Ijcp sep 2015

Indexed with IndMED

ISSN 0971-0876

www.ijcpgroup.com

Volume 26, Number 4

September 2015, Pages 301–400

Peer Reviewed Journal

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American Family Physician

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Cardiology

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Community Medicine

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Dermatology

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Drug Regulations

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Internal Medicine

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Neurosurgery

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Obstetrics and Gynecology

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Orthopedics

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Pediatrics

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Pictorial CME

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Ethics

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Around the Globe

an i c i ys ians

Phly Physic y l mi ami

Fademy of F n ica Aca

er merican m A eA

ingurnal of th t a or d Jo

rp-reviewe o c In eer AP

Full text online: http://ebook.ijcpgroup.com/ijcp/

Single Copy Rs. 300/-

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IJCP Group of Publications Dr Sanjiv Chopra Prof. of Medicine & Faculty Dean Harvard Medical School Group Consultant Editor Dr Deepak Chopra Chief Editorial Advisor

Dr KK Aggarwal Group Editor-in-Chief IJCP Group and eMedinewS

Volume 26, Number 4, September 2015 FROM THE DESK OF THE GROUP EDITOR-IN-CHIEF

306 Tackling Obesity in Children

KK Aggarwal

AMERICAN FAMILY PHYSICIAN

307 Practical Selection of Antiemetics in the Ambulatory Setting

Zachary A. Flake, Becky S. Linn, Jaime R. Hornecker

312 Practice Guidelines 313 Photo Quiz

Dr Veena Aggarwal MD, Group Executive Editor

IJCP Editorial Board Obstetrics and Gynaecology Dr Alka Kriplani Dr Thankam Verma, Dr Kamala Selvaraj Cardiology Dr Praveen Chandra, Dr SK Parashar Paediatrics Dr Swati Y Bhave Diabetology Dr CR Anand Moses, Dr Sidhartha Das Dr A Ramachandran, Dr Samith A Shetty ENT Dr Jasveer Singh Dr Chanchal Pal Dentistry Dr KMK Masthan Dr Rajesh Chandna Gastroenterology Dr Ajay Kumar Dr Rajiv Khosla Dermatology Dr Hasmukh J Shroff Dr Pasricha Dr Koushik Lahiri Nephrology Dr Georgi Abraham Neurology Dr V Nagarajan Dr Vineet Suri Journal of Applied Medicine & Surgery Dr SM Rajendran, Dr Jayakar Thomas Orthopedics Dr J Maheshwari

CARDIOLOGY

316 Chronic Alcoholism with Very High HDL Cholesterol: An Unusual Risk Factor for Hypertension

318 Emergency PCI Using Ticagrelor as a Reversible Antiplatelet Agent in the Treatment of STEMI in High-risk Patient: A Case Report

Non-Resident Indians Chamber of Commerce & Industry World Fellowship of Religions

This journal is indexed in IndMED (http://indmed.nic.in) and full-text of articles are included in medIND databases (http://mednic.in) hosted by National Informatics Centre, New Delhi.

Pasupati Rajoria, Yang Ke Ping, Zhang Yunfeng, Xu Chenghong, Yang Hua, Yang Jiawei

COMMUNITY MEDICINE

323 Seroprevalence of Hepatitis B Surface Antigen in a Tertiary Care Hospital

Shashi Chopra, Kailash Chand, Gomty Mahajan, Jaspal Kaur, Sheevani, Yadwinder Singh

DERMATOLOGY

326 Another Feather to the Tale: Pseudo-vesicular Pityriasis Rosea

Shaurya Rohatgi, Saurabh Jindal, Shahnaz Khan

DRUG REGULATIONS

330 The Drug Regulatory Scenario in India

KK Aggarwal, Prachi Garg

INTERNAL MEDICINE

337 To Study the Carotid Intima-media Thickness in Patients of Fatty Liver Disease

Sandeep Aharwar

345 Asymptomatic Hypercortisolism

Anand Gopal Bhatnagar Editorial Anchor Advisory Bodies Heart Care Foundation of India

Pradeep Nigam, Ankur Gupta, Praveen Kumar Baghel, Mahendra Kumar Jain, Dharmendra Jain

Manish N Mehta, Hemang K Acharya, Ajay C Tanna, Jemima Bhaskar, Suchitra Garhwal

NEUROSURGERY

347 Cerebroprotein Hydrolysate in Traumatic Brain Injury: A Retrospective Study

Ashutosh Agarwal, Sudeep Bharadwaj, Arun Tungaria, Shaifali Tungaria, Abhishek Dadhich

OBSTETRICS AND GYNECOLOGY

359 A Rare Case of Ovarian Pregnancy Following Intracytoplasmic Sperm Injection and Embryo Transfer

Ritu Punhani, Kundavi Shankar, Thankam Rama Varma

OBSTETRICS AND GYNECOLOGY Published, Printed and Edited by Dr KK Aggarwal, on behalf of IJCP Publications Ltd. and Published at E - 219, Greater Kailash, Part - 1 New Delhi - 110 048 E-mail: editorial@ijcp.com

363 Clinicopathological Study of Ovarian Tumors in a Referral Tertiary Hospital in West Bengal

Tamal Kumar Mandal, Barunoday Chakraborty

367 Primary Hyperparathyroidism in Pregnancy: A Case Report

Printed at New Edge Communications Pvt. Ltd., New Delhi E-mail: edgecommunication@gmail.com

Vinita Singh, Mousumi Das Ghosh, Sunita Murmu, Monimala Murmu, Suman Kumari

371 A One Year Prospective Study of Obstetrical Emergencies at a Tertiary Care Referral Hospital

Copyright 2015 IJCP Publications Ltd. All rights reserved.

Parneet Kaur, Khushpreet Kaur, Gurdip Kaur, Surya Malik

375 Use of Fetal Pillow During Cesarean Section in Deeply Engaged

The copyright for all the editorial material contained in this journal, in the form of layout, content including images and design, is held by IJCP Publications Ltd. No part of this publication may be published in any form whatsoever without the prior written permission of the publisher.

Head: A Comparative Study with Patwardhan’s Technique

Sannyasi Charan Barman, Barunoday Chakraborty, Sanjoy Saha, Ramkrishna Sahana, Swarupananda Maity, Debilina Roy

ORTHOPEDICS

381 Paget’s Disease of Bone in Indian Patients: Two Case Reports

Editorial Policies

The purpose of IJCP Academy of CME is to serve the medical profession and provide print continuing medical education as a part of their social commitment. The information and opinions presented in IJCP group publications reflect the views of the authors, not those of the journal, unless so stated. Advertising is accepted only if judged to be in harmony with the purpose of the journal; however, IJCP group reserves the right to reject any advertising at its sole discretion. Neither acceptance nor rejection constitutes an endorsement by IJCP group of a particular policy, product or procedure. We believe that readers need to be aware of any affiliation or financial relationship (employment, consultancies, stock ownership, honoraria, etc.) between an author and any organization or entity that has a direct financial interest in the subject matter or materials the author is writing about. We inform the reader of any pertinent relationships disclosed. A disclosure statement, where appropriate, is published at the end of the relevant article.

Bhavana Venkata Nagabhushana Rao, BVS Raman

PEDIATRICS

386 Letterer-Siwe Disease Presenting as a Retroauricular Swelling: A Diagnostic Dilemma

Rishav Raj, Braja Kishore Behera

PICTORIAL CME

390 Right Atrial Mass

Monika Maheshwari, Swapnil

ETHICS

391 Medical Oaths from Some European Countries AROUND THE GLOBE

394 News and Views LIGHTER READING

395 Lighter Side of Medicine

Note: Indian Journal of Clinical Practice does not guarantee, directly or indirectly, the quality or efficacy of any product or service described in the advertisements or other material which is commercial in nature in this issue.

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FROM THE DESK OF THE GROUP EDITOR-IN-CHIEF

Prof. Dr KK Aggarwal

Group Editor-in-Chief IJCP Group and eMedinewS

Tackling Obesity in Children

M

ore than 30% people of the society including children have potbelly abdominal obesity.

The incidence of metabolic syndrome, characterized by abdominal obesity, high triglyceride, low good cholesterol, high blood pressure and high blood sugar is rising in India.

Abdominal girth of >90 cm in men and 80 cm in women indicates that the person is vulnerable to future heart attack.

Normal weight obesity is the new epidemic. A person could be obese even if his body weight was within the normal range. An extra inch of fat around the abdomen increases the chances of heart disease by 1.5 times.

Normally once the height stops growing, most of the organs will also stop growing. The weight of the heart, liver of kidney cannot increase after that. Only muscles can build-up to some extent. The only thing, after that stage, which can increase the weight of the body, is deposition of fat. Therefore, any weight gain after puberty is invariably due to fat. Though the overall weight can be in the acceptable normal range but any weight gain within that range will be abnormal for that person. One should not gain weight of >5 kg after the age of 20 years in males and 18 years in females.

After the age of 50, the weight should reduce and not increase.

Potbelly obesity is linked to eating refined carbohydrates and not animal fats. General obesity is linked to eating animal fats.

Refined carbohydrate includes white rice, white maida and white sugar. Brown sugar is better than white sugar.

Refined carbohydrates are called 'bad carbohydrates' and animal fat is called bad fat.

Trans fat or vanaspati is bad for health. It increases the levels of bad cholesterol and reduces good cholesterol in the body.

Losing weight can reduce snoring, pain of arthritis, blood pressure and also check uncontrolled diabetes.

SOME TIPS ÂÂ Skip carbohydrates once in a week. ÂÂ Combine a sweet food with bitter food (prefer aloo

methi over aloo matar).

ÂÂ Walk, walk and walk… ÂÂ Consume green bitter items in foods such as karela,

methi, palak, bhindi, etc.

ÂÂ Do not eat trans fats (vanaspati). ÂÂ Do not consume >80 mL of soft drink in a day. ÂÂ Do not consume sweets with more than 30% sugar.

ÂÂ Avoid maida, rice and white sugar.

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AMERICAN FAMILY PHYSICIAN

Practical Selection of Antiemetics in the Ambulatory Setting ZACHARY A. FLAKE, BECKY S. LINN, JAIME R. HORNECKER

ABSTRACT Nausea and vomiting are mediated primarily by three neurotransmitter pathways: visceral stimulation releases dopamine and serotonin; vestibular and central nervous system activation release histamine and acetylcholine; and chemoreceptor trigger zone activation releases dopamine and serotonin. Clinicians can improve the effectiveness and cost-effectiveness of treatments by targeting the appropriate pathways. Antihistamines and anticholinergics are most effective in patients with vestibular-mediated nausea secondary to vertigo. Serotonin antagonists block serotonin in the intestines and chemoreceptor trigger zone, and are most effective for treating gastroenteritis. Dopamine antagonists block dopamine in the intestines and chemoreceptor trigger zone; indications for these agents are similar to those for serotonin antagonists. For treatment of mild pregnancy-induced nausea, pyridoxine with or without doxylamine is recommended, and ginger may also be effective. In patients with migraine headache–associated nausea, metoclopramide improves response to oral anti-migraine agents. Ondansetron reduces nausea and vomiting in children with acute gastroenteritis and in women with hyperemesis gravidarum.

Keywords: Nausea, vomiting, antihistamines, anticholinergics, serotonin antagonists, dopamine antagonists

N

ausea and vomiting are common complications of multiple conditions, procedures, and therapies, and adversely affect quality of life in millions of patients each year. Pregnancy-induced nausea alone accounts for an estimated 8.5 million lost working days and costs nearly $2 billion annually.1 Acute gastroenteritis causes 1.5 million visits to primary care clinicians annually and accounts for 10% of all hospital admissions in the United States.2 The causes and evaluation of nausea and vomiting have been reviewed in American Family Physician,3 and treatment is ideally directed at the underlying cause. By understanding the neurotransmitters involved in different types of nausea, clinicians can improve the effectiveness and cost-effectiveness of symptomatic treatments (Table 1).

Three primary pathophysiologic pathways stimulate the physiologic vomiting center in the medulla that mediates nausea and vomiting (Figure 1). This center

ZACHARY A. FLAKE, MD, is a family physician at Banner Medical Group in Loveland, Colo.

BECKY S. LINN, PharmD, BCPS, is clinical assistant professor of pharmacy practice at the University of Wyoming School of Pharmacy and Fort Collins (Colo.) Family Medicine Residency Program.

JAIME R. HORNECKER, PharmD, BCPS, is clinical assistant professor of pharmacy practice at the University of Wyoming School of Pharmacy in Casper.

Source: Adapted from Am Fam Physician. 2015;91(5):293-296.

can be stimulated by vestibular fibers, afferent visceral fibers, and input from the chemoreceptor trigger zone in the base of the fourth ventricle. The neurotransmitters histamine, acetylcholine, serotonin, and dopamine are often implicated in these pathways and are the targets of most therapies.

Table 1. Selection of Antiemetics by Clinical Situation Clinical situation

Associated neurotransmitters

Recommended antiemetic

Vestibular nausea/motion sickness

Histamine, acetylcholine

Meclizine, scopolamine

Migraineassociated nausea

Dopamine

Metoclopramide, prochlorperazine, promethazine

Gastroenteritis

Dopamine, serotonin Promethazine, serotonin antagonists

Pregnancyinduced nausea

Unknown

Mild: ginger, pyridoxine with or without doxylamine Hyperemesis: corticosteroids,* ondansetron

*Avoid use before 10 weeks’ gestation because of the increased risk of oral clefts.

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Treatment of Nausea and Vomiting Visceral stimulation

Chemoreceptor trigger zone

Vestibular stimulation

Table 2. Common Antiemetics Used in the Ambulatory Setting Medications

Dosage

Common adverse effects

Antihistamines and anticholinergics Dopamine and serotonin released

Dopamine and serotonin released

Dopamine and serotonin antagonists

Dopamine and serotonin antagonists

Histamine and acetylcholine released Antihistamines and anticholinergics

Diphenhydramine

25 mg every 6 hours

Meclizine

25 mg every 6 hours

Scopolamine

1 patch every 3 days

Medullary vomiting center stimulation

Blurred vision, exacerbation of narrow-angle glaucoma (especially in older adults), sedation, urinary retention

Dopamine antagonists Nausea and vomiting

Metoclopramide

Figure 1. Neurotransmitters involved in nausea and vomiting, and the medications used to mitigate their effects.

10 mg every 4 hours

Prochlorperazine

5 to 10 mg every 6 hours

MEDICATION CLASSES

Promethazine

12.5 to 25 mg every 6 hours

Antihistamines and Anticholinergics

Serotonin antagonist

Antihistamines and anticholinergics limit stimulation of the vomiting center through inhibition of the histamine H1 receptor and acetylcholine, respectively.

Antihistamines such as meclizine and scopolamine are particularly beneficial in vestibular-mediated nausea. Common adverse effects for both classes include sedation, constipation, dry mouth, and urinary retention.4 Antihistamines and anticholinergics are inexpensive, with most options costing less than $1 per dose5 (Table 2).

Dopamine Antagonists Dopamine antagonists include metoclopramide, promethazine, and prochlorperazine. They block dopamine stimulation in the chemoreceptor trigger zone, thereby limiting emetic input to the medullary vomiting center. Dopamine antagonists are inexpensive, but have strong antihistamine effects and can cause significant sedation.

Metoclopramide can cause extrapyramidal effects, including irreversible tardive dyskinesia, although this is rare (incidence of less than 1%).6 Because this risk may be greater in frail older adults, independent of diagnoses, the American Geriatrics Society strongly recommends avoiding the use of metoclopramide for nausea in this population.7 Metoclopramide should not be used in patients receiving antipsychotics or other dopamine antagonists.

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Ondansetron

2 mg orally or intravenously

Extrapyramidal effects, hypotension, QT prolongation, sedation

Hypersensitivity reactions (rare), QRS widening, QT prolongation

Other agents Methylprednisolone 40 mg intravenously Dexamethasone

4 to 8 mg intravenously

Ginger

250 mg every 6 hours

Doxylamine/ pyridoxine

2 to 4 tablets per day

Pyridoxine

10 to 25 mg every 8 hours

Corticosteroids: exacerbation of hypertension, fluid retention, hyperglycemia, psychiatric disturbance

Selective Serotonin Antagonists Selective serotonin antagonists inhibit serotonin at the 5-HT3 receptor in the small bowel, vagus nerve, and chemoreceptor trigger zone. They are generally effective and have largely replaced dopamine antagonists in most clinical situations. Adverse effects are uncommon but can include headache, diarrhea, and fatigue; these occur independent of dose and route of administration. All selective serotonin antagonists can cause asymptomatic,

AMERICAN FAMILY PHYSICIAN self-limited QT prolongation and QRS widening.8,9 In patients with underlying QT prolongation or who are taking concomitant medications that have the potential to prolong the QT interval, clinicians should use the lowest dose or consider alternatives.

Complementary and Alternative Therapies Ginger has been used in traditional Indian and Chinese medicine as an antiemetic. Although its mechanism of action is not completely understood, ginger is thought to antagonize the 5-HT3 and cholinergic receptors, and may have direct activity on the gastrointestinal tract.

Although ginger can cause reflux and heartburn, and may potentiate bleeding because of its anticoagulant effects, dosages of up to 2 g per day in divided doses of 250 mg are considered safe, even in pregnant women.10,11 Pyridoxine (vitamin B6), with or without doxylamine, has been recommended for treating nausea and vomiting in pregnancy. Typical dosages of 10 to 25 mg every eight hours cause minimal adverse effects12; however, there is little evidence to support the use of pyridoxine for the treatment of nausea and vomiting from other causes.

CLINICAL SITUATIONS

Vestibular Nausea/Motion Sickness Unlike other forms of nausea, which tend to be mediated by dopamine and serotonin, vestibular system–induced nausea is mediated primarily by histamine and acetylcholine. Consequently, the American Gastroenterological Association recommends the use of antihistamines and anticholinergics for nausea secondary to vertigo and motion sickness.13 Antihistamines are the most common agents used in the treatment of vestibular-mediated motion sickness.14 However, the use of antihistamines is limited by their sedative effects. Transdermal scopolamine is preferred over antihistamines for prevention of motion sickness in persons desiring wakefulness during travel.15 It can be used for up to 72 hours per dose, with the onset occurring six to eight hours after application to the mastoid.16 Ginger also relieves nausea associated with motion sickness, and is most effective if the patient believes it will work.15

Migraine-associated Nausea Migraine headaches are commonly associated with gastrointestinal symptoms. Approximately 60% of patients with migraines develop nausea and vomiting

during an acute attack.17 Nausea and vomiting associated with migraines are caused by a central process, with dopamine being a primary mediator; thus, dopamine antagonists such as metoclopramide, prochlorperazine, and chlorpromazine are logical choices for treatment. Although triptans may abort the central process contributing to nausea, they have lower oral bioavailability during an acute attack because of altered gastric motility.18 Metoclopramide increases gastric motility and response to oral anti-migraine medications. A Cochrane review found that in patients with acute migraine, a combination of metoclopramide and aspirin improved nausea and vomiting with fewer adverse events compared with sumatriptan.19

Gastroenteritis Oral rehydration solution is strongly recommended as first-line treatment of acute gastroenteritis with mild to moderate dehydration.2 When administration is limited by multiple episodes of vomiting, antiemetics may be useful. Because nausea in gastroenteritis is a result of visceral stimulation mediated primarily by serotonin, 5-HT3 antagonists are an effective treatment.13 A Cochrane review of several randomized, placebo-controlled trials concluded that a single oral dose of ondansetron controls vomiting and reduces hospitalizations and the need for intravenous fluid administration in children and adolescents.20 Ondansetron may increase episodes of diarrhea in this population. Although ondansetron costs more than promethazine, the reduced need for intravenous fluids makes it a cost-effective option.21

Pregnancy-induced Nausea Nausea and vomiting occur in more than one-half of pregnancies.10,12 Although the pathogenesis of nausea and vomiting in pregnancy is not completely understood, it is thought to be multifactorial, with hormonal changes having a key role.12,22 Several antiemetic drug classes have been used for treatment, but there is limited evidence on fetal outcomes.

The American College of Obstetricians and Gynecologists recommends the use of pyridoxine with or without doxylamine as first-line pharmacotherapy for nausea and vomiting in pregnant women.12 A delayedrelease formulation of 10 mg of doxylamine and 10 mg of pyridoxine is available in the United States. In more severe cases in which dehydration or hyperemesis gravidarum occurs, intravenous rehydration may be necessary, and may be used in combination with antiemetics. Ondansetron has comparable effectiveness

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AMERICAN FAMILY PHYSICIAN to older antiemetics, such as promethazine, and causes less sedation.23 Corticosteroids may be used in severe, persistent cases, but are not recommended before 10 weeks’ gestation because of the increased risk of oral clefts.12 Complementary and alternative medicine is often used by pregnant women who wish to avoid pharmacologic therapies. Two recent meta-analyses found that, compared with placebo, ginger improves nausea and vomiting if taken for at least four days.10,24 Note: See for complete article visit: www.aafp.org/afp.

REFERENCES

10. Thomson M, et al. Effects of ginger for nausea and vomiting in early pregnancy: a meta-analysis. J Am Board Fam Med. 2014;27(1):115-122.

11. Tiran D. Ginger to reduce nausea and vomiting during pregnancy: evidence of effectiveness is not the same as proof of safety. Complement Ther Clin Pract. 2012;18(1):22-25.

12. ACOG practice bulletin: nausea and vomiting of pregnancy. Obstet Gynecol. 2004;103(4):803-814.

13. Quigley EM, et al. AGA technical review on nausea and vomiting. Gastroenterology. 2001;120(1):263-286.

14. Motion sickness. EBM guidelines. Updated August 6, 2012. Essential Evidence Plus. http://www.essentialevidence plus.com/content/ebmg_ebm/171 [subscription required]. Accessed August 1, 2014.

1. Piwko C, et al. Economic burden of nausea and vomiting of pregnancy in the USA. J Popul Ther Clin Pharmacol.

2013;20(2):e149-e160.

15. Brainard A, et al. Prevention and treatment of motion sickness. Am Fam Physician. 2014;90(1):41-46.

2. King CK, et al. Managing acute gastroenteritis among children. MMWR Recomm Rep. 2003;52(RR-16):1-16.

16. Schmäl F. Neuronal mechanisms and the treatment of motion sickness. Pharmacology. 2013;91(3-4):229-241.

3. Anderson WD III, et al. Evaluation of nausea and vomiting [published corrections appear in Am Fam Physician.

2013;88(11):728, and Am Fam Physician. 2014;89(3):152].

Am Fam Physician. 2013;88(6):371-379.

17. Láinez MJ, et al. Optimal management of severe nausea and vomiting in migraine. Patient Relat Outcome Meas.

2013;4:61-73.

4. Sharkey KA, et al. Treatment of disorders of bowel motility and water flux; anti-emetics; agents used in biliary and pancreatic disease. In: Brunton LL, et al. Goodman and Gilman’s the Pharmacological Basis of Therapeutics. 12th ed. New York, NY: McGraw-Hill Medical; 2011:1323-1349.

5. Red Book online. http://redbook.solutions.aap.org/ redbook.aspx [subscription required]. Accessed February 21, 2014.

6. Rao AS, et al. Review article: metoclopramide and tardive dyskinesia. Aliment Pharmacol Ther. 2010;31(1):11-19.

7. American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults.

J Am Geriatr Soc. 2012;60(4):616-631.

8. De Ponti F, et al. Safety of non-antiarrhythmic drugs that prolong the QT interval or induce torsade de pointes: an overview. Drug Saf. 2002;25(4):263-286.

18. Bradley WG, et al. Bradley’s Neurology in Clinical Practice. 6th ed. Oxford, U.K.: Butterworth-Heinemann/ Elsevier; 2012.

19. Kirthi V, et al. Aspirin with or without an antiemetic for acute migraine headaches in adults. Cochrane Database Syst Rev. 2013;(4):CD008041.

20. Fedorowicz Z, et al. Antiemetics for reducing vomiting related to acute gastroenteritis in children and adolescents.

Cochrane Database Syst Rev. 2011;(9):CD005506.

21. Freedman SB, et al. Oral ondansetron administration in emergency departments to children with gastroenteritis: an economic analysis. PLoS Med. 2010;7(10):e1000350.

22. Lee NM, et al. Nausea and vomiting of pregnancy.

Gastroenterol Clin North Am. 2011;40(2):309-334.

23. Herrell HE. Nausea and vomiting of pregnancy. Am Fam Physician. 2014;89(12):965-970.

24. Matthews A, et al. Interventions for nausea and vomiting in early pregnancy. Cochrane Database Syst Rev. 2014;(3):CD007575.

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9. Keller GA, et al. Other drugs acting on nervous system associated with QT-interval prolongation. Curr Drug Saf. 2010;5(1):105-111.

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AMERICAN FAMILY PHYSICIAN

Practice Guidelines AHA/ASA RELEASE GUIDELINE ON STROKE PREVENTION IN WOMEN Stroke is the third leading cause of death in women, and its impact is becoming increasingly higher in women compared with men. The 2010 National Health Interview Survey showed that more than onehalf of the 6 million adults with stroke were women.

Another study showed that between 2006 and 2010, the prevalence of stroke survivors did not significantly change for women, whereas it declined for men.

Although risk factors such as age, history of cardiovascular disease, obesity, unhealthy diet, physical inactivity, smoking, and metabolic syndrome increase the risk of stroke in men and women, risk factors that are stronger or more prevalent in women are migraine with aura, atrial fibrillation, diabetes mellitus, and hypertension. Additionally, there are sex-specific risk factors that affect only women such as pregnancy, preeclampsia, gestational diabetes, and use of oral contraceptives or postmenopausal hormones.

The American Heart Association and American Stroke Association (AHA/ASA) have released a guideline to help physicians identify women with increased risk of stroke and initiate appropriate preventive measures. The guideline includes recommendations on pregnancy and stroke; cerebral venous thrombosis; use of oral contraceptives; use of postmenopausal hormone therapy; migraine with aura; obesity, metabolic syndrome, and lifestyle; and atrial fibrillation.

Prevention Strategies Because women are underrepresented in clinical stroke prevention trials, it is unclear whether current evidencebased practices apply to women. Differences between men and women in the anatomy of the internal carotid arteries and in the composition of plaque may mean that there are different risks and benefits to treatment. Until further research is completed, the recommendations for prevention of stroke in women with symptomatic or asymptomatic carotid disease are the same as for men.

The following recommendations are based on data derived from multiple randomized clinical trials or meta-analyses.

Prophylactic carotid endarterectomy performed with less than 3% of morbidity and mortality can be useful in highly selected patients with asymptomatic carotid stenosis (at least 60% on angiography or at least 70% on validated Doppler ultrasonography). This procedure can be recommended in women with a recent (within past six months) transient ischemic attack or ischemic stroke and ipsilateral severe carotid stenosis (70% to 99%) if the estimated perioperative morbidity and mortality risk is less than 6%.

The following recommendations are based on data derived from a single randomized trial or nonrandomized studies. Depending on patient factors such as age and comorbidities, carotid endarterectomy can be recommended in women with a recent transient ischemic attack or ischemic stroke and ipsilateral moderate carotid stenosis (50% to 69%) if the estimated perioperative morbidity and mortality risk is less than 6%. If indicated, it is reasonable for the surgery to take place within two weeks in women with no contraindications to early revascularization. Aspirin therapy is reasonable in women with diabetes and no contraindications. It can also be useful in women 65 years and older if their blood pressure is controlled and the benefit for ischemic stroke and myocardial infarction prevention is likely to outweigh the risk of gastrointestinal bleeding and hemorrhagic stroke.

Aspirin may also be useful in women younger than 65 years. Clopidogrel can be substituted in women at high risk (i.e., 10-year predicted risk of cardiovascular disease is 10% or more) who cannot take aspirin.

The following recommendations are based on consensus opinion of experts, case studies, or standard of care.

Women with asymptomatic carotid stenosis should be screened for other treatable risk factors, and lifestyle modifications should be initiated. Because aspirin was used in all major trials that demonstrated effectiveness, it should be used in women undergoing carotid endarterectomy who do not have contraindications.

PREECLAMPSIA

Source: Adapted from Am Fam Physician. 2015;91(5):330-331.

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Although stroke is uncommon in pregnancy, the risk is higher in young women who are pregnant compared Cont'd on page 314...

AMERICAN FAMILY PHYSICIAN

Photo Quiz ASYMPTOMATIC, EVOLVING LESION ON THE UPPER ARM A 63-year-old woman presented with an asymptomatic lesion on her left posterior upper arm that had been present for 18 years. Although the lesion was small initially, the patient noticed slow evolution over time.

She had applied hydrocortisone to the area and thought there was some improvement because a whitish area developed within the lesion. She had no major medical history, including no personal or family history of skin disease. She was not taking prescription medications.

On physical examination, there was an irregular 4.2-cm by 3.5-cm pink plaque with areas of irregular pigmentation, primarily at the periphery. The lesion was located over the lateral aspect of the distal left triceps. A smooth area of depigmentation was noted along the inferior aspect of the lesion (Figure 1).

There was no lymphadenopathy. The remainder of the physical examination was unremarkable.

Question Based on the patient’s history and physical examination findings, which one of the following is the most likely diagnosis?

A. Lentigo maligna.

B. Solar lentigo.

C. Superficial basal cell carcinoma.

D. Superficial spreading melanoma.

Discussion The answer is D: superficial spreading melanoma.

Superficial spreading melanoma is the most common subtype of melanoma, accounting for about 70% of all melanomas.1 It usually presents in the fourth to fifth decade of life but can affect adults of all ages.1,2 It most often occurs on the upper back in men, and on the upper back and lower legs in women.3 This malignancy of melanocytes can arise de novo or from a preexisting nevus,2 and does not have a predilection

Source: Adapted from Am Fam Physician. 2015;91(6):389-390.

Figure 1.

for sun-damaged skin.2 It typically has a slow radial growth phase before becoming invasive.4 A new flat gray or white area in a previously pigmented lesion represents regression, an immunologic reaction against the tumor that can partially or completely destroy the primary tumor but may be associated with a poorer prognosis.1,2 Histologically, the radial growth phase is characterized by a “buckshot” scatter of melanocytes throughout the epidermis. As a result, the borders tend to be more clearly defined than those of lentiginous types of melanoma.2 Malignant melanoma should be confirmed with a biopsy.3 The National Comprehensive Cancer Network guideline recommends elliptical, punch, or saucerization biopsy with narrow (1- to 3-mm) margins as the preferred methods for suspected melanoma.5 Avoiding wider margins allows for accurate lymphatic mapping, if needed later.

Lentigo maligna is the in-situ form of lentigo maligna melanoma. It is characterized by an extended radial phase of five to 20 years before invasive vertical growth develops.2 It is estimated that only 3% to 5% of lentigo maligna lesions become invasive. The risk of invasion is directly proportional to the size of the lesion.4 Lentigo maligna is more common in older persons with heavily sun-damaged skin. It often occurs on the head and neck.2 Solar lentigines can be numerous on sun-exposed skin. They appear as uniform tan or brown macules ranging in size from several millimeters to several

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AMERICAN FAMILY PHYSICIAN Summary Table Condition

Characteristics

Lentigo maligna

In-situ form of lentigo maligna melanoma; characterized by an extended radial phase (5 to 20 years) before invasive vertical growth develops; most common in older persons with heavily sundamaged skin; often occurs on the head and neck

Solar lentigo

Uniform tan or brown macules ranging in size from several millimeters to several centimeters with distinct borders; induced by sun exposure; more common as persons age; most often appears on the face, arms, dorsa of the hands, and upper trunk

Superficial basal cell carcinoma

Red, well-demarcated, dry, slightly scaly patch that may mimic eczema or psoriasis; usually occurs in light-skinned persons; most common on the trunk but also commonly affects the head, neck, and distal extremities

Superficial spreading melanoma

Slow radial growth phase before becoming invasive; affects adults of all ages; most common on the upper back in men, and upper back and lower legs in women

centimeters with distinct borders. Histologically, there are an increased number of melanocytes within the basal layer, which is induced by sun exposure. They are more common as persons get older, and most often appear on the face, arms, dorsa of the hands, and

upper trunk. Lentigines have no malignant potential.3 Superficial basal cell carcinoma most often occurs in light-skinned persons, usually appearing on the trunk, but it also commonly affects the head, neck, and distal extremities. This subtype accounts for about 15% of basal cell carcinomas. It presents as a red, welldemarcated, dry, slightly scaly patch that may mimic eczema or psoriasis. The patch enlarges very slowly and may grow to 10 to 15 cm in diameter.2 REFERENCES 1. Fleischer AB, Feldman SR, Katz AS, Clayton BD. Melanoma. In: Fleischer AB, et al., eds. 20 Common Problems in Dermatology. New York, NY: McGraw-Hill; 2000:201-217.

2. Melanoma (malignant melanoma). In: James WD, Berger TG, Elston DM, eds. Andrews’ Diseases of the Skin: Clinical Dermatology. 10th ed. Philadelphia, Pa.: Elsevier; 2006:647,694-699.

3. Malignant melanoma. In: Marks JG, Miller JJ, eds.

Lookingbill and Marks’ Principles of Dermatology. 4th ed.

Philadelphia, Pa.: Elsevier; 2006.

4. Shenenberger DW. Cutaneous malignant melanoma: a primary care perspective. Am Fam Physician.

2012;85(2):161-168.

5. Coit DG, Andtbacka R, Bichakjian CK, et al.; NCCN Melanoma Panel. Melanoma. J Natl Compr Canc Netw.

2009;7(3):250-275.

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...Cont'd from page 312

with those who are not pregnant. The highest risk is in the third trimester and postpartum. Pregnancy-related hypertension is the leading cause of hemorrhagic stroke and ischemic stenosis in pregnancy and postpartum.

The following recommendations are based on data derived from multiple randomized clinical trials or metaanalyses. Women with chronic primary or secondary hypertension, or who had hypertension in a previous pregnancy should

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take low-dose aspirin from 12 weeks of gestation until delivery. To prevent preeclampsia, calcium supplementation should be considered for women with low intake of dietary calcium (less than 600 mg per day). Pregnant women with severe hypertension should be treated with safe and effective medications such as methyldopa, labetalol, and nifedipine. Maternal and fetal adverse effects should be considered when choosing a medication.

CARDIOLOGY

Chronic Alcoholism with Very High HDL Cholesterol: An Unusual Risk Factor for Hypertension PRADEEP NIGAM*, ANKUR GUPTA†, PRAVEEN KUMAR BAGHEL‡, MAHENDRA KUMAR JAIN# , DHARMENDRA JAIN$

ABSTRACT Among the various risk factors of hypertension, high high-density lipoprotein (HDL) cholesterol is a rare cause that is not even mentioned in standard textbooks. Here, we like to report a clinical scenario, where a chronic alcoholic hypertensive patient presented with very high HDL cholesterol levels.

Keywords: Alcohol, high-density lipoprotein, cholesterol, hypertension, cholesteryl ester transfer protein

H

igh-density lipoprotein (HDL) cholesterol concentration are well-established as a major protective factor against coronary heart disease (CHD). Moderate alcohol intake has been associated with protection against CHD in observational studies, effect mediated by alcohol-induced increase in HDL concentration, the association often being described as J- or U-shaped. We report a case of chronic alcoholism with very high HDL cholesterol as an unusual risk factor for hypertension.

CASE REPORT A 35-year-old chronic alcoholic (400 mL/day) and tobacco addict male, a known case of essential hypertension for last 1 year, on irregular treatment presented with complaints of restlessness and perspiration for last 5 months. There was no dyspnea on exertion. There was no family history of hypertension or diabetes mellitus.

There was no past history of gallstones or jaundice.

*Assistant Professor †Senior Resident ‡Professor #Professor and Head Dept. of Medicine Shyam Shah Medical College, Rewa, Madhya Pradesh $Assistant Professor Dept. of Cardiology, Institute of Medical Sciences, Banaras Hindu University Varanasi, Uttar Pradesh Address for correspondence Dr Dharmendra Jain, Assistant Professor, Dept. of Cardiology Institute of Medical Sciences, Banaras Hindu University Varanasi - 221 005, Uttar Pradesh E-mail: djaincard@gmail.com

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On examination, he was conscious, oriented and afebrile.

Respiratory rate: 16/min; pulse rate: 78/min and regular blood pressure: 170/90 mmHg. Liver was palpable 2.5 cm. Testicular atrophy, gynecomastia and all other signs of liver cell failure were absent. Cardiovascular and respiratory system were essentially normal.

His complete blood counts, blood glucose and renal function tests were normal. Liver function tests revealed serum bilirubin: 1.67 (direct: 0.95) mg/dL; serum glutamic-pyruvic transaminase (SGPT): 159 U/L, serum glutamic-oxaloacetic: 141 U/L; alkaline phosphate: 254 U/L and gamma-glutamyl transferase (GGT): 430.6 U/L. Lipid profile showed total cholesterol: 297 mg/dL; low-density lipoprotein (LDL): 155 mg/dL; triglyceride (TG): 89 mg/dL and very LDL (VLDL): 17.8 mg/dL. His HDL level was extremely high (>125 mg/dL); i.e., approximately >147% above normal.

Ultrasound abdomen was suggestive of hepatomegaly with Grade II fatty liver disease.

DISCUSSION High-density lipoprotein has long been recognized as a cardioprotective lipid. Its level increases with moderate alcohol intake.1 There are few studies conducted about effect of alcohol on HDL. De Oliveira E Silva et al have shown that HDL level can increase up to 18%.2 In this case, there was >147% increase in HDL level.

Elevated level of HDL is associated with low levels of VLDL cholesterol and TG levels. LDL cholesterol may be within the reference range or elevated.

Cholesteryl ester transfer protein (CETP) deficiency increases atherogenicity of HDL.3 CETP status was not known in this patient. An HDL level above

CARDIOLOGY 65 mg/dL is called “hyperalphalipoproteinemia or HA”. There are few studies which have shown that HDL levels of >90 mg/dL promote atherosclerosis by taking cholesterol from liver to peripheral tissues.4 This increased effect of alcohol on HDL vanishes in 2 weeks time after abstinence.5 This patient who was a chronic alcoholic and a known case of hypertension for last 1 year had been found to have unusually very high HDL cholesterol with VLDL level in lower range of normal. Moreover, there was every chance that this unusually high level of HDL may be one of the risk factors for his hypertension.3

REFERENCES

CONCLUSION

4. Abnormal HDL Levels by Walli Carranza, May 16, 2010. [online] Available at: http://www.livestrong.com/ article/124361-abnormal-hdl-levels/?tk=12 [Accessed on July, 2015].

Association of chronic alcoholism with hypertension, increased total cholesterol and LDL cholesterol and high levels of HDL cholesterol is quite uncommon, which merits reporting of this case.

