 � VOL. 12 52

James Parkinson : The Real Hero

Medical History

Bhupendra Chaudhary

Involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported; with a propensity to bend the trunk forwards, and to pass from a walking to a running pace: the senses and intellects being uninjured ......

Year 2017 marks the 200th anniversary of James Parkinson's description of the disease that bears his name and that affects an estimated 5 million people worldwide. Working as a medical surgeon in London, James Parkinson was the first to connect the dots when confronted with a handful of patients with similar involuntary tremors and symptoms of muscle weakness. In 1817, he published his findings in his seminal 'Essay on shaking palsy', a 66 page essay on six cases, the three of his own patients and the three who he saw in the street.He referred to the disease that would later bear his name as paralysis agitans, or shaking palsy. He distinguished between resting tremors and the tremors with motion. It was almost 50 years after Parkinson's death before the significance of his Essay was fully appreciated and the shaking palsy renamed 'Parkinson's disease' in his memory. It was Jean-Martin Charcoat who coined the term "Parkinson's disease" some 60 years later. Parkinson erroneously predicted that the tremors in these patients were due to lesions in the cervical spinal cord.James Parkinson (11 April 1755 - 21 December 1824) was an English surgeon, apothecary, geologist, palaeontologist, and political activist. He is most famous for his 1817 work, An Essay on the Shaking Palsy in which he was the first to describe "paralysis agitans", The symptoms identified by Parkinson two centuries ago are still used to diagnose the disease today. Although unable to identify a cause for the condition, Parkinson's remarkably accurate description of the symptoms, and the disease in all its different stages, eventually led to it being named in his honour.The Enlightened Mr. Parkinson by Dr. Cherry Lewis, Honorary Research Fellow at the University of Bristol, tells the story of Parkinson's life as an apothecary surgeon (similar to today's GP) in Hoxton, then a village on the outskirts of London. It was a time when epidemics festered in the dirty and overcrowded tenements, infant mortality was fifty percent, and no anesthetics were available for those unfortunate enough to require surgery. Smallpox killed ten per cent of the population, so when Edward Jenner discovered a vaccine, Parkinson worked with him to establish vaccination stations across London.

53 © JIMI � JAN - MAR 2018 � VOL. 12


In 1812 Parkinson assisted his son with the first described case of appendicitis in English, and the first instance in which perforation was shown to be the cause of death.Parkinson's interest gradually turned from medicine to nature, specifically the relatively new field of geology, and palaeontology. He began collecting specimens and drawings of fossils in the latter part of the eighteenth century. He took his children and friends on excursions to collect and observe fossil plants and animals. His attempts to learn more about fossil identification and interpretation were frustrated by a lack of available literature in English, and so he took the decision to improve matters by writing his own introduction to the study of fossils.He revealed an unknown world, populated with 'hyenas the size of bears' and 'enormous marine animals', all of which both enthralled and terrified his readers. His exquisitely illustrated Organic Remains of a Former World placed the study of fossils on the scientific map of Britain before the subject even had a name.When awarded The Royal College of Surgeons' first Gold Medal, it was not for his medical publications that Parkinson was honoured, nor even his Essay on the Shaking Palsy, but for his ground-breaking work on fossils.Parkinson became a political activist after the French Revolution, which many in Britain supported. He wrote numerous outspoken publications which harangued a corrupt and incompetent Government using the pseudonym 'Old Hubert', for many were imprisoned and even transported to Australia for such seditious activities. When caught up in an alleged plot to kill 'mad' King George III, Parkinson put his own life on the line trying to save his friends.Parkinson also contributed several papers to William Nicholson's "A Journal of Natural Philosophy, Chemistry and the Arts", and in the first, second, and fifth volumes of the "Geological Society's Transactions". He wrote a single volume 'Outlines of Orytology' in 1822, a more popularise work.Parkinson belonged to a school of thought, Catastrophism, that concerned itself with the belief that the Earth's geology and biosphere were shaped by recent large-scale cataclysms. He cited the Noachian deluge of Genesis as an example, and he firmly believed that creation and extinction were processes guided by the hand of God. His view on Creation was that each 'day' was actually a much longer period, that lasted perhaps tens of thousands of years in length.We have come a long way since the publication of 'Essay on shaking palsy', but we haven't found what James Parkinson was looking for: a way to stop the disease in its tracks. We'll continue working until we do.April 11th, James Parkinson's birthday, is World Parkinson's Day. Each year in April, thousands of people across the globe roll up their sleeves to raise awareness for the disease and the consequences for all those affected by it. To commemorate this year's bicentennial edition, the Flemish Parkinson League has organised thought-provoking event on April 23, 2017 in Ghent, where patients, clinicians, family members and researchers got together, to look back, but more importantly, to look forward to new treatment approaches on the horizon, as a salute to this real hero.