1. Rimm EB, Williams P, Fosher K, Criqui M, Stampfer MJ. Moderate alcohol intake and lower risk of coronary heart disease: meta­-analysis of effects on lipids and haemostatic factors. BMJ. 1999;319(7224):1523-8.

2. De Oliveira E Silva ER, Foster D, McGee Harper M, Seidman CE, Smith JD, Breslow JL, et al. Alcohol consumption raises HDL cholesterol levels by increasing the transport rate of apolipoproteins A-I and A-II. Circulation. 2000;102(19): 2347-52.

3. Yamashita S, Maruyama T, Hirano K, Sakai N, Nakajima N, Matsuzawa Y. Molecular mechanisms, lipoprotein abnormalities and atherogenicity of hyperalphalipoproteinemia. Atherosclerosis. 2000;152(2):271-85.

5. Devenyi P, Robinson GM, Roncari DA. Alcohol and highdensity lipoproteins. Can Med Assoc J. 1980;123(10):981-4.

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ESC 2015 Update ÂÂ

A high-sensitivity troponin I test showed great accuracy in ruling out MI in patients with chest pain, with triage times reduced to 1 hour, and also showed better positive predictive ability than some other studies.

Presenting the data from the Biomarkers in Acute Cardiovascular Care (BACC) study, Dr Dirk Westermann (University Heart Centre Hamburg, Germany) concluded: “Use of this test in patients with suspected MI allows for highly accurate and rapid rule-out as well as rule-in, enabling safe discharge or rapid treatment initiation.” If tests at both admission and 1 hour later are negative, patients can be safely discharged. The current trial used a cutoff value of 6 ng/L and a change of 12 ng/L between the two tests for a positive result, whereas traditional tests use a much higher level of about 27 ng/L (99th percentile of a healthy reference population).

ÂÂ

Line Melgaard (Aalborg University Hospital, Denmark) report that the CHA2DS2-VASc score, which is already used to assess stroke and thromboembolic risk in patients with atrial fibrillation (AF), may also be useful for this purpose in patients with heart failure. Cautioning that these results need to be confirmed in a randomized trial, she suggested that heart-failure patients without AF who have a CHA2DS2-VASc score of 3—that means they have two additional risk factors—could be good candidates for anticoagulant therapy.

ÂÂ

Findings from a cohort of middle-aged patients with well-controlled hypertension suggest that patients who slept 60 minutes, typically after a midday meal, had an average 24-hour blood pressure reading that was 4 mmHg lower, and while they slept at night, they had a 2% greater dip in blood pressure. They also tended to use fewer blood pressure medications (Dr Manolis Kallistratos (Asklepieion Voula General Hospital, Athens, Greece).

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Emergency PCI Using Ticagrelor as a Reversible Antiplatelet Agent in the Treatment of STEMI in High-risk Patient: A Case Report PASUPATI RAJORIA*, YANG KE PING†, ZHANG YUNFENG†, XU CHENGHONG†, YANG HUA‡, YANG JIAWEI‡

ABSTRACT ST elevation myocardial infarction is one of the acute coronary syndromes, which are leading cause of mortality and one of the main reason for hospital admission as well as undergoing percutaneous coronary intervention (PCI). Aspirin has always been the drug of choice for monotherapy but dual antiplatelet agent therapy minimizes the risk of stent thrombosis and cardiovascular events in the long run. In this case report, we have used a novel drug “ticagrelor” instead of the widely used clopidogrel to ease out the limitations of clopidogrel in a high-risk patient with type 2 diabetes mellitus, hypertension and a previous history of cerebral infarction who underwent emergency PCI without any major or minor adverse effects. We also came across symptoms of lung infection which was promptly diagnosed and immediately treated, which could have mimicked the common side effects of ticagrelor. Ticagrelor is a very propitious new antiplatelet drug with impressive efficacy and reasonable safety.

Keywords: Acute coronary syndrome, dual antiplatelet agent therapy, emergency percutaneous coronary intervention, ST elevation myocardial infarction, ticagrelor, type 2 diabetes mellitus

T

he standard treatment for acute coronary syndrome (ACS) involves therapy with antiplatelet, anticoagulant and thrombolytic agents, and the performance of percutaneous coronary intervention (PCI). Platelet function disorders leading to an accelerated process of atherosclerosis and increased risk for atherothrombotic complications occurs in type 2 diabetes mellitus (T2DM).

Previous studies suggest a worse outcome for diabetic patients after acute coronary events.1 Recently, a high variability of response to clopidogrel measured by platelet function tests has been reported among patients with PCI and hyporesponsiveness to clopidogrel has

*Resident in Internal Medicine †Professor ‡Assistant Professor Dept. of Cardiology Jingzhou Central Hospital (Affiliated to Yangtze University) Jingzhou, Hubei Province, China Address for correspondence Dr Pasupati Rajoria Resident in Internal Medicine Dept. of Cardiology Jingzhou Central Hospital (Affiliated to Yangtze University) 1 Rennin Road, Jingzhou - 434 023, Hubei Province, China E-mail: pashupati577@gmail.com

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been considered to influence cardiac outcome in these patients.2 Impaired response to antiplatelet therapy in diabetic patients has been reported in small patient collectives.3 Since, the advent of reperfusion therapy for acute ST elevation myocardial infarction (STEMI) the “open artery hypothesis” proposed that the benefit is achieved from early reperfusion of occluded coronary artery, which limits the size of infarction, reduces the degree of left ventricular dysfunction and improves survival.4 PCI is one of the two coronary revascularization techniques currently used in the treatment of ischemic heart disease (IHD), the other being coronary artery bypass grafting (CABG).5 PCI involves nonsurgical widening of the coronary artery, using a balloon catheter to dilate the artery from within and deploying usually a metallic stent in the artery after dilatation.

Clopidogrel a second-generation irreversible inhibitor of antiplatelet is considered the standard care for preventing coronary thrombus in patients diagnosed with STEMI who will undergo PCI but due to its drawbacks like long onset of action and time to maximum inhibition of platelet activation (IPA) especially treating patients with risk factors like T2DM thereby leading to an increased risk of thrombotic events, a new drug “ticagrelor which not only has short

CARDIOLOGY onset of action and time to maximum IPA but also has a good response in these type of patients undergoing emergency PCI has been recently suggested by US Food and Drugs Administration (FDA) as well as in the recently published treatment guidelines”. In this case, the patient was planned for emergency PCI using this useful drug “ticagrelor” as one of the main drug for dual antiplatelet therapy (DAPT). Our case report, therefore, emphasizes on the characteristics and the management of elderly patients with diabetes with high cardiovascular risk undergoing emergency PCI using ticagrelor instead of the standard drug clopidogrel widely used today.

CASE PRESENTATION A 73-year-old male with a history of T2DM, hypertension and previous history of cerebral infarction and pulmonary tuberculosis, presented to our Emergency Department of Cardiology, Jingzhou Central Hospital, on 5th July 2014 with a chief complaint of substernal chest pain since 5 hours, which was continuous and nonradiating. His vitals were: pulse rate - 76 beats/min, blood pressure (BP) - 110/70 mmHg, respiratory rate - 20/min and temperature - 36.5°C. A 12-lead emergency electrocardiography (ECG) was done immediately which showed sinus rhythm with ST-segment elevation in leads II, III and AVF and T-wave inversion (Fig. 1). The blood reports for cardiac enzymes revealed raised troponin I (0.53 µg/L), which indicated confirmatory diagnosis of acute inferior wall myocardial infarction (MI) with ST elevation. He was immediately treated with loading doses of aspirin 300 mg and ticagrelor 180 mg as a dual antiplatelet therapy after taking strict consent from the patient and was further planned for emergency PCI. He was also given rosuvastatin 10 mg stat and nitroglycerine 5 mg intravenous through pump at 3 mL/hour. He was planned for emergency PCI and emergently rushed to the cardiac catheterization lab.

At the time of procedure, he had ongoing chest pain and showed evidence of persistent ST elevation on the ECG. After routine disinfection, the right radial artery was punctured by Seldinger method. Thereafter, 2,000 U of heparin was injected to the patient. The coronary angiography revealed normal left main coronary artery; whereas, there was 90-95% stenosis in the proximal part of left anterior descending (LAD) artery (Fig. 2) and complete occlusion of middle part of left circumflex (LCx) artery, being the culprit one (Fig. 3). The LCx also had a second site of stenosis near the proximal

part (Fig. 3). We then introduced a 6F XB-3.0 guiding catheter till the left crown and an additional 6,000 U of heparin was injected. Tirofiban 10 mL was directly

Figure 1. ECG showing ST elevation on leads II, III and AVF (thick arrows). T wave inversion (thin arrows).

Figure 2. Proximal part of (LAD) shows 90-95% stenosis (arrows).

Figure 3. Culprit artery LCx, fully occluded (striped arrow).

Second site of stenosis in LCx, near the proximal part of LCx (white arrow).

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CARDIOLOGY

The total amount of contrast agent (Omnipaque) used throughout the procedure was about 150 mL. Dopamine was also infused throughout the procedure via infusion pump at a rate of 5 mL/hour because the patient had consistently decreasing BP. The total time taken for the

PCI operation (door to balloon) was 60 minutes. After the PCI, the patient was kept in the cardiac care unit (CCU) with continuous ECG monitoring for few days and then transferred to the cardiology ward. His postPCI 12-lead ECG revealed that ST-segment elevation had decreased to a greater extent on all three leads II, III and AVF with the formation of Q-wave (Fig. 8). During his stay post-PCI, he was kept on aspirin 100 mg o.d., ticagrelor 90 mg b.i.d., isosorbide dinitrate 40 mg o.d., rosuvastatin 10 mg o.d., perindopril 4 mg o.d. and a low-dose of metoprolol 6.25 mg o.d. After normalizing his BP, he was sent for Doppler echocardiography to rule out any form of left ventricular aneurysm and evaluate the function of his heart through ejection

Figure 4. Balloon inflation, middle part of LCx, (arrow).

Figure 6. Stent deployment, proximal part of LCx (arrow).

Figure 5. Stent deployment, middle part of LCx (arrow).

Figure 7. Final result of LCx after deployment of two stents (arrows).

injected on the coronary artery keeping in mind the amount of thrombus it contained. After which, run through NS distal guidewire was introduced into the LCx and 2.0 × 20 mm balloon inflation was done with 16 atm on stenosed sites of the culprit part of the artery (Fig. 4). Then implantation of BUMA 3.5 × 20 mm (Fig. 5) and 3.0 × 25 mm (Fig. 6) bracket 2 stent were deployed at both the sites, respectively. At the end of the procedure TIMI flow 3 was established (Fig. 7).

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CARDIOLOGY DISCUSSION Coronary heart disease (CHD) is the first cause of morbidity and mortality in diabetic patients. Its incidence in elderly patient increases with the increase of their life expectancy. On the other hand, the quality-of-life of the diabetics after PCI is better to conventional therapy.

Elderly diabetic patients are very high cardiovascular risk, characterized by the severity of coronary artery disease (CAD). They are treated less aggressively than nondiabetics in spite of the fact that diabetic’s qualityof-life improves better with angioplasty in comparison with the conventional treatment.

Figure 8. Post-PCI ECG, reduced ST-segment elevation (thick arrows), formation of Q-wave (thin arrows).

fraction (EF), which luckily came out to be normal.

On the 7th post-PCI day, rales were heard on bases of both lungs during auscultation without any specific symptoms, hence computed tomography (CT) scan was ordered.

The CT scan report revealed ongoing infection on bilateral lung fields. So, the patient was started with cefaperazone 2 g b.i.d. to treat the ongoing infection.

The patient was finally discharged on the 12th postPCI day and advised to continue aspirin, rosuvastatin for rest of his life, isosorbide dinitrate for 1 month, perindopril and metoprolol according to his BP fluctuation. Ticagrelor was asked to be continued for 1 year in a dose of 90 mg b.i.d. The patient was further counseled about his diet control and was strictly suggested to change his lifestyle.

FOLLOW-UP The patient was strictly asked to come to follow-up for another PCI of LAD after 1 month. He presented at the outpatient department (OPD) at the stipulated period, but he refused to undergo second PCI due to some personal problems, financial being one of them. He was doing pretty well without any ongoing symptoms at the time. An ECG was done, which did not reveal any significant changes except the Q waves.

Cardiac biomarkers were also repeated, which were near normal range. He was therefore, advised to continue the same medications and was called for next follow-up after 3 months. At the next follow-up, 4th month post-PCI, the patient was doing well and was advised to continue same medications except for perindopril and metoprolol whose doses were changed according to his BP.

Ticagrelor is the first antiplatelet agent that achieves a significant reduction in cardiovascular mortality in STEMI patients in comparison to clopidogrel and the most important part of it is that it carries out its task without an increase in major bleeding. A similar magnitude of reduction in ischemic events has also been seen with another agent i.e., prasugrel when compared with clopidogrel but it differs from ticagrelor in the fact that the benefit of ticagrelor continues to a greater extent over the course of the therapy. Thus advantages of ticagrelor over clopidogrel and prasugrel is more regardless of whether patients receive invasive or medical management or whether PCI. So, our team found ticagrelor suitable and a boon for this high-risk patient in the management of STEMI. Treatment of patients with ACS routinely involves PCI and use of intracoronary stents. Stent thrombosis is a life-threatening complication which may occur acutely (i.e., in the first 24 hours), subacutely (i.e., from 24 hours to 30 days) or late after stent placement.6 It is more frequent when platelet inhibition by aspirin and clopidogrel is inadequate.7 As we have already discussed earlier, clopidogrel, in particular, produces a moderate and variable inhibition of P2Y12, whereas ticagrelor provides more potent and consistent platelet inhibition with faster onset and offset of action than clopidogrel.

Stent thrombosis has always been a challenging task after PCI for cardiologists today. This fast acting novel reversible antiplatelet agent “ticagrelor� lowers the rate of stent thrombosis in patients who receive stents when compared to patients taking clopidogrel,8 which has also been proved in our case by the fact that the patient did not develop stent thrombosis.

The superior clinical efficacy demonstrated by the oral, reversible, P2Y12 receptor inhibitor antiplatelet agent ticagrelor compared with the standard antiplatelet agent clopidogrel in the PLATelet inhibition and patient Outcomes (PLATO) trial may be due in

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CARDIOLOGY large part to the former’s greater platelet inhibition exhibited both during the maintenance phase and the first hours of treatment. In PLATO trial, ticagrelor reduced the primary endpoint of cardiovascular death, MI and stroke when compared with clopidogrel.9 In another substudy, PLATO PLATELET, patients were randomized to receive either clopidogrel (300-600 mg loading dose [LD], 75 mg/day) or ticagrelor (180 mg LD, 90 mg twice-daily) and the effects of maintenance therapy were studied in ACS patients pre- and 2-4 hours post-dose after at least 28 days. It was concluded that, ticagrelor achieved greater antiplatelet effect than clopidogrel in patients with ACS, both in the first hours of treatment and during maintenance therapy.9 Therefore, we can say ticagrelor demonstrates a more rapid onset and greater platelet inhibitory effect than clopidogrel in ACS patients both during maintenance therapy and in the first hours of treatment.

It is also superior to clopidogrel in reducing ischemic events, without any increase in major bleeding.

According to the PLATO trial, dyspnea was the more common side effect during the initial days of treatment in the ticagrelor group compared with the clopidogrel group.10 Thus keeping in mind these side effects, special precautions and care were taken during the procedure as well as in dosing ticagrelor throughout the treatment tenure but we did not come across any kind of adverse effects in this elderly patient except for the lung infection in the patient who was already on prophylactic antibiotic, which was diagnosed promptly and managed accordingly.

CONCLUSION In conclusion, patient with history of T2DM and hypertension as huge risk factors presenting with STEMI within 12 hours of ongoing symptom, can be treated with emergency PCI along with antiplatelet, anticoagulant and thrombolytic agents. DAPT should be started as soon as it is diagnosed with ticagrelor being one of them which is not only the first reversible, nonthienopyridine, direct P2Y12 blocker antiplatelet agent having a short onset of action and time to maximum IPA but also has a good response in these types of elderly patients with T2DM undergoing emergency PCI. Though ticagrelor is a very propitious novel antiplatelet drug with impressive efficacy and reasonable safety, special care should always be taken to deal with any kind of side effects and rule out any symptoms we come across be it during the admission,

treatment tenure, after discharge and even during follow-up because any symptom in the patient may mimic the side effects of ticagrelor stated above.

REFERENCES 1. Haffner SM, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339(4):229-34.

2. Geisler T, Langer H, Wydymus M, Gohring K, Zurn C, Bigalke B, et al. Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation. Eur Heart J. 2006;27(20):2420-5.

3. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Ramirez C, Sabate M, Jimenez-Quevedo P, et al. Platelet function profiles in patients with type 2 diabetes and coronary artery disease on combined aspirin and clopidogrel treatment. Diabetes. 2005;54(8):2430-5.

4. Braunwald E. Myocardial reperfusion, limitation of infarct size, reduction of left ventricular dysfunction, and improved survival: should the paradigm be expanded?

Circulation. 1989;79(2):441-4.

5. Kalyanasundaram A. Comparison of revascularization procedures in coronary artery disease. Medscape.

Apr 2012.

6. Ong AT, Hoye A, Aoki J, van Mieghem CA, Rodriguez Granillo GA, Sonnenschein K, et al. Thirty-day incidence and six-month clinical outcome of thrombotic stent occlusion after bare-metal, sirolimus, or paclitaxel stent implantation. J Am Coll Cardiol. 2005;45(6):947-53.

7. Mega JL, Simon T, Collet JP, Anderson JL, Antman EM, Bliden K, et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis.

JAMA. 2010;304(16):1821-30.

8. Steg PG, Harrington RA, Emanuelsson H, Katus HA, Mahaffey KW, Meier B, et al. Stent thrombosis with ticagrelor versus clopidogrel in patients with acute coronary syndromes: an analysis from the prospective randomized PLATO trial. Circulation. 2013;128(10): 1055-65.

9. Storey RF, Angiolillo DJ, Patil SB, Desai B, Ecob R, Husted S, et al. Inhibitory effects of ticagrelor compared with clopidogrel on platelet function in patients with acute coronary syndromes: the PLATO (PLATelet inhibition and patient outcomes) PLATELET substudy.

J Am Coll Cardiol. 2010;56(18):1456-62.

10. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045-57.

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COMMUNITY MEDICINE

Seroprevalence of Hepatitis B Surface Antigen in a Tertiary Care Hospital SHASHI CHOPRA*, KAILASH CHAND†, GOMTY MAHAJAN‡, JASPAL KAUR‡, SHEEVANI*, YADWINDER SINGH#

ABSTRACT Background and aim: Hepatitis B virus (HBV) is an established cause of acute and chronic liver disease. A teaching hospital based population study of hepatitis B surface antigen (HBsAg) is strong indicator of true HBV infection rate in the community as large number of patients from different backgrounds attend the hospital. The study was aimed to determine the seroprevalence of HBsAg among patients visiting tertiary care hospital. Material and methods: A total of 6,026 patients were enrolled in this study over a period of 1 year. Serum samples were collected at baseline and were tested for HBsAg by using a rapid one step HBsAg test kit. Samples reactive with this test were further confirmed by the enzyme-linked immunosorbent assay (ELISA).

Results: Of the 6,026 patients included in the study, 62 (1.02%) patients tested positive for HBsAg. The seroprevalence for HBsAg among males and females was 1.17% and 0.87%, respectively. Analysis of age distribution of HBsAg revealed a relative high prevalence (2.26%) among patients between 51 and 60 years of age. Almost 1.51% of patients in third decade of life tested positive for HBsAg. Among the rest, HBsAg prevalence ranged between 0.3% and 0.9%. Conclusion: Timely identification of individuals suffering from HBV infection is mandatory to prevent development of hepatocellular carcinoma in chronic carriers in future.

Keywords: Hepatitis B surface antigen, hepatocellular carcinoma, hepatitis B virus

V

iral hepatitis is a major public health problem and a leading cause of morbidity and mortality throughout the world. Hepatitis B virus (HBV) is a double-stranded DNA (ds-DNA) virus, and an established cause of acute and chronic liver disease with its major role in causation of hepatocellular carcinoma (HCC).1 Worldwide over 2 billion people have been infected with HBV and more than 350 million have chronic HBV infection.2

In South-East Asia, high prevalence rate of HBV infection in their populations makes it a major cause of liver cancer.3 Exactly, the same situation may not be there in our country as its prevalence in healthy population is relatively low. According to World Health Organization (WHO), the prevalence rates of HBV

*Professor †Professor and Head ‡Associate Professor #Demonstrator/Tutor Dept. of Microbiology Punjab Institute of Medical Sciences, Jalandhar, Punjab Address for correspondence Dr Shashi Chopra EJ 227-228, Chahar Bagh, Jalandhar City - 144 001, Punjab E-mail: dr.shashichopra@yahoo.com

infection in India is 2-7%.4 There are approximately 40 million HBV carriers in India alone.5 However, HBV remains the major cause of HCC when compared to other hepatitis viruses.

HBV is a blood transmitted virus and spreads in the community both via vertical as well as horizontal modes. About two-thirds of the patients with acute HBV infection have a mild, asymptomatic and subclinical illness that usually goes undetected.6 Although in majority of the cases, it resolves with time, however, nearly one-tenth of infected populations develop chronic infection that may remain asymptomatic for years.7 HBV chronic carriers are the main source for HBV infection. A number of viral antigens and their respective antibodies can be detected in serum after infection with HBV. The hepatitis B surface antigen (HBsAg) in serum is the first seromarker to indicate active HBV infection, either acute or chronic.8 To understand and assess the magnitude and dynamics of transmission of any disease in a community and for its control and prevention, the assessment and study of its prevalence is very important. So, we have made an attempt to find HBV carriers by knowing the prevalence of HBsAg in the serum of patients, attending a tertiary care hospital in Punjab.

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COMMUNITY MEDICINE MATERIAL AND METHODS A retrospective study was carried out in the Serology Section of the Dept. of Microbiology, Punjab Institute of Medical Sciences, Jalandhar after an approval from the Institutional Review Committee. The present study was conducted on 6,026 blood samples taken from patients who registered at the OPDs or for various ailments admitted to the IPDs over a period of 12 months from April 2014 to March 2015.

Five milliliter venous blood sample was collected from all patients who came with lab requisitions in the collection center for the testing of HBsAg. The blood was allowed to clot at room temperature and the serum was separated after centrifugation at a low speed. The serum sample was then tested for HBsAg by using a rapid card method, one step HBsAg test (SD Bio Standard Diagnostic Pvt. Ltd.). Samples reactive with this test were further confirmed by the enzyme-linked immunosorbent assay (ELISA) by using Hepalisa (J Mitra & Co. Pvt. Ltd.). All the tests were performed in accordance with the manufacturer’s instructions.

RESULTS In all 6,026 serum samples were processed for HBsAg detection for a period of 12-month. Out of these 51% (3,066) samples were of male and 49% (2,960) were of female patients. Of the 6,026 blood samples; 3,672 (61%) samples were from patients admitted to various IPDs and 2,354 (39%) samples from different OPDs. The maleto-female ratio was 1.03:1. The overall seroprevalence of HBsAg was found to be 1.02%. The seroprevalence for HBsAg among males and females was 1.17% and 0.87%, respectively. Analysis of age distribution of HBsAg revealed a relative high prevalence (2.26%) among patients of 51-60 years of age. Almost 1.51% of patients in third decade of life tested positive for HBsAg. Table 1. The Age-wise Distribution of HBsAg Reactive Patients Age

No. of sera tested

HBsAg reactive sera

Percentage (%)

>10

116

01

0.86

11-20

928

08

0.86

21-30

1,586

24

1.51

31-40

1,213

08

0.65

41-50

886

04

0.45

51-60

663

15

2.26

>60

634

02

0.31

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Indian Journal of Clinical Practice, Vol. 26, No. 4, September 2015

Among the rest HBsAg prevalence ranged between 0.3% and 0.9%. The age-wise distributions of HBsAg reactive patients is shown in Table 1.

DISCUSSION The burden of HBV disease is increasing globally and India is not an exception. Surveillance of carriers of viral hepatitis is essential to assess the burden of disease in the population. The result obtained for HBsAg will go a long way in providing useful information for diagnostic purposes and epidemiological studies of infection. Seroprevalence of HBsAg of 1.02% was noted in our study and almost similar results (1.06%) were reported by other workers.9 There is a wide variation in its prevalence from different regions of our country.

Recently, systematic review and meta-analysis of prevalence of hepatitis B in India was done by Batham et al and they confirm that in tribal and nontribal populations of India, the prevalence of HBsAg is 15.9% (confidence interval [CI]: 11.4-20.4%) and 2.4% (95% CI: 2.2-2.7%), respectively.10 The prevalence of hepatitis B varies from country to country and depends upon the complex mixture of behavior, environmental and host factors.

The seroprevalence of hepatitis B among males and females in our study was 1.17% and 0.87%, respectively which is almost similar to the percentages (1.04%, 0.58%, 1.82% and 1.17%, respectively) reported by other workers.11,12 Ndako et al reported much higher seroprevalence rates among males and females (25.5% and 10.9%) in their study.13 No acceptable explanation has been given for the higher prevalence in males, but it is hypothesized that females probably clear the HBV more efficiently in comparison to males.4 Relatively higher seroprevalence of HBsAg were found in the subjects in 6th and 3rd decade of life, respectively.

Similar findings have been noted by Quadri et al (6th, 3rd and 2nd decade of life).14 The observed rate of seropositivity of HBsAg likely reflect the patient population served by our hospital and do not necessary apply to other centers. However, the study does not throw light on the dynamic of viral transmission in the community in this part of the country, but it they provide a reference for future studies because of large number of cases investigated.

CONCLUSION Timely identification of people suffering from HBV infection is mandatory to prevent future HCC in chronic carriers. We recommend the addition of routine

COMMUNITY MEDICINE HBV screening program at the hospital and training of medical and paramedical staff, awareness of public on large scale, proper sterilization of instruments, double gloving and proper disposal of used needles in order to save our future generation.

REFERENCES 1. Si Ahmed SN, Zoulim F. Pathobiology of HBV mutants and clinical impact for treatment monitoring. Expert Rev Anti Infect Ther. 2009;7(3):309-20.

2. Chowdhury A. Epidemiology of hepatitis B virus infection in India. Hep B Annual. 2004;1(1):17-24.

3. Yuen MF, Hou JL, Chutaputti A; Asia Pacific Working Party on Prevention of Hepatocellular Carcinoma.

Hepatocellular carcinoma in the Asia Pacific region.

J Gastroenterol Hepatol. 2009;24(3):346-53.

4. Qamer S, Shahab T, Alam S, Malik A, Afzal K. Age-specific prevalence of hepatitis B surface antigen in pediatric population of Aligarh, North India. Indian J Pediatr.

2004;71(11):965-7.

5. Tandon BN, Acharya SK, Tandon A. Epidemiology of hepatitis B virus infection in India. Gut. 1996;38 (Suppl 2):S56-9.

6. McMahon BJ, Alward WL, Hall DB, Heyward WL, Bender TR, Francis DP, et al. Acute hepatitis B virus infection: relation of age to the clinical expression of disease and subsequent development of the carrier state. J Infect Dis. 1985;151(4):599-603.

8. Horvat RT, Tegtmeier GE. Hepatitis B and D viruses. In: Murray PR, Baron EJ, Jorgensen JH, Pfaller MA, Yolken RH (Eds.), Manual of Clinical Microbiology. Washington DC: ASM Press; 2003. pp. 1464-78.

9. Shyamala R, Rao J. The study of prevalence of hepatitis B surface antigen in a tertiary care hospital in South India.

Scholars Research Library. Der Pharmacia Lettre. 2013; 5(1):11-2.

10. Batham A, Narula D, Toteja T, Sreenivas V, Puliyel JM. Sytematic review and meta-analysis of prevalence of hepatitis B in India. Indian Pediatr. 2007;44(9):663-74.

11. Sood S, Malvankar S. Seroprevalence of hepatitis B surface antigen, antibodies to the hepatitis C virus, and human immunodeficiency virus in a hospital-based population in Jaipur, Rajasthan. Indian J Community Med. 2010;35(1):165-9.

12. Patil SS, Nikam SA, Dama SB, Chondekar RP, Kirdak RV, Dama LB. Prevalence of hepatitis B surface antigen (HBsAg) positivity in Solapur district, Maharashtra state, India. Bangladesh J Med Sci. 2011;10(2):91-4.

13. Ndako JA, Nwankiti OO, Echeonwu GON, Junaid SA, Anaele O, Anthony TJ. Studies on prevalence and risk factors for hepatitis b surface antigen among secondary school students in North-Central, Nigeria. Sierra Leone J Biomed Res. 2011; 3(3):163-8.

14. Quadri SA, Dadapeer HJ, Arifulla M, Khan N. Prevalence of hepatitis B surface antigen in hospital based population in Bijapur, Karnataka. Al Ameen J Med Sci. 2013;6(2): 7. Irshad M. Viral hepatitis in India: a report from Delhi.

180-2.

Global J Health Sci. 2010;2(2):96-103.

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Flu in Children The classical features of uncomplicated flu include abrupt onset of fever, headache, muscle pain and malaise accompanied by cough, sore throat or running nose. All of these features may not be present in children.

The symptoms may last for more than 7 days, particularly among young children.

Flu can be complicated by pneumonia, asthma or ear discharge.

Ear discharge may become manifest 3-4 days after onset of flu.

Viral flu may progress to bacterial pneumonia.

The fever is usually more than 100°F. Diagnostic tests are available but often not indicated.

Generally, it is an acute self-limiting disease.

Patients with uncomplicated flu usually improve gradually over 2-5 days.

Cough may persist for longer period.

Persistence of symptoms or weakness and easy fatigability, called post flu asthenias, may last for several weeks in older children.

Anti-flu drugs are indicated for high-risk children.

Flu vaccination is recommended on annual basis in high risk individuals.

Absence of cough in sore throat means bacterial infection.

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DERMATOLOGY

Another Feather to the Tale: Pseudo-vesicular Pityriasis Rosea SHAURYA ROHATGI*, SAURABH JINDAL*, SHAHNAZ KHAN*

ABSTRACT Pityriasis rosea (PR) is an acute, self-healing exanthema characterized by oval erythematous-squamous lesions of the trunk and limbs, usually sparing face, scalp, palms and soles. The literature is flooded with reports of increasingly diverse morphology and distribution of lesions associated with this condition. Although vesicular lesion has consistently been reported as one of the atypical presentations of PR, to the best of our knowledge, no case of PR presenting as pseudo-vesicles has been previously published. We report a case of a 29-year-old female with 2½ months of amenorrhea who presented with asymptomatic, reddish, raised lesions over the trunk and extremities of 2 days duration. She was investigated and diagnosed to have perivascular PR.

Keywords: Pseudo-vesicular, pityriasis rosea, atypical

P

ityriasis rosea (PR) continues to elude dermatologists with its controversial etiology and atypical presentations even after two centuries since it was first described. The literature is flooded with reports of increasingly diverse morphology and distribution of lesions associated with this condition.

period of loss of pregnancy. Patient was febrile (100⁰F), but vitals were stable and general examination showed no positive findings. Cutaneous examination revealed multiple bilaterally symmetrical, infiltrated, erythematous, nonscaly papules and plaques with

CASE REPORT A 29-year-old female with 2½ months of amenorrhea (G3P0L0A2) presented with asymptomatic, reddish, raised lesions over the trunk and extremities of 2 days duration. The lesions first appeared on the right breast and in the following 2 days, similar lesions appeared over the trunk and proximal extremities. Patients also complained of fever prior to the appearance of skin lesions. There was no history suggestive of preceding upper respiratory tract infection, abdominal complaints, arthralgia, myalgia, malaise and headache. She was taking no medication other than routine supplements prescribed for pregnancy. She had history of first trimester abortion in the previous two pregnancies, but never had any skin rash during the corresponding

*Dept. of Dermatology, Venereology and Leprosy MGM Medical College, Navi Mumbai, Maharashtra Address for correspondence Dr Shaurya Rohatgi 502, A-Wing, Sai Prasad Residency Kharghar, Sector 10, Navi Mumbai - 410 210, Maharashtra E-mail: shaurya023@gmail.com

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a

b

c

Figure 1. Clinical photographs at presentation. a) lateral aspect of trunk showing multiple, bilaterally symmetrical, erythematous papules and plaques; b and c) multiple erythematous papules and plaques on the chest and back.

DERMATOLOGY pseudo-vesicular surface present on the chest, abdomen, back, pubic area and proximal thighs (Fig. 1 a-c).

The lesions had coalesced to form larger plaques but the smaller ones showed some orientation along the lines of skin cleavage, especially over the lateral areas of trunk and back. Mucosa was spared, and scalp, genitals, hair and nails were unremarkable. Systemic examination showed no abnormality. We considered a differential diagnosis of Sweet syndrome and atypical PR. The previous history of first trimester abortions led us to think of an underlying antiphospholipid antibody syndrome (APLAS). Erythrocyte sedimentation rate (ESR) and hemogram were normal except for mild neutrophilia (81%), but without any rise in total leukocyte count. Blood sugar, urine routine, microscopy and liver, renal and thyroid function tests were within normal limits. Human immunodeficiency virus -

a

enzyme-linked immunosorbent assay (HIV-ELISA), hepatitis B surface antigen (HBsAg) and Venereal Disease Research Laboratory (VDRL) tests were negative. Sonography showed a single live fetus with no anomalies. Antinuclear antibodies (ANA) and antids-DNA were negative. Likewise, the antibodies against lupus anticoagulant, cardiolipin and β2-glycoprotein were also negative, thus ruling out APLAS. Skin pathergy test was negative.

Histopathology of skin lesions showed very subtle patchy spongiosis in the stratum spinosum and superficial dermal infiltration with lymphocytes, neutrophils and occasional eosinophils (Fig. 2 a-c). The patient was treated symptomatically with antihistamines and topical calamine lotion. Interestingly, the patient showed significant resolution of lesions 1 week following the first visit. The lesions had flattened and all that remained was minimally pigmented macules and patches with few areas showing slight erythema as well (Fig. 3 a-c). This event shifted the final diagnosis in favor of PR.

b

a

c

Figure 2. Histopathology: a) Epidermis showing minimal acanthosis with dermis showing perivascular and interstitial infiltrate (H&E, x100); b) mild spongiosis (arrow) seen in stratum spinosum (H&E, x200); c) high power view shows RBC extravasation and perivascular infiltrate composed of lymphocytes, neutrophils and (H&E, x400).

b

c

Figure 3. Anterior aspect of trunk showing faintly erythematous patches 1 week following presentation.

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DERMATOLOGY DISCUSSION Pityriasis rosea is an acute, self-healing exanthema characterized by oval erythematous-squamous lesions of the trunk and limbs, usually sparing face, scalp, palms and soles.1 Variations from this classical description are known to be fairly common, but difficult to quantify.2 The incidence of the herald patch varies from 40% to 76%, and similar to our patient, its absence does not exclude the diagnosis.3 Although vesicular lesion has consistently been reported as one of the atypical presentations of PR, to the best of our knowledge, no case of PR presenting as pseudo-vesicles has been previously published. Purpuric or hemorrhagic, and urticarial variants have also been commonly reported.1 Other rarer types include large patches (PR gigantea of Darier) and papular PR.1,3 Sites such as face, axillae and groins are predominantly involved in PR inversus.3 Involvement of mucous membranes is not uncommon.4 The simplest and most accurate description of the characteristic orientation of secondary eruptions should be “along lines of skin cleavages”.5 On careful examination, we noticed a similar pattern in our patient.

Clichés associated with descriptions of the orientation such as “Christmas-tree”, “inverted Christmas-tree”, “fir tree” and “parallel to the ribs” are imprecise and probably obsolete.3,5 The age of our patient and the time of outbreak of the rash correspond to a recent epidemiological study in the country.6 Out of 200 cases reported in the study, only one patient presented with PR during pregnancy. Reports of PR in pregnancy in Indian literature are infrequent. However, Corson et al7 in 1950 reported that PR is more common during pregnancy as compared to the general population (18% vs. 6%), but this finding has not been corroborated by subsequent studies.

Sweet’s syndrome patients appear dramatically-ill, whereas our patient had no constitutional signs and symptoms. Although classical Sweet’s is known to occur in pregnant females, but absence of features like mucosal lesions, systemic involvement, leukocytosis and confirmatory histopathology diminished the odds even further.8,9 Without therapeutic intervention, patients with classical Sweet’s may show resolution of lesions, but this usually takes weeks or months.10 On the other hand, self-resolution is the rule in PR and this may take an average of 45 days.1 Our patient showed signs of resolution in about 10 days from onset of rash. Cases with similar course i.e., remission within

2 weeks of appearance of rash have been reported in the past.1 A recent study1 suggests that PR developing during pregnancy may be followed by premature delivery and even fetal death. The total abortion rate reported was 13%, but it reached a staggering 57-62% if PR developed within 15th week of gestation. The authors recommended a closer follow-up for women who develop PR during the first 15 weeks of gestation, especially with atypical forms. Other than the PR episode, so far the pregnancy period in our patient has been uneventful. Nonetheless, due to the above mentioned risks and given her previous history of abortions, we are closely monitoring her for occurrence of any adverse event.

Acknowledgments We thank Dr Rajiv Joshi for his constant support to our department through his impeccable histopathological and clinical skills.

REFERENCES 1. Drago F, Broccolo F, Javor S, Drago F, Rebora A, Parodi A. Evidence of human herpesvirus-6 and -7 reactivation in miscarrying women with pityriasis rosea. J Am Acad Dermatol. 2014;71(1):198-9.

2. Chuh A, Zawar V, Lee A. Atypical presentations of pityriasis rosea: case presentations. J Eur Acad Dermatol Venereol. 2005;19(1):120-6.

3. Chuh A, Lee A, Zawar V, Sciallis G, Kempf W. Pityriasis rosea - an update. Indian J Dermatol Venereol Leprol.

2005;71(5):311-5.

4. Drago F, Broccolo F, Rebora A. Pityriasis rosea: an update with a critical appraisal of its possible herpesviral etiology.

J Am Acad Dermatol. 2009;61(2):303-18.

5. Chuh AA. Rash orientation in pityriasis rosea: a qualitative study. Eur J Dermatol. 2002;12(3):253-6.

6. Sharma L, Srivastava K. Clinicoepidemiological study of pityriasis rosea. Indian J Dermatol Venereol Leprol.

2008;74(6):647-9.

7. Corson EF, Luscombe HA. Coincidence of pityriasis rosea with pregnancy. AMA Arch Derm Syphilol. 1950;62(4):562-4.

8. Cohen PR, Kurzrock R. Sweet’s syndrome revisited: a review of disease concepts. Int J Dermatol. 2003;42(10):761-78.

9. Dabade TS, Davis MD. Diagnosis and treatment of the neutrophilic dermatoses (pyoderma gangrenosum, Sweet’s syndrome). Dermatol Ther. 2011;24(2):273-84.

10. Cohen PR, Kurzrock R. Sweet’s syndrome: a neutrophilic dermatosis classically associated with acute onset and fever. Clin Dermatol. 2000;18(3):265-82.

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DRUG REGULATIONS

The Drug Regulatory Scenario in India KK AGGARWAL*, PRACHI GARG†

ABSTRACT Several laws and regulations govern the manufacture and sale of drugs in India and are applicable to all drugs, new and those already in the market. The main regulatory bodies in India are the Central Drugs Standard Control Organization (CDSCO) and National Pharmaceutical Pricing Authority (NPPA). The Drug Technical Advisory Board (DTAB) is the highest technical body under Drugs and Cosmetics Act, which advises the central and state government on technical matters of drug regulation.

These laws and regulations need to be implemented strictly but also judiciously. International guidelines and regulations from bodies like the United States Food and Drug Administration (US FDA) are not suitable for the Indian population. Hence, if any drug, new or old, needs to be banned, the regulatory authority should do it only after careful scrutiny of all relevant facts, so that patients are not denied the benefits of a drug, which has been proven effective. As long as the drug is approved by the regulatory authority, it is of good quality and safe if used as directed, unless proved otherwise by the authorities. The time has come for us to read the DCGI recommendations on ‘off label’ use of drugs and that prescribing dose more than what has been recommended or approved is not safe. The recent Kunal Saha judgment is one such example, where an unprecedented estimated amount of Rs 11 crore was awarded (Rs 6.08 crore basic + 6% interest from the date of filing of the case) as compensation by the Supreme Court in favor of the complainant. The basic error in this case was prescribing injection Depo-Medrol in doses more than what has been recommended. This article gives a brief overview of the various laws governing drugs/pharmaceuticals in India and emphasizes on the need to strengthen the pharmacovigilance program in the country.

Keywords: Drug regulations, regulatory bodies, Drug Technical Advisory Board

LAWS AND REGULATIONS GOVERNING DRUGS/ PHARMACEUTICALS IN INDIA

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Schedule T prescribes GMP specifications for manufacture of Ayurvedic, Siddha and Unani medicines including machinery, equipment and minimum manufacturing premises required for their manufacture.1,3

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Schedule Y establishes the requirements and guidelines for permission to import and/or manufacture of new drug for sale or to undertake clinical trials.3

The Drugs and Cosmetics Act The Drugs and Cosmetics Act, 1940 and Rules 1945 is the central legislation that regulates the import, manufacture, distribution and sale of drugs in India.1 Manufacture and sale is under the respective states governments and union territories through their respective drug control organization, whereas setting standard, import, marketing authorization and monitoring of adverse drug reactions of a new drug is under Central Government.2 The regulatory provisions are covered in different schedules of the Act. Some important schedules are as follows:3 ÂÂ

Section 2.4 (a) of Schedule Y requires all phases of clinical trials for those drug substances, which are discovered in India.4

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Section 2.4 (b) of Schedule Y requires submission of data available from other countries for those drug substances, which are discovered in countries other than India; the licensing authority may require the applicant to repeat all the studies or permit him to proceed from Phase III clinical trials.4

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Section 2.8 of Schedule Y requires pharmacokinetic (bioequivalence) studies first to show that the data generated in Indian population is equal to data generated abroad and then proceed with Phase III trials.4

Schedule M specifies the Good Manufacturing Practices (GMP) and requirements for factory premises, plant and equipment for pharmaceutical products and cosmetics.3

*Senior Physician and Cardiologist Moolchand Medcity, New Delhi †Clinical Associate Dept. of Internal Medicine Moolchand Medcity, New Delhi

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DRUG REGULATIONS To establish the efficacy and safety of a new drug in the Indian population, the applicant has to conduct clinical trials as per these guidelines specified in Schedule Y, the reports of which have to be submitted in a specified format.5

control and regulation of operations relating to narcotic drugs and psychotropic substances and for matters connected therewith.8

But, there are provisions in the Drugs and Cosmetics Act, 1940 and Rules 1945 under which trials can be waived off under Rule 122-A as follows:

The Ministry of Health, along with DCGI and Indian Council for Medical Research (ICMR) has drafted guidelines for research in human subjects, which are essentially based on Declaration of Helsinki, World Health Organization (WHO) guidelines and International Conference on Harmonization (ICH) requirements for good clinical practice (GCP).1

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The licensing authority may waive requirement of submitting the results of local clinical trials and may grant permission for import of new drugs on the basis of data available from other countries in the interest of public health.3,4

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Clinical trials may also be waived for new drugs that are approved and being marketed for several years in other countries if the licensing authority is satisfied that there is adequate published evidence regarding the safety of the drug, subject to the other provisions of these rules.3,4

The Drugs and Cosmetics Act also establishes the Central Drugs Standard Control Organization (CDSCO) and the office of the Drugs Controller General India (DCGI).2 Chapter II of the Drugs and Cosmetic Act provides for the formation of regulatory bodies:3

Good Clinical Practice Guidelines

Good Laboratory Practice Guidelines The Good Laboratory Practice (GLP) guidelines promote the development of quality test data and provide a tool to ensure a sound approach to the management of laboratory studies, including conduct, reporting and archiving.1

Indian Patent Act, 1970 This Act governs the grant of patents in India. The Indian Patents Third Amendment Bill, 2005, establishes product patent protection for pharmaceuticals including agricultural chemicals in India.1

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Drugs Technical Advisory Board (DTAB)

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Drugs Consultative Committee (DCC)

The Drugs Price Control Order, 1995

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Central Drugs Laboratory

The Drug Price Control Order (DPCO), 1995 is governed

by Essential Commodities Act, 1955. It provides the list of price-controlled drugs, procedures for fixation of prices of drugs, method of implementation of prices fixed by Government and penalties for contravention of provisions.1 Prices of only 74 drugs were regulated by this Act. Prices once fixed, cannot be changed as per the Act.9 The new guideline DPCO 2013 replaced the 1995 order, which is governed by National Pharmaceutical Pricing Authority (NPPA) and is based on national list of essential medicines (NLEM). It regulates prices of 652 drugs. It authorizes NLEM to fix the prices of drugs based on new market based values.9 Last year, the NPPA withdrew guidelines for price control issued under Para 19 of DPCO, 2013, which authorizes the NPPA to control the prices of drugs that are not under the NLEM under extraordinary circumstances in public interest.10

The DTAB is the highest decision-making body and comprises of technical experts who advise central and state governments on technical matters of drug regulation.

The Pharmacy Act, 1948 This Act regulates the profession of pharmacy in India regarding registration, education, etc. The central and state pharmacy councils are formulated under the provisions of this Act.6

The Drugs and Magic Remedies (Objectionable Advertisement) Act, 1954 This Act controls the advertisement of drugs in certain cases, prohibits advertisement for remedies alleged to possess magic qualities and provides for matters connected therewith.1,7

The Narcotic Drugs and Psychotropic Substances Act, 1985 This is an Act to consolidate and amend the law relating to narcotic drugs, to make stringent provisions for the

Other Laws Some other laws that affect manufacture, distribution and sale of pharmaceuticals in India are as follows: ÂÂ

The Industries (Development and Regulation) Act, 1951

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DRUG REGULATIONS ÂÂ

The Trade and Merchandise Marks Act, 1958

ÂÂ

The Indian Patent and Design Act, 1970

ÂÂ

Factories Act

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The Medicinal and Toilet Preparations (Excise Duties) Act, 1956

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The Sale of Goods Act, 1930

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VAT Act

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Central Sales Tax Act

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IPC Section 274: Adulteration of drugs

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IPC Section 275: Sale of adulterated drugs

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IPC Section 276: Sale of drug as different drug or preparation.

of the Drugs and Cosmetics Act, 1940 vide Gazette notification G.S.R. 378(E) dated 18.06.2013) because of concerns about their side effects.12 The adverse effect cited for pioglitazone was a risk of bladder cancer and that of risk of agranulocytosis and fatal anaphylactic shocks with Analgin.12 However, a month later, after reviewing the evidence, the DTAB recommended revoking the ban but imposed conditions for the continued marketing of these drugs. ÂÂ

For Analgin, the DTAB was of the view that the drug is used as analgesic for short period as and when necessary. It is not indicated for long-term use.

It should be allowed to be marketed for severe pain or pain due to tumor only and also for bringing down temperature in refractory cases when other antipyretics fail to do so. And, these indications should be clearly mentioned in the package insert and promotional literature.12

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For pioglitazone, the DTAB recommended immediate revocation of the suspension order.

It also recommended marketing of drug with certain conditions that it should not be used as firstline of therapy for diabetes and that there should be a boxed warning in bold red letters ‘Advice for healthcare professionals’ relating to bladder cancer.

REGULATORY BODIES The drug regulatory bodies in India are the CDSCO and the various state Food and Drug Administrations (FDA). ÂÂ

CDSCO under the Dept. of Health (Ministry of Health & Family Welfare) is the central drug authority responsible for ensuring safety, efficacy and quality of drugs including medical devices.1 Its major functions are: Regulatory control over the import of drugs, approval of new drugs and clinical trials, meetings of DCC and DTAB; approval of certain licences as Central Licence Approving Authority is exercised by the CDSCO HQs.11

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DCGI: The DCGI is the executive head of CDSCO and is advised by the DTAB and DCC.

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The Dept. of Chemicals & Petrochemicals and the NPPA under the Ministry of Chemicals & Fertilizers are responsible for formulating policy, planning, development and regulations relating to Chemicals, Petrochemicals and Pharmaceuticals.1

These laws should be implemented judiciously. If any drug needs to be banned, the regulatory authority should do it only after careful scrutiny of all relevant facts, so that any drug that is beneficial is allowed to be used. International guidelines and regulations such as the United States FDA are not suitable for the Indian population.

The suspension and subsequent recall of the ban on pioglitazone and Analgin only underscores the need to proceed with caution.

In June 2013, the Union Health Ministry suspended the manufacturing for sale, sale and distribution of pioglitazone (antidiabetic drug) (under Section 26A of the Drugs and Cosmetics Act, 1940 vide Gazette notification G.S.R. 379(E) dated 18.06.2013) and Analgin (analgesic and antipyretic drug) (under Section 26A

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zz

Patients with active bladder cancer or with a history of bladder cancer, and those with uninvestigated hematuria, should not receive pioglitazone.

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Prescribers should review the safety and efficacy of pioglitazone in individuals after 3-6 months of treatment to ensure that only patients who are deriving benefit continue to be treated. Pioglitazone should be stopped in patients who do not respond adequately to treatment (e.g., reduction in glycosylated hemoglobin, HbA1C).

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Before starting pioglitazone, following known risk factors for development of bladder cancer should be assessed in individuals: age; current or past history of smoking; exposure to some occupational or chemotherapy agents such as cyclophosphamide or previous irradiation of pelvic region.

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Use in elderly patients should be considered carefully before and during treatment because the risk of bladder cancer increases with age.

Elderly patients should start on the lowest possible dose and be regularly monitored because of the risks of bladder cancer and heart failure associated with pioglitazone.

DRUG REGULATIONS Based on the recommendations of the DTAB, the Union Health Ministry revoked its decision vide a Gazette Notification GSR 520(E) dated 31-07-2013 and lifted the ban allowing the manufacture and prescription of pioglitazone.

The suspension of Analgin was subsequently revoked by the Union Health Ministry on 13th February, 2014 subject to certain conditions. This volte-face on the part of the Government only exposes the lacunae in the drug regulatory system and the need to focus and strengthen the pharmacovigilance program in the country.

The nonsteroidal anti-inflammatory drugs (NSAIDs) have come under the scanner because of the significant risk of adverse effects associated with their long-term use. The NSAIDs, both traditional and cyclooxygenase (COX)-2 selective, are the major players in the treatment of pain and inflammation13 and hence are a very widely used group of drugs. These adverse effects include alterations in renal function, hepatic injury, respiratory and skin effects, and platelet inhibition, which may result in increased bleeding. But, the most important adverse effects that are a cause of concern are the gastrointestinal (GI) and cardiovascular effects.14 ÂÂ

ÂÂ

The main clinically relevant GI side effects include GI bleeding, perforation and obstruction, which may be potentially fatal.13,14 The adverse cardiovascular effects include risk of atherothrombotic events like myocardial infarction and stroke, which can be fatal.

Individuals with previous high-risk of cardiovascular disease (CVD) are at higher risk as well as previously health individuals. The risk appears to be dose-dependent.15

Recently, in a Drug safety communication dated 9.7.2015, the US FDA strengthened its earlier warning about potential risks of a heart attack or stroke with NSAIDs like ibuprofen and naproxen, which may be life-threatening. Both beneficial and adverse effects are due to the same mechanism of action, which is inhibition of COX-dependent prostanoids.13 NIMESULIDE: AN OVERVIEW Nimesulide is the only NSAID related to the arylsulfonamide class. Chemically it is 4-nitro-2phenoxymethanesulfonanilide.16 It has been effectively used for the treatment of a variety of inflammatory and painful conditions, including osteoarthritis. The dailyrecommended dosage is 100 mg twice-daily.17

Nimesulide: Clinical Pharmacology After oral administration, nimesulide is rapidly and extensively absorbed. Mean peak concentrations (Cmax) are achieved within 1.22 to 2.75 hours of administration.

The rate and extent of absorption is not affected by food.18 Nimesulide exerts its therapeutic effect via multifactorial mode of action. Like other NSAIDs, the primary mode of action is by blocking prostaglandin synthesis by inhibiting activity of the enzyme COX.17 It is a COX-2 preferential NSAID,16 with 5- to 50‑fold more selectivity for COX‑2 then COX‑1.19 Nimesulide; however, also has many different actions in the inhibition of the inflammatory process. It blocks:17,19 ÂÂ

Histamine release from mast cells and basophils

ÂÂ

Production of platelet-activating activated platelets and other cells

ÂÂ

Production of free radicals, which are key mediators of destructive and inflammatory events

ÂÂ

Release and activity of metalloproteinases, which can cause the destruction of proteoglycans, collagens and other components of connective tissue matrix in joints

ÂÂ

Chemotaxis

ÂÂ

Chondrocyte apoptotic process

ÂÂ

Phosphodiesterase-4.

factor

from

All these actions provide it with the rather unique role of a multi-acting drug with superior activities in painful and inflammatory conditions.19

Nimesulide: Clinical Evidence Many international studies have demonstrated the effectiveness and safety of nimesulide in osteoarthritis, gouty arthritis, acute back pain, acute shoulder pain. ÂÂ

Nimesulide is osteoarthritis.20

as

ÂÂ

Nimesulide is better than ibuprofen in low backache.21

ÂÂ

Nimesulide is osteoarthritis.22

ÂÂ

Nimesulide is better than diclofenac in acute shoulder pain.23

ÂÂ

Nimesulide is better than diclofenac in acute gout attack.24

as

good

good

as

as

naproxen

piroxicam

in

in

Nimesulide has also been used effectively in psoriatic arthritis,25 dysmenorrhea26 and postoperative pain.27 It is as active and safe as paracetamol for the treatment of pyrexia in the elderly.28

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DRUG REGULATIONS There have been studies from India in patients with osteoarthritis. A study conducted in Delhi evaluated the efficacy and safety of nimesulide versus piroxicam in 49 patients with osteoarthritis of the knee joint.

Nimesulide was administered orally as 100 mg twicedaily, and piroxicam was administered as 20 mg orally in the morning and placebo in the evening.29 ÂÂ

Significant reduction in joint swelling and tenderness was observed as early as 2 weeks in the two treatment groups; but, a greater number of patients were relieved in nimesulide group.

ÂÂ

At 8 and 24 weeks, the number of patients with no joint swelling were 66.7% versus 50% and 80% versus 66.7% in the nimesulide and piroxicam groups, respectively (p < 0.05).

ÂÂ

Functional capacity at 8 weeks improved in 72.2% of nimesulide and 44.4% of piroxicam recipients.

ÂÂ

Mild adverse effects, mainly GI, considered possibly related to treatment were recorded in four patients treated with nimesulide and in 12 patients treated with piroxicam.

In another study reported in the J Indian Med Assoc, Roy et al compared nimesulide to piroxicam in patients with osteoarthritis.30 ÂÂ

A significant decrease in articular index tenderness (p < 0.05) at 8 weeks and assessment of handicap at 4 weeks (p in comparison to baseline, was observed patients receiving nimesulide.

of joint in self< 0.05), only in

ÂÂ

More patients on piroxicam required rescue therapy.

ÂÂ

Adverse effects were observed in six patients on nimesulide and nine patients on piroxicam.

Nimesulide: Safety Profile GI Safety Unlike other classical NSAIDs, nimesulide has very favorable GI safety profile due to its relatively high pKa value (6.5) and preferential COX-2 selectivity (COX-2/ COX-1 = 0.19).17 Nimesulide induces less GI damage than that seen with naproxen in the short-term.31 A multicenter populationbased case-control study found that nimesulide had one of the lowest risks for upper GI bleeding, comparable with ibuprofen and much lower than several commonly used NSAIDs such as piroxicam, ketoprofen and ketorolac, the latter two being among those NSAIDs with poor GI tolerability.19,32

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Renal Safety Nimesulide has been shown to have a low incidence of renal reactions, in line with the pharmacokinetics of the drug.19 In a study, nimesulide 400 and 600 mg daily were well-tolerated with regard to renal safety, even though these dosages are higher than those recommended for clinical use. The study showed only equivocal evidence of minor renal toxicity with nimesulide 800 mg daily.33 The pharmacokinetic profile of nimesulide is not altered in patients with moderately impaired renal function (creatinine clearance 1.8-4.8 L/ hour [30-80 mL/min]).34 Cardiac Safety Data from clinical trials and adverse drug reactions monitoring have confirmed a low-risk of cardiovascular events related to its use.19 While selective COX-2 inhibitors increase the risk for CVDs, nimesulide does not exert significant cardiotoxicity.35 Bleeding Safe Nimesulide can be used in patients with bleeding problems. In a randomized, placebo-controlled study of healthy male volunteers, nimesulide 200 mg daily for 7 days did not prolong bleeding time or modify any of the other hemostasis variables measured such as platelet count and platelet aggregation, prothrombin time, activated partial thromboplastin time, fibrinogen and factor VIII among others.36 Asthma Safe Nimesulide is safe in aspirin-sensitive asthmatic patients.37 On the basis of clinical experience, nimesulide, unlike most other NSAIDs in the recommended doses appears to be well-tolerated in aspirin-sensitive asthmatic patients.19 Nimesulide has proved to be a valid therapeutic alternative to other NSAIDs, with a similar or even superior clinical efficacy, characterized by a fast-onset of the analgesic action. Nimesulide shares the characteristic side effects of NSAIDs, such as GI, skin, renal and hepatic reactions.

Nimesulide has been available in India since 1995.

Following media reports about Nimesulide in 2011, the DTAB held deliberations on the use of Nimesulide in the Indian population. Under Section 26A of Drugs and Cosmetics Act, 1940, vide Gazette Notification No. GSR 82(E), dated 10.2.2011, the DTAB notified the use of Nimesulide in population only above 12 years of age. It recommended that a box warning should be mentioned on label and package insert of Nimesulide formulations: “Use of nimesulide should ordinarily be

DRUG REGULATIONS restricted to 10 days. If longer clinical use is warranted, liver function test should be assessed periodically.”38

ÂÂ

The effectiveness of nimesulide in treatment of pain and inflammatory conditions has been adequately demonstrated in clinical trials comparing its efficacy with placebo and with other NSAIDs.

ÂÂ

The adverse reaction profile of nimesulide is, in general, like that of other NSAIDs. It does, however, have relatively low occurrence of GI side effects.

In contrast with the coxibs, nimesulide has not been found to have appreciable cardiovascular toxicity.42

Nimesulide has a relatively low tendency to produce severe GI reactions when compared with other NSAIDs. Severe renal, cardiovascular and skin reactions are relatively rare.39 Liver reactions (hepatitis, cholestatic jaundice and liver failure) are no more frequent than with other NSAIDs.39 The individual or inherent risk factors of the patient can predispose him/her to increased risk for development of nimesulideassociated unpredictable or idiosyncratic hepatic reactions. These include specific gene abnormalities, alteration in specific gene expression or epigenetic factors.17 However, it is only in a small number of susceptible patients that genetic or nongenetic factors will cause potential hepatotoxicity to become clinically manifest. The type and incidence of the rare but severe hepatic adverse reactions are comparable to that of other NSAIDs.40 However, use of nimesulide is contraindicated in patients with hepatic impairment.41

ÂÂ

Many factors influence development of adverse drug reactions, both patient-related and/or drug-related and thereby prescribing decisions.

Presence of concomitant disease may also increase susceptibility to adverse drug reactions. Hence, appropriate patient selection for prescribing a particular drug is important.

ÂÂ

The benefit/risk profile of nimesulide remains favorable and unchanged over time.19

ÂÂ

Nimesulide can be safely used for 10 days in individuals above 12 years of age as approved by the DTAB.

The Consensus Report Group on Nimesulide (CRGN) recognized that nimesulide is an NSAID which exerts its analgesic, anti-inflammatory and antipyretic activities thanks to unique chemical and pharmacokinetic characteristics, and to a multifactorial mechanism of action, which goes beyond its preferential inhibitory activity on the COX-2 enzyme. The CRGN concluded that nimesulide remains an effective and safe therapeutic choice for the treatment of various painful inflammatory conditions, with a rapid onset of analgesic activity and an overall positive benefit/risk profile.19 Now and then, there are controversies in the media regarding various drugs. Instead of going by medial reports, the DCGI recommendations should be followed. For instance, a section of media regularly reports that nimesulide is banned in India, which is not scientifically correct. As per DCGI, nimesulide is safe for use in adults in acute conditions for 10 days.

2. Imran M, Najmi AK, Rashid MF, Tabrez S, Shah MA. Clinical research regulation in India-history, development, initiatives, challenges and controversies: Still long way to go. J Pharm Bioallied Sci. 2013;5(1):2-9.

As long as the drug is approved by a regulatory authority, the DCGI (central or state), it is of good quality.

In one of its orders (DMC/DC/F.14/Comp 642/2010/7th June, 2010), the Delhi Medical Council observed “...that Augmentin and Augapen contain the same salt and once a drug is licensed after approval, it can’t be labeled as of inferior quality unless proved by drug authorities…”

KEY POINTS ÂÂ

Nimesulide is an NSAID with a multifactorial mechanism of action, which goes beyond its preferential COX-2 inhibitory activity.

REFERENCES 1. Sarda RR, Ladkat NB, Khodade RB, Chaudhari PM, Kasture PV. The Indian pharmaceutical industry; evolution of regulatory system and present scenario. IRJP. 2012;3(6):49-55.

3. Drugs and Cosmetics Act, 1940 and Drugs and Cosmetic rules of 1945, Ministry of Health and Family Welfare, Govt. of India.

4. Prajapati V, Goswami R, Makvana P, Badjatya JK. A review on drug approval process for US, Europe and India. International Journal of Drug Regulatory Affairs.

2014;2(1):1-11.

5. Gupta NV, Reddy CM, Reddy KP, Kulkarni AR, Shivakumar HG. Process of approval of new drug in India with emphasis on clinical trials. Int J Pharm Sci Rev Res. 2012;13(2):17-22.

6. The Pharmacy Act, 1948, Ministry of Health and Family Welfare, Govt. of India.

7. The Drugs and Magic Remedies (Objectionable Advertisement) Act, 1954, Ministry of Health and Family Welfare, Govt. of India.

8. The Narcotic Drugs and Psychotropic Substances Act, 1985, Ministry of Health and Family Welfare, Govt. of India.

9. Kumar V, Gupta NV, Kumar KA. A comparison between old and latest systems in DPCO. Int J Pharm Pharm Sci. 2014;6(2):19-20.

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DRUG REGULATIONS 10. Non-essential drugs: NPPA withdraws price control order. The Hindu, September 24, 2014.

26. Pulkkinen M. Nimesulide in dysmenorrhoea. Drugs.

1993;46 Suppl 1:129-33.

11. Central Drugs Standard Control Organization, Directorate General Health Services, Ministry of Health and Family Welfare, Govt. of India.

27. Binning A. Nimesulide in the treatment of postoperative pain: a double-blind, comparative study in patients undergoing arthroscopic knee surgery. Clin J Pain.

2007;23(7):565-70.

12. Minutes of the 64th meeting of Drugs Technical Advisory Board (DTAB) held on 19th July, 2013 in the chamber of DGHS, Nirman Bhawan, New Delhi. Available at: http:// www.cdsco.nic.in/writereaddata/Minutes%20of%20 64th%20DTAB%20meeting.pdf 13. Patrignani P, Tacconelli S, Bruno A, Sostres C, Lanas A. Managing the adverse effects of nonsteroidal antiinflammatory drugs. Expert Rev Clin Pharmacol.

2011;4(5):605-21.

14. Ong CK, Lirk P, Tan CH, Seymour RA. An evidence-based update on nonsteroidal anti-inflammatory drugs. Clin Med Res. 2007;5(1):19-34.

15. Reddy KS, Roy A. Cardiovascular risk of NSAIDs: time to translate knowledge into practice. PLoS Med. 2013;10(2):e1001389.

16. Mattia C, Ciarcia S, Muhindo A, Coluzzi F. Nimesulide: 25 years later. Minerva Med. 2010;101(4):285-93.

17. Kulkarni SK. On the safety of nimesulide, a preferential COX-2 inhibitor. Curr Sci. 2002;83(12):1442-3.

18. Bernareggi A. Clinical pharmacokinetics of nimesulide.

Clin Pharmacokinet. 1998;35(4):247-74.

19. Rainsford KD; Members of the Consensus Report Group on Nimesulide. Nimesulide - a multifactorial approach to inflammation and pain: scientific and clinical consensus.

Curr Med Res Opin. 2006;22(6):1161-70.

28. Cunietti E, Monti M, Vigano A, Dâ&#x20AC;&#x2122;Aprile E, Saligari A, Scafuro E, et al. A comparison of nimesulide vs paracetamol in the treatment of pyrexia in the elderly.

Drugs 1993;46(Suppl 1):124-6.

29. Sharma S, Rastogi S, Gupta V, Rohtagi D, Gulati P. Comparative efficacy and safety of nimesulide versus piroxicam in osteoarthritis with special reference to chondroprotection. Am J Ther. 1999;6(4):191-7.

30. Roy V, Gupta U, Sharma S, Dhaon BK, Singh NP, Gulati P. Comparative efficacy and tolerability of nimesulide and piroxicam in osteoarthritis with specific reference to chondroprotection: a double blind randomised study.

J Indian Med Assoc. 1999;97(10):442-5.

31. Shah AA, Thjodleifsson B, Murray FE, Kay E, Barry M, Sigthorsson G, et al. Selective inhibition of COX-2 in humans is associated with less gastrointestinal injury: a comparison of nimesulide and naproxen. Gut. 2001;48(3):339-46.

32. Laporte JR, Ibanez I, Vidal X, Vendrell L, Leone R. Upper gastro-intestinal bleeding associated with the use of NSAIDs: newer versus older agents. Drug Saf. 2004;27:411-20.

33. Warrington SJ, Ravic M, Dawnay A. Renal and general tolerability of repeated doses of nimesulide in normal subjects. Drugs. 1993;46 Suppl 1:263-9.

20. Kriegel W, Korff KJ, Ehrlich JC, Lehnhardt K, Macciocchi A, Moresino C, et al. Double-blind study comparing the long-term efficacy of the COX-2 inhibitor nimesulide and naproxen in patients with osteoarthritis. Int J Clin Pract.

2001;55(8):510-4.

34. Kumar S. Nimesulide: how safe is it? Natl Med J India.

2003;16(4):233-4.

21. Pohjolainen T, Jekunen A, Autio L, Vuorela H. Treatment of acute low back pain with the COX-2-selective antiinflammatory drug nimesulide: results of a randomized, double-blind comparative trial versus ibuprofen. Spine (Phila Pa 1976). 2000;25(12):1579-85.

36. Marbet GA, Yasikoff Strub ML, Macciocchi A, Tsakiris DA. The effect of nimesulide versus placebo on hemostasis in healthy volunteers. Eur J Clin Pharmacol. 1998;54(5):383-7.

22. Dreiser RL, Riebenfeld D. Nimesulide in the treatment of osteoarthritis. Double-blind studies in comparison with piroxicam, ketoprofen and placebo. Drugs. 1993;46 Suppl 1: 91-5.

35. Suleyman H, Cadirci E, Albayrak A, Halici Z. Nimesulide is a selective COX-2 inhibitory, atypical non-steroidal antiinflammatory drug. Curr Med Chem. 2008;15(3):278-83.

37. Bianco S, Robuschi M, Petrigni G, Scuri M, Pieroni MG, Refini RM, et al. Efficacy and tolerability of nimesulide in asthmatic patients intolerant to aspirin. Drugs. 1993;46 Suppl 1:115-20.

38. F. No. 12-01/12-DC Pt-05. Directorate General of Health Services (Office of DCGI), dated 14th April 2012.

23. Wober W. Comparative efficacy and safety of nimesulide and diclofenac in patients with acute shoulder and a meta-analysis of controlled studies with nimesulide.

Rheumatology (Oxford). 1999;38 Suppl 1:33-8.

39. Bjarnason I, Bissoli F, Conforti A, Maiden L, Moore N, Moretti U, et al. Adverse reactions and their mechanisms from nimesulide. In: Rainsford KD (Eds.), Nimesulide Actions and Uses. Birkhäuser Verlag; 2005. p. 315.

24. Kudaeva FM, Eliseev MS, Barskova VG, Nasonova VA. Comparison of the time to analgesic and anti-inflammatory effect in the treatment of gouty arthritis with nimesulide and sodium diclofenac. Ter Arkh. 2007;79(5):35-40.

40. Boelsterli UA. Mechanisms of NSAID-induced hepatotoxicity: focus on nimesulide. Drug Saf. 2002;25(9):633-48.

25. Sarzi-Puttini P, Santandrea S, Boccassini L, Panni B, Caruso I. The role of NSAIDs in psoriatic arthritis: evidence from a controlled study with nimesulide. Clin Exp Rheumatol.

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41. Khan S. Nimesulide and adverse drug reactions: time for a database. J Postgrad Med. 2008;54(3):242.

42. Rainsford KD. Current status of the therapeutic uses and actions of the preferential cyclooxygenase-2 NSAID, nimesulide. Inflammopharmacology. 2006;14(3-4):120-37.

INTERNAL MEDICINE

To Study the Carotid Intima-media Thickness in Patients of Fatty Liver Disease SANDEEP AHARWAR

ABSTRACT Introduction: Fatty liver is associated with several atherosclerotic risk factors such as hypertension, diabetes and dyslipidemia.

It has also been related to insulin resistance. This association was found in NIDDM patients as well as in nondiabetic subjects. Although an association between hepatic steatosis and atherosclerotic risk factors has been described, possible direct relationships between hepatic steatosis and atherosclerosis remain to be investigated. The IMT of the carotid artery can be measured noninvasively by ultrasound techniques. An increased IMT has been shown to be a risk factor for myocardial infarction and stroke. Furthermore, carotid ultrasound is an accurate diagnostic tool for detecting atherosclerotic plaques and for assessing the degree of luminal narrowing caused by atherosclerotic changes of the vessel wall. The aim of the present study was to investigate associations between hepatic steatosis and the risk of atherosclerosis. Observations: The present study was conducted in the Dept. of Medicine, JA Group of Hospitals, Gwalior, Madhya Pradesh. AFLD and NAFLD patients were further divided into patients with and without risk factors for atherosclerosis. Approximately equal number of age- and sex-matched controls, not suffering from fatty liver disease were also taken up in the study. Out of 88 cases of fatty liver disease, 46 patients were of NAFLD and 42 patients were of AFLD. Out of 46 patients with NAFLD, 28 were male and 18 were female and out of 42 patients with AFLD all were male. On age-wise comparison of mean carotid IMT (CIMT) in NAFLD, AFLD and control group; CIMT was found to increase with age in all groups. Mean CIMT (both sides) increased with increase in grades of fatty liver and was statistically significant in both groups. Statistically significant difference was found in mean CIMT (left) in Grade II fatty liver (p value 0.04). On comparison of NAFLD and controls without risk factors for atherosclerosis, mean CIMT (both side) in NAFLD was found to be significantly more than control (p value 0.04) and was not having any significant difference when risk factors were present (p value 0.29 left and 0.28 right). Similarly on comparison of AFLD patients and controls without risk factors for atherosclerosis, mean CIMT of both side in AFLD patients was found to be significantly more than controls (p value for left CIMT 0.02 and for right CIMT 0.00001) and was not having any significant difference with risk factors were present (p value 8.409, 0.755 for left and right, respectively). Conclusion: CIMT was found to increase with advancing age in all three group (i.e., NAFLD, AFLD and control group). Fatty liver is associated with increase in CIMT in both alcoholic and nonalcoholic patients. CIMT was more in patients of fatty liver disease (both NAFLD and AFLD) having risk factor for atherosclerosis as compared to those without risk factors. CIMT was found to increase with increasing grades of fatty liver diagnosed by ultrasonography. Both NAFLD and AFLD are associated with increased CIMT in comparison to control group.

Keywords: Alcoholic fatty liver disease, nonalcoholic fatty liver disease, hepatic steatosis, atherosclerotic plaques, insulin resistance, intima-media thickness

F

atty liver is a common clinical and histological finding. Fatty liver can be nonalcoholic fatty liver disease (NAFLD) or alcoholic fatty liver disease (AFLD) broadly. NAFLD is defined as a fatty liver (liver

Assistant Professor Dept. of Medicine GR Medical College, Gwalior, Madhya Pradesh Address for correspondence Dr Sandeep Aharwar Assistant Professor Dept. of Medicine, GR Medical College, Gwalior, Madhya Pradesh E-mail: sandeepaharwar31@rediffmail.com

fat >5-10% of liver weight), which is not due to excess alcohol consumption or other causes of steatosis.1 NAFLD is the most common cause of elevated liver function tests (LFTs) in the US according to the National Health and Nutrition Examination Survey (NHANES).2 If there is no co-existing liver disorder such as alcoholic hepatitis or steatohepatitis, further local organ damage does not occur.3 However, excess alcohol consumption is common and could coexist with NAFLD. Merely focusing on NAFLD by excluding subjects using excessive amounts of alcohol may thus underestimate the prevalence of the metabolic syndrome (MetS) and type 2 diabetes in subjects with elevated LFTs. This would seem particularly important as the long-term

Indian Journal of Clinical Practice, Vol. 26, No. 4, September 2015

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INTERNAL MEDICINE prognosis both with respect to the development of cirrhosis and total mortality is much worse for patients with AFLD than with NAFLD.4 In the clinic, it is difficult to distinguish between subjects with NAFLD and AFLD using abnormal LFTs. Increased serum gammaglutamyl transferase (γ-GT) concentration is a marker of excessive alcohol consumption,5 but serum γGT concentrations are also increased in NAFLD.6 There are no population-based data on how serum alanine transaminase (ALT), aspartate aminotransferase (AST) and γGT concentrations, or the AST/ALT ratio may help in distinguishing between NAFLD and AFLD. Hepatic steatosis is usually diagnosed by ultrasound with high diagnostic quality. In comparison to histology, liver sonography has been shown to have an 89% diagnostic sensitivity and 93% diagnostic specificity.7 Fatty liver is associated with several atherosclerotic risk factors such as hypertension, diabetes and dyslipidemia.8 It has also been related to insulin resistance.9 This association was found in noninsulin dependent diabetes mellitus (NIDDM) patients as well as in nondiabetic subjects.10 Although an association between hepatic steatosis and atherosclerotic risk factors has been described, possible direct relationships between hepatic steatosis and atherosclerosis remain to be investigated. The intima-media thickness (IMT) of the carotid artery can be measured noninvasively by ultrasound techniques. An increased IMT has been shown to be a risk factor for myocardial infarction and stroke.11 Furthermore, carotid ultrasound is an accurate diagnostic tool for detecting atherosclerotic plaques and for assessing the degree of luminal narrowing caused by atherosclerotic changes of the vessel wall.12 The aim of the present study was to investigate associations between hepatic steatosis and the risk of atherosclerosis.

AIMS AND OBJECTIVES ÂÂ

To study the carotid IMT (CIMT) in patients of fatty liver disease in various age groups in both gender.

ÂÂ

To correlate CIMT in patients of ALFD and NAFLD.

ÂÂ

To ascertain whether there exists a difference in CIMT in patients of fatty liver with or without risk factors for atherosclerosis.

ÂÂ

To correlate grades of fatty liver with CIMT.

MATERIAL AND METHODS The present study was carried out on 88 patients of fatty liver disease and 80 controls over a period of 1 year in the Dept. of General Medicine, GR Medical College, Gwalior, Madhya Pradesh.

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Selection Criteria Patients from the medical OPD and medical wards, diagnosed as having fatty liver disease on abdominal ultrasonography (USG) were selected for the study. On the basis of history of alcohol intake, patients of fatty liver disease were further categorized into NAFLD and AFLD. Patients consuming ≤20 g (for men) and ≤10 g (for women) of ethanol per day were considered to have NAFLD, while those consuming >20 g (for men) and >10 g (for women) of ethanol per day were considered to have AFLD. An approximate equal number of ageand sex-matched persons without fatty liver were selected randomly as controls. Both fatty liver disease patients (i.e., NAFLD and AFLD) and control group were further divided into two categories, one with risk factor for atherosclerosis and other without risk factors.

Risk factors for atherosclerosis were taken according to Adult Treatment Panel III (ATP III) guidelines and were as follows: ÂÂ

Cigarette smoking

ÂÂ

Hypertension (blood pressure [BP] >140/90 mmHg or on antihypertensive medication)

ÂÂ

Diabetes mellitus (fasting blood sugar [FBS] >126 gm% and postprandial blood sugar [PPBS] >200 gm%)

ÂÂ

Low high-density lipoprotein (HDL) cholesterol (<40 mg/dL)

ÂÂ

Age > (men >45 years; women >55 years)

ÂÂ

Lifestyle risk factors: zz

Obesity (body mass index [BMI] >30 kg/m2)

zz

Atherogenic diet.

Diagnosis of fatty liver disease was made on the basis of presence of fatty liver on abdominal ultrasonographic examination. Ultrasonographic diagnosis of fatty liver was based upon findings of diffusely increased echogenicity (hyperechogenicity) of liver, increased liver contrast compared to kidney, vascular blurring mainly of hepatic veins and attenuation of echogenic level in deep seated areas. Ultrasonographically, fatty liver was graded as follows: ÂÂ

Grade I: Slight diffuse increase in the fine echoes.