ReferencesEyles, JM (September 1955). "James Parkinson; 1755-1824". Nature. 176 (4482): 580-1. doi:10.1038/176580a0. ISSN 0028-0836. PMID 13265780.Mchenry Lc , J r (September 1958) . "Surgeon and palaeontologist, James Parkinson". The Journal of the Oklahoma State Medical Association. 51 (9): 521-3. ISSN 0030-1876. PMID 13576252.Nelson, JN (October 1958). "James Parkinson". The New England Journal of Medicine. 259 (14): 686-7. doi: 10.1056/ NEJM195810022591408. ISSN 0028-4793. PMID 13590427.

Tyler, KL; Tyler, HR (February 1986). "The secret life of James Parkinson (1755-1824): the writings of Old Hubert". Neurology. 36 (2): 222-4. doi:10.1212/wnl.36.2.222. ISSN 0028-3878. PMID 3511403.Herzberg, L (1987). "Dr James Parkinson". Clinical and experimental neurology. 24:221-3. ISSN 0196-6383. PMID 3077340.Sakula, A (February 2000). "James Parkinson (1755-1824)". Journal of medical biography. 8 (1): 59. ISSN 0967-7720. PMID 10994050.

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© JIMI � JAN - MAR 2018 � VOL. 12 54

Short Sleep Duration, Diabetes Risk and Mood Disorder

Knowledge Forum

Aditya Chakravorty

It is now well known from various research work carried out all over the world that lifestyle modification significantly prevent the onset of diabetes and cardiovascular disorder as well as modifies the course of such ailment .Sleep, its duration and its quality in day to day life is suggested to be a novel behavioural risk factor for diabetes and other cardiovascular diseases. Aberrant sleeping times may lead to circadian misalignment and result in decrease in plasma insulin secretion. A large population based study at Malmo Diet and Cancer Centre Sweden conducted on 4023 individual aged between 45 to 68 with mean follow up time of 17.8 years has shown that plasma concentration of CASPASE-8 a biomarker is associated with short sleep duration and the risk of incident diabetes mellitus.The sleep duration was correlated with incident diabetes mellitus using a marker of apoptosis plasma CASPASE-8. Sleep duration is suggested to regulate tumor necrosis factor α and β-cell apoptosis may be a consequence of activated cysteinyl aspartic acid–protease-8 (CASPASE-8) a key enzyme in the tumor necrosis factor receptor pathway. The disrupted circadian rhythm in turn results in deficient pancreatic β-cell and increased susceptibility

1-2to type 2 DM . The biological mechanism associated with reduced sleep shows decrease leptin and increased ghrelin which in turn may stimulate appetite and lead to increase BMI. So based on the scientific evidence available

References:Thomas Svensson, Akiko Kishi Svensson,Mariusz Kitlinski, Plasma Concentration of Caspase-8 Is Associated With Short Sleep Duration and the Risk of Incident Diabetes Mellitus: J Clin Endocrinol Metab, April 2018, 103(4):1592–1600Mallon L, Broman JE, Hetta J. High incidence of diabetes in men with sleep complaints or short sleep duration: a 12-year follow-up study of a middle-aged population. Diabetes Care. 2005;28(11): 2762–2767The Lancet Psychiatry: Disruption of the body's internal clock linked with mood disorders and adverse wellbeing: JOURNAL The Lancet Psychiatry; PUBLIC RELEASE: 15-MAY-2018.

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till date short sleep duration is associated with risk of incident diabetes mellitus. Various biomarkers can act as potential investigation to prove the association between sleep duration and incident DM. In a recent observational study involving 91000 people published in Lancet Psychiatry has shown that disruption to normal daily circadian rhythm is associated with a greater susceptibility to mood disorder such as severe depression and bipolar disorder. With the change in life style in modern era, with overuse of electronic gadgets at night, the sleep duration has drastically gone down coupled with working at night shift especially in IT sector has led to increase in incidence of various life style disorders. Behavioural risk factor modification, increased sleep duration, regular physical activity may prevent

2-3onset of such diseases and bring in good health .

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