Liver appears bright compared to the cortex of the kidney. Normal visualization of diaphragm and intrahepatic vessel borders.

ÂÂ

Grade II: Moderate diffuse increase in the fine echoes. Slightly impaired visualization of the intrahepatic vessels and diaphragm.

ÂÂ

Grade III: Marked increase in the fine echoes. Poor or no visualization of intrahepatic vessel borders, diaphragm and the vessels.

INTERNAL MEDICINE Inclusion Criteria ÂÂ Patients of fatty liver disease (i.e., NAFLD and AFLD). ÂÂ Age more than 18 years.

Exclusion Criteria ÂÂ Conditions likely to alter serum aminotransferases levels like viral hepatic diseases; autoimmune hepatic diseases; toxic hepatic diseases; use of hepatotoxic drugs within 6 months. ÂÂ Cases of surgery like gastrointestinal surgery, biliary obstruction and primary biliary cirrhosis. ÂÂ Pregnancy.

Informed consent was obtained from the patient or from a close relative if the patient was not able to give informed consent. Cases and controls were subjected to a detailed history and thorough clinical examination as per performa. Following investigations were carried out: ÂÂ

Complete hemogram, erythrocyte sedimentation rate (ESR)

ÂÂ

Urine R/M

ÂÂ

FBS, PPBS

ÂÂ

Blood urea nitrogen (BUN), creatinine

ÂÂ

LFTs

ÂÂ

Lipid profile

ÂÂ

Hepatitis B surface antigen (HBsAg)

ÂÂ

Fundus examination

ÂÂ

ECG

ÂÂ

Ultrasound examination of abdomen

ÂÂ

Carotid Doppler.

CIMT was evaluated as a marker of atherosclerosis.

The carotid arteries were bilaterally examined with high resolution B-mode ultrasound using a 5 MHz linear array transducer. The mean thickness of CIMT of >1 mm was defined as presence of carotid atherosclerosis. The data thus obtained was subjected to standard statistical analysis.

patients (i.e., NAFLD and AFLD) and control group were further divided into two categories, one with risk factor for atherosclerosis and other without risk factors.

They were graded on the scale of I-III on USG and CIMT of both right and left common carotid artery was assessed using B-mode ultrasound. The period of study was September 2011 to October 2012. Statistical significance was considered when p value was <0.05.

The various parameters studied in these patients were as follows: In the present study, number of patients having NAFLD were 46 (52.27%) and those having AFLD were 42 (47.72%) (Table 1). In the present study, number of patients in the control group were 80, out of which 65% were male and 35% were female (Table 2). In the present study, more than 50% of the cases of AFLD were having Grade II fatty liver (54.76%), while 25 out of 46 (54.34%) of NAFLD cases were having Grade I fatty liver (Table 3). In the present study, there was no statistically significant difference found in mean CIMT in males with NAFLD and AFLD. Since, none of the female was alcoholic, so mean CIMT between NAFLD and AFLD was not compared (Table 4).

Table 5 shows that in the present study no significant difference in mean CIMT was found between males and females in NAFLD and control group. Mean CIMT between males and females of AFLD group Table 1. Distribution of Fatty Liver (n = 88) No.

%

NAFLD

46

52.27

AFLD

42

47.72

Table 2. Distribution of Control Group (n = 88) No.

%

Male

52

65

Female

28

35

OBSERVATIONS The present study entitled “To study the carotid-intima media thickness in patients of fatty liver disease” was done in Dept. of Medicine, JA Group of Hospitals, Gwalior, Madhya Pradesh. In this study, total 88 subjects with fatty liver and 80 controls were included from those who were attending OPD or were admitted in Medicine wards. Out of 88 cases of fatty liver, 46 were NAFLD and 42 were AFLD. Both fatty liver disease

Table 3. Distribution of Grades of Fatty Liver Based on Ultrasound Grades

AFLD (n = 42)

NAFLD (n = 46)

Total

No.

%

No.

%

No.

%

Grade I

17

40.47

25

54.34

42

47.72

Grade II

23

54.76

19

41.30

42

47.72

Grade III

2

4.7

2

4.34

4

4.54

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INTERNAL MEDICINE Table 4. Sex-wise Comparison of CIMT Between NAFLD and AFLD Cases CIMT (mm)

Males (n = 68) NAFLD (n = 28)

Females (n = 18)

AFLD (n = 40)

P value

NAFLD (n = 18)

AFLD (n = 0)

P value

Mean CIMT (left)

0.71 ± 0.18

0.71 ± 0.11

1

0.70 ± 0.19

-

-

Mean CIMT (right)

0.72 ± 0.17

0.72 ± 0.16

0.80

0.70 ± 0.18

-

-

Table 5. Comparison of CIMT in Patients of NAFLD, AFLD and Control Groups CIMT (mm)

NAFLD (n = 46)

AFLD (n = 42)

Control (n = 80)

M (n = 28)

F (n = 18)

P value

M (n = 42)

M (n = 52)

F (n = 28)

P value

Mean CIMT (left)

0.71 ± 0.18

0.70 ± 0.19

0.85

0.71 ± 0.11

F (n = 0) P value -

-

0.66 ± 0.12

0.62 ± 0.13

0.28

Mean CIMT (right)

0.72 ± 0.17

0.70 ± 0.18

0.70

0.71 ± 0.16

-

-

0.65 ± 0.14

0.66 ± 0.14

0.76

Table 6. Age-wise Comparison of Mean CIMT in NAFLD, AFLD and Control Groups Group Mean CIMT (mm) (left)

Mean CIMT (mm) (right)

18-29 (years)

30-39 (years)

40-49 (years)

50-59 (years)

60 & above (years)

P value

NAFLD (n = 46)

0.51 ± 0.19

0.68 ± 0.09

0.65 ± 0.10

0.78 ± 0.16

0.86 ± 0.17

0.269

4

41

AFLD (n = 42)

0.66 ± 0.10

0.66 ± 0.13

0.79 ± 0.11

0.70 ± 0.10

0.75 ± 0.09

0.0384

4

37

Control (n = 80)

0.55 ± 0.09

0.63 ± 0.13

0.64 ± 0.11

0.69 ± 0.14

0.73 ± 0.11

0.00007

4

75

NAFLD (n = 46)

0.52 ± 0.17

0.66 ± 0.12

0.68 ± 0.13

0.82 ± 0.17

0.82 ± 0.13

0.0005

4

41

AFLD (n = 42)

0.65 ± 0.16

0.68 ± 0.16

0.82 ± 0.19

0.63 ± 0.05

0.75 ± 0.13

0.108

4

37

Control (n = 80)

0.55 ± 0.10

0.63 ± 0.15

0.68 ± 0.10

0.68 ± 0.16

0.73 ± 0.13

0.003

4

79

was not compared as there was no female in AFLD group. The difference was statistically insignificant (p > 0.05). In the present study, CIMT was found to increase with age in all three groups. In control group, statistically significant difference was found in mean CIMT (both right and left) in different age groups, while in NAFLD significant difference was found in mean CIMT of right side and in AFLD difference was significant in left side as per age (Table 6).

Mean CIMT of both sides right and left increased with increasing grades of fatty liver and was statistically significant in both subgroups (Table 7).

No statistically significant difference in mean CIMT was found between NAFLD and AFLD group in all grades of fatty liver except in Grade II fatty liver on left side, where difference was statistically significant (p value 0.04) (Table 8). On comparison of mean CIMT between NAFLD and control without the risk factors for atherosclerosis, the mean CIMT in NAFLD was

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Indian Journal of Clinical Practice, Vol. 26, No. 4, September 2015

ANOVA Within Between

found to be significantly more (p value 0.04), indicating that NAFLD per se is associated with increase in CIMT (atherosclerosis) (Table 9). As was seen in NAFLD group, the mean CIMT was significantly more in AFLD group in comparison to control group when risk factors for atherosclerosis were not present (p value is 0.02, 0.001 for mean CIMT (left) and (right) common carotid artery, respectively).

In the presence of risk factors for atherosclerosis, when NAFLD group was compared with control group and similarly AFLD group was compared with control group, there was no statistically significant difference (Table 10). Mean CIMT (right) in NAFLD patients with risk factors was found to be significantly (p = 0.03) more than patients without risk factors. Mean CIMT (left) in AFLD patients with risk factors was found to be significantly (p = 0.043) more than patients without risk factors (Table 11).

INTERNAL MEDICINE Table 7. Ultrasonographic Grade-wise Comparison of Mean CIMT in Different Groups CIMT (mm) Mean CIMT (mm) (left) Mean CIMT (mm) (right)

Group

Grade I (n = 42)

Grade II (n = 42)

Grade III (n = 4)

ANOVA P value

Within

Between

NAFLD (n = 46)

0.60 ± 0.13

0.82 ± 0.16

0.95 ± 0.07

0.0001

2

43

AFLD (n = 42)

0.66 ± 0.07

0.73 ± 0.12

0.90 ± 0.14

0.0061

2

39

NAFLD (n = 46)

0.62 ± 0.13

0.81 ± 0.15

1.05 ± 0.07

0.00001

2

43

AFLD (n = 42)

0.65 ± 0.08

0.73 ± 0.18

1.05 ± 0.07

0.0022

2

39

Table 8. Comparison of Mean CIMT in NAFLD and AFLD Groups According to Ultrasonographic Grade of Fatty Liver Group

CIMT (mm) Grade I (n = 42) Right

Grade II (n = 42)

Left

Right

Grade III (n = 4)

Left

Right

Left

NAFLD (n = 46)

0.62 ± 0.13

0.60 ± 0.13

0.81 ± 0.15

0.82 ± 0.16

1.5 ± 0.07

0.95 ± 0.07

AFLD (n = 42)

0.65 ± 0.08

0.66 ± 0.07

0.73 ± 0.18

0.73 ± 0.12

1.05 ± 0.07

0.9 ± 0.14

0.4

0.09

0.13

0.04

1.0

0.69

P value

Table 9. Comparison of Mean CIMT Between NAFLD and Control Groups With and Without Risk Factor for Atherosclerosis CIMT (mm)

Risk factor absent (n = 64)

Risk factor present (n = 62)

NAFLD (n = 24)

Control (n = 40)

P value

NAFLD (n = 22)

Control (n = 40)

P value

Mean CIMT (left)

0.66 ± 0.16

0.59 ± 0.11

0.04

0.73 ± 0.16

0.73 ± 0.13

0.29

Mean CIMT (right)

0.65 ± 0.18

0.58 ± 0.10

0.04

0.76 ± 0.17

0.72 ± 0.12

0.28

Table 10. Comparison of Mean CIMT Between AFLD and Control Groups With and Without Risk Factor for Atherosclerosis CIMT (mm) Mean CIMT (left) Mean CIMT (right)

Risk factor absent (n = 61) NAFLD (n = 21) Control (n = 40) 0.66 ± 0.11 0.59 ± 0.11 0.69 ± 0.10 0.58 ± 0.10

P value 0.02 0.0001

Risk factor present (n = 61) NAFLD (n = 21) Control (n = 40) P value 0.76 ± 0.19 0.73 ± 0.13 0.469 0.73 ± 0.12 0.72 ± 0.12 0.758

Table 11. Comparison of Mean CIMT in Patients of Fatty Liver With and Without Risk Factors for Atherosclerosis CIMT (mm)

Mean CIMT (left) Mean CIMT (right)

NAFLD (n = 46) Risk factor absent Risk factor present (n = 24) (n = 22) 0.66 ± 0.16 0.73 ± 0.16 0.65 ± 0.18 0.76 ± 0.17

DISCUSSION This study assessed cardiovascular risk factors and measured carotid atherosclerosis in patients with an ultrasonographic diagnosis of NAFLD and AFLD.

Demographic In our study, maximum number of subjects were in 5th decade. The age range of patients was from 18 to

P value 0.14 0.03

Risk factor absent (n = 21) 0.66 ± 0.11 0.69 ± 0.10

AFLD (n = 42) Risk factor present (n = 21) 0.76 ± 0.19 0.73 ± 0.12

P value 0.043 0.24

82 years and the mean age was 46.41 ± 15.18 years. Mean age in male patients was 48.07 ± 13.37 years (range 24-71 years), and female patients was 43.83 ± 17.75 years (range 14-76 years).

In the present study, male preponderance was seen (i.e., males constitute 60.8% of total and male:female ratio was 3:2). In our study, all patients with AFLD were males.

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CIMT

In our study, BMI of patients with NAFLD was 25.64 ± 3.64 kg/m2; more than 50% of NAFLD patients were having normal BMI and were mostly having Grade I fatty liver. Twenty-eight percent (13 out of 46) patients were overweight and of these 6 were having Grade II and 6 Grade I fatty liver. In AFLD patients, mean BMI was 25.36 ± 3.06 kg/m2. More than 50% patients were having normal BMI and were having Grade I fatty liver more than Grade II fatty liver, while 33.33% (14 out of 42) patients were overweight.

CIMT is a valid marker of early atherosclerosis and thus has a potential to detect cardiovascular disease in its subclinical phase as shown by Hansa et al.20 There was no significant difference in mean CIMT between males and females of NAFLD group. No female was present in AFLD group, so comparison was not done.

Lipid Profile Asian Indians are more commonly predisposed to atherogenic dyslipidemia (i.e., combination) of hypertriglyceridemia, low levels of HDL cholesterol and high levels of low-density lipoprotein (LDL) cholesterol. This factor along with higher incidence of insulin resistance make a very fertile ground in Indians for having MetS and its variable manifestation including NAFLD.13 It is postulated that fatty liver reflects over supply of lipids, which marks a state conducive to hyperlipidemia.14 In NAFLD patients, hypertriglyceridemia was found in 26% (12 out of 46) patients with the mean of 132.92 ± 56.35 mg/dL. Duseja et al15 and Unchil et al16 showed hypertriglyceridemia in 53% and 43.6% patients of NAFLD, respectively. In addition, 17.39% of our NAFLD patients had raised total cholesterol, 52.17% had low HDL cholesterol and 19.5% had raised LDL cholesterol, which is in favor of an association between dyslipidemia and NAFLD. In our study, hypertriglyceridemia was present in 21.42% of patients with AFLD. The most common effect of alcohol is to increase plasma triglyceride levels.

Alcohol consumption stimulates hepatic secretion of very LDL (VLDL), possibly by inhibiting the hepatic oxidation of free-fatty acid, which than promote hepatic triglyceride synthesis and VLDL secretion.17

Severity of Fatty Liver Ultrasonographic examination was performed first as it is least expensive and carries no risk of radiation. Its sensitivity is more but is lacks specificity.18 Agarwal19 reported that 48.1%, 40.3% and 11.3% had Grade I, II and III fatty liver, respectively. In our study, in NAFLD group 25 (54.34%) patients had Grade I fatty liver, 19 (41.30%) had Grade II fatty liver and 2 (4.34%) had Grade III fatty liver.

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Indian Journal of Clinical Practice, Vol. 26, No. 4, September 2015

Comparison of CIMT with Age In our study, mean CIMT was found to increase with increasing age in all the groups. In our study, in control group statistically significant difference was found in mean CIMT (both right and left side) in different age group (p value 0.00007/0.003 for left mean CIMT and right mean CIMT, respectively), while in patients with NAFLD, significant difference was found in mean CIMT of right side and in patients with AFLD, difference was significant on left side in different age groups. These results were consistent with previous study done

by Jadhav et al,21 according to which CIMT value in general population varies between 0.4 and 1 mm.

Age is important determinant factor. CIMT increases 0.01-0.33 mm/year. This progression of thickness is 0.03-0.06 mm/year in patients with coronary artery disease.

Mean CIMT of both sides was higher in AFLD group in comparison to NAFLD and controls.

Correlation of Mean CIMT with Ultrasonographic Grades of Liver Disease Targher et al22 showed a correlation between higher CIMT and ultrasonographic grade of liver disease. In our study, the mean CIMT (left) in ultrasonographic Grades I, II and III in NAFLD group was 0.60 ± 13 mm, 0.82 ± 0.16 mm and 0.95 ± 0.07 mm, respectively and was statistically significant (p value 0.0001). Similarly in AFLD group, the mean CIMT (left) in ultrasonographic Grades I, II and III was 0.66 ± 0.07 mm, 0.73 ± 0.12 mm and 0.90 ± 0.14 mm, respectively and was statistically significant (p value 0.006). This showed that as grades of fatty liver increase, mean CIMT also increases. Similar relation is true for mean CIMT of right side. In our study, mean CIMT when compared in NAFLD patients with and without risk factors for atherosclerosis was found to be significantly more on right side (p value 0.03) in patients whom risk factors for atherosclerosis were present. Similarly in AFLD patients, mean CIMT (left) was significantly more when risk factors were present.

In both the groups, risk factors for atherosclerosis were associated with increased CIMT.

INTERNAL MEDICINE patients and reserved for patients with clinically relevant liver disease.

CIMT and Atherosclerosis Control group consist of cases without fatty liver and were further divided into cases with and without risk factors for atherosclerosis. So, on comparison of mean CIMT between NAFLD patients without risk factors and patients in control group without risk factors, mean CIMT of both side in NAFLD patients was found to be significantly more (p value 0.004) indicating that NAFLD per se was associated with increased CIMT.

ÂÂ

Diagnosis of AFLD and NAFLD was based on history. Self-reported alcohol consumption is frequently subject to under reporting.

ÂÂ

The participation rate of subjects who consume excess alcohol might be low, which might underestimate the true prevalence of AFLD.

REFERENCES

Similarly, on comparison of mean CIMT of both sides between AFLD and control group without risk factors, mean CIMT of both side in AFLD group was found to be significantly more (p value 0.02, 0.04 for left and right, respectively) indicating that AFLD per se was associated with increased CIMT. In our study, mean CIMT increased both in patients of NAFLD and AFLD. The results obtained are similar to other studies.23-27

1. Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology. 2003;37(5):1202-9.

CONCLUSION

4. Dam-Larsen S, Franzmann M,Andersen IB, Christoffersen P, Jensen LB, Sørensen TI, et al. Long term prognosis of fatty liver: risk of chronic liver disease and death. Gut. 2004;53(5):750-5.

ÂÂ

CIMT was found to increase with advancing age in all three groups (i.e., NAFLD, AFLD and control group).

ÂÂ

In patients with fatty liver disease, there was no association of CIMT with gender (i.e., males and females are equally susceptible).

2. Clark JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol. 2003;98(5):960-7.

3. Teli MR, James OF, Burt AD, Bennett MK, Day CP. The natural history of nonalcoholic fatty liver: a follow-up study. Hepatology. 1995;22(6):1714-9.

5. Sharpe PC, McBride R, Archbold GP. Biochemical markers of alcohol abuse. QJM. 1996;89(2):137-44.

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Fatty liver was associated with increase in CIMT in both alcoholic and nonalcoholic patients.

6. Thamer C, Tschritter O, Haap M, Shirkavand F, Machann J, Fritsche A, et al. Elevated serum GGT concentrations predict reduced insulin sensitivity and increased intrahepatic lipids. Horm Metab Res. 2005;37(4):246-51.

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CIMT was more in patients of fatty liver disease (both NAFLD and AFLD) having risk factor for atherosclerosis as compared to those without risk factors.

7. Joseph AE, Saverymuttu SH, Al-Sam S, Cook MG, Maxwell JD. Comparison of liver histology with ultrasonography in assessing diffuse parenchymal liver disease.

Clin Radiol. 1991;43(1):26-31.

ÂÂ

CIMT was found to increase with increasing grades of fatty liver diagnosed by USG.

ÂÂ

Both NAFLD and AFLD were associated with increased CIMT in comparison to control group.

8. Akahoshi M, Amasaki Y, Soda M, Tominaga T, Ichimaru S, Nakashima E, et al. Correlation between fatty liver and coronary risk factors: a population study of elderly men and women in Nagasaki, Japan. Hypertens Res. 2001;24(4):337-43.

ÂÂ

As such all NAFLD and AFLD patients should be investigated for carotid atherosclerosis, as its early detection and management may be helpful in limiting the inherent complications of atherosclerosis.

9. Banerji MA, Buckley MC, Chaiken RL, Gordon D, Lebovitz HE, Kral JG. Liver fat, serum triglycerides and visceral adipose tissue in insulin-sensitive and insulinresistant black men with NIDDM. Int J Obes Relat Metab Disord. 1995;19(12):846-50.

LIMITATIONS Some limitation of this study merit consideration: ÂÂ

Although USG has a relatively high-sensitivity (82-94%) and specificity (66-95%) in detecting fatty liver, it may give an incorrect diagnosis in 10-30% of cases. Biopsy is gold standard for diagnosing hepatic steatosis but was not practicable for all

10. Goto T, Onuma T, Takebe K, Kral JG. The influence of fatty liver on insulin clearance and insulin resistance in nondiabetic Japanese subjects. Int J Obes Relat Metab Disord.

1995;19(12):841-5.

11. O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK Jr. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med. 1999;340(1):14-22.

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INTERNAL MEDICINE 12. Long A, Lepoutre A, Corbillon E, Branchereau A. Critical review of non- or minimally invasive methods (duplex ultrasonography, MR- and CT-angiography) for evaluating stenosis of the proximal internal carotid artery.

Eur J Vasc Endovasc Surg. 2002;24(1):43-52.

13. Itoh S, Yougel T, Kawagoe K. Comparison between nonalcoholic steatohepatitis and alcoholic hepatitis. Am J Gastroenterol. 1987;82(7):650-4.

14. Toledo FG, Sniderman AD, Kelley DE. Influence of hepatic steatosis (fatty liver) on severity and composition of dyslipidemia in type 2 diabetes. Diabetes Care.

2006;29(8):1845-50.

15. Duseja A, Das A, Das R, Dhiman RK, Chawla Y, Bhansali A, et al. The clinicopathological profile of Indian patients with nonalcoholic fatty liver disease (NAFLD) is different from that in the West. Dig Dis Sci. 2007;52(9):2368-74.

16. Uchil D, Pipalia D, Chawla M, Patel R, Maniar S, Narayani, Juneja A. Non-alcoholic fatty liver disease (NAFLD) the hepatic component of metabolic syndrome. J Assoc Physicians India. 2009;57:201-4.

17. Longo D, Fauci A, Kasper D, Hauser S, Jameson J, Loscalzo J (Eds.). In: Harission’s Principles of Internal Medicine, 18th Edition. New York: McGraw-Hill; 2012. p. 3155.

18. Kotronen A, Yki-Järvinen H. Fatty liver: a novel component of the metabolic syndrome. Arterioscler Thromb Vasc Biol. 2008;28(1):27-38.

20. Hansa G, Bhargava K, Bansal M, Tandon S, Kasliwal RR. Carotid intima-media thickness and coronary artery disease: an Indian perspective. Asian Cardiovasc Thorac Ann. 2003;11(3):217-21.

21. Jadhav UM, Kadam NN. Carotid intima-media thickness as an independent predictor of coronary artery disease.

Indian Heart J. 2001;53(4):458-62.

22. Targher G, Bertolini L, Padovani R, Rodella S, Zoppini G, Zenari L, et al. Relations between carotid artery wall thickness and liver histology in subjects with nonalcoholic fatty liver disease. Diabetes Care. 2006;29(6):1325-30.

23. Sookoian S, Pirola CJ. Non-alcoholic fatty liver disease is strongly associated with carotid atherosclerosis: a systematic review. J Hepatol. 2008;49(4):600-7.

24. Kim JH, Kim SY, Jung ES, Jung SW, Koo JS, Kim JH, et al.

Carotid intima-media thickness is increased not only in non-alcoholic fatty liver disease patients but also in alcoholic fatty liver patients. Digestion. 2011;84(2):149-55.

25. Kim HC, Kim DJ, Huh KB. Association between nonalcoholic fatty liver disease and carotid intimamedia thickness according to the presence of metabolic syndrome. Atherosclerosis. 2009;204(2):521-5.

26. Brea A, Mosquera D, Martín E, Arizti A, Cordero JL, Ros E. Nonalcoholic fatty liver disease is associated with carotid atherosclerosis: a case-control study. Arterioscler Thromb Vasc Biol. 2005;25(5):1045-50.

27. Assy N, Djibre A, Farah R, Grosovski M, Marmor A. 19. Agarwal R, Mishra S, Dixit VK, Rai S. Association of Presence of coronary plaques in patients with nonalcoholic nonalcoholic fatty liver disease with obesity. Indian J Prev fatty liver disease. Radiology. 2010;254(2):393-400.

Soc Med. 2008;39:13-6.

■■■■

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Delhi saw 332 deaths daily in 2014 compared to 266 in the preceding year. Of this, 61.50% deaths took place in hospitals and the rest (38.50%) at home. The data is part of the annual report on registration of births and deaths in Delhi in 2014. Septicemia (8.92%) and tuberculosis (5.83%) were the biggest causes of death in hospitalized patients followed by diseases of pulmonary circulation and other forms of heart disease (4.07%) and shock (3.91%). Of the total deaths reported in 2014, 62.17% were male and 37.83% female. In 2012 and 2013, the percentage of institutional deaths caused due to septicemia was 7.32% and 8.25%, respectively.

Tuberculosis deaths for the corresponding period stood at 4.60% and 4.75%, respectively. (Source: TOI, Aug 28, 2015).

ÂÂ

The effects of sleep deprivation on physician performance has stimulated hot debate for years. A new study

by Anand Govindarajan, MD, from the Institute for Clinical Evaluative Sciences and the Dept. of Surgery, Mount Sinai Hospital, Toronto, Ontario, Canada and colleagues shows that whether a surgeon works the night before performing surgery does not change the risk for adverse outcomes. According to authors, "These data suggest that calls for broad-based policy shifts in duty hours and practices of attending surgeons may not be necessary at this time." (August 26 issue of the New England Journal of Medicine).

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Indian Journal of Clinical Practice, Vol. 26, No. 4, September 2015

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Asymptomatic Hypercortisolism MANISH N MEHTA*, HEMANG K ACHARYA†, AJAY C TANNA‡, JEMIMA BHASKAR#, SUCHITRA GARHWAL$

ABSTRACT The diagnosis of Cushing’s syndrome presents great challenges in determining the etiology of cortisol excess. It must be emphasized that iatrogenic hypercortisolism is the most common cause, the second common cause being pituitary corticotrope adenoma and Carney’s syndrome is one of the rarest of causes.

Keywords: Cushing’s syndrome, PPNAD, lentigines, bilateral adrenalectomy

C

ushing’s syndrome presents clinically with: central obesity, hypertension, glucose intolerance or diabetes mellitus, moon facies, purple striae, proximal muscle weakness, hirsutism and psychological disturbances. This patient was asymptomatic except for moon facies and family history of Cushing’s syndrome.

He was admitted for an unrelated symptom.

Hemoglobin (Hb) - 10.9 g/dL; packed cell volume (PCV) - 37.1; total count (TC) - 6,600 cells/mm3; differential count (DC) - P67L30M3; platelet count - 2,76,000; mean corpuscular volume (MCV) - 65.7; mean corpuscular hemoglobin (MCH) - 19.3 and mean corpuscular hemoglobin concentration (MCHC) - 29.4. Blood group: B-positive.

CASE HISTORY

Diabetic profile: Fasting blood sugar - 74 mg/dL; random blood sugar - 129 mg/dL.

Mr Kalpesh, an 18 year-old-male was investigated for short stature. He was symptomatic otherwise.

Family history: Sister was diagnosed to have primary pigmented nodular adrenocortical disease (PPNAD) for which bilateral adrenalectomy was done and was put on steroid replacement therapy.

Physical examination: Patient had short stature, moon face, multiple lentigines on face (freckles) but patient was not anemic.

Blood pressure: 120/80 mmHg in right arm.

Cardiovascular system: S1/S2 +.

Respiratory system: Bilateral vesicular breath sounds heard.

Abdomen: Soft, no organomegaly.

A clinical diagnosis of Cushing’s syndrome was made.

Investigations: Complete blood count (CBC) profile:

*Head of Dept. †Professor (Head of Unit) ‡Assistant Professor #Senior Resident $Resident Medical Dept., MP Shah Medical Collage, Jamnagar, Gujarat

Renal function tests: Serum creatinine - 0.7 mg/dL; blood urea - 28 mg/dL. Thyroid function tests: Serum T3 - 130 ng/dL (normal 81-178 ng/dL); serum T4 - 11.6 ng/dL (normal 4.5-12.5 ng/dL); serum thyroid-stimulating hormone (TSH) 1.46 µIU/mL (normal 0.4-4 µIU/mL).

Liver function tests: Serum alkaline phosphatase (ALP) - 262; serum albumin - 4.9 g/dL; serum glutamicoxaloacetic transaminase (SGOT) - 32 IU/L; serum glutamic-pyruvic transaminase (SGPT) - 14 IU/L; serum calcium - 9.2 mg/dL; serum phosphorus - 3.6 mg/dL. Hormone profile: Serum follicle-stimulating hormone (FSH) - 3.34 µIU/mL (normal 2.5-10 µIU/mL); serum luteinizing hormone (LH) - 1.82 µIU/mL (normal 2.5-10 µIU/mL); serum prolactin - 8.18 ng/mL (normal 5-25 ng/ mL); basal adrenocorticotropin (ACTH) - 10.3 pg/mL (0-46 pg/mL); basal cortisol - 12.64 µg/mL (normal 5-25 µg/mL); MN cortisol - 13.39 µg/mL. Dexamethasone suppression test: Serum cortisol - 12.64 µg/dL. Electrocardiogram: Within normal limits.

Chest X-ray PA view: Within normal limits.

X-ray of left hand and wrist (for bone age): 16-17 years.

CT scan neck to pelvis: NAD.

Indian Journal of Clinical Practice, Vol. 26, No. 4, September 2015

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INTERNAL MEDICINE DEXA scan of bone: Showed osteoporosis.

Other than these predominant skin lesions, patients may have Cushing’s syndrome, acromegaly, peripheral nerve schwannomas or testicular tumor. These patients frequently have mutations in the tumor suppression genes PRKARIA. Cushing syndrome is due to adrenal tumor and acromegaly is due to pituitary adenoma.

This is an ACTH independent Cushing’s syndrome diagnosed in children and young adults. There is bilateral adrenal cortical micronodular hyperplasia. It is otherwise known as PPNAD. The adrenals contain small brown-black nodules up to 0.5 cm in diameter with large eosinophilic cells laden with lipofuscin nodules. Carney’s complex has been classified in mixed syndromes of MEN 1 or 2. Some patients have gynecomastia due to excess estrogen production.

Sexual maturation rating: B1P4.

TV: Bilateral 15 mL. SPL: Adult size.

Pedigree Analysis

A correct diagnosis permits a potentially life-threatening disorder to be treated.

CONCLUSION

Evaluation of investigations showed ACTH independent endogenous hypercortisolism with nonsuppressed overnight dexamethasone suppression (ODS) cortisol.

Rest of hormone profile was normal. CT scan neck to pelvis was done to know the source of ACTH, which was normal. Clinical diagnosis of Carney’s complex was made in view of PPNAD in sister and lentigines on the face, which is a feature of Cushing’s syndrome.

He was evaluated for other components of Carney’s complex including 2D-Echo, which was normal.

Bilateral laparoscopic adrenalectomy was done. He was then given steroid replacement therapy. The biopsy result confirmed the diagnosis of PPNAD. DISCUSSION Carney’s complex is an autosomal dominant disorder.

It is also known as LAMB syndrome (Lentigines, Atrial myxomas, Mucocutaneous myxoma and Blue nevi) or NAME syndrome (Nevi, Atrial myxoma, Myxoid neurofibroma and Ephelides).

This case has been presented for its rarity as a hereditary cause of Cushing’s syndrome. In addition, the tell tale clinical features of hypercortisolism were missing and patient was asymptomatic. Only a detailed family history helped us to suspect the diagnosis and investigations proved it. Patient is doing well with steroid replacement therapy.

SUGGESTED READING 1. Longo DL, Fauci A, Kasper DL, Hauser S, Jameson J, Loscalzo J (Eds.). In: Harrison’s Principles of Internal Medicine, Volume 1, 18th Edition. New York: McGrawHill; 2012.

2. Longo DL, Fauci A, Kasper DL, Hauser S, Jameson J, Loscalzo J (Eds.). In: Harrison’s Principles of Internal Medicine, Volume 2, 18th Edition. New York: McGrawHill; 2012.

3. Rubin R, Strayer DS (Eds.). In: Rubins Pathology Clinicopathologic Foundations of Medicine, 6th Edition.

Lippincott, Williams & Wilkins; 2012.

4. Damjanov I, Linder J (Eds.). In: Anderson’s Pathology, 10th Edition. New York: Mosby; 1996. pp. 496-9.

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346

Indian Journal of Clinical Practice, Vol. 26, No. 4, September 2015

NEUROSURGERY

Cerebroprotein Hydrolysate in Traumatic Brain Injury: A Retrospective Study ASHUTOSH AGARWAL*, SUDEEP BHARADWAJ*, ARUN TUNGARIA†, SHAIFALI TUNGARIA‡, ABHISHEK DADHICH*

ABSTRACT Introduction: There is a rapid increase in the incidence of traumatic brain injury (TBI) in our country. Increased motor vehicle accidents and population driving these vehicles has rapidly increased, in last few years. Apart from conventional medical and surgical management of TBI, there are numerous neuroprotective agents, which help in recovery and remodeling of the brain tissue. Latest in this category is cerebroprotein hydrolysate, which is believed to increase neuronal recovery with several different mechanisms. In the present study, we have retrospectively evaluated benefits of cerebroprotein hydrolysate in clinical set-up. Material and methods: Data from the medical record section of a tertiary level healthcare center located in Sirsa city of Haryana was collected. Twenty-five patients were categorized as Group A, who received injection cerebroprotein hydrolysate for 1 week in addition to standard treatment for TBI. Patients who received only standard treatment were kept in Group B. Both groups were compared in terms of eye opening, verbal response, motor response and total Glasgow Coma Scale (GCS), at admission, at 7 days of treatment and at 3 months of admission. Statistical methods applied was student t-test. Results: Total GCS in patients of Group A, at the time of admission was 9.44, while it was 8.28 in Group B. At Day 7, in Group A, total GCS improved to 13.48 and in Group B patients, GCS improved to 11.56. Hence, both group of patients showed a significant improvement in total GCS at Day 7, but in Group A, it increased by a score of 4.04 as compared to 3.28 in Group B. At the end of 3 months, mean total GCS in Group A of patients was 14.6. In Group B, mean GCS was 14.44. P value is 0.1875, which is not significant. Improvement in total GCS in Group A was 5.16 points increase at 3 months. In comparison, total GCS in Group B improved by 6.16 points. Therefore, it is evident that there is no significant difference in the neurological status at 3 months in patients receiving cerebroprotein. Conclusion: In our study, there was a significant increase in the amount of GCS in both groups, but the degree of increase of the GCS was significantly higher in case rather than control group at 7 days of treatment.

However, study group failed to show significant increase in total GCS at the end of 3 months. Hence, there can be faster early neurological recovery in patients receiving cerebroprotein. In accordance with the results and the useful effect of cerebroprotein hydrolysate in TBI patients, it is recommended to use this drug in patients in cases it is not contraindicated.

Keywords: Traumatic brain injury, motor vehicle accidents, neuroprotective agents, cerebroprotein hydrolysate

H

ead injury or traumatic brain injury (TBI) implies trauma to the brain caused by an external force affecting the head and brain.

National level data in India is not available for TBI as in many developed countries. The only epidemiological

study undertaken in Bangalore has revealed that the incidence, mortality and case fatality rates were 150/1,00,000, 20/1,00,000 and 10%. The survivors of injuries had various problems in day-to-day life affecting almost every sphere of life.1 PATHOPHYSIOLOGY OF TBI

*Dept. of Pharmacolgy, Seth GL Bihani SD College of Technical Education Institute of Pharmaceutical Sciences and Drug Research, Sri Ganganagar, Rajasthan †Consultant Neurosurgeon Astha Neurocare and Multispeciality Hospital, Sirsa, Haryana ‡Consultant Gynecologist Sigma Hospital, Sirsa, Haryana Address for correspondence Dr Ashutosh Agarwal Assistant Professor Dept. of Pharmacolgy Seth GL Bihani SD College of Technical Education Institute of Pharmaceutical Sciences and Drug Research Sri Ganganagar - 335 001, Rajasthan Email: ashutoshagg@yahoo.com

Traumatic brain injury can be localized, diffuse axonal or secondary brain injury. A good example of localized injury is contusion (bruising) to the brain in a particular area. When there is acceleration and deceleration the brain can strike the inside of the skull. It can bounce back and forth, hitting the back of the skull and the front of the skull, causing bruising to the brain. Other types of localized injuries are subarachnoid hemorrhage, subdural hematoma or an epidural hematoma on the surface of the brain.2 Diffuse axonal injury occurs in an acceleration/deceleration event, when axons get pulled,

Indian Journal of Clinical Practice, Vol. 26, No. 4, September 2015

347

NEUROSURGERY stretched and torn. If there is sufficient injury to the axon, the cell will not survive. When this happens all over the brain, not just in one area, it is called diffuse axonal injury.

Secondary brain injury can be hypoxia, or not getting sufficient oxygen to the brain. Another problem leading to secondary brain injury can be increased intracranial pressure (ICP), which can come from significant swelling of the brain, often referred to as edema.

ICP should be reduced because if the edema is great enough, it prevents blood flow into the tissues.2 AT THE CELLULAR LEVEL: DEVELOPMENT, BASIC STRUCTURE AND REPAIR OF NEURONS Neuron is the basic structural and functional unit of the nervous system. They contain four parts: cell body, dendrites, axon and axon terminal. They develop from the neural stem cells known as type 1 cells which produce progeny called amplifying neural progenitor cells (also known as type 2 cells), which proliferate and differentiate into mature neurons. Till recent past, it was believed that there is no way to repair a damaged neuron.

Main goals of researchers is to develop drugs to stimulate areas of the brain to repair itself by replacing its own cells. Several drugs like edaravone, citicoline and piracetam have been developed based on these neurotrophic factors. Neurotrophic factors are small proteins that exert survival-promoting and trophic (derived from the Greek meaning “to nourish”) actions on neuronal (or nerve) cells. These neurotrophic factors are nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), glial cell-derived neurotrophic factor (GDNF), growthassociated protein-43 (GAP-43) and cilliary neurotrophic factor (CNFT). Neuron cells cannot divide, but they undergo a lot of activity after injury. Cerebroprotein hydrolysate consists of short biological peptides, which act like endogenous neurotrophic factors.3 MEASURING THE SEVERITY OF TBI A common method used to measure the severity of a TBI is the Glasgow Coma Scale (GCS) score. It is a score of a patient’s state of consciousness or coma. It is a universally used, reliable scale that is obtained by evaluating the patient clinically. The components measured are the motor (M), verbal (V) and eyeopening (E) scores. The sum of the resulting points gives a patient score between 3 (indicating deep unconsciousness) and 15 (fully alert).

348

Indian Journal of Clinical Practice, Vol. 26, No. 4, September 2015

CEREBROPROTEIN HYDROLYSATE Cerebroprotein hydrolysate is a brain protein, usually extracted and derived from an animal sources, consisting of amino acids and neuropeptides. Cerebroprotein hydrolysate is most often extracted through a process of enzymatic hydrolysis.

Pharmacokinetics Cerebroprotein hydrolysate is given in a dose of 60-180 mg once-daily for 10-20 days. It should be slowly infused in 250 mL saline in 60-120 minutes.

Cerebroprotein improved the viability of cultured neurons in vitro. It showed effects as a synaptic modulator, potentially improving the integrity of neuronal circuits in a transgenic mouse model of Alzheimer’s disease (mThy1-hAPP751), and various in vitro and in vivo studies showed that cerebroprotein promotes neurogenesis.

Behavioral effects, including amelioration of performance deficits in transgenic mice (mThy1hAPP751), have also been demonstrated with cerebroprotein. Taken together, preclinical and radiolabeling studies indicate that, following peripheral administration, cerebroprotein crosses the bloodbrain barrier in sufficient concentrations to produce pharmacodynamic effects in the central nervous system (CNS).4

Therapeutic Efficacy Several randomized, double-blind, placebo-controlled studies of up to 28 weeks’ duration in patients with Alzheimer’s disease have demonstrated that, compared with placebo, intravenously administered cerebroprotein produced a consistent, statistically significant improvement on outcome measures.

Several of these studies also showed statistically significant improvements on cognition, as assessed by the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog) or its extended version (ADAScog-plus). In patients with vascular dementia, cerebroprotein was superior to placebo, as assessed by various objective clinical status measures.

Tolerability Tolerability data from studies in patients with dementia indicate that cerebroprotein was generally well-tolerated in all clinical trials. The incidence of any treatment-emergent adverse event was 43.4-64% with cerebroprotein compared with 38.0-73% with placebo in three larger, placebo-controlled trials in patients

NEUROSURGERY with Alzheimer’s disease. Commonly reported adverse events with both cerebroprotein and placebo-included dizziness (or vertigo), headache, increased sweating, nausea, urinary tract infection, depression and fever, although there was marked variability between studies in terms of the type and incidence of adverse events.4

Mechanism of Action and Pharmacological Effects Cerebroprotein hydrolysate acts by: ÂÂ

Regulation and improvement of the neuronal metabolism

ÂÂ

Modulation of the synaptic plasticity

ÂÂ

Neuronal differentiation and protection against ischemic and neurotoxic lesions

ÂÂ

Reducing excitotoxic damage, blocks overactivation of calcium-dependent proteases and scavenges free oxygen radicals.3

Cerebroprotein hydrolysate has been shown to counteract the negative effect of the elevated fibroblast growth factor-2 (FGF-2) on neurogenesis and neuromodulation. Cerebroprotein hydrolysate augmented proliferation, differentiation and migration of adult subventricular zone (SVZ) neural progenitor cells results in increased number of neural progenitor cells and neuroblasts to contribute to neurogenesis. This may be the mechanism for its beneficial effect in acute ischemic stroke and TBI. Enhancement of neuronal survival is produced through effect on calpain. The hyperactivation of calpain is implicated in a number of neurodegenerative disorders. Calpain is inhibited by cerebroprotein hydrolysate. Neuromodulatory effect is produced by increasing glucose transporter 1 (GLUT1) expression, which is responsible for more than 90% of glucose transport to brain. Neuronal plasticity is produced by reduction of amyloid beta accumulation, increased microtubule associated protein-2 (MAP-2) and synaptophysin synthesis.

Neuroimmunotrophic activity is produced by inhibition of microglial activation and expression of interleukin (IL)-1 β. This results in reduction of inflammation.2 In the present study, we have compared the clinical status of TBI patients, who had been given standard conventional treatment (control group) with patients who in addition to conventional treatment received injection cerebroprotein hydrolysate.

MATERIAL AND METHODS Present study has been done on traumatic head injury patients admitted to a tertiary level healthcare center in

Sirsa city of Haryana. This hospital is a multispecialty hospital with neurosurgery department and wellequipped operation theater and intensive care unit.

Head injury patients admitted in the hospital from period 1 July, 2014 to 31 December, 2014 were included in the study. The study protocol was approved by the Institutional Ethics Committee of Seth GL Bihani SD College Technical Education, Sriganganagar, Rajasthan.

Inclusion Criteria ÂÂ Traumatic head injury patients with documented cerebral injuries on computed tomogram.

Exclusion Criteria ÂÂ Patients with multiple injuries like orthopedic injuries, chest injuries or abdominal injuries were excluded. ÂÂ Patients with pre-existing medical conditions like hypertension, diabetes, ischemic heart diseases, etc. were excluded.

In the present study, patients were divided into two groups. In Group A, cerebroprotein hydrolysate 60 mg was administered intravenously twice-daily for at least 7 days with the standard treatment; in Group B, patients were given standard treatment with intravenous medications and intensive care. Surgery was performed where it was necessary for improving neurological outcome.

GCS was taken as the measure of neurological status of the patients. GCS consists of three components, eye opening, motor response and verbal response. Each of the three components are observed clinically and given a score from 1 to 4 for eye opening (E), 1 to 6 for motor (M) response and 1 to 5 for verbal response (V).

Addition of scores given to each component gives the total score of GCS. Hence, the total score can vary from minimum score of 3 to the maximum score of 15. Total score of all three components GCS of the patients was recorded at the time of admission, on the 7th day of the treatment and at the 3 months follow-up.

Observations for both the groups were recorded and compared according to improvement in GCS at 3 months. Statistical method applied was student t-test.

RESULTS In the present study, medical records of total 50 patients were obtained retrospectively from the medical record section of the hospital. Twenty-five patients who were given injection cerebroprotein hydrolysate along with standard treatment for TBI, were kept in study group

Indian Journal of Clinical Practice, Vol. 26, No. 4, September 2015

349

NEUROSURGERY significant. Mean score of motor response in Group A was 4.68 with SD of 0.9452. In Group B, it was 3.72 with SD of 0.8907. P value was 0.0003, which is significant.

that is, Group A. Rest 25 patients who were given standard medical treatment were kept in Group B. Table 1 shows the comparison between the ages of the patients in both groups. Mean age in Group A was 33.68 years with standard deviation (SD) 13.375, while it was 39.4 years with SD of 13.72 in Group B. P value was 0.0643, which is not quite significant.

In Table 3, score of E, V and M of the patients at Day 7 is shown. Mean score of eye opening in Group A was 3.68 with SD 0.4761, while in Group B it was 2.92 with SD of 0.7024. One tail p value was 0.0001, which is significant. Mean score of verbal response in Group A was 4.08 with SD of 0.7594 compared to the mean score of 3.68 with SD 0.6272, in Group B patients. P value was 0.02981, which is significant. Mean score of motor response in Group A was 5.72 with SD of 0.4583.

In Group B, mean score was 4.96 with SD of 0.6758.

P value was <0.0001, which is significant.

Table 2 shows the status of the patients of both groups in form of E, V and M, at the time of admission. Mean score of eye opening in Group A, was 2.44 with SD of 1.044, in comparison mean score in Group B was 2.04 with SD 0.6758. P value was 0.0573, which is not significant. Mean score of verbal response in Group A was 2.4 with SD of 1.414, while in Group B it was 2.72 with SD 0.7371. P value was 0.1604, which is not

Table 4 is showing comparison between Group A and B at 3 months. Mean score of eye opening in Group A was 3.96 with SD 0.2, while in Group B it was 3.88 with SD 0.3317 and the p value was 0.1636, which is not significant. Mean score of verbal response in Group A was 4.72 with SD of 0.4583. In Group B, mean score was 4.76 with SD of 0.4359. P value was 0.3849, which is not significant. Mean score of motor response was 5.92 with SD of 0.2769 in Group A and it was 5.8 with SD of 0.4082, in Group B. P value was 0.1326, which is not significant.

Table 5 is showing the improvement in the score of eye opening, verbal and motor response in Group A patients at 3 months. In eye opening, there was improvement

Table 1. Age of Patients in Both Groups Groups (States)

Study group (A)

Controlled group (B)

Mean

33.68

39.4

Standard deviation

13.375

13.720

25

25

2.675

2.744

Sample size Standard error of mean P value

One tail p value 0.0643 is not quite significant

Table 2. Status of Eye Opening, Verbal Response and Motor Response at Admission in Both Groups Groups (States)

Eye opening (A)

Eye opening (B)

Verbal response (A)

Verbal response (B)

Motor response (A)

Motor response (B)

Mean

2.44

2.04

2.4

2.72

4.68

3.72

Standard deviation

1.044

0.6758

1.414

0.7371

0.9452

0.8907

25

25

25

25

25

25

0.2088

0.1352

0.2828

0.1474

0.1890

0.1781

Sample size Standard error of mean P value

One tail p value 0.0572 is not quite significant

One tail p value 0.1604 is not significant

One tail p value 0.0003 is extremely significant

Table 3. Eye Opening, Verbal Response and Motor Response at Day 7 in Both Groups Groups (States) Mean Standard deviation Sample size

Eye opening (A)

Eye opening (B)

Verbal response (A)

Verbal response (B)

Motor response (A)

Motor response (B)

3.68

2.92

4.08

3.68

5.72

4.96

0.4761

0.7024

0.7594

0.6272

0.4583

0.6758

25

25

25

25

25

25

Standard error of mean

0.09522

0.1405

0.1519

0.1254

0.09165

0.1352

P value

One tail p value 0.0001 is extremely significant

350

One tail p value 0.02981 is considered significant

Indian Journal of Clinical Practice, Vol. 26, No. 4, September 2015

One tail p value <0.0001 is considered significant

3 Dimensional Approach To Win Over Diabetes

Lowers FPG & HbA1c

Sustained Improvement In Glycaemic Control

2014 2015

Delays Insulin Therapy

Every citizen of India should have the right to accessible, affordable, quality and safe heart care irrespective of his/her economical background

Sameer Malik Heart Care Foundation Fund An Initiative of Heart Care Foundation of India

E-219, Greater Kailash, Part I, New Delhi - 110048 E-mail: heartcarefoundationfund@gmail.com Helpline Number: +91 - 9958771177

“No one should die of heart disease just because he/she cannot afford it” About Sameer Malik Heart Care Foundation Fund

Who is Eligible?

“Sameer Malik Heart Care Foundation Fund” it is an initiative of the Heart Care Foundation of India created with an objective to cater to the heart care needs of people.

Objectives Assist heart patients belonging to economically weaker sections of the society in getting affordable and quality treatment.

Raise awareness about the fundamental right of individuals to medical treatment irrespective of their religion or economical background.

Sensitize the central and state government about the need for a National Cardiovascular Disease Control Program.

Encourage and involve key stakeholders such as other NGOs, private institutions and individual to help reduce the number of deaths due to heart disease in the country.

To promote heart care research in India.

All heart patients who need pacemakers, valve replacement, bypass surgery, surgery for congenital heart diseases, etc. are eligible to apply for assistance from the Fund. The Application form can be downloaded from the website of the Fund. http://heartcarefoundationfund.heartcarefoundation. org and submitted in the HCFI Fund office.

Important Notes The patient must be a citizen of India with valid Voter ID Card/ Aadhaar Card/Driving License.

The patient must be needy and underprivileged, to be assessed

by Fund Committee.

The HCFI Fund reserves the right to accept/reject any application for financial assistance without assigning any reasons thereof.

The review of applications may take 4-6 weeks.

All applications are judged on merit by a Medical Advisory Board who meet every Tuesday and decide on the acceptance/rejection of applications.

The HCFI Fund is not responsible for failure of treatment/death of patient during or after the treatment has been rendered to the patient at designated hospitals.

To promote and train hands-only CPR.

Activities of the Fund Financial Assistance

The HCFI Fund reserves the right to advise/direct the beneficiary to the designated hospital for the treatment.

Financial assistance is given to eligible non emergent heart patients.

Apart from its own resources, the fund raises money through donations, aid from individuals, organizations, professional bodies, associations and other philanthropic organizations, etc.

The financial assistance granted will be given directly to the treating hospital/medical center.

After the sanction of grant, the fund members facilitate the patient in getting his/her heart intervention done at state of art heart hospitals in Delhi NCR like Medanta – The Medicity, National Heart Institute, All India Institute of Medical Sciences (AIIMS), RML Hospital, GB Pant Hospital, Jaipur Golden Hospital, etc. The money is transferred directly to the concerned hospital where surgery is to be done.

Drug Subsidy

The HCFI Fund has the right to print/publish/webcast/web post details of the patient including photos, and other details. (Under taking needs to be given to the HCFI Fund to publish the medical details so that more people can be benefitted).

The HCFI Fund does not provide assistance for any emergent heart interventions.

Check List of Documents to be Submitted with Application Form Passport size photo of the patient and the family A copy of medical records Identity proof with proof of residence Income proof (preferably given by SDM)

The HCFI Fund has tied up with Helpline Pharmacy in Delhi to facilitate

BPL Card (If Card holder)

patients with medicines at highly discounted rates (up to 50%) post surgery.

Details of financial assistance taken/applied from other sources (Prime Minister’s Relief Fund, National Illness Assistance Fund Ministry of Health Govt of India, Rotary Relief Fund, Delhi Arogya Kosh, Delhi Arogya Nidhi), etc., if anyone.

The HCFI Fund has also tied up for providing up to 50% discount on imaging (CT, MR, CT angiography, etc.)

Free Diagnostic Facility

Free Education and Employment Facility

The Fund has installed the latest State-of-the-Art 3 D Color Doppler EPIQ 7C Philips at E – 219, Greater Kailash, Part 1, New Delhi.

HCFI has tied up with a leading educational institution and an export house in Delhi NCR to adopt and to provide free education and employment opportunities to needy heart patients post surgery. Girls and women will be preferred.

This machine is used to screen children and adult patients for any heart disease.

Laboratory Subsidy HCFI has also tied up with leading laboratories in Delhi to give up to 50% discounts on all pathological lab tests.

About Heart Care Foundation of India

Help Us to Save Lives The Foundation seeks support, donations and contributions from individuals, organizations and establishments both private and governmental in its endeavor to reduce the number of deaths due to heart disease in the country. All donations made towards the Heart Care Foundation Fund are exempted from tax under Section 80 G of the IT Act (1961) within India. The Fund is also eligible for overseas donations under FCRA Registration (Reg. No 231650979). The objectives and activities of the trust are charitable within the meaning of 2 (15) of the IT Act 1961.

Heart Care Foundation of India was founded in 1986 as a National Charitable Trust with the basic objective of creating awareness about all aspects of health for people from all walks of life incorporating all pathies using low-cost infotainment modules under one roof.

HCFI is the only NGO in the country on whose community-based health awareness events, the Government of India has released two commemorative national stamps (Rs 1 in 1991 on Run For The Heart and Rs 6.50 in 1993 on Heart Care Festival- First Perfect Health Mela). In February 2012, Government of Rajasthan also released one Cancellation stamp for organizing the first mega health camp at Ajmer.

Objectives Preventive Health Care Education Perfect Health Mela Providing Financial Support for Heart Care Interventions Reversal of Sudden Cardiac Death Through CPR-10 Training Workshops Research in Heart Care

Donate Now...

Heart Care Foundation Blood Donation Camps The Heart Care Foundation organizes regular blood donation camps. The blood collected is used for patients undergoing heart surgeries in various institutions across Delhi.

Committee Members

Chief Patron

President

Raghu Kataria

Dr KK Aggarwal

Entrepreneur

Padma Shri, Dr BC Roy National & DST National Science Communication Awardee

Governing Council Members Sumi Malik Vivek Kumar Karna Chopra Dr Veena Aggarwal Veena Jaju Naina Aggarwal Nilesh Aggarwal H M Bangur

Advisors Mukul Rohtagi Ashok Chakradhar

Executive Council Members Deep Malik Geeta Anand Dr Uday Kakroo Harish Malik Aarti Upadhyay Raj Kumar Daga Shalin Kataria Anisha Kataria Vishnu Sureka

This Fund is dedicated to the memory of Sameer Malik who was an unfortunate victim of sudden cardiac death at a young age.

Rishab Soni

HCFI has associated with Shree Cement Ltd. for newspaper and outdoor publicity campaign HCFI also provides Free ambulance services for adopted heart patients HCFI has also tied up with Manav Ashray to provide free/highly subsidized accommodation to heart patients & their families visiting Delhi for treatment.

http://heartcarefoundationfund.heartcarefoundation.org

NEUROSURGERY Table 4. Eye Opening, Verbal Response and Motor Response at 3 Months Groups (States)

Eye opening (A)

Eye opening (B)

Verbal response (A)

Verbal response (B)

3.96

3.88

4.72

4.76

5.92

5.8

0.2000

0.3317

0.4583

0.4359

0.2769

0.4082

25

25

25

25

25

25

0.04000

0.06633

0.09165

0.08718

0.05538

0.08165

Mean Standard deviation Sample size Standard error of mean P value

One tail p value 0.1636 is not significant

Motor response Motor response (A) (B)

One tail p value 0.3849 is not significant

One tail p value 0.1326 is not significant

Table 5. Improvement of Eye Opening, Verbal Response and Motor Response in Group A, at 3 Months Group (States)

Eye opening At admission

Verbal response

At 3 months

At admission

Motor response

At 3 months

At admission

At 3 months

Mean

2.44

3.96

2.4

4.72

4.6

5.92

Standard deviation

1.044

0.200

1.414

0.4583

1.000

0.2769

Sample size Standard error of mean P value

25

25

25

25

25

25

0.2088

0.0400

O.2828

0.09165

0.2000

0.05538

One tail p value <0.0001 is extremely significant

One tail p value <0.0001 is extremely significant

One tail p value <0.0001 is extremely significant

Table 6. Improvement in Eye Opening, Verbal and Motor Response in Group B, at 3 Months Group (States) Mean Standard deviation Sample size Standard error of mean P value

Eye opening

Verbal response

At 3 months

At admission

At 3 months

At admission

At 3 months

1.96

3.88

2.76

4.76

3.68

5.8

0.6110

0.3317

0.7234

0.4359

0.8524

0.4082

25

25

25

25

25

25

0.1222

0.06633

0.1447

0.08718

0.1705

0.08165

One tail p value <0.0001 is extremely significant

from a mean score of 2.44 at admission to 3.96 at the end of 3 months. It means that all the patients in Group A had nearly spontaneous eye opening at the end of 3 months. In verbal response, mean score increased from 2.4 at admission to 4.72 at the end of 3 months.

P value was <0.0001, which is significant. In motor response, there was an increase in the mean score of 4.6 at admission, to 5.92 at the end of 3 months. P value was <0.0001, which is extremely significant.

Table 6 is showing improvement in the score of eye opening verbal and motor response in the patients of Group B, at the end of 3 months. In eye opening, there was an increase in the mean score of 1.96 at admission to 3.88 at the end of 3 months. P value was <0.0001,

354

Motor response

At admission

Indian Journal of Clinical Practice, Vol. 26, No. 4, September 2015

One tail p value <0.0001 is extremely significant

One tail p value <0.0001 is extremely significant

which is very significant. In verbal response, mean score of 2.76 at admission, improved to 4.76 at the end of 3 months. P value was <0.0001, which is significant.

In motor response, mean score of 3.68 at admission, increased to 5.8 at the end of 3 months. P value was <0.0001, which is significant.

Improvement in eye opening, verbal and motor response in Group A patients at Day 7 was shown in Table 7.

Mean eye opening score of 2.44 at the time of admission was improved to 3.64 at Day 7. P value was <0.0001, which is significant. In verbal response, the mean score of 2.4 at admission, improved to 4.08 at Day 7.

P value was significant (<0.0001). In motor response, mean score increased from 4.6 at admission to

NEUROSURGERY Table 7. Improvement in Eye Opening, Verbal and Motor Response in Group A at Day 7 Group (States)

Eye opening At admission

Verbal response

At Day 7

At admission

Motor response

At Day 7

At admission

At Day 7

Mean

2.44

3.64

2.4

4.08

4.6

5.72

Standard deviation

1.044

0.4899

1.414

0.7594

1.000

0.4583

25

25

25

25

25

25

0.2088

0.09798

0.2828

0.1519

0.2000

0.9165

Sample size Standard error of mean P value

One tail p value <0.0001 is extremely significant

One tail p value <0.0001 is extremely significant

One tail p value <0.0001 is extremely significant

Table 8. Improvement in Eye Opening, Verbal and Motor Response in Group B at Day 7 Group (States) Mean Standard deviation Sample size

Eye opening

Verbal response

Motor response

At admission

At Day 7

At admission

At Day 7

At admission

At Day 7

2

2.88

2.72

3.72

3.68

4.96

0.6455

0.6658

0.7371

0.5416

0.8524

0.6758

25

25

25

25

25

25

Standard error of mean

0.1291

0.1332

0.1474

0.1083

0.1705

0.1352

P value

One tail p value <0.0001 is extremely significant

One tail p value <0.0001 is extremely significant

One tail p value <0.0001 is extremely significant

Table 9. Total GCS Score at Admission, at Day 7 and at 3 Months in Both Groups Groups (States)

At admission (A)

At admission (B) At Day 7 (A) At Day 7 (B) At 3 months (A) At 3 months (B)

Mean

9.44

8.28

13.48

11.48

14.64

14.44

Standard deviation

2.844

1.745

1.475

1.610

0.6377

0.9165

25

25

25

25

25

25

0.5689

0.3489

0.2951

0.3221

0.1275

0.1833

Sample size Standard error of mean P value

One tail p value 0.0443 is considered significant

5.72 at Day 7. P value was significant (<0.0001).

Table 8 is showing the improvement in score of eye opening in 25 patients of Group B. Mean eye opening score increased from 2 at admission to 2.88 at Day 7.

P value was significant (<0.0001). Mean score of verbal response improved from 2.72 at admission to 3.72 at Day 7. P value was significant (<0.0001). Motor response showed an improvement in the mean score of 3.68 at admission to 4.96 at Day 7. P value was significant (<0.0001).

Table 9 is showing total GCS out of 15, in both groups at admission, at Day 7 and at end of 3 months. Mean GCS in 25 patients of Group A was 9.44 with SD of 2.844. In Group B, mean total GCS was 8.28 with SD of 1.745. P value was significant (0.0443). At Day 7, mean GCS in study group was 13.48, while it was 11.48 in

One tail p value <0.0001 is extremely significant

One tail p value 0.1875 is not significant

control group (B). P value was significant (<0.0001).

At 3 months in Group A, mean score was 14.64 with SD of 0.6377. In Group B, mean GCS was 14.44 with SD of 0.9165. P value was 0.1875, which is not significant.

DISCUSSION The present study is a retrospective study done at a tertiary level healthcare center in the city of Sirsa, Haryana. With an urban and rural population of around 6 lacs, road traffic accidents are frequently encountered in this part of the state. Being a tertiary level hospital with all the facilities required in a trauma center, a large number of TBI patients are admitted and treated here. Data from the medical record section of hospital revealed that a total of 184 patients of TBI admitted in year 2014.

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NEUROSURGERY There is a rapid increase in the incidence of TBI in our country. Increased motor vehicle accidents and population driving these vehicles has rapidly increased, in last few years. Apart from this, other reasons are increasing industrialization and violence.

The data compiled by the Ministry of Road Transport and Highways revealed that there were 4.97 lac accidents in 2011 or one accident every minute.

This resulted in 1,42,485 deaths annually or one death every 3.7 minutes. Road traffic accidents most commonly affect young males in the age-group of 15-29 years-people in the most productive phase of life. There is a tremendous economic loss both in terms of direct medical costs and indirectly in lost wages and productivity. Survivors of TBI are often left with significant cognitive, behavioral and communicative disabilities and some patients develop long-term medical complications, such as epilepsy.5 Apart from the conventional treatment followed in TBI, there are number of neurotrophic agents now being used, which help in increased neurological recovery.

Citicoline (pyridine diphosphate-choline), edaravone and piracetam are now essential part of standard treatment for recovery of neurons. They all have different mechanisms of action at the cellular level.

Exogenous administration of citicoline (CDP-choline) provides both choline and cytidine which access the brain and serve as substrates for the synthesis of phosphatidylcholine, a primary neuronal membrane component; choline also enhances brain acetylcholine synthesis.

Cerebroprotein hydrolysate is the latest neuroprotective agent, which has shown some usefulness in certain studies. A few studies have shown some benefit in infarction and dementia, but research on TBI patients is limited. In the present study, we have compared the clinical status of the TBI patients, who had been given standard conventional treatment (control group) with patients, who were to standard therapy given injection cerebroprotein hydrolysate.5 TBI frequently occurs in relatively younger group which were at the maximum risk, attributable to a high incidence of alcohol and drug consumption, poor overall sense of judgment and decision-making ability. Similar observation were made in our study. In a large population-based study on 1,545 head injury patients admitted in Post Graduate Institute of Medical Education and Research, Chandigarh.6 Mean age of the patients in study group was 33.68 years and 39.4 in control group. Male outnumbered female patients

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in our study. In Group B, only one female patient was there, out of 25 patients. Similarly, there are three female patients, out of total 25 patients.

All the patients in the present study received standard treatment for head injury, based on guidelines.

Apart from this, Group A patients received injection cerebroprotein hydrolysate 60 mg intravenous, twicedaily. All patients were examined by the consultant neurosurgeon of the hospital, at the time of admission and their condition recorded in the patient file. GCS is the standard objective way to record the neurological status of the patients all over the world. Three components, namely eye opening, verbal response and motor response of the patients were recorded and documented in patientâ&#x20AC;&#x2122;s progress chart everyday during their stay and on subsequent visits.

Total score can be as low as 3 out of 15, in a fully comatose patient and 15 out of 15 in a fully conscious patient. Total GCS in patients of Group A, at the time of admission was 9.44, while it was 8.28 in Group B. At Day 7, in Group A, total GCS improved to 13.48, which shows a significant improvement in patients receiving cerebroprotein hydrolysate. On the other hand, in Group B patients, GCS improved to 11.56. Hence, both group of patients showed a significant improvement in total GCS at Day 7, but in Group A, it increased by a score of 4.04 as compared to 3.28 in Group B. Therefore, cerebroprotein hydrolysate, in patients with traumatic head injury can lead to faster improvement in neurological recovery. Individual components of GCS showed similar response in both group of patients.

Mean score of eye opening at the time of admission, in Group A was 2.44 out of 4, which improved to 3.64 at Day 7. In comparison, it was 2 in Group B at admission and improved to 2.88 at Day 7. Hence, increase is by 1.2 points in Group A and 0.88 in Group B. Mean score of verbal response of the patients showed an improvement of 1.68 (from 2.4 at admission to 4.08 at Day 7) in Group A. There was an improvement of 1 point in Group B (from 2.72 at admission to 3.72 at Day 7).

Motor response showed an improvement of 1.12 (from 4.6 to 5.72) in Group A and an improvement of 1.28 (from 3.68 to 4.96) in Group B, during same time period of observation. Hence, it is evident that patients who received cerebroprotein showed marked improvement in total GCS, in eye opening and verbal response at Day 7, but not in motor response.

NEUROSURGERY At the end of 3 months all patients were evaluated.

The mean total GCS in Group A of patients at the end of 3 months was 14.6. In Group B, mean GCS was 14.44.

P value was 0.1875, which is not significant.

Improvement in total GCS in Group A was 5.16 points increase at 3 months. In comparison, total GCS in Group B improved by 6.16 points. Therefore, it is evident that there is no significant difference in the neurological status at 3 months in patients receiving cerebroprotein.

Interestingly, patients in the study group showed marked improvement in total GCS, more than Group B, after 7 days of treatment but same was not the case at the end of 3 months.

It can be inferred that this drug is effective in accelerating the process of treatment of patients in comparison with the placebo. Individual components of GCS showed somewhat similar picture in patients at the end of 3 months. In Group A, eye opening mean score improved by 1.52 points, in comparison it increased by 1.92 points in Group B. However, improvement from Day 1 to 3 months was statistically significant in both groups. Mean verbal response showed an improvement in Group A patients by 2.32 points, while it was 2 points in group B, at the end of 3 months. Improvement in the motor response showed response similar to eye opening as there was increase of 1.32 points in Group A patients, as compared to increase of 2.12 points in Group B. Hence, it is suggested that at the end of 3 months, there was no significant increase in the motor response, eye opening and total GCS in the patient receiving cerebroprotein as compared to control group.

CONCLUSION In our study, there was a significant increase in the amount of GCS in both groups but the degree of increase of the GCS was significantly higher in case rather than control group at 7 days of treatment. However, study group failed to show significant increase in total GCS at the end of 3 months. Hence, there can be faster early neurological recovery in patients receiving cerebroprotein. In accordance with the results and the useful effect of cerebroprotein hydrolysate in TBI patients, it is recommended to use this drug in patients in case it is not contraindicated. Further studies with high sample size are recommended.

REFERENCES 1. Gururaj G. An epidemiological approach to prevention: Prehospital care and rehabilitation in neurotrauma.

Neurology India. 1995;43(3):95-105.

2. Gupta P, Yadav S, Singal KK. Cerebroprotein hydrolysate: innovation in the treatment of neurodegenerative disorders. J Indian Acad Clin Med. 2014;15(2):132-3.

3. Jain N, Yadav S, Goyal M, Singal KK, Gupta P, Bansal M. Cerebroprotein hydrolysate: innovation in neurodegenerative disorders. Int J Med Dent Sci. 2014;3(1):382-5.

4. Plosker GL, Gauthier S. Cerebrolysin: a review of its use in dementia. Drugs Aging. 2009;26(11):893-915.

5. Singh VP, Banerji AK. Head injury due to vehicular accidents. Neurol India. 2014;62:585-7.

6. Tripathi M, Tewari MK, Mukherjee KK, Mathuriya SN. Profile of patients with head injury among vehicular accidents: an experience from a tertiary care centre of India. Neurol India. 2014;62(6):610-7.

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New research suggests that smokers who had a stroke in a brain region called the insular cortex were more likely to quit smoking than those who had strokes in other regions of the brain. The new research, in the form of two studies, is published in the journals Addiction and Addictive Behaviors, respectively.

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Dr. Reddyâ&#x20AC;&#x2122;s Laboratories Ltd., Global Generics - India, 7-1-27, Ameerpet, Hyderabad - 500 016, India. www.drreddys.com

OBSTETRICS AND GYNECOLOGY

A Rare Case of Ovarian Pregnancy Following Intracytoplasmic Sperm Injection and Embryo Transfer RITU PUNHANI*, KUNDAVI SHANKAR†, THANKAM RAMA VARMA‡

ABSTRACT Ovarian pregnancy after in vitro fertilization is rare and can be easily missed unless there is a high index of suspicion.

Preservation of ovarian tissue during surgery is of utmost importance especially in subfertility patients, where the goal is to preserve the fertility. We present a case of ovarian pregnancy who had a successful intracytoplasmic sperm injection conception after preserving the ovary.

Keywords: Embryo transfer, ovarian pregnancy, in vitro fertilization, intracytoplasmic sperm injection conception

O

varian pregnancy is a rare form of the nontubal ectopic pregnancy.1 It ends with rupture before the end of the first trimester.2 The incidence of primary ovarian pregnancy is 3.3% of all ectopic pregnancies,3 and the incidence reported following in vitro fertilization and embryo transfer (IVF-ET) is 0.27% per clinical pregnancy.4

An increased incidence of ectopic pregnancies up to 5% after IVF and ET is a well-known phenomenon.5,6 The first pregnancy achieved by IVF-resulted in an ectopic pregnancy in 1976.7 However, primary ovarian pregnancy is a rare phenomenon following natural conception or IVF-ET; twin ovarian pregnancy is extremely rare.

In spite of advances in clinical sciences, diagnosis of ovarian ectopic is rarely made before the surgery.

With few exceptions, the initial diagnosis is made on the operating table and the final diagnosis only on histopathology on the basis of the four Spiegelberg’s criteria, establishing that the pregnancy is limited to the ovary and does not involve the tube.8 Because initial diagnosis in ovarian pregnancy is difficult, many

*FNB (Fellowship of National Board) Fellow of Reproductive Medicine †Senior Consultant ‡Medical Director Dept. of IRM (Institute of Reproductive Medicine) Madras Medical Mission Hospital, Chennai, Tamil Nadu Address for correspondence Dr Ritu Punhani 32, Gazebo Inn Guest House, Spartan Nagar Mogappair East, Chennai - 600 037, Tamil Nadu E-mail: ritupunhani@yahoo.co.in

of these cases will be diagnosed as possible tubal pregnancies only.9 We report a case of primary ovarian pregnancy following intracytoplasmic sperm injection (ICSI) for primary infertility treatment. The case reported here is interesting because of its rarity and the successful outcome of ICSI after preserving the ovary.

CASE REPORT She was a 31 years, primary subfertility patient, married since 3 years and had regular cycles. She was diagnosed to have stage 4 endometriosis 1 year back and was referred to our institute for IVF. She also had a septal resection prior to coming to our unit.

After her basic evaluation, she underwent controlled ovarian stimulation with ultra long protocol for controlled ovarian stimulation, for total 10 days and triggered her with injection human chorionic gonadotropin (hCG) 10,000 units, 35 hours following which oocyte retrieval was done and 4 mature M2 oocytes were collected. Four Grade A embryos were transferred on Day 3, under ultrasound guidance. She was given full luteal support, and the b-hCG done on the 16th day following ET, was 839 mIU/mL. The subsequent b-hCG value which was done 1 week later, was found to be about 15,099 mIU/mL. The ultrasound done on the same day, at 5 weeks and 6 days of gestation showed ? ectopic gestation of the left adnexa, with normal sized uterus and normal appearing right adnexa. Second expert opinion for ultrasound was taken and the report was suggestive of

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OBSTETRICS AND GYNECOLOGY a left adnexal mass, with a yolk sac, but no fetal pole.

As the patient was hemodynamically stable, a plan for medical management was made.

Injection methotrexate 75 mg IM (intramuscular) was given and after 4 days, the repeat b-hCG was 19,900.

We repeated the ultrasound on that day, and to our surprise we found a live twin ectopic gestation.

Thus, patient was taken up for emergency operative laparoscopy.

Three port laparoscopy was done, uterus appeared normal, right ovary was adherent to the back of the uterus, right tube appeared dilated and unhealthy.

Omental adhesions were also found and adhesiolysis was done.

Figure 2. Chorionic villi (H&E-100X).

Left ovary was only partially seen and was adherent to the lateral pelvic wall. As ectopic gestation could not be clearly visualized, we proceeded with the laparotomy after taking the consent. Both the ovaries were dissected free. Bleeding from the left ovary was seen and hemorrhagic material was removed and sent for histopathological examination. Right ovary was apparently normal. Few hemostatic sutures were given on the left ovary. Bilateral salpingectomy was done as both the tubes appeared unhealthy.

Histopathology report was consistent with left ovarian ectopic pregnancy; both the tubes did not show any evidence of chorionic villi (Figs. 1-3).

She had ICSI twice later and oocytes were retrieved only from the left ovary, due to inaccessibility of the right ovary. She conceived in the second attempt and delivered a healthy baby girl.

Figure 1. Chorionic villi surrounded by ovarian tissue (H&E-40X).

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Indian Journal of Clinical Practice, Vol. 26, No. 4, September 2015

Figure 3. Ovarian tissue showing decidualization (H&E-100X).

DISCUSSION Ovarian pregnancy is an uncommon form of ectopic pregnancy. The first case of ovarian pregnancy was reported by St. Maurice in 1689. Marcus and Brinsden reported an incidence of 6% following IVF-ET following 135 ectopic.6 But, the incidence following natural conception is much lower, ranging from 1/16,000 to 1/1,500 deliveries accounting for 3.3% of all ectopic pregnancies. Rarely, ovarian pregnancy can be a part of heterotopic or of a twin ovarian pregnancy.

The four Spiegelbergâ&#x20AC;&#x2122;s criteria for ovarian ectopic gestation are: (1) fallopian tubes including fimbria must be intact and separate from the ovary; (2) the pregnancy must occupy the normal position of the ovary; (3) the ovary must be attached to the uterus through the uteroovarian ligament and (4) there must be ovarian tissue attached to the pregnancy in the specimen.8 Our case met all the diagnostic criteria for ovarian pregnancy.

OBSTETRICS AND GYNECOLOGY Ovarian pregnancy following IVF is a rare entity. With intensive review of literature, very few case reports were found.10-12 The cause for development of an ovarian pregnancy is a result of secondary implantation or failure of follicular extrusion. In the case, we have described, the exact mechanisms of ovarian pregnancy after ICSI are not very clear. The presence of tubal pathology and pelvic inflammatory disease could be predisposing factors as with tubal pregnancies. One of the predisposing factors for ectopic pregnancy in this case could be endometriosis, and second factor could be transfer of four embryos.

There are very few reports of an accurate preoperative diagnosis, utilizing sonography. Ovarian pregnancy on ultrasound is typically described as a wide echogenic ring with a small internal echolucent area on the surface or within the substance of the ovary, the echogenicity of the ring usually being greater than the ovary.18 A high-degree of suspicion is needed, particularly in stimulated ovaries, wherein it can easily be mistaken for hemorrhagic corpora lutea. Doppler ultrasonography (USG) seems to offer little additional diagnostic value due to the high vascularity of the ovary.18

One of the most likely probabilities is reverse migration of one of these embryos toward the fallopian tube and implantation in the ovary.13 This unusual event could also be the result of the volume and pressure of culture medium injected during ET. Another contributory factor in the pathogenesis could be head tilted down position after the ET, which was not done in our case.

Knutzen introduced the reverse migration concept and demonstrated the fate of embryos “in utero” by observing that radiopaque dye could enter the fallopian tubes in 38.2% of the patients easily after a mock ET.14

The correct diagnosis is mostly made at the surgery and requires histopathological confirmation. Diagnosis of ovarian pregnancy should be suspected from elevated b-hCG, lack of intrauterine gestation, a complex ovarian mass on USG, patient’s risk factors, in addition to the Spiegelberg’s criteria. Patients most often undergo surgery for suspected tubal ectopic pregnancy or hemorrhagic corpus luteum.

When an ectopic pregnancy occurs after assisted reproductive technology (ART), it is mostly a result of uterine contractions, which cause the carefully placed embryos to be ejected into the fallopian tube. Various strategies to reduce the risk of this occurring are typically employed. The use of ultrasound guidance to place embryos and the use of minimal fluid to transfer them helps. There is some evidence that transferring blastocysts that are ready to implant instead of earlier embryos may also reduce the incidence. Sometimes; however, despite the best-laid plans, ectopic pregnancies do occur.15 Difficult ET may be another possible factor which could be due to additional stimulation of junctional zone contractions, which increases the risk of ectopic pregnancy. Lesny et al showed that a difficult ET stimulates junctional zone contractions and that strong endometrial waves in the fundal area of uterus could move mock embryos into the fallopian tubes. They also noted that manipulation with tissue forceps, for the purpose of facilitating ET, could affect uterine contractility,16 but such events were not encountered at the time of embryo replacement in our patient. Reverse migration of an embryo also could be due to high estrogen levels after ovarian stimulation.17 In our case, serum estradiol concentration was 1,656 pg/mL on the day of hCG injection. Twenty microliters of the media was used and the ET was smooth and it was done under ultrasound guidance.

In our case, we could identify the ovarian pregnancy only after the histopathology report.

Diagnosis of primary ovarian pregnancy is very difficult because of the rarity and the asymptomatic nature before rupture. Although the combination of serum β-hCG and transvaginal sonography increases the diagnostic accuracy of ectopic pregnancy, the diagnosis of ovarian pregnancy depends on the physicians suspicion and experience.

Treatment of almost all known ovarian ectopic pregnancies has been surgical. Also case reports have described successful medical management with methotrexate.1 The most common surgical treatment for unruptured ovarian pregnancy is either ovarian wedge resection or oophorectomy,19,20 either laparoscopic or via minilaparotomy. The outcome of subsequent pregnancy is successful, with a low incidence of subsequent ectopic pregnancy after the ovarian pregnancy is treated by surgery.21 Our patient was taken for ovarian wedge resection by laparoscopy we had to resort to laparatomy due to poor accessibility because of dense adhesions caused by endometriosis.

Although like other ectopic pregnancies, ovarian pregnancy can be treated with methotrexate, it is not known whether same criteria would apply. Kudo et al,22 first reported the successful use of methotrexate to treat an ovarian pregnancy. Because of the limited literature available, unlike in tubal pregnancies, the factors predicting success with systemic methotrexate in ovarian pregnancy are not well-defined.

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OBSTETRICS AND GYNECOLOGY Fertility after conservative surgical procedure does not appear to be affected, and ovarian wedge resection is the treatment of choice.9 Patients with ovarian pregnancy have a good prognosis for future fertility and, therefore, conservative surgical management is advocated.

CONCLUSION Ovarian pregnancy after ICSI is rare and can be easily missed unless there is a high index of suspicion.

Underlying pathophysiological mechanism of ovarian ectopic pregnancy after ICSI-ET are unclear. Indeed, gynecologists should be aware about the development of the ovarian ectopic pregnancy after ICSI-ET. Early diagnosis will give the opportunity to use conservative management for infertile patients. The therapy of early diagnosed ovarian pregnancy is surgical in the first place, and in the event that the patient desires a future pregnancy, the conservation of ovarian tissue is the clinical goal of our treatment. In our case, we preserved the ovaries and thus she could conceive later (delivered a healthy girl child).

REFERENCES 1. Fritz MA, Speroff L. Clinical Gynecologic Endocrinology and Infertility, 8th Edition. Philadelphia: 2011. p. 1409.

2. Shrestha A, Chawla CD, Shrestha RM. Ruptured primary ovarian pregnancy: a rare case report.

Kathmandu Univ Med J (KUMJ). 2012;10(39):76-7.

3. Oliveira FG, Abdelmassih V, Costa AL, Balmaceda JP, Abdelmassih S, Abdelmassih R. Rare association of ovarian implantation site for patients with heterotopic and with primary ectopic pregnancies after ICSI and blastocyst transfer. Hum Reprod. 2001;16(10):2227-9.

4. Han M, Kim J, Kim H, Je G, Hwang T. Bilateral ovarian pregnancy after in vitro fertilization and embryo transfer in a patient with tubal factor infertility. J Assist Reprod Genet. 2004;21(5):181-3.

5. Ferland RJ, Chadwick DA, O‘Brien JA, Granai CO 3rd.

An ectopic pregnancy in the upper retroperitoneum following in vitro fertilization and embryo transfer.

Obstet Gynecol. 1991;78(3 Pt 2):544-6.

6. Marcus SF, Brinsden PR. Primary ovarian pregnancy after in vitro fertilization and embryo transfer: a report of seven cases. Fertil Steril. 1993;60(1):167-9.

7. Steptoe PC, Edwards RG. Reimplantation of a human embryo with subsequent tubal pregnancy. Lancet. 1976; 1(7965):880-2.

9. Bagga R, Suri V, Verma P, Chopra S, Kalra J. Failed medical management in ovarian pregnancy despite favorable prognostic factors - a case report.

MedGenMed. 2006;8(2):35.

10. Marcus SF, Brinsden PR. Analysis of the incidence and risk factors associated with ectopic pregnancy following in-vitro fertilization an embryo transfer.

Hum Reprod. 1995;10(1):199-203.

11. Carter JE, Jacobson A. Reimplantation of a human embryo with subsequent ovarian pregnancy. Am J Obstet Gynecol. 1986;155(2):282-3.

12. Narvekar SA, Vijay Kumar PK, Shetty N, Gupta N, Ashwini GB, Rao KA. Unruptured ovarian pregnancy following in vitro fertilization: missed diagnosis followed by successful laparoscopic management.

J Hum Reprod Sci. 2008;1:3941.

13. Pope CS, Cook EK, Arny M, Novak A, Grow DR. Influence of embryo transfer depth on in vitro fertilization and embryo transfer outcomes. Fertil Steril. 2004;81(1):51-8.

14. Knutzen V, Stratton CJ, Sher G, McNamee PI, Huang TT, Soto-Albors C. Mock embryo transfer in early luteal phase, the cycle before in vitro fertilization and embryo transfer: a descriptive study. Fertil Steril.

1992;57(1):156-62.

15. Sher G. Ectopic pregnancy: causes, diagnosis and treatment. [online] Available from http://www. ivfauthority.com/2009/11/ectopicpregnancy-causesdiagnosis-and.html. [Accessed on June, 2015].

16. Lesny P, Killick SR, Robinson J, Raven G, Maguiness SD. Junctional zone contractions and embryo transfer: is it safe to use a tenaculum? Hum Reprod. 1999;14(9): 2367-70.

17. Atabekoglu CS, Berker B, Dunder I. Ovarian ectopic pregnancy after intracytoplasmic sperm injection. Eur J Obstet Gynecol Reprod Biol. 2004;112(1):104-6.

18. Comstock C, Huston K, Lee W. The ultrasonographic appearance of ovarian ectopic pregnancies. Obstet Gynecol. 2005;105(1):42-5.

19. Patel Y, Wanyonyi SZ, Rana FS. Laparoscopic management of an ovarian ectopic pregnancy: case report. East Afr Med J. 2008;85(4):201-4.

20. Marret H, Hamamah S, Alonso AM, Pierre F. Case report and review of the literature: primary twin ovarian pregnancy. Hum Reprod. 1997;12(8):1813-5.

21. Koo YJ, Choi HJ, Im KS, Jung HJ, Kwon YS. Pregnancy outcomes after surgical treatment of ovarian pregnancy.

Int J Gynaecol Obstet. 2011;114(2):97-100.

22. Kudo M, Tanaka T, Fujimoto S. A successful treatment of left ovarian pregnancy with methotrexate. Acta 8. Spiegelberg O. Zur kasuistik der ovarialschObstetrica et Gynaecologica Japonica. 1988;40(6):811-3. wangerschaft. Arch Gynaecol. 1878;13:73-9.

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OBSTETRICS AND GYNECOLOGY

Clinicopathological Study of Ovarian Tumors in a Referral Tertiary Hospital in West Bengal TAMAL KUMAR MANDAL*, BARUNODAY CHAKRABORTYâ&#x20AC;

ABSTRACT Introduction: Ovarian tumors account for 5th most common cause of cancer-related deaths in women worldwide. They account for 6% of all cancers among women. Though ovarian tumor is one of the treatable cancers due to its sensitivity to different modalities of anticancer therapy, it is frequently asymptomatic until it reaches an advanced stage. Objectives: To study the incidence, histopathological spectrum and clinical correlates of ovarian tumors at a tertiary care teaching hospital. Material and methods: A study was undertaken during a period of 1 year (1st January 2014 to 31st December 2014). The tumors were classified according to World Health Organization (WHO) classification after thorough examination of hematoxylin and eosin (H&E) slides. Data on clinical presentation were recorded in each case. Results: There were a total of 107 cases. Surface epithelial tumors emerged as the commonest variety accounting for 57.01%, followed by germ cell tumors (23.36%). Sex-cord stromal tumors (0.93%) and metastatic tumors accounted for 1.87%. The age range was 8-70 years. Metastatic tumors involved younger age groups. Abdominal mass was the commonest clinical presentation followed by pain abdomen. Conclusion: Ovarian tumors were found to occur in a wide range of ages (8-70 years) with abdominal mass and pain abdomen being the commonest clinical presentation. Surface epithelial tumors and germ cell tumors together constituted the majority of the cases (80.37%). An accurate histological diagnosis and staging are the factors therapeutically and prognostically important.

Keywords: Surface epithelial tumors, germ cell tumors, sex-cord stromal tumors, borderline tumor, functional cysts

O

varian tumors include wide-spectrum of neoplasms involving epithelial tissue, connective tissue, specialized hormone secreting cells, germinal and embryonal cells.1 These are treatable tumors because of sensitivity to anticancer therapies.2 They account for 6% of total cancers among women and are the 5th most common form of cancer-related deaths among women worldwide and almost half of the deaths due to gynecological cancers.

The disease has highest fatality-to-case ratio among all the gynecologic cancers.2 The risk of developing ovarian cancer is highest around the age of 55 years. The benign tumors mostly occur in young women between ages of 20 and 45, whereas the malignant tumors are common in older women between ages of 40 and 65. The incidence

*RMO cum Clinical Tutor â&#x20AC; Associate Professor Dept. of Obstetrics and Gynecology Bankura Sammilani Medical College, Bankura, West Bengal Address for correspondence Dr Tamal Kumar Mandal C/o: Bhim Bhabani Mandal North Pratapbagan, Sarani No. 5, Bankura - 722 001, West Bengal E-mail: tamal.cool2011@gmail.com

is high in postmenopausal women, unmarried women or in married women with low parity.3 It is estimated that about 1 in every 70 women have a life-time risk of developing ovarian cancer. Unfortunately, the survival rate is <50% because of a lack of sensitive and specific screening test and asymptomatic presentation of the cases till an advanced stage.4 It is important to determine the histopathological pattern of ovarian tumors from a diagnostic as well as prognostic point of view. The aim of this study was to study the incidence, histopathological spectrum and clinical correlates of ovarian tumors.

MATERIAL AND METHODS This is a retrospective study done in the Dept. of Obstetrics and Gynecology of Bankura Sammilani Medical College, Bankura, West Bengal from 1st January 2014 to 31st December 2014. All the cases of ovarian tumors operated during that period were included in this study. Data including age, clinical presentation, related history, involvement (unilateral or bilateral) were obtained and recorded.

Gross findings of all cases were also noted from the operation theater note and biopsy report.

Histopathology reports of all the cases were recorded

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OBSTETRICS AND GYNECOLOGY from the data base. Hematoxylin and eosin (H&E) stained slides of each case were studied. The tumors were classified according to the World Health Organization (WHO) classification of ovarian tumors.5

Table 1. Histological Pattern of Ovarian Tumors Diagnosis

Benign Borderline Malignant

Total

Surface epithelial tumor

42

1

18

61

RESULTS

Serous tumor

33

-

10

43

A total of 107 ovarian tumors were operated in the study period. Amongst them, 83 (77.57%) were benign, 1 (0.93%) was borderline while 23 (21.50%) were malignant (Table 1 and Fig. 1).

Mucinous tumor

9

1

5

15

Clear cell carcinoma

-

-

1

1

Endometrioid tumor

-

-

1

1

Malignant Brenner tumor

-

-

1

1

Germ cell tumor

22

-

3

25

Mature cystic teratoma/dermoid cyst

21

-

-

21

Mixed germ cell tumor (dysgerminoma + yolk sac)

-

-

1

1

Mixed germ cell tumor (dermoid + mucinous cystadenoma)

1

-

-

1

Dysgerminoma

1

1

Yolk sac tumor

1

1

Surface epithelial tumor was the most common class of tumor and was seen in 61 (57.01%) cases, followed by germ cell tumors which was seen in 25 (23.36%) cases (Table 2 and Fig. 2).

Of the 83 benign tumors, 42 (50.60%) were surface epithelial tumors while 22 (26.51%) were germ cell tumors. Out of the 23 malignant tumors, 18 (78.26%) were surface epithelial tumors while 3 (13.04%) were of germ cell origin (Table 1).

Out of the 61 surface epithelial tumors, 42 (68.85%) were benign, 1 (1.64%) was borderline, whereas 18 (29.51%) were malignant. Most of these tumors were serous or mucinous in origin and were seen in 43 (70.49%) and 15 (24.59%) cases, respectively (Table 1).

Out of the 25 germ cell tumors, 22 (88%) were benign, most being mature cystic teratoma (95.45%).

Dysgerminoma and yolk sac tumor were the common germ cell malignancy.

Sex-cord stromal tumor

1

-

-

1

Fibroma

1

-

-

1

Secondary (metastatic) tumor

-

-

2

2

Krukenberg tumor

-

-

2

2

Functional cysts

18

-

-

18

Follicular cyst

4

-

-

4

Only one case of borderline tumor was found in our study, which was mucinous in type.

Corpus luteal cyst

8

-

-

8

Chocolate cyst

6

-

-

6

Serous carcinoma was the most common malignancy and was seen in 10/23 (43.48%) patients (Table 1).

Grand total

83

1

23

107

Fibroma was the only sex-cord stromal tumor in our study, which was benign.

Overall, serous cyst adenoma was the most common benign type and was seen in 33/83 (39.76%) cases.

Metastatic tumor constituted two cases (1.87%), all of them were Krukenberg tumors. Out of the 107 cases of ovarian tumors, 18 (20.56%) cases were functional cysts (hemorrhagic corpus luteal cyst, follicular cyst, endometriotic cysts).

The age distribution of the cases ranged from 8 to 70 years with a median age of 35.39 years. The youngest patient (8-year-old girl) presented with benign cystic teratoma and the oldest patient (70-year-old woman) with benign serous cyst adenoma. Approximately, 59 (55.14%) tumors were seen in the 20-40 years age group (Table 3 and Fig. 3). Benign tumors were more

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Benign Borderline Malignant

21.50%

0.93%

77.57%

Figure 1. Frequency of different categories of ovarian tumors.

OBSTETRICS AND GYNECOLOGY common than malignancies in all age groups. Most benign tumors 50/83 (60.24%) were diagnosed in the 3rd and 4th decades of life, whereas most malignant tumors 21/23 (91.30%) were seen in 3rd decade onward, with the exception of malignant germ cell tumors, which were mostly seen below the age of 20. The only borderline tumor was seen at the age of 14 (Table 3).

Commonest clinical presentation was distension of abdomen and lower abdominal mass followed by pain

abdomen. Irregular bleeding per vagina was seen in 12 cases. Ascites and urinary symptoms were seen in three malignant cases. Loss of weight was a common presentation of malignant tumors comprising of eight cases. Symptoms related to torsion were seen in 17 cases and one incidental finding of ovarian tumor in patient who presented with subacute intestinal obstruction and surgical help was called for during laparotomy. Pregnancy was associated with four cases among which two were of serous cyst adenoma and two of mature cystic teratoma.

Table 2. Frequency of Different Classes of Ovarian Tumors Classes of tumor

No. of cases

%

Surface epithelial tumor

61

57.01

Germ cell tumor

25

23.36

Sex cord-stromal tumor

1

0.93

Secondary (metastatic) tumor

2

1.87

Functional cysts

18

16.82

Total

107

100

Surface epithelial tumor Germ cell tumor

Gross examination of the specimens revealed that majority of the tumors were cystic (44.5%) followed by solid (13.2%) and mixed (42%). In the benign group, majority of the cases (42.1%) were cystic, 4.8% solid and 32.5% were mixed. The borderline tumor was cystic grossly. In malignant group, both solid and mixed tumors were almost equal. Unilateral tumors were observed in 84 (78.5%) cases. Involvement of left ovary (65%) was more common than the right (35%).

Bilaterality was seen in 23 cases (21.50%).

Secondary Functional cyst

35

Sex-cord stromal tumor

32

1.87% 0.93%

No. of tumors

30

16.82%

23.36%

57.01%

27

25 20

17

15

14 10

10

7

5 0 <20

20-29

30-39

40-49

â&#x2030;Ľ60

50-59

Age

Figure 3. Frequency of ovarian tumors in different age group.

Figure 2. Frequency of different classes of ovarian tumors.

Table 3. Frequency of Different Classes of Ovarian Tumors in Different Age Group Classes of tumor

Types

<20

20-29

30-39

40-49

50-59

â&#x2030;Ľ60

Total

Surface epithelial (n = 61)

Benign

1

13

9

10

6

3

42

Borderline

1

-

-

-

-

-

1

Malignant

-

2

5

4

4

3

18

Benign

8

10

3

1

-

-

22

Malignant

2

1

-

-

-

-

3

Sex-cord stromal (n = 1)

Benign

-

-

-

1

-

-

1

Secondary (n = 2)

Malignant

-

-

1

-

-

1

2

Functional cyst (n = 18)

Benign

Germ cell (n = 25)

Total (n = 107)

2

6

9

1

-

-

18

14

32

27

17

10

7

107

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OBSTETRICS AND GYNECOLOGY DISCUSSION Ovarian tumors have become increasingly important because of their large variety of histomorphological patterns and a high mortality rate.1 The incidence, clinical appearance and the behavior is extremely variable. It is impossible to diagnose the nature of the ovarian tumor preoperatively just by clinical examination, ultrasound and even by an fine-needle aspiration cytology (FNAC) and hence an early exploration followed by staging and optimal debulking and biopsy of the excised tissue is the gold standard of management.6 A total of 107 cases were documented, out of which 77.57% were benign tumors, 0.93% was borderline and 21.50% were malignant tumors. Similar results were seen in studies by Pilli et al and Nowak et al where incidence of benign, borderline and malignant ovarian tumor comprised of 75.2, 2.8, 21.9 and 79.5, 2.1, 18.4%, respectively.7,8 Epithelial tumors were predominant (50.60%) among the benign group followed by germ cell tumors (26.51%). Serous cyst adenoma were found to be more common than mucinous cyst adenoma in our study. This compares well with studies by Swamy and Prabhakar et al.9,10 In our study, mature cystic teratoma (95.45%) was the commonest type of germ cell tumor.

In a study by Yasmin et al, mature cystic teratomas were the 2nd commonest after serous cystadenoma.11 The commonest malignant tumor in this series were of surface epithelial tumor (78.26%). This finding is similar to findings of Shy et al and Di Bonito et al.12,13 In this study, serous cystadenocarcinoma constituted the most common malignant variety (43.48%) as shown by various other studies.14-16 In agreement with other studies, most ovarian tumors were seen in the reproductive age group, between 20 and 40 years.17,18 Benign tumors were found in all age groups. Malignant surface epithelial tumors occurred mostly in the 4th decade onward. Similar observations were also made in other studies.19,20 In patients under the age of 30 years, approximately 21/46 (45.65%) of the ovarian tumors are of germ cell origin, accounting for two-thirds of ovarian cancers (3 out of 5).21 Unilateral (78.5%) involvement was more common than bilateral (21.5%) coinciding with the findings of other studies.12,22 Majority were grossly cystic, 44.5% followed by solid and mixed tumors. Majority of benign groups, were cystic (42.1%). In malignant group, solid and mixed tumors were common. This goes in agreement with findings of Fusey et al who reported that most of the cystic swellings were either benign or non-neoplastic,

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while almost all solid and mixed tumors were malignant.23 Chhanda et al in a 10 years study of ovarian tumors revealed that in the benign group, majority of the cases were cystic (86.7%) while in malignant group, majority cases (69.2%) were solid.24 The most common presentation was abdominal mass with or without distension and pain. This is in agreement with majority of studies.6,23,25,26 CONCLUSION Though ovarian cysts and tumors can be diagnosed clinically, origin and nature of the tumors cannot be determined clinically. Histopathological examination of the ovarian tumor is a must to find out the origin and the nature of the tumor. Benign tumors can be safely removed by surgery and malignant tumors are managed according to the type, grading and stage of the tumor. Clinical evaluation, radiological evaluation and histopathological examination are important in the management of the ovarian tumors. The combined efforts of gynecologist, radiologist, oncologist and pathologist will not only hit the right diagnosis but also track the patient to the right path of management.

This study has shown occurrence of younger age groups in the primary malignant ovarian tumors and the metastatic tumors also. Hence, this study emphasizes that in young women with ovarian mass, possibility of malignancy and metastatic tumors should not be underestimated.

REFERENCES 1. Howkins, Bourne. Fibromyomas of the uterus. In: Padubidri VG, Daffany SN (Eds.). Shawâ&#x20AC;&#x2122;s Textbook of Gynecology, 13th Edition. Churchill Livingstone: Elsevier; 2006. pp. 337-51.

2. Berek JS, Thomas GM. Ovarian cancer. Practical Gynaecologic Oncology, 3rd Edition. Lippincott Williams & Wilkins; 2000.

3. Crum CP. The female genital tract. In: Cotran RS, Kumar V, Collins (Eds.). Pathologic Basis of Disease, 7th Edition.

Philadelphia: Elsevier; 2004. pp. 1092-104.

4. Rosai J. Ovary. In: Rosai and Ackermanâ&#x20AC;&#x2122;s, 9th Edition.

Missouri: Elsevier; 2004.

5. WHO Classification of Tumors. Pathology and genetics.

In: Tavasolli FA, Devilee P (Eds.). Tumors of Breast and Female Genital Organs, 7th Edition. Lyon: IARC Press; 2003. p.114.

6. Bhattacharya M, Shinde SD, Purandare VN. A clinicopathological analysis of 270 ovarian tumors.

J Postgrad Med. 1980;26(2):103-7.

Contâ&#x20AC;&#x2122;d on page 370...

OBSTETRICS AND GYNECOLOGY

Primary Hyperparathyroidism in Pregnancy: A Case Report VINITA SINGH*, MOUSUMI DAS GHOSH†, SUNITA MURMU†, MONIMALA MURMU‡, SUMAN KUMARI#

ABSTRACT Primary hyperparathyroidism in pregnancy is rare. Only 200 cases have been reported in literature so far. This clinical condition is associated with high maternal complication rate (67%) and high-risk for fetus and newborn (80%). We present a case of primigravida at 28 weeks, presented with fracture femur with trivial injury, diagnosed as primary hyperparathyroidism during the course of treatment. Her antenatal period managed successfully and a male baby of 1.69 kg delivered by LSCS for fetal distress. Baby had unremarkable neonatal period with normal serum calcium level and thyroid level. Baby discharged from nursery on Day 4. This case report is presented to highlight the possibility of hyperparathyroidism, if fracture occurs with minimal injury and need for early diagnosis and management to avoid complications.

Keywords: Primary hyperparathyroidism, pregnancy, maternal complication, lower segment cesarean section, fetal distress

CASE REPORT Mrs RK, 23-year-old primigravida was admitted in Dept. of Orthopedics, Tata Main Hospital, Jamshedpur, Jharkhand on 21/8/11 at 28 weeks gestation with history of minimal trauma leading to fracture shaft of right femur. There was no past history of pain abdomen, dysuria, polyuria, polydypsia, anorexia, weakness or bone pain. Obstetric evaluation was done and ultrasonography (USG) showed fetal growth corresponding to the period of gestation. Open reduction and internal fixation of fracture shaft femur with K-nailing was done on 30/8/11 (Fig. 1).

The fracture site was friable and tissue from fracture site was sent for histopathological examination and serum parathormone was evaluated. Patient was discharged from hospital on 12/9/11. Patient again got admitted in labor room on 14/9/11 with complaints of pain abdomen. Histopathological report from the

*Senior Specialist †Associate Specialist ‡Registrar #Senior Registrar Dept. of Obstetrics and Gynecology Tata Main Hospital, Jamshedpur, Jharkhand Address for correspondence Dr Vinita Singh Senior Specialist Dept. of Obstetrics and Gynecology Tata Main Hospital, Jamshedpur - 831 001, Jharkhand

fracture site showed giant cell rich neoplasm suggestive of osteitis fibrosa cystica of hyperparathyroidism with metaphyseal fibrosing defect with nonossifying fibrosa (Fig. 2).

Serum calcium was within normal range at 10.48 mg% (normal range: 8.5-10.5). Serum inorganic phosphorus was 1.92 mg% which was less (normal range: 2.5-4.5 mg%) and serum parathyroid hormone (PTH) was 588.3 pg/mL, which was markedly higher than normal (12-88 pg/mL) 25-hydroxyvitamin D was less at 6.85 ng/mL, (normal values: 8.9-46.7 ng/mL). In her past history, she had a history of surgical treatment for a maxillary swelling in April 2010. She also gave

Figure 1. Fracture shaft of femur with K-nail in situ.

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OBSTETRICS AND GYNECOLOGY history of severe pain in right thigh, while getting up from sitting posture. There was no history of longterm exposure to drugs like heparin or steroids. Her medical history, family history and personal history were unremarkable. On clinical examination, she had mild pallor, was afebrile and there was no icterus or edema, pulse was 82/min and blood pressure (BP) was 110/80 mmHg. No clinically obvious neck swelling was seen.

Examination of respiratory and cardiovascular system was unremarkable. Uterus corresponded to 30-32 weeks gestation, was irritable with cephalic presentation. Fetal heart beat (FHB) was 140/min and regular. USG showed fetal measurements corresponding to gestational age.

Cardiotocography was reactive on admission.

Two doses of injection betamethasone 12 mg at 24 hours interval were given to promote fetal lung maturity as she was preterm. Emergency lower segment cesarean section (LSCS) was done on 16/9/11 under gestational age for fetal distress. Prior information was given to the pediatrician who attended the baby immediately at birth. A single live male baby of weight 1.69 kg was delivered with Apgar score 5/10 and 7/10 at 1 minute and 5 minutes, respectively. Baby was transferred to the nursery. On 4th postoperative day, USG was done which revealed parathyroid adenoma and nephrocalcinosis (Figs. 3 and 4).

Surgical review was done and patient was discharged on 20/9/11 with advice to keep follow-up in Orthopedic, Surgery, Obstetrics and Gynecology, Pediatrics and Physiotherapy Department. Baby remained stable in nursery and accepted feeding well. Baby was discharged from nursery on 20/9/11 with advice of syrup calcium, multivitamin drops and exclusive breastfeeding. Serum calcium, inorganic phosphorus and serum thyroidstimulating hormone reports were normal.

Patient chose to go to Christian Medical College, Vellore for further treatment of hyperparathyroidism.

She got admitted there on 29/2/12. Her diagnosis was confirmed there as primary hyperparathyroidism (right inferior parathyroid adenoma), osteitits fibrosa cystica, nephrocalcinosis and vitamin D deficiency by USG neck, dual-energy X-ray absorptiometry (DEXA) scan, singlephoton emission computed tomography (SPECT)-CT, bone scintigraphy and CT neck and thorax, respectively.

Right inferior parathyroid adenectomy was done there on 6/3/12 and patient was discharged on 13/3/12 with advice of follow-up after 3 months. Both mother and baby are doing well and being followed up at Tata Main Hospital, Jamshedpur.

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Figure 2. Histopathology of fracture site showing giant cell rich neoplasm.

Figure 3. Parathyroid adenoma.

Figure 4. Nephrocalcinosis.

OBSTETRICS AND GYNECOLOGY DISCUSSION The exact cause of primary hyperparathyroidism is not known. In 85% of cases, there is parathyroid adenoma.1 It is mostly sporadic but autosomal dominant disorder may be associated with this condition (e.g. jaw tumor syndrome).

In nonpregnant patients, parathyroid glands maintain the calcium homeostasis.

Whenever serum calcium level is decreased in the body, there is increased secretion of parathormone by the parathyroid glands which causes increased bone resorption and increased level of 1,25-dihydroxyvitamin D3, which further augments the calcium absorption from the gastrointestinal tract (GIT). All these lead to increased serum calcium level and it has got a negative feedback effect on the parathyroid glands.

In pregnancy, there is hemodilution due to increased intravascular fluids and hypercalciuria due to raised glomerular filtration rate (GFR), which make diagnosis of hypercalcemia challenging.2 There is increased calcium demand in pregnancy as a term infant requires 25-30 g calcium for its bone development.3 There is no routine prenatal testing.4 High index of suspicion should be maintained when patient comes with history of pancreatitis, fractures or peptic ulcers.5 Our patient had history of fracture shaft of femur associated with trivial trauma, history of maxillary swelling and leg pain. USG neck is the investigation of choice in pregnancy.6 CT and scintigraphy are contraindicated. Magnetic resonance imaging (MRI) may be done. DEXA scan, SPECT-CT, bone scintigraphy, CT neck and thorax and X-ray help in confirmation of diagnosis.

About 23-80% of patients are asymptomatic. Symptoms include nausea, vomiting, anorexia, weakness, fatigue, neurological and psychiatric manifestations, constipation, depression and blurred vision.

Maternal complications include nephrolithiasis (most common), bone disease, pancreatitis (ominous sign of disease severity and occurs with hypercalcemic crisis), hyperemesis gravidarum, pre-eclampsia, tremors, fractures, uremia, seizures and coma.7 There is also high-risk of late first to early second trimester pregnancy loss in untreated cases of primary hyperparathyroidism (85%).8 Hypercalcemic crisis is a life-threatening complication and occurs when serum calcium level is >14 mg% and can progress to uremia, coma and even death.7 It is associated with 25% perinatal mortality and 50% neonatal tetany.

In normal pregnancy, there is a higher concentration of calcium in the fetus and suppression of fetal parathyroid until after delivery, which results in relative hypercalcemia and suppressed PTH level in neonate.

In maternal hyperparathyroidism, calcium gradient is elevated resulting in suppression of fetal parathyroid gland. As a result, there is fetal hypocalcemia and tetany in neonatal period.

Fetal complications in maternal hyperparathyroidism include neonatal tetany, stillbirths, miscarriages; which are most serious.5 Others include preterm birth, intrauterine growth restriction (IUGR), low-birth weight (LBW), transient or permanent hypoparathyroidism, intrauterine fetal death (IUFD), rhythm problem during labor/delivery, seizures due to low calcium level (<8 mg%).

Regarding management, no official recommendation is available. Individualization of the cases is done according to the symptoms, severity and gestational age. Medical management is recommended in symptomatic patients and in mild hypercalcemia (serum calcium <12 mg%).

The aim of medical management is to keep calcium level <12 mg% by oral hydration or by intravenous (IV) fluids, oral phosphates, furosemide, etc.9 Close perinatal (maternal and fetal) surveillance is required. Patient should be monitored for hyperparathyroid crisis and immediate hospitalization is required if serum calcium is >12 mg%.8 Surgical management is indicated in cases of hypercalcemia when serum calcium is >12 mg% or when there are symptoms during medical treatment regardless of gestational age. It is superior to conservative management. Definitive surgery is parathyroidectomy during second trimester. Intraoperative PTH monitoring confirms successful removal of adenoma.

During pregnancy, management is based on gestational age of the fetus. In first trimester, conservative management is done with medical therapies.9 In second trimester surgery is recommended when serum calcium is >12 mg%.9 In third trimester, there is high-risk of neonatal mortality hence conservative management is preferred. However, urgent parathyroidectomy is recommended, regardless of gestational age, if conservative management fails. Contraception is advised as a routine in postpartum period.

CONCLUSION Primary hyperparathyroidism is a rare disorder during pregnancy but it is a preventable cause of maternal and fetal morbidity and mortality. Proper timely diagnosis and

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OBSTETRICS AND GYNECOLOGY effective management leads to optimization of fetal and maternal outcome.

5. Kristoffersson A, Dahlgren S, Lithner F, Järhult J. Primary hyperparathyroidism in pregnancy. Surgery.

1985;97(3):326-30.

REFERENCES

6. Reading CC, Charboneau JW, James EM, Karsell PR, Purnell DC, Grant CS, et al. High-resolution parathyroid sonography. AJR Am J Roentgenol. 1982;139(3):539-46.

1. Kohlmeier L, Marcus R. Calcium disorders of pregnancy.

Endocrinol Metab Clin North Am. 1995;24(1):15-39.

2. Gertner JM, Coustan DR, Kliger AS, Mallette LE, Ravin N, Broadus AE. Pregnancy as state of physiologic absorptive hypercalciuria. Am J Med. 1986;81(3):451-6.

7. Schnatz PF, Thaxton S. Parathyroidectomy in the third trimester of pregnancy. Obstet Gynecol Surv.

2005;60(10):672-82.

3. Kovacs CS, Kronenberg HM. Maternal-fetal calcium and bone metabolism during pregnancy, puerperium, and lactation. Endocr Rev. 1997;18(6):832-72.

8. Norman J, Politz D, Politz L. Hyperparathyroidism during pregnancy and the effect of rising calcium on pregnancy loss: a call for earlier intervention. Clin Endocrinol (Oxf).

2009;71(1):104-9.

4. Malekar-Raikar S, Sinnott BP. Primary hyperparathy9. Schnatz PF, Curry SL. Primary hyperparathyroidism in roidism in pregnancy - a rare cause of life-threatening pregnancy: evidence-based management. Obstet Gynecol hypercalcemia: case report and literature review. Case Rep Endocrinol. 2011;2011:520516.

Surv. 2002;57(6):365-76.

■■■■

...Cont’d from page 366 7. Pilli GS, Suneeta KP, Dhaded AV, Yenni VV. Ovarian tumors: a study of 282 cases. J Indian Med Assoc.

2002;100(7):420, 423-4, 447.

8. Nowak M, Szpakowski M, Malinowski A, Romanowicz H, Wieczorek A, Szpakowski A, et al. Ovarian tumors in the reproductive age group. Ginekol Pol. 2002;73(4):354-8.

9. Swamy GG, Satyanarayana N. Clinicopathogical analysis of ovarian tumors - a study on five years samples. Nepal Med Coll J. 2010;12(4):221-3.

10. Prabhakar BR, Maingi K. Ovarian tumors - prevalence in Punjab. Indian J Pathol Microbiol. 1989;32(4):276-81.

11. Yasmin S, Yasmin A, Asif M. Clinicohistological pattern of ovarian tumors in Peshawar region. J Ayub Med Coll Abbottabad. 2008;20(4):11-3.

12. Shy Y. Histological classification in 10,288 cases of ovarian malignant tumors in China. Zhinghua Fu Chan Ke Za Zhi. 2002;37(2):97-100.

13. Di Bonito L, Patriarca S, Delendi M, Alberico S. Ovarian tumors: anatomohistopathological contribution to their interpretation. Eur J Gynaecol Oncol. 1988;9(4):324-30.

14. Sarkar R. Ovarian neoplasms: a 14 years study. J Obstet Gynecol India. 1996;46(1):156-9.

15. Ahmad Z, Kayani N, Hasan SH, Muzaffar S, Gill MS. Histological pattern of ovarian neoplasm. J Pak Med Assoc. 2000;50(12):416-9.

16. Levi F, Franceschi S, La Vecchia C, Ruzicka J, Gloor E, Randimbison L. Epidemiologic pathology of ovarian cancer. Ann Oncol. 1993;4(4):289-94.

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17. Jha R, Karki S. Histological pattern of ovarian tumors and their age distribution. Nepal Med Coll J. 2008;10(2):81-5.

18. Khan AA, Luqman M, Jamal S, Mamoon N, Mushtaq S. Clinicopathological analysis of ovarian tumors. Pak J Pathol. 2005;16:28-32.

19. Scully RE, Young RH, Clement PB (Eds.). Tumors of the ovary, maldeveloped gonads, fallopian tube and broad ligament. Atlas of Tumor Pathology, 3rd series.

Washington, D.C: Fascicle 23, Armed Forces Institute of Pathology; 1999.

20. Amatya S, Gurung G, Rana A. Annual clinicopathological analysis of ovarian tumors at TUTH. Nepal J Obstet Gynecol. 2010;4:18-24.

21. Lack EE, Goldstein DP. Primary ovarian tumors in childhood and adolescence. Curr Prob Obstet Gynecol.

1984;7:8.

22. Kaku T, Ogawa S, Kawano Y, Ohishi Y, Kobayashi H, Hirakawa T, et al. Histological classification of ovarian cancer. Med Electon Microsc. 2003;36(1):9-17.

23. Fusey SS, Wairagade SR. Ovarian tumors in teenage.

J Obstet Gynecol India. 1992:118-21.

24. Chhanda M, Dasgupta A, Ghosh RN, Sengupta J. Ovarian tumors: a ten year study. J Obstet Gynecol India. 1990: 691-5.

25. Tyagi SP, Maheswari V, Tyagi N, Saxena K, Sharma R, Hameed F. Solid tumors of the ovary. J Indian Med Assoc.

1993;91(9):227-30.

26. Oumachigui A, Narasimhan KL. Ovarian tumors in children. J Obstet Gynecol India. 1989:441-5.

OBSTETRICS AND GYNECOLOGY

A One Year Prospective Study of Obstetrical Emergencies at a Tertiary Care Referral Hospital PARNEET KAUR*, KHUSHPREET KAUR†, GURDIP KAUR*, SURYA MALIK‡

ABSTRACT Objective: To study relative preponderance of critical obstetrical emergencies and to study the contribution of each emergency to maternal mortality and morbidity and fetal outcome. Material and methods: The present study was conducted on a prospective basis for 1 year, from 1st February 2011 to 31st January 2012 in the Dept. of Obstetrics and Gynecology, Govt. Medical College and Rajindra Hospital, Patiala. All the cases referred as critical emergency from nearby areas during their antenatal period or within 42 days of delivery were included in the study. A detailed history was taken and thorough general physical examination and local examination was done in every case. Results: Incidence of obstetric emergencies came out to be 11.3%. Various obstetric emergencies encountered were: hemorrhage (47.97%), hypertensive disorders of pregnancy (35.32%), obstructed labor (12.3%), puerperal sepsis (3.18%) and rupture uterus (2.78%). Maternal mortality was 8.8%. Hemorrhage was leading cause of death in 36.36% cases followed by puerperal sepsis (13.64%), hypertensive disorders of pregnancy (13.64%), rupture uterus (9.09%).

Conclusion: Obstetric emergencies are more common in unbooked patients who belong to low socioeconomic status with poor access to antenatal care. Hemorrhage is still a leading cause of maternal and fetal mortality.

Keywords: Obstetric emergency, maternal mortality, hemorrhage, obstructed labor

A

n emergency by definition is “an unforeseen combination of circumstances or the resulting state that calls for immediate action”. Despite improvements in prenatal care and advancements in medical technology, the practice of obstetrics will always provide the clinician with “life-or-death” situations that call for immediate response.1 During the last decade, it has become apparent that a large portion of the young women and children at greatest risk of obstetric and gynecological emergencies increasingly fall out of the healthcare system. In several areas of the country up to 25% of women receive no prenatal care. In other areas, close to 50% of young women have no primary care providers to handle emergencies.2

The maternal mortality ratio (MMR), expressed as maternal deaths per 1,00,000 live births over a given period, is a major measure of quality of obstetric care.3,4 Only by assessing maternal mortality can one place this alongside other causes of death and determine its relative magnitude and public health importance. Estimates of maternal mortality (at least both the numerator and the ratio) comprise important components; therefore, of a health situation analysis for any country.5 The World Health Organization (WHO) analysis of cause of maternal death reveals the following causes of maternal deaths: hemorrhage (30.8%), hypertensive disorders (9.1%), sepsis/infections (11.6%), obstructed labor (9.4%), abortion (5.7%), anemia (12.8%), other indirect causes of death (12.5%), other direct causes of death (1.6%), embolism (0.4%), ectopic pregnancy (0.1%) and unclassified (6.1%).6 Cases presenting with all these morbid conditions are included in the present study.

*Associate Professor tProfessor and Head ‡Junior Resident Dept. of Obstetrics and Gynecology Govt. Medical College and Rajindra Hospital, Patiala, Punjab Address for correspondence Dr Parneet Kaur H. No.: 52, Phulkian Enclave, Patiala - 147 001, Punjab E-mail: parneetkd@yahoo.co.in

MATERIAL AND METHODS The present study was conducted on a prospective basis for 1 year, from 1st February 2011 to 31st January 2012 in the Dept. of Obstetrics and Gynecology, Govt.

Medical College and Rajindra Hospital, Patiala. All the cases referred as critical emergency from nearby areas

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OBSTETRICS AND GYNECOLOGY

All the relevant investigations were done in each and every case. Attention was paid on the management received by each case including blood transfusion, surgical interventions, intensive care unit (ICU) admission, etc.

Biochemical evaluation was done by performing routine and special investigations (e.g., USG, ECG, CT scan, 24hour urinary protein, pus for C/S, color Doppler study and blood culture whenever required).

Age (years)

No. of cases Percentage (%)

18-23

98

38.89

24-29

125

49.60

30-35

27

10.71

>35

2

0.79

Mean age

25.04 years

Parity 0

104

41.27

1

70

27.78

2

42

16.67

>2

36

14.29

Mean parity

1.04

Residence Rural

165

65.48

Urban

87

34.52

OBSERVATIONS

Literacy

There were 252 cases of obstetric emergencies. The percentage of obstetric emergencies came out to be 11.37%. The demographic profile of the cases is given in Table 1.

Educated

74

29.37

Uneducated

178

70.63

Booked

58

23.02

The most common diagnosis was hypertensive disorders of pregnancy (HDP) followed by antepartum hemorrhage (APH), postpartum hemorrhage (PPH), ectopic pregnancy and obstructed labor (Fig. 1).

Unbooked

194

76.98

Lower

100

39.68

Upper lower

80

31.75

Table 2 shows the obstetric management of patients.

Only 27 (10.71%) cases were treated conservatively comprising of postpartum eclampsia 11 cases, PPH 5 cases, puerperal sepsis 6 cases, septic abortion 1 case, antepartum eclampsia 2 cases and pneumonitis 2 cases.

Forty-eight cases had vaginal delivery and 90 cases underwent emergency lower segment cesarean section (LSCS). Thirty-six cases underwent laparotomy with salpingectomy and oophorectomy. Eight cases were taken up for subtotal hysterectomy. Uterine repair was done in 5 cases. Laparotomy with peritoneal lavage was done in 3 cases. Manual removal of placenta (MROP) was done in 7 cases. Cesarean hysterectomy was done in three patients. Hydrostatic reduction was done in 3 cases. One hundred seventy-six (69.84%) of the cases needed blood transfusion and 22 (8.73%) were shifted to ICU due to unstable vitals and need for ventilator support.

Lower middle

53

21.03

Upper middle

15

5.95

Upper

4

1.59

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Indian Journal of Clinical Practice, Vol. 26, No. 4, September 2015

Socioeconomic status

40

Percentage (%)

35

35.32

30 25 19

20

14.68 14.28

15

12.3

abortio

Cardia

Viral h epatitis

n uteru s

Septic

ral sep sis

Puerpe

ncy

cted la bor

Rupture

Obstru

PPH

pregna

APH

HDP

n

1.19 1.98 1.98 1.19 0.78

c failure

2.78 3.18

0

Inversio

5

uterus

10

Ectopic

Excluding the first trimester complications and postpartum cases, a total of 208 fetuses were delivered including a twin gestation. There were 146 (70.2%) live births and 62 (29.8%) stillbirths.

Booking status

onitis

A detailed history including age, parity, gestational age, antenatal care during pregnancy, socioeconomic status, obstetrical history, medical or surgical disorders was taken into account. A thorough general physical examination, local examination including per abdomen and per vaginum examination was done in every case.

Table 1. Demographic Profile of Cases (Total = 252)

Pneum

during their antenatal period or within 42 days of delivery were included in the study.

Diagnosis

Figure 1. Distribution of subjects according to diagnosis.

OBSTETRICS AND GYNECOLOGY Table 2. Management of Cases Obstetric management

No. of Percentage cases (%)

Conservative

27

10.71

Vaginal deliveries

48

19.05

Emergency LSCS

90

35.71

Laparotomy with salpingectomy and/or oophorectomy

36

14.28

Laparotomy with subtotal hysterectomy

8

3.17

Laparotomy with peritoneal lavage

3

1.19

Laparotomy with uterine repair

5

1.98

Cesarean hysterectomy

3

1.19

Exploration under anesthesia

22

8.73

MROP

7

2.78

3

1.19

252

100

Hydrostatic reduction Total

Hemorrhage Puerperal sepsis Hypertensive disorders

9.09

Rupture uterus

4.55

Inversion uterus Viral hepatitis

9.09

36.36

Pneumonitis

9.09

13.64

The maximum incidence of HDP (35.32%) in our study is comparable to that reported by Oladapo.8 Siddiqui9 also had a higher incidence of HDP in their study (i.e., 23.84%). Nineteen percent incidence of APH in present study is comparable to Prual.7 About 14.68% of PPH in present study is similar to the studies done by Adelaja10 and Siddiqui.9 Obstructed labor constituted 12.3% cases, which is comparable to studies of Oladapo,8 Omo-Aghoja,11 and Adelaja.10 Most common cause of maternal mortality in present study was hemorrhage, which is comparable to Prual,7 and less than reported by Purandare.3 Present study shows HDP as cause of maternal mortality in 13.64% of cases, which is almost similar to Siddiqui9 and Prual.7 We had 95.45% cases of maternal mortality as unbooked, which is comparable to Oladapo8 but Purandare3 reported 90% cases and Omo-Aghoja;11 78.57% cases of maternal mortality as booked.

Cardiac failure due to severe anemia

4.55

which is comparable to the study of Prual.7 In our study, 76.98% of patients were unbooked, which is almost similar to the study done by Oladapo and Siddiqui.8,9

13.64

Figure 2. Causes of death percentage.

Out of the total 250 cases, 22 cases could not be saved giving a maternal mortality of 8.8%. Two cases got referred to higher institute. Hemorrhage was the most common cause of death. Other contributing causes were puerperal sepsis, HDP, rupture uterus, inversion uterus, viral hepatitis, cardiac failure due to severe anemia and pneumonitis (Fig. 2).

About 95.45% of cases of maternal death were unbooked and only 13.64% were referred from a distance <20 km.

Rest all (86.36%) referred from a distance of >20 km.

DISCUSSION There were 252 cases of obstetric emergency during the period. Thus, incidence came out to be 11.37%.

The mean age in our study came out to be 25.04 years,

CONCLUSIONS From the present study, we concluded that obstetric emergencies are more common in subjects who are unbooked, belong to low socioeconomic status and have poor access to antenatal care.

Distance of referral institute from hospital is directly proportional to the propensity of obstetric complications.

Most of the maternal complications occur in the third trimester of pregnancy.

Anemia has a major bearing on maternal morbidity and mortality. Hemorrhage, HDP, puerperal sepsis, rupture uterus, inversion uterus, cardiac failure due to severe anemia and viral hepatitis during pregnancy are the major causes of maternal mortality.

Most of the mortality occurs in those cases that are unbooked and are referred from greater distances.

Fetal morbidity and mortality is also high in cases that are unbooked and have no antenatal care.

Thus, there is a dire need of proper antenatal care including treatment of anemia, timely referral from periphery of high-risk cases to prevent maternal and fetal morbidity and mortality.

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OBSTETRICS AND GYNECOLOGY REFERENCES 1. Gary DA. Obstetric emergencies. Clin Obstet Gynecol.

2002;45(2):307-29.

7. Prual A, Bouvier-Colle MH, de Bernis L, Breart G. Severe maternal morbidity from direct obstetric causes in West Africa: incidence and case fatality rates. Bull World Health Organ. 2000;78(5):593-602.

2. Benrubi GI. Handbook of Obstetric and Gynecologic Emergencies, 4th Edition. Wolter Kluwers (India) Pvt. Ltd. Publishers; 2010:p.VII.

8. Oladapo OT, Sule-Odu AO, Olatunji AO, Daniel OJ. “Near miss” obstetric events and maternal deaths in Sagamu, Nigeria: a retrospective study. Reprod Health. 2005;2:9.

3. Purandare N, Chandock AS, Upadhya S, Sanjanwala SM, Saraogi RM. Maternal mortality at a referral centre: a five year study. J Obstet Gynecol India. 2007;57(3):248-50.

9. Siddiqui SA, Soomro N, Shabih-ul-Hasnain F. Severe obstetric morbidity and its outcome in patients presenting in tertiary care hospital of Karachi. J Pak Med Assoc.

2012;62(3):226-31.

4. Hill K, AbouZahr C, Wardlaw T. Estimates of maternal mortality for 1995. Bull World Health Organ. 2001; 79(3):182-93.

5. Buekens P. Is estimating maternal mortality useful? Bull World Health Organ. 2001;79(3):179.

10. Adelaja LM, Taiwo OO. Maternal and fetal outcome of obstetric emergencies in a tertiary health institution in South-Western Nigeria. ISRN Obstet Gynecol.

2011;2011:160932.

11.

6. Khan KS, Wojdyla D, Say L, Gulmezoglu AM, Van Look PF. WHO analysis of causes of maternal death: a systematic review. Lancet. 2006;367(9516):1066-74.

■■■■

Omo-Aghoja LO, Aisien OA, Akuse JT, Bergstrom S, Okonufua FE. Maternal mortality and emergency obstetric care in Benin city, South-South Nigeria. J Clin Med Res. 2010;2(4):55-60.

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Although the majority of women with peripartum cardiomyopathy make a full recovery within a year of giving birth and after receiving “conventional heart failure therapy,” those with severe left ventricular (LV) dysfunction and significant remodeling at first visit are at risk for future cardiovascular events. Results from the prospective HYPERLINK “https://clinicaltrials.gov/ct2/show/NCT01085955” Investigations of Pregnancy Associated Cardiomyopathy (IPAC) study are published in the August 25 issue of the Journal of the American College of Cardiology.

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Indian Journal of Clinical Practice, Vol. 26, No. 4, September 2015

OBSTETRICS AND GYNECOLOGY

Use of Fetal Pillow During Cesarean Section in Deeply Engaged Head: A Comparative Study with Patwardhan’s Technique SANNYASI CHARAN BARMAN*, BARUNODAY CHAKRABORTY†, SANJOY SAHA‡, RAMKRISHNA SAHANA*, SWARUPANANDA MAITY#, DEBILINA ROY$

ABSTRACT Objectives: To compare the maternal and neonatal outcome in second stage cesarean delivery by using fetal pillow with the result obtained by Patwardhan’s technique. Material and methods: This prospective interventional study was conducted in the Dept. of Obstetrics and Gynecology, Bankura Sammilani Medical College, Bankura, West Bengal, from January 2012 to April 2013, among the 147 mothers with single fetus in cephalic presentation and deeply engaged fetal head. Fetal pillow was used in 75 cases (study group) and results were compared with Patwardhan’s technique in 72 cases (control group). Cases were allocated in 1:1 ratio. Statistical calculations were done with Excel and Epi-Info version 3.5 software. Results and analysis: Obstetric features and indications of cesarean section were matched with both groups. Delivery of fetal head was 6.75 times easier in study group than control group, p < 0.0001. Time required for cesarean section was 36.75 ± 7.01 minutes in study group versus 40.21 ± 7.47. minutes in control group (Student’s ‘t’ value 2.90, degree of freedom-145, p = 0.004). Extension of uterine angle, uterine artery tear, blood loss and need for blood transfusion (5.33% vs. 6.94%) were comparable in both groups. Baby delivery time was less in study group (180 ± 29.18 sec vs. 270 ± 49.59 sec), p ≤ 0.00,01. Apgar score at 1st minute and 5th minute were better in study group than control group (6.23 ± 2.15, 3.93 ± 2.13 vs. 7.79 ± 2.03, 5.96 ± 2.29), p < 0.0001. NICU admission was less in study group than control group, 13 (17.33%) versus 24 (33.33%), p = 0.025. Conclusion: Fetal pillow facilitates easy delivery of impacted fetal head and thereby reduces the maternal and neonatal complications.

Keywords: Cesarean section, deeply impacted fetal head, fetal pillow, neonatal outcome

T

emptation for vaginal delivery when condition is suboptimal or when mother is referred late may lead to both maternal and fetal complications.

In this situation, there is no other way and the baby has to be delivered by abdominal route. It is very difficult to do a cesarean section in this situation. Fetal head is deeply engaged, lower segment is stretched, edematous and thinned out, liquor amnii is drained out, fetus is

*Assistant Professor †Associate Professor Dept. of Obstetrics and Gynecology ‡Assistant Professor Dept. of Community Medicine #RMO cum Clinical Tutor Dept. of Pediatric Medicine $Dept. of Obstetrics and Gynecology Bankura Sammilani Medical College, Bankura, West Bengal Address for correspondence Dr Sannyasi Charan Barman Qt. No.: 2/4/26, Gobindanagar, Bankura - 722 102, West Bengal E-mail: dr.barman.at need@gmail.com

in compromised state and mother is exhausted. It is very difficult to deliver the fetal head as there is lack of space between bony pelvis, pelvic soft tissues and fetal head, which is associated with contracting uterus.

When excessive manipulation is done to deliver the fetal head, there is high-risk of uterine angle extension laterally tearing uterine artery or vertically downwards into bladder and even into vaginal vault which can cause torrential hemorrhage; this is difficult to control.1,2 Incidence of cesarean section varies from country to country. It is about 21.1% in most developed countries and 14.3% in underdeveloped countries.1 Our tertiary maternity care teaching hospital is draining mainly three districts: Bankura, Purulia, Paschim Medinipur with annual delivery more than 20,000 and cesarean section incidence is around 26%. Although incidence of cesarean section is known, but true incidence of cesarean section in second stage of labor in not known.

It is probably around 2-3% and accounts for 25% of all cesarean section.3 There are several techniques that have been reported for delivery of deeply engaged

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OBSTETRICS AND GYNECOLOGY head. In push method, an assistant pushes the head up vaginally. In pull methods, reverse breech extraction is done. Abdominovaginal delivery has been described by Landsman.

In Patwardhan’s method incision is given at the level of anterior shoulder, over lower uterine segment. Anterior shoulder, posterior shoulder, trunk and breech are successively delivered, then the head is lifted out of pelvis by traction on leg.

All this techniques rely on extensive experience that is often not immediately available in labor ward. In our hospital, cesarean sections were usually performed by junior doctors who were unlikely to be experienced enough to deviate from normal conventional technique of cesarean section. The Sentinel audit report published by the Royal College of Obstetricians and Gynecologists (RCOG) recommended constant presence of senior doctors when cesarean section is performed at full dilatation.4 Although there are different techniques to deliver the impacted fetal head none of them is cent percent appropriate. So, we are continuously searching for newer methods. In our present interventional prospective study, we apply specially designed device called fetal pillow to deliver the impacted fetal head (study group), and results were compared with Patwardhan’s technique (control group).

MATERIAL AND METHODS This was an interventional prospective study conducted at the Dept. of Obstetrics and Gynecology, Bankura Sammilani Medical College, Bankura, West Bengal.

One hundred forty-seven mother with single fetus with cephalic presentation at late stage of labor when head was deep in pelvis and needed emergency. Cesarean

section were included in this study during the period January 2012 to April 2013. Women having local infective vulvovaginal lesions and severe vulval edema were excluded from this study. Seventy-five women in the study group were delivered by using fetal pillow and 72 women in the control group were delivered by Patwardhan’s technique. They were alternately allotted to the study group and control group. All the cases were done under spinal anesthesia. The ethical approval was obtained from the College Ethical Committee. Our primary objectives were - How much fetal pillow is helpful to deliver impacted fetal head during cesarean section and to evaluate the fetomaternal outcome in the form of - extension of uterine angle and injury to the bladder, vagina, uterine artery tear, blood loss and need for blood transfusion, neonatal intensive care unit (NICU) admission.

Instrument-fetal Pillow In this study, we have used a specially designed device, named fetal pillow (Fig. 1). The Fetal Disimpacting System® is manufactured by Safe Obstetric Systems UK Ltd (Essex, UK). It consists of a base plate 11 cm long and 4.5 cm wide, foldable along the midline of the short axis towards the superior surface, to which a balloon is attached. The balloon is attached through a connector to a tube 80 cm in length that is, in turn, attached to a 50 mL syringe through a two-way connector. It is inserted vaginally below the fetal head at the time of insertion of a urinary catheter, just before cesarean section.

Once in the vagina, the device is placed posteriorly, like a ventouse cup for an occipitoposterior position.

Once inserted, the woman’s legs are straightened (this closes the vaginal opening and prevents the downward movement of the base plate) and now she is prepared for cesarean section. The time taken for this maneuver

50 mL syringe

Tube 80 cm Silicon balloon

Folding base plate with rounded, atraumatic edges

Figure 1. Fetal pillow.

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Indian Journal of Clinical Practice, Vol. 26, No. 4, September 2015

OBSTETRICS AND GYNECOLOGY is around 30 seconds. An assistant uses 140-160 mL of saline to inflate the balloon using 50 cc syringe. The balloon inflates and gently elevates the fetal head 2-3 cm from its position, making it easier to deliver the fetal head.

As soon as delivery is achieved, the balloon is deflated.

The device is removed during vaginal swabbing after completion of cesarean section by gently pulling through tube or by hooking a finger into the base plate.

Both the vagina and fetal head are examined carefully after cesarean section for any traumatic injury.

The women in the study group were delivered by cesarean section using the fetal pillow by the technique described above.

Statistical Analysis Statistical calculations like descriptive statistics, Chisquare test, Students t-test, were done with the help of Excel and Epi-Info version 3.5 software. A probability value p < 0.05 was regarded as statistically significant.

RESULTS AND ANALYSIS Maternal profile of the study group (with pillow) and control group (Patwardhan’s) are summarized in Table 1.

Mean maternal age was 21.88 ± 3.16 years in study group and 22.35 ± 3.53 years in control group. Mean gestational age was 272.57 ± 10.59 days and 274.83 ± 9.41 days in study and control group, respectively.

Indications of cesarean section were similar in both the groups (Table 2). Most common cause of emergency, cesarean section was fetal distress in late first stage of labor (30.67% vs. 26.39%) and next common causes were with or without fetal distress in second stage of labor with unanticipated CPD (21.33% vs. 26.67%), followed by obstructed labor (21.33% vs. 26.39%) in study group as compared to control group.

Maternal outcome in the study and control group are summarized in Table 3. Out of 75 cases in the study group, delivery of fetal head was easy in 57 (76%) cases and it was 23 (31.94%) cases in control group. Delivery of fetal head was difficult in 18 (24%) cases in study

Table 1. Maternal Profile Study group (n = 75)

Control group (n = 72)

<20

18 (24%)

19 (26.39%)

20-30

54 (72%)

51 (70.83%)

Student t-test

P value

Age (years)

03 (4%)

02 (2.78%)

21.88 ± 3.16

22.35 ± 3.53

0.85 (df = 145)

0.396

Primi para

67 (89.33%)

65 (90.28%)

-

-

Multi para

08 (10.67%)

07 (9.33)

1.37 (df = 145)

0.174

>30 Mean age ± SD Parity

Gestational age <259 days (37 weeks)

06 (8%)

04 (5.55%)

259-280 days (37-40 weeks)

51 (68%)

56 (77.78%)

>280 days (40 weeks)

18 (24%)

12 (16.67)

272.57 ± 10.59

274.83 ± 9.41

Mean gestational age (days) ± SD

Table 2. Indication of Cesarean Section Study group (n = 75)

Control group (n = 72)

Fetal distress in late first stage of labor

23 (30.67%)

19 (26.39%)

Unanticipated CPD with or without fetal distress in late stage of labor

16 (21.33%)

20 (26.67%)

Deep transverse arrest

11 (14.67%)

08 (11.11%)

Obstructed labor

16 (21.33%)

19 (26.39%)

Persistent occipito posterior position

06 (8%)

04 (5.55%)

Fail forceps

03 (4%)

02 (2.67%)

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OBSTETRICS AND GYNECOLOGY Table 3. Labor Event Study group (n = 75)

Control group (n = 72)

t-test

P value

OR (95% CI)

St - 0

41 (54.67%)

33 (45.83%)

-

-

-

St + 1 or below

34 (45.33%)

39 (54.17%)

-

-

-

“+”

43 (57.33%)

33 (45.83%)

-

-

-

“++ or more”

29 (38.67%)

39 (54.17%)

-

-

-

03 (4%)

0

-

-

-

Easy

57 (76%)

23 (31.94%)

28.74

<0.0001

Difficult

18 (24%)

49 (68.05%)

6.75 (3.08-14.95)

Baby delivery time (sec), mean ± SD

180 ± 29.18 sec

270 ± 49.59 sec

t = 13.47 (df = 145)

<0.0001

-

Skin to skin time (mins), mean ± SD

36.75 ± 7.01 mins

40.21 ± 7.47 mins

t = 2.90 (df = 145)

0.004

-

Yes

19 (25.33%)

13 (18.05%)

1.14

0.285

1.54 (0.65 -3.07)

No

56 (74.67%)

59 (81.94%)

Yes

15 (20%)

07 (9.72%)

3.05

0.081

No

60 (80%)

65 (90.28%)

2.32 (0.82-6.08)

Average

58 (77.33%)

56 (77.78%)

Fisher’s exact

>average

13 (17.33%)

11 (15.28%)

(p = 0.87)

Need for blood transfusion

04 (5.33%)

05 (6.94%)

Urinary bladder injury

Nil

Nil

-

-

-

Skin infection

03

02

-

-

-

Easy in all cases

-

Station of head (St)

Caput

No caput Delivery of fetal head

Time

Extension of uterine angle

Uterine artery tear

Blood loss

Insertion and removal of fetal pillow

Table 4. Fetal Profile Study group (n = 75)

Control group (n = 72)

Student t-test

P value

Male baby

44 (58.67%)

42 (58.33%)

-

-

Female baby

31 (41.33%)

30 (41.67%)

-

-

<2.5 kg

08 (10.67%)

11 (14.28%)

2.5-3 kg

42 (56%)

44 (61.11%)

Sex

Baby weight

>3 kg, Mean body weight ± SD Admission in NICU

378

25 (33.33%)

17 (23.61%)

2.90 kg ± 0.43

2.77 kg ± 0.36

1.98 (df = 145)

0.049

13 (17.33%)

24 (33.33%)

4.99

0.025

Indian Journal of Clinical Practice, Vol. 26, No. 4, September 2015

OBSTETRICS AND GYNECOLOGY Table 5. Apgar Score Study group

Control group

Student t-test

P value

6.51 (df = 145)

<0.0001

5.13 (df = 145)

<0.0001

Apgar at 1st min No distress (7-10)

36

7

Mild-to-moderate distress (4-6)

24

17

Severe distress (0-3)

15

46

0

02

6.23 ± 2.15

3.93 ± 2.13

No distress (7-10)

56

20

Mild-to-moderate distress (4-6)

11

37

Severe distress (4-6)

8

13

Stillborn

0

02

7.79 ± 2.03

5.96 ± 2.29

Stillborn Mean ± SD Apgar at 5th min

Mean ± SD

group, as compared to 49 (68.05%) cases in control group, p < 0.0001. Baby delivery time was 180 ± 29.18 seconds in the study group, as compared to 270 ± 49.59 seconds in the control group, p < 0.001. Total operative time was 36.75 ± 7.01 minutes in the study group as compared to 40.21 ± 7.47 minutes in the control group, p = 0.004. In the study group, extension of uterine angle occurred in 19 (25.33%) cases as compared to 13 (18.05%) cases in control group. Uterine artery tear and need for blood transfusion was there in 15 (20%) and 4 (5.33%) cases of pillow group as compared to 7 (9.72%) and 5 (6.94%) cases of control group, respectively.

Table 4 summarized the fetal profile. Mean birth weight was 2.90 ± 0.43 kg and 2.77 ± 0.36 kg in study group and control group, respectively. NICU admission was 13 (17.33%) in study group and 24 (33.33%) in control groups with p = 0.025. Table 5 showed the fetal Apgar score. Study showed 1st minute Apgar score 6.23 ± 2.15 in study group and 3.93 ± 2.13 in control group with p < 0.0001. Study showed the Apgar score at 5th minute 7.79 ± 2.03 and 5.69 ± 2.29 in study and control group, respectively with p < 0.0001.

DISCUSSION Obstetric features and indications of cesarean section in the current study were comparable and were similar to the study by Ziyauddin et al,1 Mukhopadhyay et al,2 Singh et al3 and Khosla et al.5 Cesarean section is commonly perceived as a simple and safe alternative to difficult vaginal birth.6 Sethuram et al7 reported that 80% junior doctor (registrars) agreed that they faced difficulties during delivery of deeply engaged head and agreed for supervised session. RCOG also

recommended this supervised training.4 Our study showed that the delivery of fetal head, after application of pillow was very much safe and easy, even in the hands of a less experienced junior doctor. Study showed that delivery of baby was 6.75 times easier in study group than control group, (95% confidence interval [CI] 3.0-14.95, p < 0.0001).

In the present study, it was found that the insertion and removal of pillow was easy in all cases and there was no device related trauma to the baby or mother. Singh et al3 reported a similar finding in 2008. Chopra et al,8 Fasubaa et al9 and Frass et al10 showed the uterine angle extension up to 40.6% by head pushing method. Rodriguez et al11 reported the extension of uterine angle up to 35% in deeply engaged head. Ziyauddin et al1 reported that the blood loss (11.43% vs. 67.14%) and need for blood transfusion (17.14% vs. 40%) were more in head pushing method than breech extraction method. But in our study, uterine angle extension was only 19 (25.33%), uterine artery tear was only 15 (20%), thereby blood loss (assessed clinically) was much less and requirement of blood transfusion was only 4 (5.33%) in study group, p = 0.87. The results of this study are similar to those observed in study by Mukhopadhyay et al.2 In the present study, skin-to-skin time was less in study group as compared to control group (36.75 ± 7.01 minutes vs. 40.21 ± 7.47 min, p = 0.004). Results were comparable with studies by Khosla et al,5 and Fasubaa et al9 (longer operative time, more blood loss, extension of uterine angle, longer hospital stay, higher hospital bills by push method than the pull method).

Mukhopadhyay et al2 reported that technique of delivery was not responsible for birth asphyxia. In the

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OBSTETRICS AND GYNECOLOGY present study, baby delivery time was less in study group than control group (180 ± 29.18 sec vs. 270 ± 49.59 sec, p < 0.0001). Study also showed that Apgar score at 1st minute and 5th minute was much better in study group than control group (6.23 ± 2.15 and 7.79 ± 2.03 vs. 3.93 ± 2.13 and 5.96 ± 2.29, p < 0.0001). Thereby NICU admissions were less in study group than in control group, 13 (17.35%) versus 24 (33.23%), which is statically significant (p = 0.025).

CONCLUSION There are different methods of delivery of deeply impacted fetal head but none of them is cent percent appropriate. We are continuously searching for the most suitable technique. Application of fetal pillow to deliver the deeply engaged head during cesarean section is one such innovative approach. Fetal pillow is helpful in delivering deeply engaged head and results in decreased maternal and perinatal morbidity during cesarean section. Initial experience is small but promising and further larger trials are required before coming to a conclusion.

REFERENCES 1. Ziyauddin F, Hakim S, Khan T. Delivery of the deeply engaged fetal head during cesarean section in advanced labour: a comparative study of head pushing versus reverse breech extraction. Cur Pediatr Res. 2013;17(1):41-3.

3. Singh M, Varma R. New developments reducing complications associated with a deeply engaged head at caesarean section: a simple instrument. New Develop Obstet Gynecol. 2008;10:38-41.

4. Royal College of Obstetrics and Gynecology. RCOG Clinical Effectiveness Support Unit. The National Sentinel Caesarean Section Audit Report. London: RCOG; 2001.

Available at: https://www.rcog.org.uk/globalassets/ documents/guidelines/research--audit/nscs_audit.pdf.

5. Khosla AH, Dahiya K, Sangwan K. Cesarean section in a wedged head. Indian J Med Sci. 2003;57(5):187-91.

6. Blickstein I. Difficult delivery of the impacted fetal head during cesarean section: intraoperative disengagement dystocia. J Perinat Med. 2004;32(6):465-9.

7. Sethuram R, Jamjute P, Kevelighan E. Delivery of the deeply engaged head: a lacuna in training. J Obstet Gynaecol. 2010;30(6):545-9.

8. Chopra S, Bagga R, Keepanasseril A, Jain V, Kalra J, Suri V. Disengagement of the deeply engaged fetal head during cesarean section in advanced labor: conventional method versus reverse breech extraction. Acta Obstet Gynecol Scand. 2009;88(10):1163-6.

9. Fasubaa OB, Ezechi OC, Orji EO, Ogunniyi SO, Akindele ST, Loto OM, et al. Delivery of the impacted head of the fetus at caesarean section after prolonged obstructed labour: a randomised comparative study of two methods.

J Obstet Gynaecol. 2002;22(4):375-8.

10. Frass KA, Al Eryani A, Al-Harazi AH. Reverse breech extraction versus head pushing in cesarean section for obstructed labor. A comparative study in Yemen. Saudi Med J. 2011;32(12):1261-6.

2. Mukhopadhyay P, Naskar T, Dalui R, Hazra S, 11.

Bhattacharya D. Evaluation of Patwardhan’s technic - a four year study in a rural teaching hospital. J Obstet Gynecol India. 2005;55(3):244-6.

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Rodriguez AI, Porter KB, O’Brien WF. Blunt versus sharp expansion of the uterine incision in low-segment transverse cesarean section. Am J Obstet Gynecol.

1994;171(4):1022-5.

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A woman's weight at birth, education level and marital status pre-pregnancy can have repercussions for two generations, putting her children and grandchildren at higher risk of low-birth weight, suggested a new study published in the Journal of Health and Social Behavior.

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Treating psychiatric disorders in pregnant women with commonly used antidepressants (selective serotonin reuptake inhibitors or SSRIs) lowers the risk of several pregnancy complications including preterm birth and Cesarean section. But, use of this medication is also associated with an increased risk of neonatal problems, reported a new study published in the American Journal of Psychiatry.

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ORTHOPEDICS

Paget’s Disease of Bone in Indian Patients: Two Case Reports BHAVANA VENKATA NAGABHUSHANA RAO*, BVS RAMAN*

ABSTRACT Paget’s disease of bone is rare in India but getting reported more often. Is a disease of defective remodeling of bone of unknown etiology, incidentally diagnosed by finding unexplained elevation of alkaline phosphatase or abnormal skiagram as most of the sufferers are asymptomatic. It is disease of elderly and of European ancestry. Alkaline phosphatase is a simple investigation of choice to diagnose, monitor and screen the patients. Availability of bone scans made it easy to diagnose polyostotic or early disease. Single dose of intravenous zoledronic acid is the drug of choice with high response rates. It is presumed that the incidence of Paget’s disease may increase in India as many Indians are living up to 80 years, the age of Paget’s disease.

Keywords: Paget’s disease, alkaline phosphatase, abnormal skiagram, bone scans, zoledronic acid

P

aget’s disease (osteitis deformans) is a localized disorder of bone remodeling that typically begins with excessive bone resorption followed by an increase in bone formation. This osteoclastic overactivity followed by compensatory osteoblastic activity leads to a structurally disorganized mosaic of bone (woven bone), which is mechanically weaker, larger, less compact, more vascular and more susceptible to fracture than normal adult lamellar bone. It is also called British disease, highest prevalence being in Europe. Due to significant population with European ancestry and British immigrants USA, Australia and New Zealand also have higher prevalence.

It is rare in Asian countries. It is a very ancient disease, archeologists discovered the disease in the bones of people from Roman era 20 BC, though first described

by Sir James Paget in 1876. This is a disease of elderly, rare before age of 40, except rare autosomal recessive juvenile form. Prevalence varies between 1% and 3%, and in people aged above 80 years in Europe, 10% were suffering from this disorder. This is the commonest bone disorder in Europe second to osteoporosis. Men and women are equally affected.

*Dept. of Medicine NRI Hospital, Seethammadhara, Visakhapatnam, Andhra Pradesh Address for correspondence Dr Bhavana Venkata Nagabhushana Rao Dept. of Medicine NRI Hospital, Seethammadhara, Visakhapatnam - 530 013, Andhra Pradesh E-mail: bhavanavnrao@gmail.com, bhavanavnrao@me.com

Paget’s disease is rare in India. The first case was reported by Dr Vyagreswarudu from Visakhapatnam in 1953, the same city from where we are reporting two cases of Paget’s disease. Dr Anjali et al reported a series of 51 patients seen in Vellore over 8 years; they did not differ in clinical presentation from that seen in West.

Dr Joshi et al reported 17 cases scattered over Western India.

Dr Bhadada and coworkers reported 21 cases from a multicentric study involving seven centers. Dr Bhatt reported three cases from Mumbai. Dr Mohan from Chennai reported 0.66% prevalence in diabetic patients.1 Here we present two cases of Paget’s disease, one followed up for 8 years and second one recently diagnosed.

CASE PRESENTATION

First Case A 72-year-old male patient consulted us on 05-04-2007 at our hospital for his regular follow-up of hypertension and coronary artery disease as he shifted his residence close to our hospital. He was asymptomatic at that time. As we were going through his previous reports, we found that alkaline phosphatase was abnormally elevated. One of his ultrasound scan of abdomen was reported to have cholelethiasis. Appearance of his face and skull were abnormal, suspicious of Paget’s disease.

We were skeptical as we were seeing a Indian patient (Fig. 1). We did his serum calcium, liver function test

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ORTHOPEDICS including alkaline phosphatase, contrast-enhanced computed tomography (CECT) abdomen, X-ray of skull anteroposterior and lateral view. Serum calcium was normal, alkaline phosphatase was elevated 1,401 U/L (40-140). CT scan of abdomen did not show any biliary pathology. His skull X-ray showed enlargement with osteolytic and osteoblastic lesions suggestive of Paget’s disease (Fig. 2). We started him on ibandronate 150 mg to be taken first in the morning on empty stomach once monthly and not to lie down for

Figure 3. Thickened skull vault with osteolytic and osteoblastic lesions on CT scan.

60 minutes after the tablet. He responded well to the treatment, his alkaline phosphatase came to baseline in 6 months and has remained so until now.

In 2012, he developed hearing problem and he consulted ENT surgeon and his CT scan was showing Paget’s disease of cranial vault and base of skull (Fig. 3). He has both conductive and sensorineural deafness. He never lived out of India and none of his family members has similar disease. He is on regular follow-up until now.

Figure 1. Photo case 1.

Second Case A 67-year-old female patient was admitted to our hospital for weakness and excessive sleepiness. She is a known hypertensive on telmisartan 40 mg twice-daily.

Recently, she was diagnosed to have major depression and is on antidepressant medications for the last 2 months. Her facial appearance was not abnormal except a little prominence of forehead (Fig. 4).

She has no body pains or headache. Her magnetic resonance imaging (MRI) scan brain was done in the view of altered sensorium to exclude organic pathology, which showed diffuse thickening of skull vault suspicious of Paget’s disease (Fig. 5).

Figure 2. X-ray skull showing cotton wool appearance.

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X-ray skull showed sclerotic and osteolytic lesions confirming Paget’s disease (Fig. 6). Her alkaline phosphatase was 476 (60-306). Technetium bone scan revealed hot lesions of skull, right humerus and left sacroiliac joint (Fig. 7). She was given zoledronate 4 mg intravenously over 15 minutes and had no complication.

ORTHOPEDICS

Figure 6. X-ray skull showing lytic and sclerotic lesions.

Figure 4. Photo case 2.

Figure 7. Bone scan showing hot areas in skull, right humerus, left sacroiliac joint.

DISCUSSION Figure 5. MRI skull showing enlargement, osteolytic and osteoblastic lesions.

The cause of Pagetâ&#x20AC;&#x2122;s disease is not known, it is postulated that genes, environment and virus as

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ORTHOPEDICS etiological factors. Patients are mostly asymptomatic and accidentally discovered due to elevated alkaline phosphatase as shown in first case or abnormal bone skiagram as in second case. Three stages are described in Paget’s disease lytic, mixed and sclerotic. Multiple stages of disease may be demonstrated in different skeletal regions.

Alkaline phosphatase is a marker of osteoblastic activity, it correlates well with disease activity. It declines with successful treatment.2 Bone-specific alkaline phosphatase is more specific, it is a superior marker if the patient has limited disease or liver disease. Urinary hydroxyproline, N-telopeptide, alpha-C telopeptide are markers of bone resorption but they have limited usage in clinical practice. They are useful to evaluate response to bisphosphonate treatment.

The two cases we presented had abnormal skull X-rays with osteolytic and osteoblastic lesions classical of Paget’s disease. Radiographic appearance of pagetic bones are very specific; not only they confirm the diagnosis, they stage the disease and are useful for evaluating therapeutic response. Any bone may be involved but small bones of hand and ribs are rarely affected and fibulae are spared.

Sparing of fibula is an excellent observation made

by Dr Paget in his first case. CT scan and MRI are of advantage if brain and spinal cord are involved. Paget’s disease has predilection for axial skeleton-spine, pelvis, sacrum, skull and femur are involved in that order of frequency. The disease does not spread from one bone to another and new sites of involvement are rare after initial diagnosis.

Facial bone involvement3 and autosomal recessive juvenile Paget’s disease4 have also been reported from India. Thirty percent of familial Paget’s disease may have genetic mutation in sequestosome SQSTM1/ p62 gene. Familial clustering was also reported from India.5 Bone pain is the commonest symptom which may exacerbate in the night and at times bones are deformed. Subtrochanteric fracture is commonest fracture in this disorder. Fractures may heal with medical management.6 When cranium is involved hat size may progressively increase and the patient may have vertigo and deafness and occasionally visual loss. Our first patient had progressive deafness. If platybasia occurs due to softening of bones of the base of skull, the disease may precipitate brainstem and cerebellar compression

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syndromes. Vertebral fractures or canal stenosis may lead to compression of spinal cord and lead to paraparesis and incontinence of bowel and bladder.

In the second case, patient had abnormal skull bones on MRI and pagetic disease was confirmed by skull X-ray. She also had abnormal technetium scan which was suggestive of involvement of skull, right shoulder and left sacroiliac joint. Periarticular involvement of bone may lead to secondary osteoarthritis.

Though technetium scan detects disease early, evaluates disease extent and activity, at least one site of lesion must be X-rayed to confirm the disease as the test is not specific. Dr Sujata reported 9 cases of Paget’s disease in 3,050 cases referred for bone scan over 7-year period.

Bisphosphonates are the drugs of choice; therapeutic response is evaluated by normalization of alkaline phosphatase at 6 months. First case responded well, by normalizing alkaline phosphatase within 6 months and second case has not yet completed the stipulated duration. Introduction of zoledronic acid revolutionized the treatment of Paget’s disease; with one single dose 90% patients normalize their alkaline phosphatase within 6 months and most of them remain so even after 5 years and rarely require second dose. The concept of treating patients with symptomatic disease, severe osteolytic lesions, alkaline phosphatase two times of normal and disease close to joint is changing.

Though controversial, people are opting to treat the disease with single dose of zoledronic acid irrespective stage and activity unless contraindicated. Zoledronic acid is drug of choice and rarely it may cause influenza like symptoms in some patients.2 Contraindicated if glomerular filtration rate is less than 30%, calcitonin can be used in such a situation. Calcium and vitamin D should be supplemented, more so if the patient is on bisphosphonate therapy. If surgery is planned on pagetic bone and if it is elective at least he must on 3 months bisphosphonate therapy to prevent excessive bleeding.

Patients should be followed up for life. Untreated patients should undergo annual check-up with alkaline phosphatase and X-ray. Treated patients should have alkaline phosphatase checked 3-4 months and X-rays done annually. A person having family history of Paget’s disease and aged above 40 years should check his alkaline phosphatase every 2-3 years and if alkaline phosphatase is in upper limit, he should undergo bone scan.

ORTHOPEDICS CONCLUSION Paget’s disease can be found in India, though rarely.

The incidence of disease may go up as good numbers of Indians are living beyond the seventh decade. It is prudent to think of Paget’s if no other reason could be found for elevated alkaline phosphatase and if we find both lytic and sclerotic lesions in a bone on skiagram.

REFERENCES

society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(12):4408-22.

3. Subbarao K. Paget’s disease of skeleton - pictorial essay.

J Med Sci Res. 2014;2(1):34-40.

4. Indumathi CK, Dinakar C, Paget’s disease.

Indian 354-6.

Roshan R. Juvenile Pediatr.

2009;46(4):

5. Naik D, Asha HS, Mathews SS, Paul TV. Two siblings with Paget’s disease of bone. BMJ Case Rep. 2014;2014. pii: bcr2013203219.

1. Mithal A. Editorial - Paget’s disease in India. J Assoc Physicians India. 2006;54:521-2.

6. Hampannavar AS, Tripathy S, Sen R, Akkina N, Sharma A. Pagets disease of humerus presenting with recurrent fractures: a case report. Webmed Central Orthop.

2. Singer FR, Bone HG 3rd, Hosking DJ, Lyles KW, Murad MH, Reid IR, et al. Paget’s disease of bone: an endocrine 2011;2(3):WMC001622.

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Exercise Impact on the Knee Different exercises produce different impacts on the knee joints. The best and safest exercises causing minimum impact on the knee after knee replacement or patients with knee arthritis are walking, biking, hiking, riding an exercise bike, riding an elliptical trainer and walking on the treadmill. In sports one can play doubles tennis and not singles. One can also participate in downhill or cross-country skiing. The maximum stress-producing exercises are jogging and golf swings. Impact ÂÂ

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Jogging produced forces of 4.3 times body weight.

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Golf swings produces forces of 4.5 times body weight on the forward knee and 3.2 times body weight in the opposite knee.

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PEDIATRICS

Letterer-Siwe Disease Presenting as a Retroauricular Swelling: A Diagnostic Dilemma RISHAV RAJ*, BRAJA KISHORE BEHERA*

ABSTRACT Langerhans cell histiocytosis (LCH) is a rare disorder involving clonal proliferation of cells in mononuclear phagocyte system. Clinical forms of LCH are Letterer-Siwe disease, Hand-Schuller-Christian disease, eosinophilic granuloma. LCH involves skeleton in 80% of cases. One and half year old male child presented with a left retroauricular swelling 2 × 3 cm in size for 2 months and intermittent fever for 15 days. FNAC and excisional biopsy showed admixture of Langerhans cells.

Immunohistochemistry showed CD1a-positive Langerhans cells. MRI of brain was suggestive of bi-temporal mastoid osteolytic lesion. Final diagnosis was acute disseminated form of LCH-Letterer-Siwe disease. Child was treated with chemoradiotherapy and followed up for 8 months.

Keywords: Langerhans cell histiocytosis, Hand-Schuller-Christian disease, eosinophilic granuloma, CD1a-positive

H

istiocytic disorder constitute heterogeneous group of disease characterized by accumulation of reactive or neoplastic histiocytes in various tissues. The disease spectrum results from clonal accumulation and proliferation of cells resembling the epidermal dendritic cells called “Langerhans cells”, hence it is sometimes called “Dendritic cell histiocytosis”. Langerhans cell histiocytosis (LCH) is clinically divided into unifocal, multifocal unisystem, multifocal multisystem. Three basic clinical forms of LCH are Letterer-Siwe disease (acute or subacute disseminated form), Hand-Schuller-Christian disease (disseminated chronic form) and eosinophilic granuloma (localized chronic form). These all are characterized by accumulation of proliferating Langerhans cells, which have surface markers and ultrastructural features similar to cutaneous Langerhans cells and variably admixed with eosinophils. LCH usually affects children between 1 and 15 years old, peak incidence is between 5 and 10 years of age. Incidence of children less than 10 years is 1 in 2,00,000. It is most prevalent in Caucasians,

*Post Graduate Resident (Final Year) Dept. of Pediatrics Hi-Tech Medical College, Bhubaneswar, Odisha Address for correspondence Dr Rishav Raj Dept. of Pediatrics Hi-Tech Medical College, Pandra, Rasulgarh, Bhubaneswar - 751 010, Odisha E-mail: drrishavaraj@gmail.com

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and affects males twice as often as females. LCH is usually a sporadic and nonhereditary condition but familial in limited cases.

CASE REPORT A 1½-year-old male child weighing 10 kg product of nonconsanguineous marriage, born after a full-term normal vaginal delivery with a birth weight of 2.8 kg, was referred to our institute with chief complaint of retroauricular swelling for 2 months and fever for 15 days (Fig. 1). The child was apparently normal 2 months

Figure 1. Patient presenting with retroauricular swelling.

PEDIATRICS back, when he developed a left retroauricular swelling which gradually increased in size not associated with any ear discharge, or pain or itching, followed by the child developing fever, intermittent in nature, ranging from 99 to 101°F not associated with chills and rigor.

The child was misdiagnosed outside as a lymph node swelling due to some infective etiology and treated with oral antibiotics for 5 days before he reported to our hospital.

Distension of abdomen started along with fever and this increased gradually. Urine frequency was normal.

Appetite decreased over a period of 2 months. On examination, he was conscious, irritable, febrile (100 °F) and respiratory rate was 28/min, regular. Pulse was 110/min, regular, normovolumic, all peripheral pulses palpable with blood pressure 90/54 mmHg in right upper arm in supine position. Bilateral anterior cervical and postauricular lymph nodes were palpable. There was no cyanosis, edema and jugular venous pressure was not raised. On local examination, the swelling was 2.5 × 3 cm in size, soft, nontender, nonfluctuant, mobile with normal overlying skin and no punctum. A healed lesion was present over the parietal region of left scalp.

No other punctum or abnormal bony prominence, rash, seborrheic areas were present over scalp. Abdominal examinations revealed hepatomegaly (liver span of 12 cm) (Fig. 2).

Normal bowel sounds were heard. All other systems revealed no clinical abnormality. Fundoscopy was within normal limits.

Diagnostic Work-up Complete blood cell (CBC) examination revealed hemoglobin - 10.3 g/dL, total leukocyte count (TLC) 12,200/mm3, TPC - 5.42 lacs/mm3, absolute eosinophil count - 440/mm3, erythrocyte sedimentation rate (ESR) - 38 mm/1st hour (modified Westergren method), peripheral smear examination revealed microcytic hypochromic blood picture. No hemoparasites were found. Liver function tests (LFTs) showed serum bilirubin total 0.3 mg/dL, direct 0.2 mg/dL with mild raised serum glutamic-oxaloacetic transaminase (SGOT) - 61 U/L, serum glutamic-pyruvic transaminase (SGPT) - 72 U/L and alkaline phosphatase (ALP) 371 U/L. Urine examination revealed trace albumin, 20-25 pus cells, 2-3 epithelial cells; bacterial content was present. Urine culture revealed insignificant bacteriurea.

Stool examination revealed normal finding.

Liver was firm with smooth margin and nontender.

Spleen was enlarged 4 cm below left costal margin and firm. Shifting dullness and fluid thrill were absent.

A thorough radiological evaluation was performed.

Digital X-ray of skull revealed multiple osteolytic lesions (Fig. 3). Ultrasonography (USG) of whole abdomen and pelvis showed hepatomegaly (liver span 12.6 cm) with irregular multiple hypoechoic distal shadowing lesions in both lobes, coarse echo-texture with periportal cuffing, intrahepatic biliary radicals showed diffuse irregular thickening of walls, enlarged spleen.

Figure 2. Patient presenting with hepatosplenomegaly.

Figure 3. X-ray of the skull showing osteolytic lesions.

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PEDIATRICS MRI of brain revealed bi-temporal mastoid osteolytic lesions with soft tissue mass extending to both labyrinths with involvement of both middle ears (Fig. 4) and both ossicular chains, tegmen were tympani eroded but no obvious extracranial extension feature suggestive of LCH. Magnetic resonance cholangiopancreatography (MRCP) (3D) showed hepatomegaly with periportal infiltrates. Dilated proximal and peripheral segmental intrahepatic biliary radicles with intraluminal sludge/infiltrates suggestive of hepatic involvement in LCH were seen. Fine-needle aspiration cytology (FNAC) of the retroauricular swelling showed high cellularity, numerous large histiocytes, multinucleated giant cell and inflammatory cells. Histiocytes were large, vesicular, folded/indented nuclei having prominent nucleoli. Among inflammatory cells predominant eosinophils, many binucleated and multinucleated cells seen scattered among histiocytes.

Cytomorphological feature suggestive of eosinophilic granuloma was made as a presumptive diagnosis. An excisional biopsy from retroauricular swelling revealed a cellular lesion with polymorphic appearance having few lymphoid follicles with variable areas of fibrosis.

Mixture of Langerhans cells, histiocytes, lymphocytes and eosinophils with few plasma cells and neutrophils, numerous multinucleate giant cells were found.

Predominantly Langerhans cells having eosinophilic cytoplasm and elongated nuclei in lobulated pattern were demarcated. Immunohistochemically, the Langerhans cell were CD1a-positive; hence, a final diagnosis of LCH was made. Bone-marrow aspiration from right posterior superior iliac spine showed normal hematopoiesis (Fig. 5), mild eosinophilia (eosinophils and metamyelocytes together constitutes 16% of marrow nucleated cells), M:E - 6:1 without any neoplastic Langerhans cells.

Treatment For localized disease or single bony lesion-curettage, bisphosphonate, low dose local radiation therapy.

Multisystem disease is treated with chemotherapy, combining vinblastine, prednisolone, 6- mercaptopurine.

Children are treated for total duration of 12 months.

Figure 4. MRI of brain revealed bi-temporal mastoid osteolytic lesions with soft tissue mass extending to both labyrinths with involvement of both middle ears.

From all above findings, a final diagnosis of acute disseminated form of LCH-Letterer-Siwe disease was made. It has been categorized into high-risk group as there was multiple systemic involvement of bone, lymph node and liver. The patient was on treatment with chemotherapy with prednisolone 40 mg/m2/day × 5 days, 3 weeks cycle: 6-mercaptopurine 50 mg/m2/ day × 12 months, vinblastine 6 mg/m2 × 3 weeks and methotrexate 20 mg/m2 orally weekly × 12 months.

He was followed up for 8 months without any disease progression except for nonhealing ulcer over the biopsy site of left retroauricular area.

DISCUSSION

Figure 5. Normal bone marrow.

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Childhood histiocytosis is a diverse group of disorders, which through rare but may be severe in their clinical expression. Generic term “histiocyte” refers to several types of cells and these cells have an important role in the immune system acting as scavengers and most importantly Langerhans cells act as antigen presenting cells. Alfred Hand was the first to report a case of histiocytosis in 1893. In 1941, Farber described his condition when reporting the overlap among diseases that would later be termed “histiocytosis X”

by Lichtenstein in 1953. Letterer-Siwe syndrome was used to describe an acute disseminated multisystem disease process of the reticuloendothelial system that typically affected children younger than 3 years of age.

PEDIATRICS International Histiocyte Society in 1987 established a classification of histiocytoses into three groups: (1) LCH; (2) histiocytoses of mononuclear phagocytes other than Langerhans cell and (3) malignant histiocytic disorders. But such classification is not recommended by the World Health Organization (WHO).

LCH is a rare nonmalignant disease characterized by clonal proliferation of pathologic cells with characteristics of Langerhans cells in single/multiple sites and an unpredictable course. It is a sporadic and nonhereditary condition. The clinical presentation is heterogeneous, ranging from single system to multisystem involvement. Hallmark of LCH in all forms of disease is characteristic electron microscopic finding of Langerhans cells. Birbeck granule, a tennis racket shaped bi-lamellar granule, when seen in the cytoplasm of lesional cells in LCH is diagnostic of the disease. Birbeck granules express CD-207. Definitive diagnosis of LCH can be established by demonstrating CD1a-positivity of lesional cells. The lesion may contain Langerhans granule containing cells, lymphocytes, granulocytes, monocytes and eosinophils.

Pathogenesis is not well-established. Langerhans cells are thought to arise from epidermal Langerhans cells in response to some external hyperinflammatory stimulus or cell autonomous stimulus or as a result of activation of a cell autonomous genetic event. These activated Langerhans cells undergo transcriptional reprogramming which subsequently causes epithelialmesenchymal cell transformation (EMT). Activation and EMT are necessary for the spread and invasion of these cells to the particular site. Accumulation of Langerhans cells along with other inflammatory cells create cytokine cascade through autocrine and paracrine amplification of cell signals resulting in development of LCH through recruitment, maturation and proliferation of Langerhans cells.

The clinical course of LCH varies depending on the extent and number of organs involved as well as the age of the patient at the time of the diagnosis.

Most common involvement is of skeleton (80%).

Bony lesions can be single or multiple affecting skull bones, long bones, vertebrae, mastoid and mandibles.

Lesions may be painless or present with pain and local swelling. In flat and long bones, osteolytic lesions with sharp borders and no evidence of reactive new bone formation are seen until the lesions begin to heal. Vertebral collapse, spinal cord compression, pathological fracture, chronically draining infected ear are the common clinical manifestations. Free floating teeth due to destruction in mandible and maxilla appear on radiograph. Skin involvement occurs in 50% of cases leading to scaly, papular, seborrheic

dermatitis of scalp, axilla, posterior auricular, diaper region and sometimes involves back, palm and soles.

Localized or disseminated lymphadenopathy is found in approximately 33% of cases.

Hepatosplenomegaly occurs in 20% of cases. Liver involvement may lead to sclerosing cholangitis and cirrhosis. Otitis media is present in 30-40% of patients, deafness may follow destructive lesion of the middle ear. Pulmonary infiltrates are found on radiograph in 10-15% cases. The lesions may range from diffuse fibrosis and disseminated nodular infiltrates to diffuse cystic changes. Bilateral involvement of retro-orbital area may lead to exophthalmos. Bone-marrow involvement leads to anemia and thrombocytopenia. Pituitary and hypothalamic involvement leads to growth retardation, diabetes insipidus and panhypopituitarism. Central nervous system manifestation may be ataxia, dysarthria and other neurological symptoms. Systemic manifestations are fever, weight loss, malaise, irritability and failure to thrive.

CONCLUSION Langerhans cell histiocytosis has diverse spectrum of clinical manifestations. A differential diagnosis of LCH in pediatric age group when the child presents with lymph node swelling hepatosplenomegaly should not be neglected from the beginning. The prognosis depends chiefly upon the involvement of multiple organ system, organ dysfunction and the patients response to chemotherapy during the initial 6 weeks of treatment.

Even after getting therapy for more than 8 months our patient was still surviving but not in remission phase.

In view of bad prognosis of Letterer-Siwe disease, an early diagnosis by fine-needle aspiration biopsy with a thorough radiological investigation should be emphasized. Clinicians should have an eagle’s eye vision to differentiate a benign and an extremely rare but emergency situation.

SUGGESTED READING 1. Hoover KB, Rosenthal DI, Mankin H. Langerhans cell histiocytosis. Skeletal Radiol. 2007;36(2):95-104.

2. Chevrant-Breton J, Jambon N, Danrigal A, Kernec J, de Labarthe B, Ferrand B. Letterer-Siwe’s disease in the adult: a report of two cases. Ann Dermatol Venereol.

1978;105(3):309-11.

3. Stefanato CM, Andersen WK, Calonje E, Swain FA, Borghi S, Massone L, et al. Langerhans cell histiocytosis in the elderly: a report of three cases. J Am Acad Dermatol.

1998;39(2 Pt 2):375-8.

4. Chevrant-Breton J. Adult Letterer-Siwe’s disease: review of literature. Ann Dermatol Venereol. 1978;105:301-5.

5. Vollum DI. Letterer-Siwe disease in the adult. Clin Exp Dermatol. 1979;4(4):395-406.

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PICTORIAL CME

Right Atrial Mass MONIKA MAHESHWARI*, SWAPNIL†

R

ight atrial masses are rare entities often detected incidentally during imaging studies. They are most commonly due to thrombi in the presence of atrial fibrillation or due to vegetations in the setting of tricuspid valve endocarditis. Incidentally, intracardiac tumors may be detected which are usually metastatic, from malignancies of the breast, lung or malignant melanoma. Primary cardiac tumors occur less frequently and are usually benign. Myxomas constitute nearly one-half of reported primary cardiac tumors.

Characteristics of myxoma is that, it is rarely calcified and usually present as a solitary mass in the atrium.

The left atrium is more commonly involved than right atrium and an attachment stalk is often identified in or near the fossa ovalis. On the other hand, thrombus is usually located in atrial appendages and in dependent parts posteriorly.

However, appearance of myxomas and thrombi is highly variable and definitive diagnosis requires pathologic examination. We report here a 45-yearold man presenting with a history of breathlessness

Figure 1. Transthoracic echocardiogram (apical 4 chamber view) showing right atrial mass attached to interatrial septum with dilated right atrium and right ventricle.

since 2 months, who underwent transthoracic echocardiography, which revealed a mass in right atrium attached to the interatrial septum, probably myxoma (Fig. 1).

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*Associate Professor †2nd Year Resident JLN Medical College, Ajmer, Rajasthan Address for correspondence Naveen Niwas, 434/10, Bapu Nagar, Ajmer, Rajasthan E-mail: opm11@rediffmail.com

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ETHICS

Medical Oaths from Some European Countries

I

n 2014, the Swedish Medical Association sent a short questionnaire to medical associations in a number of European countries asking whether or not there was a medical oath in their country. The following is what we gathered from the answers received:

Denmark

dignity, contributing to global peace and decency, and I will always aspire to truth and justice, upholding ethical standards of medicine.

May I succeed in practicing, upholding the principles I have been taught by my professors and dear teachers and with God’s help”.

The Graduate has taken the Doctoral Oath:

Hungary

“Having been publicly tested in my knowledge of the medical-surgical subjects, I hereby make the solemn pledge that I will always in my practice as a doctor zealously use my knowledge to the best of my judgment to the benefit of society and my fellow beings; that I shall attend the poor as conscientiously as the rich; that I shall not without authority divulge what I learn in my capacity as a doctor; that I shall endeavor always to improve my knowledge, and, moreover, observe the decrees and instructions relating to myself and my profession”.

”I, ............................... swear that I will devote myself to the medical profession at all times. I will use the knowledge acquired in the field of medicine to prevent and cure diseases, and to benefit the physical and mental well-being of my patients. I will not betray the confidence of those who turn to me, nor will I take advantage of their defenselessness, nor will I disclose their secrets. I will treat every person with equal care and attention. I will maintain the high quality of my knowledge and skills by continuous education, but will also acknowledge the limits of my knowledge and abilities. I will submit myself to the ethical requirements of my medical practice. I will strive to enhance the reputation of the medical profession and Semmelweis University. So help me God!”

Greece The oath in ancient Greek: “Του πτυχίου της Ιατρικής αξιωθείς, όρκον ομνύω προ του Πρυτάνεως και του Προέδρου της Ιατρικής Σχολής και πίστιν καθομολογώ τήνδε: Από του ιερού περιβόλου του σεπτού τούτου τεμένους των Μουσών εξερχόμενος κατ΄ επιστήμην βιώσομαι, ασκών ταύτην δίκην θρησκείας εν πνεύματι και αληθεία. Ούτω χρήσιμον εμαυτόν καταστήσω προς άπαντας τους δεομένους της εμής αρωγής, και εν πάση ανθρώπων κοινωνίας αεί προς ειρήνην και χρηστότητα ηθών συντελέσω, βαίνων εν ευθεία του βίου οδώ, προς την αλήθειαν και το δίκαιον αποβλέπων και τον βίον ανυψών εις τύπον αρετής υπό την σκέπην της σοφίας. Ταύτην την επαγγελίαν επιτελούντι είη μοι, συν τη ευλογία των εμών καθηγητών και πεφιλημένων δασκάλων, ο θεός εν τω βίω βοηθός”.

Unofficial translation “Since being judged worthy of the medical diploma, before the Rector and the President of the Μedical School, I take this oath: When I leave this Holly Court of the respectable home of the Muses I will practice medical profession dedicating my life to the service of humanity, as in religion, spiritually and truthfully. In this way, I will become useful to everyone who needs my assistance and services. I will practice with

Spain Normally the Hippocratic oath is used: “I swear by Apollo the physician that I will observe and keep this underwritten oath, to the utmost of my power and judgment.

I will reverence my master who taught me the art. Equally with my parents, will I allow him things necessary for his support and will consider his sons as brothers. I will teach them my art without reward or agreement; and I will impart all my acquirement, instructions, and whatever I know, to my master’s children, as to my own; and likewise to all my pupils, who shall bind and tie themselves by a professional oath, but to none else.

With regard to healing the sick, I will devise and order for them the best diet, according to my judgment and means; and I will take care that they suffer no hurt or damage.

Nor shall any man’s entreaty prevail upon me to administer poison to anyone; neither will I counsel any man to do so.

Moreover, I will get no sort of medicine to any pregnant woman, with a view to destroy the child.

Further, I will comport myself and use my knowledge in a godly manner.

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ETHICS Whatsoever house I may enter, my visit shall be for the convenience and advantage of the patient; and I will willingly refrain from doing any injury or wrong from falsehood, and (in an especial manner) from acts of an amorous nature, whatever may be the rank of those who it may be my duty to cure, whether mistress or servant, bond or free.

If I faithfully observe this oath, may I thrive and prosper in my fortune and profession, and live in the estimation of posterity; or on breach thereof, may the reverse be my fate!”

In some places this oath is modified, principally the part that refers to pregnant women. In other places Maimonides´ oath is used (Maimonides was from the city Cordoba in southern Spain):

Grant me the strength, time and opportunity always to correct what I have acquired, always to extend its domain; for knowledge is immense and the spirit of man can extend indefinitely to enrich itself daily with new requirements.

Today, he can discover his errors of yesterday and tomorrow he can obtain a new light on what he thinks himself sure of today.

Oh, God, Thou has appointed me to watch over the life and death of Thy creatures; here am I ready for my vocation and now I turn unto my calling.”

Other Countries

“The eternal providence has appointed me to watch over the life and health of Thy creatures. May the love for my art actuate me at all time; may neither avarice nor miserliness, nor thirst for glory or for a great reputation engage my mind; for the enemies of truth and philanthropy could easily deceive me and make me forgetful of my lofty aim of doing good to Thy children.

In Romania, the Hippocratic Oath seems to be used.

Finland and Iceland have short medical oaths, but I do not have them in English. In the Netherlands, there is a noncompulsory oath that may be used by those who wish to do so (I do not have the wording). Sweden, Norway, Switzerland and the UK do not have national medical oaths. (I leave it to the German representatives in the DoG working group to explain about the use of medical oath in Germany.)

May I never see in the patient anything but a fellow creature in pain.

Tomas Hedmark, The Swedish Medical Association, September 2015.

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2015

AROUND THE GLOBE

News and Views ÂÂ

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Another action of metformin has been reported in a study published online August 5 in Diabetes Care. Metformin has also been found to lower LDLcholesterol levels. It does so by activating AMPactivated protein kinase (AMPK) and consequently suppressing fatty-acid desaturase (FADS) genes, which leads to reduced levels of lipid metabolites and LDL cholesterol.

Results from a population-based Rotterdam study suggest that poor kidney function negatively affects cerebral blood flow and may be linked to both stroke and dementia independent of known cardiovascular disease risk factors. The study, by Sanaz Sedaghat, MSc, from the Dept. of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands, and colleagues, was published online August 6 in the Journal of the American Society of Nephrology.

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Live birth rates for in vitro fertilization (IVF) cycles using frozen oocytes appear to be slightly lower than for those using fresh ones, according to a research letter published in the August 11 issue of JAMA.

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An American Thyroid Association (ATA) statement describing how to assess patients with goiter and providing recommendations for ways to manage goiter surgery to minimize complications is now published online for open access. Originally published in Thyroid in 2014, these are the first comprehensive recommendations for goiter surgery.

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394

Dr Genevieve Healy (University of Queensland, Brisbane, Australia) and colleagues report that cardiovascular health benefits—particularly for glucose and lipid metabolism—can be achieved if an individual replaces sitting with standing.

Excessive sitting is associated with various cardiometabolic risk factors, including larger waist circumferences, higher triglycerides, and lower HDL cholesterol levels.

Major depression and bipolar disorder put teenagers at greater risk for heart disease and should be considered as independent risk factors for the condition. This is according to a scientific statement from the American Heart Association, published in the journal Circulation.

Indian Journal of Clinical Practice, Vol. 26, No. 4, September 2015

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Intermittent episodes of hypoxemia lasting more than 1 minute during the first 2-3 months after extremely preterm birth are associated with severe disability at age 18 months, according to a report published online Aug 11 in JAMA.

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A study from Turkey reported Aug 11 in the journal Coronary Artery Disease concluded that serum fibrinogen level is associated independently with a higher risk of contrast-induced acute kidney injury in patients with acute coronary syndrome undergoing percutaneous coronary intervention.

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According to a study reported Aug 11 in the journal Blood Pressure Monitoring, patients do not have a great deal of confidence in office BP measurements, but have a higher degree of confidence in home BP and ambulatory BP assessment methods may be helpful in guiding strategies to diagnose hypertension and improve antihypertensive medication adherence.

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A new study suggests that patients who undergo an organ transplant are at greater risk of developing melanoma, the deadliest form of skin cancer, and are at even higher risk of dying from the disease, compared with individuals who do not have a transplant. The findings were published in the Journal of Investigative Dermatology.

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Cutting fat intake results in greater body fat loss as compared to a low-carbohydrate diet, suggests a new study published in Cell Metabolism.

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New research finds many parents become unhappy following the birth of their first child, which may deter them from having any more. Researchers noted that more than 70% of parents reported a decline in happiness following the birth of their first child. The findings are published in the journal Demography.

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The presence of autoantibodies in healthy relatives of patients with rheumatoid arthritis (RA) predicts a higher risk of developing the disease, suggests a 5-year follow-up cohort study published in Arthritis and Rheumatology.

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Scientists at Helmholtz Zentrum München and TU München have discovered a new mechanism as to how nonallergenic pollen mediators can enhance allergic reactions. Researchers revealed that B cells play a critical role in this process. The results were published in the journal Allergy.

LIGHTER READING

The other frogs kept telling them to stop, that they were as good as dead. Finally, one of the frogs took heed to what the other frogs were saying and simply gave up. He fell down and died. The other frog continued to jump as hard as he could. Once again, the crowd of frogs yelled at him to stop the pain and suffering and just die. He jumped even harder and finally made it out. When he got out, the other frogs asked him, “Why did you continue jumping?

Didn’t you hear us?”The frog explained to them that he was deaf.

He thought they were encouraging him the entire time. This story holds two lessons: 1.

There is power of life and death in the tongue.

An encouraging word to someone who is down can lift them up and help them make it through the day 2. A destructive word to someone who is down can be what it takes to kill them.

HUMOR

Be careful of what you say. Speak life to those who cross your path. The power of words… it is sometimes hard to understand that an encouraging word can go such a long way.

Anyone can speak words that tend to rob another of the spirit to continue in difficult times.

Special is the individual who will take the time to encourage another.

The vendor puts the bill in the cash box and closes it. “Excuse me, but where’s my change?” asks the Buddhist monk. The vendor replies, “Change must come from within.”

MEN DON’T LISTEN A young man was driving up a steep, winding and narrow mountain road. Going round a tight corner, he notices a woman driver, who is coming in the opposite direction, begin to lean out of her window. As they pass each other she yells at him – “PIG!!!!” The man immediately leans out of his window and screams back at her, “WITCH!!!” Each continues on their way, and as the man rounds the next bend he crashes into a pig, right in the middle of the road…If only men would listen…

“Take the attitude of a student, never be too big to ask questions, never know too much to learn something new”.

—Og Mandino

Dr. Good and Dr. Bad SITUATION: A 30-year-old male with suspected migraine came with runny nose.

It cannot be migraine

It can be migraine

©IJCP Academy

A group of frogs were traveling through the woods, and two of them fell into a deep pit. All the other frogs gathered around the pit. When they saw how deep the pit was, they told the unfortunate frogs they would never get out. The two frogs ignored the comments and tried to jump up out of the pit.

HUMOR

THE POWER OF GOOD WORDS

QUOTE

INSPIRATIONAL STORY

Lighter Side of Medicine

THE HOT DOG VENDOR A Buddhist monk approaches a hot dog stand and says, “Make me one with everything.” The vendor has heard this one before, and without a word he simply makes the hot dog and hands it to the Buddhist monk, who pays with a $20 bill.

LESSON: Migraine can also cause nasal stuffiness and a runny nose, or teary eyes in some individuals so they may be sometimes mistaken for sinus headaches.

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Information for Authors Manuscripts should be prepared in accordance with the ‘Uniform requirements for manuscripts submitted to biomedical journals’ compiled by the International Committee of Medical Journal Editors (Ann. Intern. Med. 1992;96: 766-767).

Indian Journal of Clinical Practice strongly disapproves of the submission of the same articles simultaneously to different journals for consideration as well as duplicate publication and will decline to accept fresh manuscripts submitted by authors who have done so.

The boxed checklist will help authors in preparing their manuscript according to our requirements. Improperly prepared manuscripts may be returned to the author without review. The checklist should accompany each manuscript.

Authors may provide on the checklist, the names and addresses of experts from Asia and from other parts of the World who, in the authors’ opinion, are best qualified to review the paper.

Covering letter –

–

–

The covering letter should explain if there is any deviation from the standard IMRAD format (Introduction, Methods, Results and Discussion) and should outline the importance of the paper.

Principal/Senior author must sign the covering letter indicating full responsibility for the paper submitted, preferably with signatures of all the authors.

Articles must be accompanied by a declaration by all authors stating that the article has not been published in any other Journal/Book. Authors should mentioned complete designation and departments, etc. on the manuscript.

Manuscript Three complete sets of the manuscript should be – submitted and preferably with a CD; typed double spaced throughout (including references, tables and legends to figures).

–

The manuscript should be arranged as follow: Covering letter, Checklist, Title page, Abstract, Keywords (for indexing, if required), Introduction, Methods, Results, Discussion, References, Tables, Legends to Figures and Figures.

–

All pages should be numbered consecutively beginning with the title page.

Note: Please keep a copy of your manuscript as we are not responsible for its loss in the mail. Manuscripts will not be returned to authors.

Title page Should contain the title, short title, names of all the authors (without degrees or diplomas), names and full location of the departments and institutions where the work was performed,

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name of the corresponding authors, acknowledgment of financial support and abbreviations used.

– The title should be of no more than 80 characters and should represent the major theme of the manuscript.

A subtitle can be added if necessary.

– A short title of not more than 50 characters (including inter-word spaces) for use as a running head should be included.

– The name, telephone and fax numbers, e-mail and postal addresses of the author to whom communications are to be sent should be typed in the lower right corner of the title page.

– A list of abbreviations used in the paper should be included. In general, the use of abbreviations is discouraged unless they are essential for improving the readability of the text.

Summary – The summary of not more than 200 words. It must convey the essential features of the paper.

– It should not contain abbreviations, footnotes or references.

Introduction – The introduction should state why the study was carried out and what were its specific aims/objectives.

Methods – These should be described in sufficient detail to permit evaluation and duplication of the work by others.

– Ethical guidelines followed by the investigations should be described.

Statistics The following information should be given: – The statistical universe i.e., the population from which the sample for the study is selected.

– Method of selecting the sample (cases, subjects, etc. from the statistical universe).

– Method of allocating the subjects into different groups.

– Statistical methods used for presentation and analysis of data i.e., in terms of mean and standard deviation values or percentages and statistical tests such as Student’s ‘t’ test, Chi-square test and analysis of variance or non-parametric tests and multivariate techniques.

–

Confidence intervals for the measurements should be provided wherever appropriate.

Results – These should be concise and include only the tables and figures necessary to enhance the understanding of the text.

Discussion –

This should consist of a review of the literature and relate the major findings of the article to other publications on the subject. The particular relevance of the results to healthcare in India should be stressed, e.g., practicality and cost.

References These should conform to the Vancouver style. References should be numbered in the order in which they appear in the texts and these numbers should be inserted above the lines on each occasion the author is cited (Sinha12 confirmed other reports13,14...). References cited only in tables or in legends to figures should be numbered in the text of the particular table or illustration. Include among the references papers accepted but not yet published; designate the journal and add ‘in press’ (in parentheses). Information from manuscripts submitted but not yet accepted should be cited in the text as ‘unpublished observations’ (in parentheses).

At the end of the article the full list of references should include the names of all authors if there are fewer than seven or if there are more, the first six followed by et al., the full title of the journal article or book chapters; the title of journals abbreviated according to the style of the Index Medicus and the first and final page numbers of the article or chapter. The authors should check that the references are accurate. If they are not this may result in the rejection of an otherwise adequate contribution.

Examples of common forms of references are: Articles Paintal AS. Impulses in vagal afferent fibres from specific pulmonary deflation receptors. The response of those receptors to phenylguanide, potato S-hydroxytryptamine and their role in respiratory and cardiovascular reflexes.

Q. J. Expt. Physiol. 1955;40:89-111.

Figures – Two complete sets of glossy prints of high quality should be submitted. The labelling must be clear and neat.

– All photomicrographs should indicate the magnification of the print.

– Special features should be indicated by arrows or letters which contrast with the background.

The back of each illustration should bear the first – author’s last name, figure number and an arrow indicating the top. This should be written lightly in pencil only. Please do not use a hard pencil, ball point or felt pen.

Color illustrations will be accepted if they make a – contribution to the understanding of the article.

–

Do not use clips/staples on photographs and artwork.

–

Illustrations must be drawn neatly by an artist and photographs must be sent on glossy paper. No captions should be written directly on the photographs or illustration. Legends to all photographs and illustrations should be typed on a separate sheet of paper. All illustrations and figures must be referred to in the text and abbreviated as “Fig.”.

Please complete the following checklist and attach to the manuscript: 1. Classification (e.g. original article, review, selected summary, etc.)_______________________________ 2. Total number of pages ________________________ 3. Number of tables ____________________________ 4. Number of figures ___________________________

Books

5. Special requests _____________________________

Stansfield AG. Lymph Node Biopsy Interpretation Churchill Livingstone, New York 1985.

Indian 1.____________Foreign 1.________________

Articles in Books

2.____________ 2.________________

Strong MS. Recurrent respiratory papillomatosis. In: Scott Brown’s Otolaryngology. Paediatric Otolaryngology Evans JNG (Ed.), Butterworths, London 1987;6:466-470.

3.____________ 3.________________

4.____________ 4.________________

Tables –

These should be typed double spaced on separate sheets with the table number (in Roman Arabic numerals) and title above the table and explanatory notes below the table.

Legends These should be typed double spaces on a separate – sheet and figure numbers (in Arabic numerals) corresponding with the order in which the figures are presented in the text.

–

The legend must include enough information to permit interpretation of the figure without reference to the text.

6. Suggestions for reviewers (name and postal address)

7. All authors’ signatures________________________ 8.

Corresponding author’s name, current postal and e-mail address and telephone and fax numbers __________________________________________

Online Submission Also e-Issue @ www.ijcpgroup.com For Editorial Correspondence

Dr KK Aggarwal Group Editor-in-Chief Indian Journal of Clinical Practice E-219, Greater Kailash, Part-1 New Delhi - 110 048. Tel: 40587513 E-mail: editorial@ijcp.com Website: www.ijcpgroup.com

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